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Auditory verbal hallucinations (AVHs) in schizophrenia have been suggested to arise from failure of corollary discharge mechanisms to correctly predict and suppress self-initiated inner speech. However, it is unclear whether such dysfunction is related to motor preparation of inner speech during which sensorimotor predictions are formed. The contingent negative variation (CNV) is a slow-going negative event-related potential that occurs prior to executing an action. A recent meta-analysis has revealed a large effect for CNV blunting in schizophrenia. Given that inner speech, similar to overt speech, has been shown to be preceded by a CNV, the present study tested the notion that AVHs are associated with inner speech-specific motor preparation deficits.
Objectives
The present study aimed to provide a useful framework for directly testing the long-held idea that AVHs may be related to inner speech-specific CNV blunting in patients with schizophrenia. This may hold promise for a reliable biomarker of AVHs.
Methods
Hallucinating (n=52) and non-hallucinating (n=45) patients with schizophrenia, along with matched healthy controls (n=42), participated in a novel electroencephalographic (EEG) paradigm. In the Active condition, they were asked to imagine a single phoneme at a cue moment while, precisely at the same time, being presented with an auditory probe. In the Passive condition, they were asked to passively listen to the auditory probes. The amplitude of the CNV preceding the production of inner speech was examined.
Results
Healthy controls showed a larger CNV amplitude (p = .002, d = .50) in the Active compared to the Passive condition, replicating previous results of a CNV preceding inner speech. However, both patient groups did not show a difference between the two conditions (p > .05). Importantly, a repeated measure ANOVA revealed a significant interaction effect (p = .007, ηp2 = .05). Follow-up contrasts showed that healthy controls exhibited a larger CNV amplitude in the Active condition than both the hallucinating (p = .013, d = .52) and non-hallucinating patients (p < .001, d = .88). No difference was found between the two patient groups (p = .320, d = .20).
Conclusions
The results indicated that motor preparation of inner speech in schizophrenia was disrupted. While the production of inner speech resulted in a larger CNV than passive listening in healthy controls, which was indicative of the involvement of motor planning, patients exhibited markedly blunted motor preparatory activity to inner speech. This may reflect dysfunction in the formation of corollary discharges. Interestingly, the deficits did not differ between hallucinating and non-hallucinating patients. Future work is needed to elucidate the specificity of inner speech-specific motor preparation deficits with AVHs. Overall, this study provides evidence in support of atypical inner speech monitoring in schizophrenia.
The Central Mental Hospital is the Republic of Ireland's only secure forensic hospital and the seat of its National Forensic Mental Health Service (NFMHS). We scrutinised admission patterns in the NFMHS during the period 01/01/2018–01/10/2023; before and after relocating from the historic 1850 site in Dundrum to a modern facility in Portrane on 13/11/2022.
Methods
This prospective longitudinal cohort study included all patients admitted during the above period. The study initially commenced in Dundrum and continued afterwards in Portrane. Data gathered included demographics, diagnoses, capacity to consent to treatment, and the need for intramuscular medication (IM) after admission. Therapeutic security needs and urgency of need for admission were collated from DUNDRUM-1 and DUNDRUM-2 scores rated pre-admission. Hours spent in seclusion during the first day, week, and month after admission were calculated. Data were collected as part of the Dundrum Forensic Redevelopment Evaluation Study (D-FOREST).
Results
There were 117 admissions during the 69-month period. The majority were male (n = 98). Most were admitted from prisons (87%). Schizophrenia was the most common diagnosis (55.8%). Mean DUNDRUM-1 triage security scores were in the medium-security range (2.84–3.15) during this period. At the time of admission, 53.8% required seclusion, 25.6% required IM medication, and 79.5% lacked capacity to consent to treatment. Those who required seclusion on admission had worse scores on the DUNDRUM-2 triage urgency scale (F = 20.9, p < 0.001). On linear logistic regression, the most parsimonious model resolved with five predictors of hours in seclusion during the first day and week, which were: D1 item 8 – Victim sensitivity/public confidence issues, D1 item 10 – Institutional behaviour, D2 item 2 – Mental health, D2 item 4 – Humanitarian, and D2 item 6 – Legal urgency. 50% required IM medication during their first week of admission and these patients had significantly worse scores on: D1 item 8 – Victim sensitivity/public confidence issues, D1 item 10 – Institutional behaviour, D2 item 2 – Mental health, and D2 item 4 – Humanitarian (all p < 0.05).
Conclusion
There was an increase in the frequency of admissions since relocating to Portrane. The results suggest that there was no change in overall triage security and urgency needs during the time period in question. Major mental illness related factors impacted the need for seclusion early in the admission, whereas factors linked to prison behaviour or personality-related factors were more associated with an ongoing need for seclusion at month one.
Forensic psychiatric services address the therapeutic needs of mentally disordered offenders in a secure setting. Clinical, ethical, and legal considerations underpinning treatment emphasize that the Quality of Life (QOL) of patients admitted to forensic hospitals should be optimised. This study aims to examine changes in the QOL in Ireland's National Forensic Mental Health Service (NFMHS) following its relocation from the historic 1850 site in Dundrum to a new campus in Portrane, Dublin.
Methods
This multisite prospective longitudinal study is part of the Dundrum Forensic Redevelopment Evaluation Study (D-FOREST). Repeated measures were taken for all inpatients in the service at regular 6 monthly intervals. The WHOQOL-BREF questionnaire was offered to all inpatients. An anonymised EssenCES questionnaire was used to measure atmosphere in wards. Data were obtained at 5 time points for each individual patient and ward. WHOQOL-BREF ratings were obtained across 5 time points with comparisons available for 4 time intervals, including immediately before and after relocation. For 101 subjects across 4 time intervals, 215 sets of data were obtained; 140 before and 65 after relocation with 10 community patients who did not move. Using Generalised Estimating Equations (GEE) to correct for multiple comparisons over time, the effect of relocation, with community patients as a control, was analysed by ward cluster and whether patients moved between wards. Observations were categorised according to security level – high dependency, medium secure, rehabilitation, or community – and trichotomised based on positive moves to less secure wards, negative moves to more secure wards, or no moves.
Results
Relocation of the NFMHS was associated with a significant increase in environmental QOL (Wald X2 = 15.9, df = 1, p < 0.001), even when controlling for cluster location, positive and negative moves. When controlling for ward atmosphere, environmental QOL remained significantly increased after the move (Wald X2 = 10.0, df = 1, p = 0.002). EssenCES scores were obtained within the hospital for 3 time points before relocation and 2 time points afterwards. No significant differences were found on the three subscales before and after the move. All three EssenCES subscales progressively improved with decreasing security level (Patient Cohesion: Wald X2 = 958.3, df = 1, p < 0.001; Experiencing Safety: Wald X2 = 152.9, df = 5, p < 0.001; Therapeutic Hold: Wald X2 = 33.6, df = 3, p < 0.001).
Conclusion
The GEE model demonstrated that the move of the NFMHS improved self-reported environmental QOL. The cluster location made significant differences, as expected for a system of stratified therapeutic security, with a steady improvement in scores on all three atmosphere subscales.
This updated edition of Seminars in Forensic Psychiatry is an invaluable guide for consultants and specialist trainees working in forensic psychiatry. Written by leading international contributors, topics include models of care, the management of in-patient violence, forensic psychotherapy, and psychological treatments. The evolution of policy and mental health law is discussed, demonstrating how it has shaped the provision of forensic psychiatry services. Legal aspects include considerations of mentalistic defences in criminal law, mental health law, as well as the law on negligence. The book also includes sections on specialist areas of need, including cultural and gender specific needs, terrorism, stalkers, and sex offenders. Woven into the chapters are practical approaches, and 'how to' guides. The volume ends with advice for each of the transitions in the career of a forensic psychiatrist. A truly practical guide, this is a must-read for psychiatrists and mental health professionals working within a forensic setting.
Chapter 11 focuses on ancient ‘contracts’, with specific reference to commerce, property and other economic activities for which there is relevant evidence. The chapter begins with urbanization in southern Mesopotamia in the fourth millennium bce, bringing together archaeological, material and written evidence in order to introduce a broad working idea of ‘contracts’. The next section moves on to a discussion of technical ancient terms and concepts, noting the ‘considerable terminological instability in the common English translations of the original terms’. The following section turns to ‘contracts’ between states, whilst the next develops a comparative analysis of ‘oaths in interpersonal agreements’. The following two sections analyse specific questions surrounding the use of writing and ’the contract of sale’, noting that there is surviving evidence for the use of (different forms of) contacts of sale across every ancient legal system. The chapter concludes by drawing together a set of generalized conceptions of ‘contract’ and briefly suggesting that long-distance trade - among other factors - may lie behind some of the similarities - for example the use of seals - evident across the extant ancient evidence.
Chapter 10 surveys the history, the concepts and the institutions of property in premodern India, China, the Near East, Egypt, Greece and Rome. Formal rules of ownership and inheritance formed the basis of all premodern legal regimes and undergirded economic performance (for instance, growth), as has been frequently stressed by New Institutional Economists. The enforcement of property rights reveals a good deal about the diverse economies, environments and cultures of premodern societies. The chapter summarizes the sources for property rights, which are rich and varied; and the control and use of resources occupy a considerable part of private legal documentation in all premodern systems that have yielded written material.
In our paper testing the Cutler–Hawkins hypothesis that suffixes are easier to process than prefixes (Harris & Samuel 2025), we report little experimental support for the hypothesis. Several sources treat clitics as being similar to affixes (e.g. Himmelmann 2014, Asao 2015), and some argue that there is a parallel preference for enclitics over proclitics (Cysouw 2005, Dryer 2017). On this basis, we test an extension of the Cutler–Hawkins hypothesis to clitics because if true, that too could explain the suffixing preference (as well as the putative enclitic preference). Cutler et al. (1985) also state a hypothesis about the processing of infixes. Udi provides an excellent language for testing both hypotheses, since each person clitic in this language can occur before the verb, after the verb, between morphemes of the verb or inside the verbal root, under certain circumstances (Harris 2002). Although European Portuguese does not place clitics inside roots, it utilizes the other three placements. We have conducted three experiments on each language. The results demonstrate that an explanation for either the suffixing preference or the putative enclitic preference is unlikely to be grounded in the processing factors suggested by Cutler & Hawkins.
The hypothesis that affixes following a stem are easier to process than ones preceding has not been tested in a straightforward manner in any language, as far as we know. Cutler, Hawkins & Gilligan (1985) and Hawkins & Cutler (1988) adduce some evidence that supports this hypothesis indirectly, but they do not conduct experiments to test it directly. They use this hypothesis to explain in part the suffixing preference. Some others, such as Asao (2015), continue to assume the correctness of the hypothesis. We do not aim to explain the suffixing preference at all but to test the hypothesis that affixes preceding the stem (informally, prefixes) disrupt the comprehension of a word more than affixes that follow (informally, suffixes) do. In this paper we test this hypothesis (henceforth the ‘Cutler--Hawkins hypothesis’) on Georgian, because it has a wide variety of prefixes and suffixes, and in a single experiment on English. In Georgian we test a prefix and a suffix that mark the person of the subject in a verb, a circumfix and a suffix that mark derivation in nouns, and a prefix and a suffix that form intransitive verbs (usually called ‘passives’ in Georgian). Across the set of experiments, we find little support for the Cutler--Hawkins hypothesis.
Dysregulation of immune responses results in the development of chronic inflammatory conditions. The current frontline therapy, glucocorticoids, are effective immunosuppressive drugs but come with a trade-off of cumulative, debilitating side effects with sustained use. Clearly, alternative drug options with improved safety profiles are urgently needed. Macrophage Migration Inhibitory Factor (MIF) is a pleotropic pro-inflammatory cytokine and integral component of immune and inflammatory responses. MIF counter-regulates the immunosuppressive effects of glucocorticoids and promotes NLRP3 inflammasome activation.1, 2 Elevated MIF is a feature of multiple diseases, including multiple sclerosis, rheumatoid arthritis, and systemic lupus erythematous. Given the association of increased MIF in serum with multiple disease models, it is considered MIF may be a plausible, specific druggable target in treatment of chronic inflammatory and autoimmune diseases, particularly as a target for glucocorticoid-sparing therapy to reduce the dose or duration of glucocorticoid treatment. The organosulfur isothiocyanate phytochemical sulforaphane (SFN) is extracted from cruciferous vegetables, including broccoli and Brussel sprouts following hydrolysis of its inactive precursor, glucoraphanin. SFN has antioxidant and cancer chemoprotective properties, and promotes NRF2 antioxidant signalling to upregulate the expression of numerous antioxidant enzymes. SFN has been shown to covalently modify MIF with high reactivity and is a potent inhibitor of MIF tautomerase activity. However, to date, no such study has evaluated the role of SFN as a novel inhibitor of MIF-mediated inflammatory pathway activation. Using cell-based assays, we have sought to investigate the role of SFN as an inhibitor of multiple inflammatory pathways which have previously implicated MIF as a possible regulator. Our initial work has examined SFN as an inhibitor of NF-κB activity, inflammasome activation, and evaluated if MIF is required for this effect. RAW264.7 murine macrophage cells stably expressing NF-κB-luciferase reporter construct were pre-treated with SFN (2.5 µM) before the induction of inflammation, via LPS (100ng/mL). For NLRP3 inflammasome activation, cells were subsequently treated with the NLRP3-specific inflammasome activator, nigericin (10 µM). TNF, IFN-β and IL-1β cytokine expression was measured by ELISA and NF-κB activity by luciferase reporter assay. We found SFN is a potent inhibitor of NF-κB activity and inhibits release of the pro-inflammatory cytokine IL-1β through inhibition of NLRP3 inflammasome activation. Finally, co-incubation of SFN with the glucocorticoid dexamethasone significantly suppressed TNF and IFN-β expression, demonstrating steroid sparing activity of SFN in vitro. Thus, SFN may be a suitable treatment for disruption of inflammatory pathways and suggest some of these effects may be mediated through direct interactions with MIF.
OBJECTIVES/GOALS: Childhood Sjögren’s disease (cSD) is a rare autoimmune disease. Despite the profound impact on children and their families, pediatric-specific clinical trials to inform therapeutic strategies in cSD are lacking. In 2022 we participated in the Trial Innovation Network (TIN) Design Lab with the purpose of designing a series of N-of-1 trials for cSD. METHODS/STUDY POPULATION: New medications have the potential to be safe/effective treatments for cSD but must be evaluated in randomized trials. To overcome limitations of traditional parallel-group designs given the rarity of cSD, we developed an N-of-1 trial approach. Our proposal was selected by the Tufts TIN Design Lab. The Design Lab multi-stakeholder process involved parents of and patients with cSD, pediatric and adult rheumatologists, and experts in clinical trial design and outcomes. We engaged all stakeholders in protocol development to maximize the impact of the proposed approach on clinical care, ensure a successful recruitment plan, and inform the choice of endpoints as there are no widely accepted cSD outcome measures to determine treatment efficacy. RESULTS/ANTICIPATED RESULTS: Using the Design Lab methodology, we clarified the N-of-1 study goals and engaged in an iterative process to develop a “briefing book” that ensured a sound premise for our study. We reviewed and accumulated published literature to support our focus on mucosal/glandular manifestations, identified potential interventions to be used in the N-of-1 trials, and enumerated possible outcomes, including outcomes important to patient/parents. This work culminated in a full-day Design Lab event that included multiple stakeholders who provided expertise from different perspectives on the full drug development pathway. Study design feedback focused on three specific areas. 1) Inclusion and exclusion criteria; 2) Identification of outcome measures; 3) Treatment and washout periods. DISCUSSION/SIGNIFICANCE: To address the critical need and move treatment of cSD forward, we are designing a prototype N-of-1 trial in children with rheumatic disease. We will continue to engage stakeholders by using a series of Delphi surveys and an in-person meeting to create composite outcome measures to test cSD therapies in personalized trials.
The effect of heat treatments on the total charge and water adsorption by Ca-, Na- and Li-saturated kaolinite was studied using extraction techniques and thermal gravimetric analysis, respectively. Measurements of cation exchange capacity indicated that the total charge of Li-kaolinite was reduced by approximately 50% after heating to 110 or 130°C. In contrast, the total charge of Ca-kaolinite remained essentially constant while that of Na-kaolinite decreased slightly. Water adsorption and desorption on Ca- and Li-kaolinite following heat treatments at 150°C were consistent with the total charge of the respective kaolinites. Ion extraction of Li-kaolinite using NH4C1 revealed that only 6% of the Li remained exchangeable after heating, while Al and H were released. Thus, non-exchangeable Li ions not only reduced the total charge of the kaolinite but also displaced Al and H from the kaolinite structure. Infrared spectroscopy also indicated that Li migrated into the kaolinite structure and replaced a portion of the Al from the octahedral sheet. The results presented here indicate that Li-kaolinite represents a surface of reduced charge rather than a surface free of cation-hydration effects. Therefore, Li-kaolinite is not recommended as a reference for the study of vapor-phase adsorption, and conclusions based on such a reference material should be reevaluated.