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Abstract Background RNA-seq is being increasingly adopted for gene expression studies in a panoply of non-model organisms, with applications spanning the fields of agriculture, aquaculture, ecology, and environment. For organisms that lack a well-annotated reference genome or transcriptome, a conventional RNA-seq data analysis workflow requires constructing a de-novo transcriptome assembly and annotating it against a high-confidence protein database. The assembly serves as a reference for read mapping, and the annotation is necessary for functional analysis of genes found to be differentially expressed. However, assembly is computationally expensive. It is also prone to errors that impact expression analysis, especially since sequencing depth is typically much lower for expression studies than for transcript discovery. Results We propose a shortcut, in which we obtain counts for differential expression analysis by directly aligning RNA-seq reads to the high-confidence proteome that would have been otherwise used for annotation. By avoiding assembly, we drastically cut down computational costs – the running time on a typical dataset improves from the order of tens of hours to under half an hour, and the memory requirement is reduced from the order of tens of Gbytes to tens of Mbytes. We show through experiments on simulated and real data that our pipeline not only reduces computational costs, but has higher sensitivity and precision than a typical assembly-based pipeline. A Snakemake implementation of our workflow is available at: https://bitbucket.org/project_samar/samar . Conclusions The flip side of RNA-seq becoming accessible to even modestly resourced labs has been that the time, labor, and infrastructure cost of bioinformatics analysis has become a bottleneck. Assembly is one such resource-hungry process, and we show here that it can be avoided for quick and easy, yet more sensitive and precise, differential gene expression analysis in non-model organisms.

Abstract Background The fishery and aquaculture of the widely distributed mangrove crab Scylla serrata is a steadily growing, high-value, global industry. Climate change poses a risk to this industry as temperature elevations are expected to threaten the mangrove crab habitat and the supply of mangrove crab juveniles from the wild. It is therefore important to understand the genomic and molecular basis of how mangrove crab populations from sites with different climate profiles respond to heat stress. Towards this, we performed RNA-seq on the gill tissue of S. serrata individuals sampled from 3 sites (Cagayan, Bicol, and Bataan) in the Philippines, under normal and heat-stressed conditions. To compare the transcriptome expression profiles, we designed a 2-factor generalized linear model containing interaction terms, which allowed us to simultaneously analyze within-site response to heat-stress and across-site differences in the response. Results We present the first ever transcriptome assembly of S. serrata obtained from a data set containing 66 Gbases of cleaned RNA-seq reads. With lowly-expressed and short contigs excluded, the assembly contains roughly 17,000 genes with an N50 length of 2,366 bp. Our assembly contains many almost full-length transcripts – 5229 shrimp and 3049 fruit fly proteins have alignments that cover >80% of their sequence lengths to a contig. Differential expression analysis found population-specific differences in heat-stress response. Within-site analysis of heat-stress response showed 177, 755, and 221 differentially expressed (DE) genes in the Cagayan, Bataan, and Bicol group, respectively. Across-site analysis showed that between Cagayan and Bataan, there were 389 genes associated with 48 signaling and stress-response pathways, for which there was an effect of site in the response to heat; and between Cagayan and Bicol, there were 101 such genes affecting 8 pathways. Conclusion In light of previous work on climate profiling and on population genetics of marine species in the Philippines, our findings suggest that the variation in thermal response among populations might be derived from acclimatory plasticity due to pre-exposure to extreme temperature variations or from population structure shaped by connectivity which leads to adaptive genetic differences among populations.

Research on cognitive processes has primarily focused on cognitive control and inhibitory processes to the detriment of other psychological processes, such as defense mechanisms (DMs), which can be used to modify aggressive impulses as well as self/other images during interpersonal conflicts. First, we conducted an in-depth theoretical analysis of three socio-cognitive models and three psychodynamic models and compared main propositions regarding the source of aggression and processes that influence its enactment. Second, 32 participants completed the Hostile Expectancy Violation Paradigm (HEVP) in which scenarios describe a hostile vs. non-hostile social context followed by a character's ambiguous aversive behavior. The N400 effect to critical words that violate expected hostile vs. non-hostile intent of the behavior was analyzed. Prepotent response inhibition was measured using a Stop Signal task (SST) and DMs were assessed with the Defense Style Questionnaire (DSQ-60). Results showed that reactive aggression and HIA were not significantly correlated with response inhibition but were significantly positively and negatively correlated with image distorting defense style and adaptive defense style, respectively. The present article has highlighted the importance of integrating socio-cognitive and psychodynamic models to account for the full complexity underlying psychological processes that influence reactive aggressive behavior.

BACKGROUND: The impact of co-morbid substance use in first-episode schizophrenia has not been fully explored.MethodThis naturalistic follow-up of a cohort of 152 people with first-episode schizophrenia examined substance use and clinical outcome in terms of symptoms and social and neuropsychological function. RESULTS: Data were collected on 85 (56%) of the patient cohort after a median period of 14 months. Over the follow-up period, the proportion of smokers rose from 60% at baseline to 64%. While 30% reported lifetime problem drinking of alcohol at baseline, only 15% had problem drinking at follow-up. Furthermore, while at baseline 63% reported lifetime cannabis use and 32% were currently using the drug, by the follow-up assessment the latter figure had fallen to 18.5%. At follow-up, persistent substance users had significantly more severe positive and depressive symptoms and greater overall severity of illness. A report of no lifetime substance use at baseline was associated with greater improvement in spatial working memory (SWM) at follow-up. CONCLUSIONS: Past substance use may impede recovery of SWM performance in people with schizophrenia in the year or so following first presentation to psychiatric services. The prevalence of substance use other than tobacco tends to diminish over this period, in the absence of specific interventions. Persistent substance use in first-episode schizophrenia is associated with more severe positive and depressive symptoms but not negative symptoms, and should be a target for specific treatment intervention. [ABSTRACT FROM AUTHOR]

Oral food challenges (OFC) confirm or exclude the presence of a food allergy. The outcome can be positive (allergic symptoms), inconclusive, or negative (no symptoms). In the case of a negative OFC, parents and children are advised to introduce the challenged food allergen into their diet. However, previous studies showed difficulties in a successful introduction at home. The aim of this prospective non-randomized intervention study is to evaluate the effect of a new strategy with more guidance regarding the dietary introduction after a negative food challenge test. We compared two cohorts: an historical (retrospective) control group of 157 children, previously described, who did not receive any special advice after a negative OFC, versus a new cohort consisting of 104 children, who were guided according to our new strategy of written introduction schemes, food diaries, and several phone calls. In the historical control group, introduction was successful in 56%, partially successful in 16%, and 28% failed to introduce at home. After introduction of our new strategy, complete introduction was found in 82%, 11% had partially introduced, and only 8% failed to introduce the allergen. In conclusion, comprehensive advice and dietary recommendation after a negative OFC results in an increase in successful home introduction. Therefore, more attention, guidance, and follow-up of children and parents are desirable after a negative OFC.

According to theories of addictive behaviors, approach and attentional biases towards smoking-related cues play a crucial role in tobacco dependence. Several studies have investigated these biases by using various paradigms in different sample types. However, this heterogeneity makes it difficult to compare and evaluate the results. The present study aimed to address this problem, via i) a structural comparison of different measures of approach-avoidance and a measure of smoking-related attentional biases, and ii) using within one study different representative samples in the context of tobacco dependence. Three measures of approach-avoidance were employed: an Approach Avoidance Task (AAT), a Stimulus Response Compatibility Task (SRC), and a Single Target Implicit Association Test (ST-IAT). To assess attentional biases, a modified Stroop task including smoking-related words was administered. The study included four groups: n = 58 smokers, n = 57 non-smokers, n = 52 cravers, and n = 54 ex-smokers. We expected to find strong tobacco-related approach biases and attentional biases in smokers and cravers. However, the general pattern of results did not confirm these expectations. Approach responses assessed during the AAT and SRC did not differ between groups. Moreover, the Stroop did not show the expected interference effect. For the ST-IAT, cravers had stronger approach associations towards smoking-related cues, whereas non-smokers showed stronger avoidance associations. However, no such differences in approach-avoidance associations were found in smokers and ex-smokers. To conclude, these data do not provide evidence for a strong role of implicit approach and attentional biases towards smoking-related cues in tobacco dependency.

O trabalho teve como objetivo estudar o efeito de diferentes substratos e a concentração de nutrientes na solução nutritiva na produção de couve manteiga em ambiente protegido. O experimento foi desenvolvido em casa de vegetação do Centro de Ciências e Tecnologia Agroalimentar, Campus pombal – Pombal/PB, pertencente a Universidade Federal de Campina Grande (CCTA – UFCG), no período de 13/03 a 19/04/2010, utilizando a cultivar de couve manteiga da Geórgia (Brassica oleraceae var. acephala). Os tratamentos foram constituídos por dois tipos de substrato (fibra de coco e esterco bovino) e cinco níveis de concentração de nutrientes na solução nutritiva (12,5, 25, 50 75 e 100%), com quatro repetições. A solução nutritiva utilizada como base foi a de Hoagland & Arnon na concentração de 100%. A partir desta solução obteve-se por diluição as demais concentrações. A unidade experimental foi composta por um vaso contendo duas plantas. Os vasos foram dispostos no espaçamento de 1,0 x 0,5 m. A utilização do substrato fibra de coco proporcionou maior eficiência no crescimento e acúmulo de massa seca em plantas de couve em relação ao esterco bovino. A presença de nutrientes na solução nutritiva na concentração de 100% proporciou maior eficiência no crescimento e acúmulo de massa seca em plantas de couve em relação a 12,5, 25, 50 e 75%. O incremento no crescimento e acúmulo de massa seca em couve na concentração de 100% de nutrientes na solução nutritiva foi em média de 61% em relação a concentração de 12,5% no substrato fibra de coco.O incremento no crescimento e acúmulo de massa seca em couve na concentração de 50% de nutrientes na solução nutritiva foi em média de 15% em relação a concentração de 12,5% no substrato esterco bovino.

O trabalho teve como objetivo avaliar o efeito de diferentes fontes de esterco e concentrações de nutrientes na solução nutritiva em alface cultivada em solo. O experimento foi realizado em casa de vegetação no Centro de Ciências e Tecnologia Agroalimentar (CCTA/UFCG) – Pombal - PB, no período de 13/03 a 19/04/2010, utilizando a cultivar de alface ‘Babá de Verão’. Os tratamentos foram constituídos por duas fontes de esterco (bovino e caprino) na dose de 80 t ha-1, quatro níveis de concentração de nutrientes na solução nutritiva (12,5, 25, 50 e 100%) e uma testemunha adicional. A solução nutritiva utilizada como base foi a de Hoagland & Arnon na concentração de 100%. A partir desta solução obteve-se por diluição as demais concentrações. Como testemunha adicional utilizou-se zero de esterco e solução nutritiva na concentração de 100%. Os maiores valores de área foliar, número de folhas por planta, massa seca total, de folha e caule e produção foram verificados na alface adubada com esterco caprino em relação ao bovino. Os maiores valores de fotossíntese líquida, área foliar, número de folhas por planta, massa seca de folha, caule e total e produção foram obtidos no intervalo de 75 a 100% na concentração de nutrientes na solução nutritiva aplicada na alface. A aplicação do esterco caprino e solução nutritiva com concentração dos nutrientes acima de 50% proporcionaram melhor performance no crescimento, acúmulo de massa seca e produção da alface.

IntroductionCognitive deficits are a side-effect of chemotherapy, however pre-treatment research is limited. This study examines neurofunctional differences during working memory between breast cancer (BC) patients and controls, prior to chemotherapy. MethodsEarly stage BC females (23), scanned after surgery but before chemotherapy, were individually matched to non-cancer controls. Participants underwent fMRI while performing a Visuospatial N-back task and data was analyzed by multiple group comparisons. fMRI task performance, neuropsychological tests, hospital records and salivary biomarkers were also collected.ResultsThere were no significant group differences on neuropsychological tests, estrogen or cortisol. Patients made significantly fewer commission errors but had less overall correct responses and were slower than controls during the task. Significant group differences were observed for the fMRI data, yet results depended on the type of analysis. BC patients presented with increased activations during working memory compared to controls in areas such as the inferior frontal gyrus, insula, thalamus, and midbrain. Individual group regressions revealed a reverse relationship between brain activity and commission errors. ConclusionsThis is the first fMRI investigation to reveal neurophysiological differences during visuospatial working memory between BC patients pre-chemotherapy and controls.SignificanceThis highlights the need to better understand the pre-chemotherapy BC patient and the effects of associated confounding variables.

O trabalho teve como objetivo avaliar o efeito de diferentes fontes e tempos de incorporação de estercos no cultivo da beterraba. O experimento foi realizado em casa de vegetação no Centro de Ciências e Tecnologia Agroalimentar (CCTA/UFCG) – Pombal - PB, no período de 12/12/2009 a 15/04/2010, utilizando a cultivar de beterraba ‘Early Wonder’. Os tratamentos foram constituídos por duas fontes de esterco (bovino e caprino) na dose de 80 t ha-1, quatro tempos de incorporação dos estercos (0, 15, 30 e 60 dias antes do plantio - DAP) e uma testemunha adicional (sem esterco). O delineamento experimental utilizado foi o blocos casualizados, no esquema fatorial 2 x 4 + 1, com quatro repetições. Os maiores valores de massa seca total, de raiz e produção foram verificados na beterraba adubada com esterco caprino em relação ao esterco bovino. Os maiores valores de fotossíntese líquida, condutância estomática, área foliar, massa seca de total e de folha foram obtidos com 0 e 60 dias e massa seca de raiz e produção por planta com 60 dias de incorporação dos estercos ao solo antes do plantio. A aplicação do esterco caprino e a antecipação no tempo de incorporação proporcionaram melhor desempenho no crescimento, acúmulo de massa seca e produção da beterraba.

Angiosperms are the cornerstone of most terrestrial ecosystems and human livelihoods 1,2 . A robust understanding of angiosperm evolution is required to explain their rise to ecological dominance. So far, the angiosperm tree of life has been determined primarily by means of analyses of the plastid genome 3,4 . Many studies have drawn on this foundational work, such as classification and first insights into angiosperm diversification since their Mesozoic origins 5-7 . However, the limited and biased sampling of both taxa and genomes undermines confidence in the tree and its implications. Here, we build the tree of life for almost 8,000 (about 60%) angiosperm genera using a standardized set of 353 nuclear genes 8 . This 15-fold increase in genus-level sampling relative to comparable nuclear studies 9 provides a critical test of earlier results and brings notable change to key groups, especially in rosids, while substantiating many previously predicted relationships. Scaling this tree to time using 200 fossils, we discovered that early angiosperm evolution was characterized by high gene tree conflict and explosive diversification, giving rise to more than 80% of extant angiosperm orders. Steady diversification ensued through the remaining Mesozoic Era until rates resurged in the Cenozoic Era, concurrent with decreasing global temperatures and tightly linked with gene tree conflict. Taken together, our extensive sampling combined with advanced phylogenomic methods shows the deep history and full complexity in the evolution of a megadiverse clade., (© 2024. The Author(s).)

Background: To provide precision cognitive remediation therapy (CR) for schizophrenia, we need to understand whether the mechanism for improved functioning is via cognition improvements. This mechanism has not been rigorously tested for potential moderator effects., Study Design: We used data (n = 377) from a randomized controlled trial using CIRCuiTS, a therapist-supported CR, with participants from first-episode psychosis services. We applied structured equation modeling to test whether: (1) CR hours explain the goal attainment functional outcome (GAS) at posttreatment, (2) global cognitive improvement mediates GAS, and if (3) total symptoms moderate the CR hours to cognitive improvement pathway, and/or negative symptoms moderate the cognition to functioning pathway, testing moderator effects via the mediator or directly on CR hours to functioning path., Study Results: CR produced significant functioning benefit for each therapy hour (Coeff = 0.203, 95% CI 0.101-0.304, P < .001). The mediated path from CR hours to cognition and cognition to functioning was small and nonsignificant (Coeff = 0.014, 95% CI = -0.010, 0.037, P = .256). Total symptoms did not moderate the path to cognition (P = .211) or the direct path to outcome (P = .896). However, negative symptoms significantly moderated the effect of cognitive improvements on functioning (P = .015) with high negative symptoms reducing the functional gains of improved cognition., Conclusions: Although cognitive improvements were correlated with functioning benefit, they did not fully explain the positive effect of increased therapy hours on functioning, suggesting additional CR factors also contribute to therapy benefit. Negative symptoms interfere with the translation of cognitive improvements into functional gains so need consideration., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center.)

Frontal circuits play a critical role in motor, cognitive and affective processing, and their dysfunction may result in a variety of brain disorders. However, exactly which frontal domains mediate which (dys)functions remains largely elusive. We studied 534 deep brain stimulation electrodes implanted to treat four different brain disorders. By analyzing which connections were modulated for optimal therapeutic response across these disorders, we segregated the frontal cortex into circuits that had become dysfunctional in each of them. Dysfunctional circuits were topographically arranged from occipital to frontal, ranging from interconnections with sensorimotor cortices in dystonia, the primary motor cortex in Tourette's syndrome, the supplementary motor area in Parkinson's disease, to ventromedial prefrontal and anterior cingulate cortices in obsessive-compulsive disorder. Our findings highlight the integration of deep brain stimulation with brain connectomics as a powerful tool to explore couplings between brain structure and functional impairments in the human brain., (© 2024. The Author(s).)

Functional neurological disorder (FND) is a common and disabling disorder, often misunderstood by clinicians. Although viewed sceptically by some, FND is a diagnosis that can be made accurately, based on positive clinical signs, with clinical features that have remained stable for over 100 years. Despite some progress in the last decade, people with FND continue to suffer subtle and overt forms of discrimination by clinicians, researchers and the public. There is abundant evidence that disorders perceived as primarily affecting women are neglected in healthcare and medical research, and the course of FND mirrors this neglect. We outline the reasons why FND is a feminist issue, incorporating historical and contemporary clinical, research and social perspectives. We call for parity for FND in medical education, research and clinical service development so that people affected by FND can receive the care they need., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY. Published by BMJ.)

Cognitive Remediation (CR) improves cognition and functioning but is implemented in a variety of ways (independent, group and one-to-one). There is no information on whether service users find these implementation methods acceptable or if their satisfaction influences CR outcomes. We used mixed participatory methods, including focus groups, to co-develop a CR satisfaction scale. This was refined using three psychometric criteria (Cronbach's alpha, item discrimination, test-retest agreement) to select items. Factor analysis explored potential substructures. The refined measure was used in structural equation joint modelling to evaluate whether satisfaction with CR is affected by implementation method and treatment engagement or influences recovery outcome, using data from a randomised controlled trial. Four themes (therapy hours, therapist, treatment effects, computer use) generated a 31-item Cognitive Remediation Satisfaction scale (CRS) that reduced to 18 Likert items, 2 binary and 2 open-ended questions following psychometric assessment. CRS had good internal consistency (Alpha = 0.814), test-retest reliability (r= 0.763), and concurrent validity using the Working Alliance Inventory (r = 0.56). A 2-factor solution divided items into therapy engagement and therapy effects. Satisfaction was not related to implementation method but was significantly associated with CR engagement. Therapy hours were significantly associated with recovery, but there was no direct effect of satisfaction on outcome. Although satisfaction is important to therapy engagement, it has no direct effect on outcome. CR therapy hours directly affect outcome irrespective of which implementation model is used, so measuring satisfaction early might help to identify those who are likely to disengage. The study has mixed methods design., (© 2023. Springer Nature Limited.)

Faunal turnover in Indo-Australia across Wallace's Line is one of the most recognizable patterns in biogeography and has catalyzed debate about the role of evolutionary and geoclimatic history in biotic interchanges. Here, analysis of more than 20,000 vertebrate species with a model of geoclimate and biological diversification shows that broad precipitation tolerance and dispersal ability were key for exchange across the deep-time precipitation gradient spanning the region. Sundanian (Southeast Asian) lineages evolved in a climate similar to the humid "stepping stones" of Wallacea, facilitating colonization of the Sahulian (Australian) continental shelf. By contrast, Sahulian lineages predominantly evolved in drier conditions, hampering establishment in Sunda and shaping faunal distinctiveness. We demonstrate how the history of adaptation to past environmental conditions shapes asymmetrical colonization and global biogeographic structure.

Background and Hypothesis: Cognitive remediation (CR) benefits cognition and functioning in psychosis but we do not know the optimal level of therapist contact, so we evaluated the potential benefits of different CR modes., Study Design: A multi-arm, multi-center, single-blinded, adaptive trial of therapist-supported CR. Participants from 11 NHS early intervention psychosis services were independently randomized to Independent, Group, One-to-One, or Treatment-as-usual (TAU). The primary outcome was functional recovery (Goal Attainment Scale [GAS]) at 15-weeks post randomization. Independent and TAU arms were closed after an interim analysis, and three informative contrasts tested (Group vs One-to-One, Independent vs TAU, Group + One-to-One vs TAU). Health economic analyses considered the cost per Quality Adjusted Life Year (QALY). All analyses used intention-to-treat principles., Study Results: We analyzed 377 participants (65 Independent, 134 Group, 112 One-to-One, 66 TAU). GAS did not differ for Group vs One-to-One: Cohen's d: 0.07, -0.25 to 0.40 95% CI, P = .655; Independent vs TAU: Cohen's d: 0.07, -0.41 to 0.55 95% CI, P = .777. GAS and the cognitive score improved for Group + One-to-One vs TAU favoring CR (GAS: Cohen's d: 0.57, 0.19-0.96 95% CI, P = .003; Cognitive score: Cohens d: 0.28, 0.07-0.48 95% CI, P = .008). The QALY costs were £4306 for Group vs TAU and £3170 for One-to-One vs TAU. Adverse events did not differ between treatment methods and no serious adverse events were related to treatment., Conclusions: Both active therapist methods provided cost-effective treatment benefiting functional recovery in early psychosis and should be adopted within services. Some individuals benefited more than others so needs further investigation., Trial Registration: ISRCTN14678860 https://doi.org/10.1186/ISRCTN14678860Now closed., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center.)

Background: Evidence suggests that cognitive subtypes exist in schizophrenia that may reflect different neurobiological trajectories. We aimed to identify whether IQ-derived cognitive subtypes are present in early-phase schizophrenia-spectrum disorder and examine their relationship with brain structure and markers of neuroinflammation., Method: 161 patients with recent-onset schizophrenia spectrum disorder (<5 years) were recruited. Estimated premorbid and current IQ were calculated using the Wechsler Test of Adult Reading and a 4-subtest WAIS-III. Cognitive subtypes were identified with k-means clustering. Freesurfer was used to analyse 3.0 T MRI. Blood samples were analysed for hs-CRP, IL-1RA, IL-6 and TNF- α ., Results: Three subtypes were identified indicating preserved (PIQ), deteriorated (DIQ) and compromised (CIQ) IQ. Absolute total brain volume was significantly smaller in CIQ compared to PIQ and DIQ, and intracranial volume was smaller in CIQ than PIQ ( F (2, 124) = 6.407, p = 0.002) indicative of premorbid smaller brain size in the CIQ group. CIQ had higher levels of hs-CRP than PIQ ( F (2, 131) = 5.01, p = 0.008). PIQ showed differentially impaired processing speed and verbal learning compared to IQ-matched healthy controls., Conclusions: The findings add validity of a neurodevelopmental subtype of schizophrenia identified by comparing estimated premorbid and current IQ and characterised by smaller premorbid brain volume and higher measures of low-grade inflammation (CRP).

Background: Antipsychotic treatment resistance affects up to a third of individuals with schizophrenia, with recent research finding systematic biological differences between antipsychotic resistant and responsive patients. Our aim was to determine whether cognitive impairment at first episode significantly differs between future antipsychotic responders and resistant cases., Methods: Analysis of data from seven international cohorts of first-episode psychosis (FEP) with cognitive data at baseline (N = 683) and follow-up data on antipsychotic treatment response: 605 treatment responsive and 78 treatment resistant cases. Cognitive measures were grouped into seven cognitive domains based on the pre-existing literature. We ran multiple imputation for missing data and used logistic regression to test for associations between cognitive performance at FEP and treatment resistant status at follow-up., Results: On average patients who were future classified as treatment resistant reported poorer performance across most cognitive domains at baseline. Univariate logistic regressions showed that antipsychotic treatment resistance cases had significantly poorer IQ/general cognitive functioning at FEP (OR = 0.70, p = .003). These findings remained significant after adjusting for additional variables in multivariable analyses (OR = 0.76, p = .049)., Conclusions: Although replication in larger studies is required, it appears that deficits in IQ/general cognitive functioning at first episode are associated with future treatment resistance. Cognitive variables may be able to provide further insight into neurodevelopmental factors associated with treatment resistance or act as early predictors of treatment resistance, which could allow prompt identification of refractory illness and timely interventions., Competing Interests: Declaration of competing interest J.T.R.W. is an investigator on a grant from Takeda Pharmaceuticals Ltd. to Cardiff University, for a project unrelated to the work presented here. S.E.S. is employed on this grant. M.D.F. has received a fee for educational seminars from Lundbeck and Janssen. O.A.A. is a consultant to HealthLytix and has received speakers honorarium from Lundbeck and Sunovion. T.R.E.B. has been a member of an advisory board for Gedeon Richter. B.C.F. has received honoraria for participation as a consultant and/or as a speaker at educational events from ADAMED, Mylan, Angelini, Janssen Johnson & Johnson, Lundbeck, and Otsuka Pharmaceuticals. R.M.M. has received payments for non-promotional lectures from Janssen, Otsuka, Sunovian, and Lundbeck. J.H.M. has received research funding from H Lundbeck., (Copyright © 2023. Published by Elsevier B.V.)

Sapindales is an angiosperm order of high economic and ecological value comprising nine families, c. 479 genera, and c. 6570 species. However, family and subfamily relationships in Sapindales remain unclear, making reconstruction of the order's spatio-temporal and morphological evolution difficult. In this study, we used Angiosperms353 target capture data to generate the most densely sampled phylogenetic trees of Sapindales to date, with 448 samples and c. 85% of genera represented. The percentage of paralogous loci and allele divergence was characterized across the phylogeny, which was time-calibrated using 29 rigorously assessed fossil calibrations. All families were supported as monophyletic. Two core family clades subdivide the order, the first comprising Kirkiaceae, Burseraceae, and Anacardiaceae, the second comprising Simaroubaceae, Meliaceae, and Rutaceae. Kirkiaceae is sister to Burseraceae and Anacardiaceae, and, contrary to current understanding, Simaroubaceae is sister to Meliaceae and Rutaceae. Sapindaceae is placed with Nitrariaceae and Biebersteiniaceae as sister to the core Sapindales families, but the relationships between these families remain unclear, likely due to their rapid and ancient diversification. Sapindales families emerged in rapid succession, coincident with the climatic change of the Mid-Cretaceous Hothouse event. Subfamily and tribal relationships within the major families need revision, particularly in Sapindaceae, Rutaceae and Meliaceae. Much of the difficulty in reconstructing relationships at this level may be caused by the prevalence of paralogous loci, particularly in Meliaceae and Rutaceae, that are likely indicative of ancient gene duplication events such as hybridization and polyploidization playing a role in the evolutionary history of these families. This study provides key insights into factors that may affect phylogenetic reconstructions in Sapindales across multiple scales, and provides a state-of-the-art phylogenetic framework for further research., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Yanã Campos Rizzieri, School of Integrative Plant Sciences, Plant Biology Section, Cornell University, in collaboration with reviewer JO., (Copyright © 2023 Joyce, Appelhans, Buerki, Cheek, de Vos, Pirani, Zuntini, Bachelier, Bayly, Callmander, Devecchi, Pell, Groppo, Lowry, Mitchell, Siniscalchi, Munzinger, Orel, Pannell, Nauheimer, Sauquet, Weeks, Muellner-Riehl, Leitch, Maurin, Forest, Nargar, Thiele, Baker and Crayn.)

(1) Background: Major depressive disorder (MDD) generates a large proportion of global disease burden. Stereotactic radiofrequency ablation (SRA) may be beneficial for selected patients with its most debilitating and refractory forms, but effect size is uncertain. (2) Methods: A systematic literature review and meta-analysis on SRA for MDD was carried out. Patient-level data were extracted from articles reporting validated depression measures (Beck Depression Inventory (BDI), Montgomery-Åsberg Depression Rating Scale (MADRS)), pre- and at least six months post surgery. To accommodate different outcome measures, the standardised mean difference (SMD) between both scores was used as the principal effect size. Data were synthesised using a random-effects model. (3) Results: Five distinct studies were identified, comprising 116 patients (64 included in meta-analysis). Effect size comparing post- vs. pre-operative scores was 1.66 (CI 1.25-2.07). Anterior cingulotomy (two studies, n = 22) and anterior capsulotomy (three studies, n = 42) showed similar effect sizes: 1.51 (CI 0.82-2.20) vs. 1.74 (CI 1.23-2.26). Multiple procedures were performed in 30 of 116 (25.9%) patients. Based on patient-level data, 53% ( n = 47) were responders (≥50% improvement), of which 34% reached remission (MADRS ≤ 10 or BDI ≤ 11). BDI mean improvement was 16.7 (44.0%) after a second procedure ( n = 19). (4) Conclusions: The results are supportive of the benefit of SRA in selected patients with refractory MDD., Competing Interests: The authors declare no conflict of interest.

Background: Neuropsychiatric symptoms are common in Parkinson's disease (PD) and predict poorer outcomes. Reward processing dysfunction is a candidate mechanism for the development of psychiatric symptoms including depression and impulse control disorders (ICDs). We aimed to determine whether reward processing is impaired in PD and its relationship with neuropsychiatric syndromes and dopamine replacement therapy., Methods: The Ovid MEDLINE/PubMed, Embase and PsycInfo databases were searched for articles published up to 5 November 2020. Studies reporting reward processing task performance by patients with PD and healthy controls were included. Summary statistics comparing reward processing between groups were converted to standardised mean difference (SMD) scores and meta-analysed using a random effects model., Results: We identified 55 studies containing 2578 participants (1638 PD and 940 healthy controls). Studies assessing three subcomponent categories of reward processing tasks were included: option valuation (n=12), reinforcement learning (n=37) and reward response vigour (n=6). Across all studies, patients with PD on medication exhibited a small-to-medium impairment versus healthy controls (SMD=0.34; 95% CI 0.14 to 0.53), with greater impairments observed off dopaminergic medication in within-subjects designs (SMD=0.43, 95% CI 0.29 to 0.57). Within-subjects subcomponent analysis revealed impaired processing off medication on option valuation (SMD=0.57, 95% CI 0.39 to 0.75) and reward response vigour (SMD=0.36, 95% CI 0.13 to 0.59) tasks. However, the opposite applied for reinforcement learning, which relative to healthy controls was impaired on-medication (SMD=0.45, 95% CI 0.25 to 0.65) but not off-medication (SMD=0.28, 95% CI -0.03 to 0.59). ICD was the only neuropsychiatric syndrome with sufficient studies (n=13) for meta-analysis, but no significant impairment was identified compared tonon-ICD patients (SMD=-0.02, 95% CI -0.43 to 0.39)., Conclusion: Reward processing disruption in PD differs according to subcomponent and dopamine medication state, and warrants further study as a potential treatment target and mechanism underlying associated neuropsychiatric syndromes., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.)

Importance: About 20% to 30% of people with schizophrenia have psychotic symptoms that do not respond adequately to first-line antipsychotic treatment. This clinical presentation, chronic and highly disabling, is known as treatment-resistant schizophrenia (TRS). The causes of treatment resistance and their relationships with causes underlying schizophrenia are largely unknown. Adequately powered genetic studies of TRS are scarce because of the difficulty in collecting data from well-characterized TRS cohorts., Objective: To examine the genetic architecture of TRS through the reassessment of genetic data from schizophrenia studies and its validation in carefully ascertained clinical samples., Design, Setting, and Participants: Two case-control genome-wide association studies (GWASs) of schizophrenia were performed in which the case samples were defined as individuals with TRS (n = 10 501) and individuals with non-TRS (n = 20 325). The differences in effect sizes for allelic associations were then determined between both studies, the reasoning being such differences reflect treatment resistance instead of schizophrenia. Genotype data were retrieved from the CLOZUK and Psychiatric Genomics Consortium (PGC) schizophrenia studies. The output was validated using polygenic risk score (PRS) profiling of 2 independent schizophrenia cohorts with TRS and non-TRS: a prevalence sample with 817 individuals (Cardiff Cognition in Schizophrenia [CardiffCOGS]) and an incidence sample with 563 individuals (Genetics Workstream of the Schizophrenia Treatment Resistance and Therapeutic Advances [STRATA-G])., Main Outcomes and Measures: GWAS of treatment resistance in schizophrenia. The results of the GWAS were compared with complex polygenic traits through a genetic correlation approach and were used for PRS analysis on the independent validation cohorts using the same TRS definition., Results: The study included a total of 85 490 participants (48 635 [56.9%] male) in its GWAS stage and 1380 participants (859 [62.2%] male) in its PRS validation stage. Treatment resistance in schizophrenia emerged as a polygenic trait with detectable heritability (1% to 4%), and several traits related to intelligence and cognition were found to be genetically correlated with it (genetic correlation, 0.41-0.69). PRS analysis in the CardiffCOGS prevalence sample showed a positive association between TRS and a history of taking clozapine (r2 = 2.03%; P = .001), which was replicated in the STRATA-G incidence sample (r2 = 1.09%; P = .04)., Conclusions and Relevance: In this GWAS, common genetic variants were differentially associated with TRS, and these associations may have been obscured through the amalgamation of large GWAS samples in previous studies of broadly defined schizophrenia. Findings of this study suggest the validity of meta-analytic approaches for studies on patient outcomes, including treatment resistance.

(Appeared originally in Biological Psychiatry 2019; 85:726-734) Reprinted under Creative Commons CC-BY license., (Copyright © 2022 by the American Psychiatric Association.)

Background: Multiple deep brain stimulation (DBS) targets have been proposed for treating intractable obsessive-compulsive disorder (OCD). Here, we investigated whether stimulation effects of different target sites would be mediated by one common or several segregated functional brain networks., Methods: First, seeding from active electrodes of 4 OCD patient cohorts (N = 50) receiving DBS to anterior limb of the internal capsule or subthalamic nucleus zones, optimal functional connectivity profiles for maximal Yale-Brown Obsessive Compulsive Scale improvements were calculated and cross-validated in leave-one-cohort-out and leave-one-patient-out designs. Second, we derived optimal target-specific connectivity patterns to determine brain regions mutually predictive of clinical outcome for both targets and others predictive for either target alone. Functional connectivity was defined using resting-state functional magnetic resonance imaging data acquired in 1000 healthy participants., Results: While optimal functional connectivity profiles showed both commonalities and differences between target sites, robust cross-predictions of clinical improvements across OCD cohorts and targets suggested a shared network. Connectivity to the anterior cingulate cortex, insula, and precuneus, among other regions, was predictive regardless of stimulation target. Regions with maximal connectivity to these commonly predictive areas included the insula, superior frontal gyrus, anterior cingulate cortex, and anterior thalamus, as well as the original stereotactic targets., Conclusions: Pinpointing the network modulated by DBS for OCD from different target sites identified a set of brain regions to which DBS electrodes associated with optimal outcomes were functionally connected-regardless of target choice. On these grounds, we establish potential brain areas that could prospectively inform additional or alternative neuromodulation targets for obsessive-compulsive disorder., (Copyright © 2021 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Background: Deep brain stimulation (DBS) targeting the globus pallidus internus (GPi) can improve tics and comorbid obsessive-compulsive behavior (OCB) in patients with treatment-refractory Tourette syndrome (TS). However, some patients' symptoms remain unresponsive, the stimulation applied across patients is variable, and the mechanisms underlying improvement are unclear. Identifying the fiber pathways surrounding the GPi that are associated with improvement could provide mechanistic insight and refine targeting strategies to improve outcomes., Methods: Retrospective data were collected for 35 patients who underwent bilateral GPi DBS for TS. Computational models of fiber tract activation were constructed using patient-specific lead locations and stimulation settings to evaluate the effects of DBS on basal ganglia pathways and the internal capsule. We first evaluated the relationship between activation of individual pathways and symptom improvement. Next, linear mixed-effects models with combinations of pathways and clinical variables were compared in order to identify the best-fit predictive models of tic and OCB improvement., Results: The best-fit model of tic improvement included baseline severity and the associative pallido-subthalamic pathway. The best-fit model of OCB improvement included baseline severity and the sensorimotor pallido-subthalamic pathway, with substantial evidence also supporting the involvement of the prefrontal, motor, and premotor internal capsule pathways. The best-fit models of tic and OCB improvement predicted outcomes across the cohort and in cross-validation., Conclusions: Differences in fiber pathway activation likely contribute to variable outcomes of DBS for TS. Computational models of pathway activation could be used to develop novel approaches for preoperative targeting and selecting stimulation parameters to improve patient outcomes., (Copyright © 2020 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

SARS-CoV-2 is associated with new-onset neurological and psychiatric conditions. Detailed clinical data, including factors associated with recovery, are lacking, hampering prediction modelling and targeted therapeutic interventions. In a UK-wide cross-sectional surveillance study of adult hospitalized patients during the first COVID-19 wave, with multi-professional input from general and sub-specialty neurologists, psychiatrists, stroke physicians, and intensivists, we captured detailed data on demographics, risk factors, pre-COVID-19 Rockwood frailty score, comorbidities, neurological presentation and outcome. A priori clinical case definitions were used, with cross-specialty independent adjudication for discrepant cases. Multivariable logistic regression was performed using demographic and clinical variables, to determine the factors associated with outcome. A total of 267 cases were included. Cerebrovascular events were most frequently reported (131, 49%), followed by other central disorders (95, 36%) including delirium (28, 11%), central inflammatory (25, 9%), psychiatric (25, 9%), and other encephalopathies (17, 7%), including a severe encephalopathy ( n  = 13) not meeting delirium criteria; and peripheral nerve disorders (41, 15%). Those with the severe encephalopathy, in comparison to delirium, were younger, had higher rates of admission to intensive care and a longer duration of ventilation. Compared to normative data during the equivalent time period prior to the pandemic, cases of stroke in association with COVID-19 were younger and had a greater number of conventional, modifiable cerebrovascular risk factors. Twenty-seven per cent of strokes occurred in patients <60 years. Relative to those >60 years old, the younger stroke patients presented with delayed onset from respiratory symptoms, higher rates of multi-vessel occlusion (31%) and systemic thrombotic events. Clinical outcomes varied between disease groups, with cerebrovascular disease conferring the worst prognosis, but this effect was less marked than the pre-morbid factors of older age and a higher pre-COVID-19 frailty score, and a high admission white cell count, which were independently associated with a poor outcome. In summary, this study describes the spectrum of neurological and psychiatric conditions associated with COVID-19. In addition, we identify a severe COVID-19 encephalopathy atypical for delirium, and a phenotype of COVID-19 associated stroke in younger adults with a tendency for multiple infarcts and systemic thromboses. These clinical data will be useful to inform mechanistic studies and stratification of patients in clinical trials., (© The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain.)

Premise: Universal target enrichment kits maximize utility across wide evolutionary breadth while minimizing the number of baits required to create a cost-efficient kit. The Angiosperms353 kit has been successfully used to capture loci throughout the angiosperms, but the default target reference file includes sequence information from only 6-18 taxa per locus. Consequently, reads sequenced from on-target DNA molecules may fail to map to references, resulting in fewer on-target reads for assembly, and reducing locus recovery., Methods: We expanded the Angiosperms353 target file, incorporating sequences from 566 transcriptomes to produce a 'mega353' target file, with each locus represented by 17-373 taxa. This mega353 file is a drop-in replacement for the original Angiosperms353 file in HybPiper analyses. We provide tools to subsample the file based on user-selected taxon groups, and to incorporate other transcriptome or protein-coding gene data sets., Results: Compared to the default Angiosperms353 file, the mega353 file increased the percentage of on-target reads by an average of 32%, increased locus recovery at 75% length by 49%, and increased the total length of the concatenated loci by 29%., Discussion: Increasing the phylogenetic density of the target reference file results in improved recovery of target capture loci. The mega353 file and associated scripts are available at: https://github.com/chrisjackson-pellicle/NewTargets., (© 2021 McLay et al. Applications in Plant Sciences published by Wiley Periodicals LLC on behalf of the Botanical Society of America.)

The neural circuits responsible for animal behavior remain largely unknown. We summarize new methods and present the circuitry of a large fraction of the brain of the fruit fly Drosophila melanogaster . Improved methods include new procedures to prepare, image, align, segment, find synapses in, and proofread such large data sets. We define cell types, refine computational compartments, and provide an exhaustive atlas of cell examples and types, many of them novel. We provide detailed circuits consisting of neurons and their chemical synapses for most of the central brain. We make the data public and simplify access, reducing the effort needed to answer circuit questions, and provide procedures linking the neurons defined by our analysis with genetic reagents. Biologically, we examine distributions of connection strengths, neural motifs on different scales, electrical consequences of compartmentalization, and evidence that maximizing packing density is an important criterion in the evolution of the fly's brain., Competing Interests: LS, CX, ZL, ST, KH, GH, KS, SB, JC, PH, WK, LU, TZ, DA, JB, TD, DK, TK, KK, NN, DO, HO, ET, MI, AB, JG, TW, RS, PS, EN, CK, CA, DB, SB, JB, BC, NC, MC, MD, OD, BE, KF, SF, NF, AF, GH, EJ, SK, NK, JK, SL, AL, CM, EM, SM, CM, MN, OO, NO, CO, NP, CP, TP, EP, EP, NR, CR, MR, JR, SR, MS, AS, AS, AS, CS, KS, NS, MS, AS, JS, ST, IT, DT, ET, TT, JW, TY, JH, FL, RP, PR, VJ, MC, GJ, KI, SS, RG, IM, GR, HH, SP No competing interests declared, MJ, JM, TB, LL, PL, LL, VJ is an employee of Google., (© 2020, Scheffer et al.)

Objectives: We aimed to identify existing outcome measures for functional neurological disorder (FND), to inform the development of recommendations and to guide future research on FND outcomes., Methods: A systematic review was conducted to identify existing FND-specific outcome measures and the most common measurement domains and measures in previous treatment studies. Searches of Embase, MEDLINE and PsycINFO were conducted between January 1965 and June 2019. The findings were discussed during two international meetings of the FND-Core Outcome Measures group., Results: Five FND-specific measures were identified-three clinician-rated and two patient-rated-but their measurement properties have not been rigorously evaluated. No single measure was identified for use across the range of FND symptoms in adults. Across randomised controlled trials (k=40) and observational treatment studies (k=40), outcome measures most often assessed core FND symptom change. Other domains measured commonly were additional physical and psychological symptoms, life impact (ie, quality of life, disability and general functioning) and health economics/cost-utility (eg, healthcare resource use and quality-adjusted life years)., Conclusions: There are few well-validated FND-specific outcome measures. Thus, at present, we recommend that existing outcome measures, known to be reliable, valid and responsive in FND or closely related populations, are used to capture key outcome domains. Increased consistency in outcome measurement will facilitate comparison of treatment effects across FND symptom types and treatment modalities. Future work needs to more rigorously validate outcome measures used in this population., Competing Interests: Competing interests: AAA-P reports honoraria from Cobel Daruo, Sanofi and RaymandRad, and royalty from Oxford University Press (book publication). AJC reports independent expert testimony work for personal injury and medical negligence claims, is a paid associate editor of JNNP and runs a free non-profit self-help website (www.headinjurysymptoms.org). AJE has received personal compensation as a consultant/scientific advisory board member for Abbvie, Adamas, Acadia, Acorda, Neuroderm, Impax/Amneal, Sunovion, Lundbeck, Osmotica Pharmaceutical and US WorldMeds; publishing royalties from Lippincott Williams & Wilkins, Cambridge University Press and Springer; and honoraria from US WorldMeds, Lundbeck, Acadia, Sunovion, the American Academy of Neurology and the Movement Disorders Society. BM has received honoraria from The Cleveland Clinic and runs a free non-profit self-help website (www.fndhope.org). WCLF has served on the editorial boards of Epilepsia, Epilepsy & Behavior; Journal of Neurology, Neurosurgery and Psychiatry and Journal of Neuropsychiatry and Clinical Neurosciences; receives editor’s royalties from the publication of Gates and Rowan’s Nonepileptic Seizures, 3rd ed. (Cambridge University Press, 2010) and 4th ed. (2018); author’s royalties for Taking Control of Your Seizures: Workbook and Therapist Guide (Oxford University Press, 2015); has received research support from the Department of Defense (DoD W81XWH-17-0169), National Institutes of Health (NIH) (NINDS 5K23NS45902 [PI]), Providence VAMC, Center for Neurorestoration and Neurorehabilitation, Rhode Island Hospital, the American Epilepsy Society (AES), the Epilepsy Foundation (EF), Brown University and the Siravo Foundation; serves on the Epilepsy Foundation New England Professional Advisory Board; received honoraria for the American Academy of Neurology Meeting Annual Course; served as a clinic development consultant at University of Colorado Denver, Cleveland Clinic, Spectrum Health, Emory University and Oregon Health Sciences University; and provided medicolegal expert testimony. DLP has received honoraria from the American Academy of Neurology, Movement Disorder Society and Harvard Medical School. JS reports independent expert testimony work for personal injury and medical negligence claims, receives royalties from UpToDate for articles on functional neurological disorder and runs a free non-profit self-help website (www.neurosymptoms.org). KLF has received honoraria from the American Academy of Neurology and the Movement Disorder Society. MH may accrue revenue on a US patent for an Immunotoxin (MAB-Ricin) for the treatment of focal movement disorders and for a coil for magnetic stimulation and methods for using the same (H-coil); in relation to the latter, he has received licence fee payments from the NIH (from Brainsway). He is on the medical advisory boards of CALA Health, Brainsway and Cadent. He is on the editorial board of approximately 15 journals and receives royalties and/or honoraria from publishing from Cambridge University Press, Oxford University Press, Springer and Elsevier. Grant research funds have come from Merz for treatment studies of focal hand dystonia; Allergan for studies of methods to inject botulinum toxins; Medtronic, Inc. for a study of DBS for dystonia; and CALA Health for studies of a device to suppress tremor. MJE reports independent expert testimony work for personal injury and medical negligence claims and receives royalties from the Oxford Specialist Handbook of Parkinson’s Disease and Other Movement Disorders. He has received honoraria from Merz Pharma and Boeringher Ingleheim. AEL reports consultancy support from Abbvie, AFFiRis, Biogen, Janssen, Lilly, Lundbeck, Merck, Paladin, Roche, Sun Pharma, Theravance, and Corticobasal Degeneration Solutions; advisory board support form Jazz Pharma, PhotoPharmics, Sunovion; other honoraria from Sun Pharma, AbbVie, Sunovion, American Academy of Neurology and the International Parkinson and Movement Disorder Society; grants from Brain Canada, Canadian Institutes of Health Research, Corticobasal Degeneration Solutions, Edmond J Safra Philanthropic Foundation, Michael J. Fox Foundation, the Ontario Brain Institute, Parkinson Foundation, Parkinson Canada, and W. Garfield Weston Foundation and royalties from Elsevier, Saunders, Wiley-Blackwell, Johns Hopkins Press, and Cambridge University Press., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background The Sunda-Sahul Convergence Zone, defined here as the area comprising Australia, New Guinea, and Southeast Asia (Indonesia to Myanmar), straddles the Sunda and Sahul continental shelves and is one of the most biogeographically famous and important regions in the world. Floristically, it is thought to harbour a large amount of the world's diversity. Despite the importance of the area, a checklist of the flora has never before been published. Here we present the first working checklist of vascular plants for the Sunda-Sahul Convergence Zone. The list was compiled from 24 flora volumes, online databases and unpublished plot data. Taxonomic nomenclature was updated, and each species was coded into nested biogeographic regions. The list includes 60,415 species in 5,135 genera and 363 families of vascular plants. New information This is the first species-level checklist of the region and presents an updated census of the region's floristic biodiversity. The checklist confirms that species richness of the SSCZ is comparable to that of the Neotropics, and highlights areas in need of further documentation and taxonomic work. This checklist provides a novel dataset for studying floristic ecology and evolution in this biogeographically important region of very high global biodiversity., (Elizabeth M. Joyce, Kevin R. Thiele, Ferry J.W. Slik, Darren M. Crayn.)

These updated guidelines from the British Association for Psychopharmacology replace the original version published in 2011. They address the scope and targets of pharmacological treatment for schizophrenia. A consensus meeting was held in 2017, involving experts in schizophrenia and its treatment. They were asked to review key areas and consider the strength of the evidence on the risk-benefit balance of pharmacological interventions and the clinical implications, with an emphasis on meta-analyses, systematic reviews and randomised controlled trials where available, plus updates on current clinical practice. The guidelines cover the pharmacological management and treatment of schizophrenia across the various stages of the illness, including first-episode, relapse prevention, and illness that has proved refractory to standard treatment. It is hoped that the practice recommendations presented will support clinical decision making for practitioners, serve as a source of information for patients and carers, and inform quality improvement.

Gilles de la Tourette syndrome (GTS) is a neurological condition characterized by motor and vocal tics. Previous studies suggested that this syndrome is associated with abnormal sensorimotor cortex activity at rest, as well as during the execution of voluntary movements. It has been hypothesized that this abnormality might be interpreted as a form of increased tonic inhibition, probably to suppress tics; however, this hypothesis has not been tested so far. The present study was designed to formally test how voluntary tic suppression in GTS influences the activity of the sensorimotor cortex during the execution of a motor task. We used EEG to record neural activity over the contralateral sensorimotor cortex during a finger movement task in adult GTS patients, in both free ticcing and tic suppression conditions; these data were then compared with those collected during the same task in age-matched healthy subjects. We focused on the levels of activity in the beta frequency band, which is typically associated with the activation of the motor system, during three different phases: a pre-movement, a movement, and a post-movement phase. GTS patients showed decreased levels of beta modulation with respect to the healthy controls, during the execution of the task; however, this abnormal pattern returned to be normal when they were explicitly asked to suppress their tics while moving. This is the first demonstration that voluntary tic suppression in GTS operates through the normalization of the EEG rhythm in the beta frequency range during the execution of a voluntary finger movement., (© 2019 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)

Background: Deep brain stimulation (DBS) can be an effective therapy for tics and comorbidities in select cases of severe, treatment-refractory Tourette syndrome (TS). Clinical responses remain variable across patients, which may be attributed to differences in the location of the neuroanatomical regions being stimulated. We evaluated active contact locations and regions of stimulation across a large cohort of patients with TS in an effort to guide future targeting., Methods: We collected retrospective clinical data and imaging from 13 international sites on 123 patients. We assessed the effects of DBS over time in 110 patients who were implanted in the centromedial (CM) thalamus (n=51), globus pallidus internus (GPi) (n=47), nucleus accumbens/anterior limb of the internal capsule (n=4) or a combination of targets (n=8). Contact locations (n=70 patients) and volumes of tissue activated (n=63 patients) were coregistered to create probabilistic stimulation atlases., Results: Tics and obsessive-compulsive behaviour (OCB) significantly improved over time (p<0.01), and there were no significant differences across brain targets (p>0.05). The median time was 13 months to reach a 40% improvement in tics, and there were no significant differences across targets (p=0.84), presence of OCB (p=0.09) or age at implantation (p=0.08). Active contacts were generally clustered near the target nuclei, with some variability that may reflect differences in targeting protocols, lead models and contact configurations. There were regions within and surrounding GPi and CM thalamus that improved tics for some patients but were ineffective for others. Regions within, superior or medial to GPi were associated with a greater improvement in OCB than regions inferior to GPi., Conclusion: The results collectively indicate that DBS may improve tics and OCB, the effects may develop over several months, and stimulation locations relative to structural anatomy alone may not predict response. This study was the first to visualise and evaluate the regions of stimulation across a large cohort of patients with TS to generate new hypotheses about potential targets for improving tics and comorbidities., Competing Interests: Competing interests: JLO has received research grant support from the Michael J Fox Foundation, Boston Scientific, Cala Health, NIH, DARPA, PCORI and Biogen, and she has also received training grant support from Boston Scientific and Medtronic, and has served as a consultant for Acadia Pharmaceuticals and Medtronic. AL serves as a consultant for Boston Scientific and holds intellectual property in the field of DBS. JK has received financial support for investigator-initiated trials from Medtronic and grants from the German Research Foundation (KU2665/1-2) and the Marga and Walter Boll Foundation. CZ has received honoraria and travel expenses from the deep brain stimulation industry (Medtronic, PINS, SceneRay). MSO serves as a consultant for the National Parkinson Foundation, and has received research grants from NIH, NPF, the Michael J Fox Foundation, the Parkinson Alliance, Smallwood Foundation, the Bachmann-Strauss Foundation, the Tourette Syndrome Association, and the UF Foundation. MSO DBS research is supported by R01 NR014852 and R01NS096008. MSO has previously received honoraria, but in the past >60 months has received no support from the industry. MSO has received royalties for publications with Demos, Manson, Amazon, Smashwords, Books4Patients and Cambridge (movement disorders books). MSO is an associate editor for New England Journal of Medicine Journal Watch Neurology. MSO has participated in CME and educational activities on movement disorders (in the last 36 months) sponsored by PeerView, Prime, QuantiaMD, WebMD, Medicus, MedNet, Henry Stewart and by Vanderbilt University. The institution and not MSO receives grants from Medtronic, AbbVie, Allergan and ANS/St Jude, and the PI has no financial interest in these grants. MSO has participated as a site PI and/or co-I for several NIH, foundation and industry sponsored trials over the years but has not received honoraria. CRB has served as a consultant for NeuroPace, Advanced Bionics, Boston Scientific, Intelect Medical, St Jude Medical and Functional Neuromodulation, and he holds intellectual property related to DBS., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: To determine whether neighbourhood-level socioenvironmental factors including deprivation and inequality predict variance in psychotic symptoms after controlling for individual-level demographics., Design: A cross-sectional design was employed., Setting: Data were originally collected from secondary care services within the UK boroughs of Ealing, Hammersmith and Fulham, Wandsworth, Kingston, Richmond, Merton, Sutton and Hounslow as part of the West London First-Episode Psychosis study., Participants: Complete case analyses were undertaken on 319 participants who met the following inclusion criteria: aged 16 years or over, resident in the study's catchment area, experiencing a first psychotic episode, with fewer than 12 weeks' exposure to antipsychotic medication and sufficient command of English to facilitate assessment., Outcome Measures: Symptom dimension scores, derived from principal component analyses of the Scale for the Assessment of Positive Symptoms and Scale for the Assessment of Negative Symptoms, were regressed on neighbourhood-level predictors, including population density, income deprivation, income inequality, social fragmentation, social cohesion, ethnic density and ethnic fragmentation, using multilevel regression. While age, gender and socioeconomic status were included as individual-level covariates, data on participant ethnicity were not available., Results: Higher income inequality was associated with lower negative symptom scores (coefficient=-1.66, 95% CI -2.86 to -0.46, p<0.01) and higher levels of ethnic segregation were associated with lower positive symptom scores (coefficient=-2.32, 95% CI -4.17 to -0.48, p=0.01) after adjustment for covariates., Conclusions: These findings provide further evidence that particular characteristics of the environment may be linked to specific symptom clusters in psychosis. Longitudinal studies are required to begin to tease apart the underlying mechanisms involved as well as the causal direction of such associations., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY. Published by BMJ.)

Background: Deep brain stimulation (DBS) is an emerging treatment for severe obsessive-compulsive disorder (OCD). We compared the efficacy of ventral capsule/ventral striatal (VC/VS) and anteromedial subthalamic nucleus (amSTN) DBS in the same patients and tested for mechanistic differences on mood and cognitive flexibility and associated neural circuitry. The possible synergistic benefit of DBS at both sites and cognitive behavioral therapy was explored., Methods: Six patients with treatment-refractory OCD (5 men; Yale-Brown Obsessive Compulsive Scale score >32) entered double-blind counterbalanced phases of 12-week amSTN or VC/VS DBS, followed by 12-week open phases when amSTN and VC/VS were stimulated together, in which optimal stimulation parameters were achieved and adjunctive inpatient cognitive behavioral therapy was delivered. OCD and mood were assessed with standardized scales and cognitive flexibility with the Cambridge Neuropsychological Test Automated Battery Intra-Extra Dimensional Set-Shift task. Diffusion-weighted and intraoperative magnetic resonance imaging scans were performed for tractography from optimally activated electrode contacts., Results: DBS at each site significantly and equivalently reduced OCD symptoms with little additional gain following combined stimulation. amSTN but not VC/VS DBS significantly improved cognitive flexibility, whereas VC/VS DBS had a greater effect on mood. The VC/VS effective site was within the VC. VC DBS connected primarily to the medial orbitofrontal cortex, and amSTN DBS to the lateral orbitofrontal cortex, dorsal anterior cingulate cortex, and dorsolateral prefrontal cortex. No further improvement followed cognitive behavioral therapy, reflecting a floor effect of DBS on OCD., Conclusions: Both the VC/VS and amSTN are effective targets for severe treatment-refractory OCD. Differential improvements in mood and cognitive flexibility and their associated connectivity suggest that DBS at these sites modulates distinct brain networks., (Copyright © 2019 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)