Memory systems modulate crosslinguistic influence on third language morphosyntactic acquisition.

Previous studies on crosslinguistic influence (CLI) on third language (L3) morphosyntactic acquisition have provided support for competing theories about the source(s) of CLI. The present study aimed to test if both L1 and L2 can be the source of CLI, and whether they influence L3 learning in similar or different ways. In particular, we aimed to add to our knowledge of the neural correlates of CLI by conducting an exploratory EEG study to investigate how L1 and L2 CLI affect L3 neural processing. Predictions based on the D/P model, which posited different memory systems sustaining L1 and L2, were tested. The findings confirmed both L1-sourced and L2-sourced facilitation on L3 morphosyntactic acquisition. Specifically, we suggest that L1-similarity showed a consolidating effect on L3 implicit knowledge and neurocognitive internalization, whereas L2-similarity contributed to enhanced L3 metalinguistic knowledge. This preliminary study is the first to investigate the neurocognitive mechanisms underlying CLI in L3 learning by natural language learners.

Pervasive conservation of intron number and other genetic elements revealed by a chromosome-level genomic assembly of the hyper-polymorphic nematode Caenorhabditis brenneri.

With within-species genetic diversity estimates that span the gambit of that seen across the entirety of animals, the Caenorhabditis genus of nematodes holds unique potential to provide insights into how population size and reproductive strategies influence gene and genome organization and evolution. Our study focuses on Caenorhabditis brenneri, currently known as one of the most genetically diverse nematodes within its genus and metazoan phyla. Here, we present a high-quality gapless genome assembly and annotation for C. brenneri, revealing a common nematode chromosome arrangement characterized by gene-dense central regions and repeat rich peripheral parts. Comparison of C. brenneri with other nematodes from the 'Elegans' group revealed conserved macrosynteny but a lack of microsynteny, characterized by frequent rearrangements and low correlation iof orthogroup sizes, indicative of high rates of gene turnover. We also assessed genome organization within corresponding syntenic blocks in selfing and outcrossing species, affirming that selfing species predominantly experience loss of both genes and intergenic DNA. Comparison of gene structures revealed strikingly small number of shared introns across species, yet consistent distributions of intron number and length, regardless of population size or reproductive mode, suggesting that their evolutionary dynamics are primarily reflective of functional constraints. Our study provides valuable insights into genome evolution and expands the nematode genome resources with the highly genetically diverse C. brenneri, facilitating research into various aspects of nematode biology and evolutionary processes.

Chronic electrical stimulation with a peripheral suprachoroidal retinal implant: a preclinical safety study of neuroprotective stimulation.

Purpose: Extraocular electrical stimulation is known to provide neuroprotection for retinal cells in retinal and optic nerve diseases. Currently, the treatment approach requires patients to set up extraocular electrodes and stimulate potentially weekly due to the lack of an implantable stimulation device. Hence, a minimally-invasive implant was developed to provide chronic electrical stimulation to the retina, potentially improving patient compliance for long-term use. The aim of the present study was to determine the surgical and stimulation safety of this novel device designed for neuroprotective stimulation. Methods: Eight normally sighted adult feline subjects were monocularly implanted in the suprachoroidal space in the peripheral retina for 9-39 weeks. Charge balanced, biphasic, current pulses (100 µA, 500 µs pulse width and 50 pulses/s) were delivered continuously to platinum electrodes for 3-34 weeks. Electrode impedances were measured hourly. Retinal structure and function were assessed at 1-, 2-, 4-, 6- and 8-month using electroretinography, optical coherence tomography and fundus photography. Retina and fibrotic thickness were measured from histological sections. Randomized, blinded histopathological assessments of stimulated and non-stimulated retina were performed. Results: All subjects tolerated the surgical and stimulation procedure with no evidence of discomfort or unexpected adverse outcomes. The device position was stable after a post-surgery settling period. Median electrode impedance remained within a consistent range (5-10 kΩ) over time. There was no change in retinal thickness or function relative to baseline and fellow eyes. Fibrotic capsule thickness was equivalent between stimulated and non-stimulated tissue and helps to hold the device in place. There was no scarring, insertion trauma, necrosis, retinal damage or fibroblastic response in any retinal samples from implanted eyes, whilst 19% had a minimal histiocytic response, 19% had minimal to mild acute inflammation and 28% had minimal to mild chronic inflammation. Conclusion: Chronic suprathreshold electrical stimulation of the retina using a minimally invasive device evoked a mild tissue response and no adverse clinical findings. Peripheral suprachoroidal electrical stimulation with an implanted device could potentially be an alternative approach to transcorneal electrical stimulation for delivering neuroprotective stimulation.

Incretin-based therapy and the risk of diabetic foot ulcers and related events.

AIM: To investigate the effect of dipeptidyl peptidase-4 inhibitors (DPP4-Is) and glucagon-like peptide-1 receptor agonists (GLP1-RAs) on diabetic foot ulcer (DFU) and DFU-related outcomes (lower limb amputation [LLA], DFU-related hospitalization and mortality). METHODS: We performed a cohort study with data from the Clinical Practice Research Datalink Aurum database with linkage to hospital data. We included people with type 2 diabetes starting treatment with metformin. Then we propensity score matched new users of DPP4-Is and sulphonylureas (N = 98 770), and new users of GLP1-RAs and insulin (N = 25 422). Cox proportional hazards models estimated the hazard ratios (HRs) for the outcomes. RESULTS: We observed a lower risk of DFU with both DPP4-I use versus sulphonylurea use (HR 0.88, 95% confidence interval [CI]: 0.79-0.97) and GLP1-RA use versus insulin use (HR 0.44, 95% CI: 0.32-0.60) for short-term exposure (≤ 400 days) and HR 0.74 (95% CI: 0.60-0.92) for long-term exposure (>400 days). Furthermore, the risks of hospitalization and mortality were lower with both DPP4-I use and GLP1-RA use. The risk of LLA was lower with GLP1-RA use. The results remained consistent across several sensitivity analyses. CONCLUSIONS: Incretin-based therapy was associated with a lower risk of DFU and DFU-related outcomes. This suggests benefits for the use of this treatment in people at risk of DFU.

Description, life cycle, and development of the myxozoan Myxobolus rasmusseni n. sp. in fathead minnows, Pimephales promelas: A possible emerging pathogen in southern Alberta, Canada.

Morphological, gene sequence, host tissue tropism, and life cycle characteristics were utilized to describe the myxozoan, Myxobolus rasmusseni n. sp. from fathead minnow, Pimephales promelas, collected from reservoirs in southern Alberta. Results from serial histological sections of whole heads showed that myxospores were contained within irregular-shaped and sized coelozoic capsules (=plasmodia). Clusters of membrane-bound, myxospore-filled plasmodia filled the head cavities of juvenile fathead minnows, leading to the development of large, white, disfiguring lesions in mid to late summer. Bilateral exopthalmia (pop-eye disease) was a common outcome of M. rasmusseni n. sp. development. BLASTn search of a 1974 bp sequence of the 18S rDNA gene isolated from myxospores indicated that M. rasmusseni n. sp. was distinct from other coelozoic and histozoic Myxobolus spp. cataloged in GenBank. 18S rDNA gene sequences from triactinomyxon spores released from the oligochaete Tubifex were 100% identical to sequences from myxospores collected from syntopic fathead minnows. Results from a longitudinal survey of the 2020 cohort of fathead minnows showed that young-of-the-year are exposed at 1-5 mo and that 60-90% of these had developed myxospore-filled lesions approximately one year later. Data regarding potential sources and timing of M. rasmusseni n. sp. emergence in fathead minnow populations are needed.

Enhancing running injury prevention strategies with real-time biofeedback: A systematic review and meta-analysis.

The number of runners and the incidence of running-related injuries (RRIs) are on the rise. Real-time biofeedback gait retraining offers a promising approach to RRIs prevention. However, due to the diversity in study designs and reported outcomes, there remains uncertainty regarding the efficacy of different forms of feedback on running gait biomechanics. Three databases: MEDLINE, PUBMED, and SPORTDiscus were searched to identify relevant studies published up to March 2024, yielding 4646 articles for review. The quality of the included studies was assessed using the Downs and Black Quality checklist. Primary outcomes, including Peak Tibial Acceleration (PTA), Vertical Average Loading Rate (VALR), and Vertical Instantaneous Loading Rate (VILR), were analysed through meta-analysis. 24 studies met the inclusion criteria and were analysed in this review.17 used visual biofeedback (VB) while 14 chose auditory biofeedback (AB). The meta-analysis revealed a reduction in loading variables both immediately following the intervention and after extended training, with both visual and auditory feedback. Notably, the decrease in loading variables was more pronounced post-training and VB proved to be more effective than AB. Real-time biofeedback interventions are effective in lowering loading variables associated with RRIs. The impact is more substantial with sustained training, and VB outperforms AB in terms of effectiveness.

Evolution of the Umbilical Cord Blood Proteome Across Gestational Development.

Neonatal health is dependent on early risk stratification, diagnosis, and timely management of potentially devastating conditions, particularly in the setting of prematurity. Many of these conditions are poorly predicted in real-time by clinical data and current diagnostics. Umbilical cord blood may represent a novel source of molecular signatures that provides a window into the state of the fetus at birth. In this study, we comprehensively characterized the cord blood proteome of infants born between 24 to 42 weeks using untargeted mass spectrometry and functional enrichment analysis. We determined that the cord blood proteome at birth varies significantly across gestational development. Proteins that function in structural development and growth (e.g., extracellular matrix organization, lipid particle remodeling, and blood vessel development) are more abundant earlier in gestation. In later gestations, proteins with increased abundance are in immune response and inflammatory pathways, including complements and calcium-binding proteins. Furthermore, these data contribute to the knowledge of the physiologic state of neonates across gestational age, which is crucial to understand as we strive to best support postnatal development in preterm infants, determine mechanisms of pathology causing adverse health outcomes, and develop cord blood biomarkers to help tailor our diagnosis and therapeutics for critical neonatal conditions.

Antibody modulation of B cell responses-Incorporating positive and negative feedback.

Antibodies are powerful modulators of ongoing and future B cell responses. While the concept of antibody feedback has been appreciated for over a century, the topic has seen a surge in interest due to the evidence that the broadening of antibody responses to SARS-CoV-2 after a third mRNA vaccination is a consequence of antibody feedback. Moreover, the discovery that slow antigen delivery can lead to more robust humoral immunity has put a spotlight on the capacity for early antibodies to augment B cell responses. Here, we review the mechanisms whereby antibody feedback shapes B cell responses, integrating findings in humans and in mouse models. We consider the major influence of epitope masking and the diverse actions of complement and Fc receptors and provide a framework for conceptualizing the ways antigen-specific antibodies may influence B cell responses to any form of antigen, in conditions as diverse as infectious disease, autoimmunity, and cancer.

Genomic, immunologic, and prognostic associations of TROP2 (TACSTD2) expression in solid tumors.

BACKGROUND: TROP2 (TACSTD2) expression is associated with decreased overall survival (OS) in some solid tumors, and the TROP2-targeting antibody-drug conjugate (ADC) sacituzumab govitecan has been approved in breast and urothelial carcinomas. We aimed to explore the multi-omic landscape associated with TACSTD2 gene expression in various solid tumors to identify patients most likely to benefit from this approach. METHODS: Breast (N = 11 246), colorectal (N = 15 425), hepatocellular (N = 433), pancreatic (N = 5488), and urothelial (N = 4125) tumors were stratified into quartiles by TACSTD2 gene expression, analyzed by next-generation DNA sequencing, whole transcriptome sequencing, and immunohistochemistry at Caris Life Sciences (Phoenix, AZ). Survival data were obtained from insurance claims, and Kaplan-Meier estimates were calculated for molecularly defined cohorts. RESULTS: Several pathogenic mutations were associated with TACSTD2-high tumors, including TP53 in breast, colorectal (CRC), pancreatic, and hepatocellular cancers; KRAS in pancreatic and CRC cancers; ARID1A and FGFR3 in urothelial cancer; and CTNNB1 in hepatocellular cancer. TACSTD2-low breast tumors were enriched for copy number amplifications in CCND1 and FGF/R family member genes. TACSTD2 high was generally associated with more immune cell infiltration and greater T-cell inflammation scores. Patients with TACSTD2-high breast, CRC, and pancreatic cancers demonstrated a significantly shorter OS than TACSTD2-low tumors. This was restricted to CRC with microsatellite stable tumors and patients with pancreatic cancer with KRAS-mutant tumors. Patients with breast cancer with TACSTD2-high tumors also experienced significantly worse OS following immune checkpoint inhibitors. CONCLUSIONS: TACSTD2 expression is associated with key driver alterations and a more active immune microenvironment, suggesting possible combinatorial strategies with TROP2-targeting ADCs plus immunotherapy in various solid tumors.

Comparative evaluation of selected concentrations of sodium hypochlorite on the outcome of endodontic therapy among Ghanaians.

BACKGROUND: Endodontic treatment is one of the main dental treatments to manage inflamed or infected root canal systems of teeth. The success of endodontic treatment principally depends on eradicating microorganisms in the root canal by chemo-mechanical debridement with irrigation solutions like sodium hypochlorite (NaOCl). NaOCl has been used in concentrations ranging from 0.5% to 5.25%. This study determined the antimicrobial effectiveness of selected concentrations (0.5%, 1.0%, 2.6%, and 5.2%) of NaOCl in endodontic treatment. METHODS: The study sites were the University of Ghana Dental School (UGDS) and Noguchi Memorial Institute for Medical Research (NMIMR). Sixty infected single-rooted single-canal teeth were used. Before (S1) and after (S2), root canal samples during the endodontic treatment with the selected concentrations of NaOCl were examined via anaerobic and aerobic cultures. The isolates were identified using Matrix Assisted Laser Desorption Ionization-Time Of Flight Mass Spectrometry (MALDI-TOF MS). RESULTS: All S1 samples were positive for cultivable bacteria. Fifty-three (53) different microbial species belonging to 20 different microbial genera were isolated. Streptococcus viridans was the most frequently isolated microbe. There were zero isolates in the root canals irrigated with 2.6% and 5.2% NaOCl. Two teeth had isolates in the groups irrigated with the lower concentrations (0.5% and 1.0%) of NaOCl. The persistent bacteria were one species each of Streptococcus mitis and Streptococcus oralis, respectively. CONCLUSION: Root canal treatments using chemo-mechanical preparation with the selected concentrations (0.5%, 1.0%, 2.6%, and 5.2%) of NaOCl were effective in significantly reducing the microbial load, and for the 5.2% and 2.6% concentrations, in eliminating all the microorganisms.

Lack of memory recall in human CD4 T cells elicited by the first encounter with SARS-CoV-2.

The studies reported here focus on the impact of pre-existing CD4 T cell immunity on the first encounter with SARS-CoV-2. They leverage PBMC samples from plasma donors collected after a first SARS-CoV-2 infection, prior to vaccine availability and compared to samples collected prior to the emergence of SARS-CoV-2. Analysis of CD4 T cell specificity across the entire SARS-CoV-2 proteome revealed that the recognition of SARS-CoV-2-derived epitopes by CD4 memory cells prior to the pandemic are enriched for reactivity toward non-structural proteins conserved across endemic CoV strains. However, CD4 T cells after primary infection with SARS-CoV-2 focus on epitopes from structural proteins. We observed little evidence for preferential recall to epitopes conserved between SARS-CoV-2 and seasonal CoV, a finding confirmed through use of selectively curated conserved and SARS-unique peptides. Our data suggest that SARS-CoV-2 CD4 T cells elicited by the first infection are primarily established from the naive CD4 T cell pool.

The Risks for HIV and Sexually Transmitted Infections Among Men Who Have Sex with Men Who Engage in Chemsex in Low- and Middle-Income Countries: A Mixed Methods Systematic Review and Meta-Analysis.

Chemsex, the use of drugs during and/or prior to sex, has been found to increase the risk of HIV and sexually transmitted infections (STI) among men who have sex with men (MSM). Many studies and reviews on chemsex were focused among MSM in high-income countries (HIC), with less attention given to understanding chemsex in low- and middle-income countries (LMIC). We estimated the prevalence of chemsex and its association with sexual risk behaviors, HIV, and STI among MSM in LMIC. We searched MEDLINE, Embase, GlobalHealth, PsychINFO, and CINAHL for quantitative, qualitative, and mixed-methods studies describing chemsex and its association with sexual risk behaviors, HIV, and STI among MSM in LMIC, published January 1, 2000-October 15, 2023. We used the Mixed Methods Appraisal Tool to assess study quality. We developed a narrative review and performed meta-analysis using a random effects model and the DerSimonian and Laird approach (PROSPERO #CRD42022339663). Thirty-two studies from LMIC, particularly from Asia, Africa, Latin America, and the Middle East, were included. MSM who engaged in chemsex had higher prevalence of condomless anal intercourse, group sex, having multiple sexual partners, and of HIV and STI compared to MSM who did not. We estimated a pooled prevalence for recent chemsex (≤ 12 months) of 16% (95% CI 11%-22%, τ = 0.01, I2 = 99.07%, p < 0.01). Chemsex and its associated behaviors are associated with HIV and STI among MSM in LMIC. Integration of harm reduction and sexual health services and structural changes could prevent HIV and STI prevention among MSM who engage in chemsex in LMIC.

Hyperscanning to explore social interaction among autistic minds.

Hyperscanning - the monitoring of brain activity of two or more people simultaneously - has emerged to be a popular tool for assessing neural features of social interaction. This perspective article focuses on hyperscanning studies that use functional near-infrared spectroscopy (fNIRS), a technique that is very conducive to studies requiring naturalistic paradigms. In particular, we are interested in neural features that are related to social interaction deficits among individuals with autism spectrum disorders (ASD). This population has received relatively little attention in research using neuroimaging hyperscanning techniques, compared to neurotypical individuals. The study is outlined as follows. First, we summarize the findings about brain-behavior connections related to autism from previously published fNIRS hyperscanning studies. Then, we propose a preliminary theoretical framework of inter-brain coherence (IBC) with testable hypotheses concerning this population. Finally, we provide two examples of areas of inquiry in which studies could be particularly relevant for social-emotional/behavioral development for autistic children, focusing on intergenerational relationships in family units and learning in classroom settings in mainstream schools.

A hybrid demultiplexing strategy that improves performance and robustness of cell hashing.

Cell hashing, a nucleotide barcode-based method that allows users to pool multiple samples and demultiplex in downstream analysis, has gained widespread popularity in single-cell sequencing due to its compatibility, simplicity, and cost-effectiveness. Despite these advantages, the performance of this method remains unsatisfactory under certain circumstances, especially in experiments that have imbalanced sample sizes or use many hashtag antibodies. Here, we introduce a hybrid demultiplexing strategy that increases accuracy and cell recovery in multi-sample single-cell experiments. This approach correlates the results of cell hashing and genetic variant clustering, enabling precise and efficient cell identity determination without additional experimental costs or efforts. In addition, we developed HTOreader, a demultiplexing tool for cell hashing that improves the accuracy of cut-off calling by avoiding the dominance of negative signals in experiments with many hashtags or imbalanced sample sizes. When compared to existing methods using real-world datasets, this hybrid approach and HTOreader consistently generate reliable results with increased accuracy and cell recovery.

Fear of Re-Injury, Psychological Factors, and Sport Played Have Negative Impact on Return to Sport Following Medial Patellofemoral Ligament Reconstruction for Patellar Instability.

PURPOSE: To analyze factors that affect return to sport after medial patellofemoral ligament reconstruction (MPFLR), such as psychological factors, sport played, and a positive apprehension test following surgery, and to determine the average return to sport rates and time to return to sport. METHODS: A literature search was conducted according to PRISMA guidelines. Included studies met the following criteria: patients underwent MPFLR for patellar instability, return to sport was recorded, and a factor that affected return to sport was mentioned. Search terms included medial patellofemoral ligament, tibial tubercle osteotomy, tibial tubercle transfer, return to play, and return to sport. RESULTS: 18 of 632 identified studies met inclusion criteria. 1,072 patients that underwent MFPLR were recorded. Return to sport rates and mean/median time ranged from 60.0-100% and 3-10.4 months, respectively. 55.6-84.0% of patients returned to sport without decreasing level of competition. Six of 12 studies (50.0%) reported fear of re-injury as the top reason for patients not returning or returning at a lower level of sport. Volleyball/handball had the lowest return to the same level following surgery (18.2-50.0%). CONCLUSION: Athletes that underwent MPFLR following recurrent patellar instability returned to sport at a range of 60.0-100%. Return to sport at the same level or higher was found to have a lower maximum rate at 55.6-84.0%. Fear of re-injury and sport played were found to have a substantial impact on ability to return to sport. Surgeons can use this information to advise patients on expectations following surgery. LEVEL OF EVIDENCE: IV, systematic review of level III and IV studies.

Induction and antiviral activity of ferret myxovirus resistance (Mx) protein 1 against influenza A viruses.

Myxovirus resistance (Mx) proteins are products of interferon stimulated genes (ISGs) and Mx proteins of different species have been reported to mediate antiviral activity against a number of viruses, including influenza A viruses (IAV). Ferrets are widely considered to represent the 'gold standard' small animal model for studying pathogenesis and immunity to human IAV infections, however little is known regarding the antiviral activity of ferret Mx proteins. Herein, we report induction of ferret (f)Mx1/2 in a ferret lung cell line and in airway tissues from IAV-infected ferrets, noting that fMx1 was induced to higher levels that fMx2 both in vitro and in vivo. Overexpression confirmed cytoplasmic expression of fMx1 as well as its ability to inhibit infection and replication of IAV, noting that this antiviral effect of fMx1was modest when compared to cells overexpressing either human MxA or mouse Mx1. Together, these studies provide the first insights regarding the role of fMx1 in cell innate antiviral immunity to influenza viruses. Understanding similarities and differences in the antiviral activities of human and ferret ISGs provides critical context for evaluating results when studying human IAV infections in the ferret model.

The role of genetically-influenced phospholipid transfer protein activity in lipoprotein metabolism and coronary artery disease.

BACKGROUND: Phospholipid transfer protein (PLTP) transfers surface phospholipids between lipoproteins and as such plays a role in lipoprotein metabolism, but with unclear effects on coronary artery disease (CAD) risk. We aimed to investigate the associations of genetically-influenced PLTP activity with 1-H nuclear magnetic resonance (1H-NMR) metabolomic measures and with CAD. Furthermore, using factorial Mendelian randomization (MR), we examined the potential additional effect of genetically-influenced PLTP activity on CAD risk on top of genetically-influenced low-density lipoprotein-cholesterol (LDL-C) lowering. METHODS: Using data from UK Biobank, genetic scores for PLTP activity and LDL-C were calculated and dichotomised based on the median, generating four groups with combinations of high/low PLTP activity and high/low LDL-C levels for the factorial MR. Linear and logistic regressions were performed on 168 metabolomic measures (N = 58,514) and CAD (N = 318,734, N-cases=37,552), respectively, with results expressed as ß coefficients (in standard deviation units) or odds ratios (ORs) and 95% confidence interval (CI). RESULTS: Irrespective of the genetically-influenced LDL-C, genetically-influenced low PLTP activity was associated with a higher HDL particle concentration (ß [95% CI]: 0.03 [0.01, 0.05]), smaller HDL size (-0.14 [-0.15, -0.12]) and higher triglyceride (TG) concentration (0.04 [0.02, 0.05]), but not with CAD (OR 0.99 [0.97, 1.02]). In factorial MR analyses, genetically-influenced low PLTP activity and genetically-influenced low LDL-C had independent associations with metabolomic measures, and genetically-influenced low PLTP activity did not show an additional effect on CAD risk. CONCLUSIONS: Low PLTP activity associates with higher HDL particle concentration, smaller HDL particle size and higher TG concentration, but no association with CAD risk was observed.

Personalized brain circuit scores identify clinically distinct biotypes in depression and anxiety.

There is an urgent need to derive quantitative measures based on coherent neurobiological dysfunctions or 'biotypes' to enable stratification of patients with depression and anxiety. We used task-free and task-evoked data from a standardized functional magnetic resonance imaging protocol conducted across multiple studies in patients with depression and anxiety when treatment free (n = 801) and after randomization to pharmacotherapy or behavioral therapy (n = 250). From these patients, we derived personalized and interpretable scores of brain circuit dysfunction grounded in a theoretical taxonomy. Participants were subdivided into six biotypes defined by distinct profiles of intrinsic task-free functional connectivity within the default mode, salience and frontoparietal attention circuits, and of activation and connectivity within frontal and subcortical regions elicited by emotional and cognitive tasks. The six biotypes showed consistency with our theoretical taxonomy and were distinguished by symptoms, behavioral performance on general and emotional cognitive computerized tests, and response to pharmacotherapy as well as behavioral therapy. Our results provide a new, theory-driven, clinically validated and interpretable quantitative method to parse the biological heterogeneity of depression and anxiety. Thus, they represent a promising approach to advance precision clinical care in psychiatry.