Definition, assessment and treatment of cognitive impairment associated with schizophrenia: expert opinion and practical recommendations.

A considerable proportion of patients with schizophrenia perform below population norms on standardized neuropsychological tests, and the performance of those performing within normal range is lower than predicted based on parental education. Cognitive impairment predates the onset of psychosis, is observed during symptom remission and in non-affected first-degree relatives of patients. At the present time, cognitive deficits are regarded as key features of schizophrenia, important determinants of poor psychosocial outcome and targets for both pharmacological and non-pharmacological treatment strategies. A group of eight key opinion leaders reviewed and discussed latest advances in scientific research and current good clinical practices on assessment, management, and treatment of CIAS. In the present paper they summarize the current evidence, identify main gaps between current knowledge and mental health services clinical practice, and provide practical recommendations to reduce the gap.

Finding the right dose: NMDAR modulating treatments for cognitive and plasticity deficits in schizophrenia and the role of pharmacodynamic target engagement.

Cognitive impairment associated with schizophrenia (CIAS) and related deficits in learning (plasticity) are amongst the leading causes of disability in schizophrenia. Despite this, there are no FDA approved treatments for CIAS, and the development of treatments has been limited by numerous Phase II/III failures of compounds that showed initial promise in small-scale studies. N-methyl-d-aspartate-type glutamate receptors (NMDAR) have been proposed to play an important role in schizophrenia; moreover, NMDAR has a well characterized role in cognition, learning and neuroplasticity. We review prior published clinical trials in CIAS focusing on NMDAR modulator treatments, focusing on published and recent developments of the use of novel NMDAR-modulating treatments for CIAS both alone and combined with plasticity/learning paradigms to enhance learning. We will use this discussion of prior studies to highlight the importance of incorporating pharmacodynamic target engagement biomarkers early in treatment development, which can help predict which compounds will succeed or fail in Phase III. A range of direct and indirect NMDAR modulators will be covered, including d-serine, d-cycloserine, memantine, glycine and "first generation" glycine transport inhibitors (GTI, e.g. sarcosine and bitopertin), as well as recent positive studies of iclepertin, a novel GTI and luvadaxistat, a D-amino acid oxidase inhibitor (DAAO-I) that increases brain d-serine levels and indirect non-invasive brain stimulation NMDAR modulating treatments. Several examples of successful use of pharmacodynamic target engagement biomarkers for dose/drug discovery will be emphasized, including mismatch negativity (MMN), auditory steady state (ASSR) and time-frequency event-related potential (TF-ERP) approaches.

Treatment of Cognitive Impairment Associated with Schizophrenia Spectrum Disorders: New Evidence, Challenges, and Future Perspectives.

Cognitive impairment associated with schizophrenia (CIAS) represents one of the core features of the disorder and has a significant impact on functional and rehabilitation outcomes of people living with schizophrenia spectrum disorders (SSD). The aim of this critical review is to highlight the most recent evidence on effective treatments available for CIAS, to discuss the current challenges in this field, and to present future perspectives that may help to overcome them. Concerning psychopharmacological approaches, among the most indicated strategies for the management and prevention of CIAS is to favor second-generation antipsychotic medications and avoid long-term and high-dose treatments with anticholinergic medications and benzodiazepines. Moreover, non-pharmacological approaches such as cognitive remediation and physical exercise-based programs represent evidence-based interventions in the treatment of CIAS that have shown reliable evidence of effectiveness on both cognitive and functional outcomes. These treatments, however, are still delivered to people accessing mental health services with a diagnosis of CIAS in an uneven manner, even in high-income countries. Academic and clinical partnership and collaboration, as well as advocacy from service users, families, carers, and stakeholders' organizations could help to reduce the bench to bedside gap in the treatment of CIAS. Future perspectives include the development of novel pharmacological agents that could be effective in the treatment of CIAS, the implementation of novel technologies such as telemedicine and virtual reality in the delivery of evidence-based interventions to improve accessibility and engagement, and further research in the field of non-invasive brain stimulation.

Psychometric evaluation of the patient-reported experience of cognitive impairment in schizophrenia (PRECIS) scale.

BACKGROUND: Cognitive impairment associated with schizophrenia (CIAS) represents a distinct, persistent, and core group of schizophrenia symptoms. Cognitive symptoms have been shown to have an impact on quality of life. There are several published CIAS measures, but none based on direct patient self-report. It is important to capture the patient's perspective to supplement performancebased outcome measures of cognition to provide a complete picture of the patient's experience. This paper describes additional validation work on the Patient-Reported Experience of Cognitive Impairment in Schizophrenia (PRECIS) instrument. METHODS: Data from two large, international, pharmaceutical clinical trials in medically and psychiatrically stable English-speaking patients with schizophrenia and 88 healthy controls were analyzed. An exploratory factor analysis (EFA) was conducted in one trial (n = 215), using the original 35-item PRECIS. The factor structure suggested by EFA was further evaluated using item response theory (IRT; Samejima's graded response model), and tested using confirmatory factor analysis (CFA). Both EFA and CFA results were tested in a second trial with similar inclusion/exclusion characteristics (n = 410). Additional statistical properties were evaluated in healthy controls. RESULTS: EFA suggested that the best solution after item reduction suggested a factor structure of 6 factors based on 26 items (memory, communication, self-control, executive function, attention, sharpness of thought), supporting a total score, with an additional 2-item bother score (28 items in all). IRT analysis indicated the items were well-ordered within each domain. The CFA demonstrated excellent model fit, accounting for 69% of the variance. The statistical properties of the 28-item version of the PRECIS were confirmed in the second trial. Evidence for internal consistency and test-retest reliability was robust. Known-groups validity was supported by comparison of healthy controls with patients with schizophrenia. Correlations indicated moderate associations between PRECIS and functioning instruments like the Schizophrenia Cognition Rating Scale (SCoRS), but weak correlations with performance-based outcomes like MATRICS Consensus Cognitive Battery (MCCB). DISCUSSION: Using two clinical trial samples, we identified a robust factor structure for the PRECIS and were able to replicate it in the second sample. Evaluation of the meaningful score difference (MSD) should be repeated in future studies, as these samples did not show enough change for it to be evaluated. CONCLUSIONS: This analysis provides strong evidence for the reliability and validity of the PRECIS, a 28-item, patient-reported instrument to assess cognitive impairment associated with schizophrenia. The correlation with functioning and the weak correlation with performance on cognitive tasks suggests that patient reports of cognitive impairment measure a unique aspect of patient experience.

Identification of Ligands for Ion Channels: TRPM2.

Transient receptor potential melastatin 2 (TRPM2) is a calcium-permeable, nonselective cation channel with a widespread distribution throughout the body. It is involved in many pathological and physiological processes, making it a potential therapeutic target for various diseases, including Alzheimer's disease, Parkinson's disease, and cancers. New analytical techniques are beneficial for gaining a deeper understanding of its involvement in disease pathogenesis and for advancing the drug discovery for TRPM2-related diseases. In this work, we present the application of collision-induced affinity selection mass spectrometry (CIAS-MS) for the direct identification of ligands binding to TRPM2. CIAS-MS circumvents the need for high mass detection typically associated with mass spectrometry of large membrane proteins. Instead, it focuses on the detection of small molecules dissociated from the ligand-protein-detergent complexes. This affinity selection approach consolidates all affinity selection steps within the mass spectrometer, resulting in a streamlined process. We showed the direct identification of a known TRPM2 ligand dissociated from the protein-ligand complex. We demonstrated that CIAS-MS can identify binding ligands from complex mixtures of compounds and screened a compound library against TRPM2. We investigated the impact of voltage increments and ligand concentrations on the dissociation behavior of the binding ligand, revealing a dose-dependent relationship.

Geographical Influence on Morphometric Variability of Genetically "Pure" Schistosoma haematobium Eggs from Sub-Saharan Migrants in Spain.

Schistosome eggs play a key role in schistosomiasis diagnosis and research. The aim of this work is to morphogenetically study the eggs of Schistosoma haematobium found in sub-Saharan migrants present in Spain, analyzing their morphometric variation in relation to the geographical origin of the parasite (Mali, Mauritania and Senegal). Only eggs considered "pure" S. haematobium by genetic characterization (rDNA ITS-2 and mtDNA cox1) have been used. A total of 162 eggs obtained from 20 migrants from Mali, Mauritania and Senegal were included in the study. Analyses were made by the Computer Image Analysis System (CIAS). Following a previously standardized methodology, seventeen measurements were carried out on each egg. The morphometric analysis of the three morphotypes detected (round, elongated and spindle) and the biometric variations in relation to the country of origin of the parasite on the egg phenotype were carried out by canonical variate analysis. Mahalanobis distances, when all egg measurements were analyzed, showed differences between: (i) Mali-Mauritania, Mali-Senegal and Mauritania-Senegal in the round morphotype; (ii) Mali-Mauritania and Mauritania-Senegal in the elongated morphotype; and (iii) Mauritania-Senegal in the spindle morphotype. Mahalanobis distances, when spine variables were analyzed, showed differences between Mali-Senegal in the round morphotype. In conclusion, this is the first phenotypic study performed on individually genotyped "pure" S. haematobium eggs, allowing the assessment of the intraspecific morphological variations associated with the geographical origin of the schistosome eggs.

Use of bedside ultrasound in the evaluation of acute dyspnea: a comprehensive review of evidence on diagnostic usefulness / Uso de ecografía a pie de cama en la evaluación de la disnea aguda: una revisión exhaustiva de la evidencia sobre su utilidad diagnóstica / Uso de ultrassom à beira do leito na avaliação da dispneia aguda: uma revisão abran-gente das evidencias sobre sua utilidade diagnostica

Introduction: Acute dyspnea is one of the most frequently observed symptoms in emergency departments, which can be caused mainly by pulmonary or cardiac system involvement. Bedside ultrasound is postulated as an inno-vative tool for basic use by the physician, which can complement the physical examination and quickly explore the integrity of thoracic structures. Objectives: To synthesize recent evidence on the use of bedside ultrasound in the evaluation of acute dyspnea. Materials and methods: A bibliographic search was carried out using search terms such as "Bedside Ultrasound" and "Acute Dyspnea," as well as synonyms, which were combined with Boolean operators, in the databases PubMed, ScienceDirect, Embase, EBSCO, and MEDLINE. Results: During the literature review, 10 observational studies, 2 clinical trials and 2 systematic reviews met the inclusion criteria and were ana-lyzed. The use of bedside ultrasound changes the main diagnosis associated with acute dyspnea in more than 60% of cases, the most frequent being acute decompensated heart failure and pneumonia. Protocols such as SEARCH 8Es for the evaluation of dyspnea in the emergency department, has a performance with sensitivity, specificity, positive and negative predictive value parameters above 95%. Conclusions: The current evidence on the use of bedside ultrasound in the management of patients with acute dyspnea in the emergency department is limited, Although the level of evidence is not the best, it suggests that this tool may promote the diagnostic perfomance of acute dyspnea of pulmonary or cardiac causes, improve the time to diagnosis, and enhance physician diagno-stic confidence.

Introducción: La disnea aguda es uno de los síntomas más observados en los servicios de urgencias, que puede estar causada por la afectación del sistema pulmonar o cardiaco. La ecografía a pie de cama se postula como una herramienta innovadora, al complementar la exploración física con la eva-luación rápida de las estructuras intratorácicas. Objetivo: Sintetizar la evidencia reciente sobre el uso de la ecografía a pie de cama en la evaluación de la disnea aguda. Materiales y métodos: Búsqueda bibliográfica utilizando términos de búsqueda como Bedside Ultra-sound y Acute Dyspnea, así como sinónimos, que se combinaron con operadores booleanos, en cinco bases de datos. Resultados: Se evidenció que el uso de la ecografía a pie de cama cambia el diagnóstico principal asociado con la disnea aguda en más del 60 % de los casos, entre los cuales los más frecuentes fueron la insuficiencia cardiaca aguda descompensada y la neumonía. Protocolos como el SEARCH 8Es para la evaluación de la disnea en el servicio de urgencias tiene un rendimiento con parámetros de sensibi-lidad, especificidad, valor predictivo positivo y negativo superiores al 95 %. Conclusión: La evidencia actual sobre el uso de la ecografía a pie de cama en el tratamiento de los pacientes con disnea aguda en el servicio de urgencias es limitada. No obstante, sugiere que esta herramienta puede favorecer el rendimiento diagnóstico de la disnea aguda de causa pulmonar o cardiaca, mejorar el tiempo de diagnóstico y aumentar la confianza del médico en el diagnóstico

Introdução: A dispneia aguda é um dos sintomas mais observados no departamento de emergência, que pode ser causado pela afetação do sistema pulmonar o cardíaco. O ultrassom à beira do leito é proposto como uma ferramenta inovadora, complementando o exame físico com uma rápida ava-liação das estruturas intratorácicas. Objetivo: sintetizar evidências recentes sobre o uso do ultrassom à beira do leito na avaliação da dispneia aguda. Materiais e métodos: Pesquisa de literatura usando termos de busca tais como Bedside Ultrasound e Acute Dyspnea, bem como sinônimos, que foram combinados com operadores booleanos, em cinco bancos de dados. Resultados: O uso do ultrassom á beira do leito mostrou a mudança do principal diagnóstico associa-do com a dispneia aguda em mais de 60% dos casos, sendo o mais frequente a insuficiência cardíaca descompensada aguda e a pneumonia. Protocolos como o SEARCH 8Es para a avaliação da dispneia no serviço de emergência tem um desempenho com parâmetros de sensibilidade, especificidade, valor preditivo positivo e negativo superiores ao 95%. Conclusão: As evidencias atuais sobre o uso do ultrassom á beira do leito no gerenciamento de pa-cientes com dispneia aguda no serviço de emergências são limitadas. No entanto, sugere que esta ferramenta pode favorecer o rendimento diagnóstico da dispneia aguda de causa pulmonar ou car-díaca, melhorar o tempo de diagnóstico e aumentar a confiança do médico no diagnóstico.

DNA Multi-Marker Genotyping and CIAS Morphometric Phenotyping of Fasciola gigantica-Sized Flukes from Ecuador, with an Analysis of the Radix Absence in the New World and the Evolutionary Lymnaeid Snail Vector Filter.

Fascioliasis is a disease caused by Fasciola hepatica worldwide transmitted by lymnaeid snails mainly of the Galba/Fossaria group and F. gigantica restricted to parts of Africa and Asia and transmitted by Radix lymnaeids. Concern has recently risen regarding the high pathogenicity and human infection capacity of F. gigantica. Abnormally big-sized fasciolids were found infecting sheep in Ecuador, the only South American country where F. gigantica has been reported. Their phenotypic comparison with F. hepatica infecting sheep from Peru, Bolivia and Spain, and F. gigantica from Egypt and Vietnam demonstrated the Ecuadorian fasciolids to have size-linked parameters of F. gigantica. Genotyping of these big-sized fasciolids by rDNA ITS-2 and ITS-1 and mtDNA cox1 and nad1 and their comparison with other countries proved the big-sized fasciolids to belong to F. hepatica. Neither heterozygotic ITS position differentiated the two species, and no introgressed fragments and heteroplasmic positions in mtDNA were found. The haplotype diversity indicates introductions mainly from other South American countries, Europe and North America. Big-sized fasciolids from Ecuador and USA are considered to be consequences of F.gigantica introductions by past livestock importations. The vector specificity filter due to Radix absence should act as driving force in the evolution in such lineages.

An experimental medicine study of the phosphodiesterase-4 inhibitor, roflumilast, on working memory-related brain activity and episodic memory in schizophrenia patients.

RATIONALE: Schizophrenia is associated with impairments in cognitive functioning yet there are no approved drugs to treat these deficits. OBJECTIVES: Based on animal models, we investigated the potential for roflumilast, a selective inhibitor of phosphodiesterase type 4 (PDE4), to improve cognition, which may act by increasing intracellular cyclic adenosine monophosphate in brain regions underlying cognitive deficits in schizophrenia. METHODS: This study consisted of a randomised, double-blind, placebo-controlled, crossover design involving 15 schizophrenia patients. In 3 treatment periods, patients were given 8 days of placebo or one of the two doses of roflumilast (100 and 250 µg daily) with 14 days of washout between treatments. The primary endpoints were dorsolateral prefrontal cortex (DLPFC) activation during a visuospatial working memory task measured with fMRI on dosing day 8 and verbal memory and working memory performance change from baseline to day 8. Least square mean change scores were calculated for behavioural outcomes; fMRI data were analysed in SPM12 with bilateral DLPFC as regions of interest. RESULTS: Verbal memory was significantly improved under 250 µg roflumilast (effect size (ES) = 0.77) compared to placebo. fMRI analyses revealed that increasing dose of roflumilast was associated with reduction of bilateral DLPFC activation during working memory compared to placebo, although this was not statistically significant (ES = 0.31 for the higher dose). Working memory was not improved (ES = 0.03). CONCLUSIONS: Results support the mechanistic validation of potential novel strategies for improving cognitive dysfunction in schizophrenia and suggest that PDE4 inhibition may be beneficial for cognitive dysfunction in schizophrenia. TRIAL REGISTRATION: NCT02079844 .

Association of Internet Addiction with Emotional and Behavioral Characteristics of Adolescents.

Objective: This study aimed to measure the prevalence of internet addiction and its impact on the psychological well-being of adolescents in Tehran, considering the sociodemographic characteristics. Method : In this cross sectional study, a total of 945 (mean age of 14.85) students (522 boys and 423 girls) were recruited by 2-stage clustering sampling method in 2017. The Chen Internet Addiction Scale (CIAS) and Youth Self-Report (YSR) were used to measure internet addiction and psychological characteristics, respectively. The data were analyzed using multiple-logistic regression analysis adjusted for internet addiction and sociodemographic variables. Results: Overall, 20% of the adolescents were internet addicts. Gender, consanguineous marriage, and father's education level were significantly associated with internet addiction. Regarding emotional and behavioral characteristics, internet addiction was significantly associated with the scores of internalizing (OR = 5.03; 95% CI: 3.05-8.28) and externalizing problems (OR = 5.84; 95% CI: 3.61-9.43), the total score of empirical scales (OR = 6.51; 95% CI: 3.71-11.6), and all DSM-oriented scales of the YSR (p < 0.001). Except for school performance, other competency scales had no correlations with internet addiction. Conclusion: Regarding the high prevalence of the internet addiction and its correlation with emotional and behavioral characteristics, students and their parents should be advised of the detrimental impacts of internet addiction and try to focus on its constructive application.

The Clinical Utility of the Chen Internet Addiction Scale-Gaming Version, for Internet Gaming Disorder in the DSM-5 among Young Adults.

Objectives: The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) includes the diagnostic criteria for Internet gaming disorder (IGD). This study evaluated (1) the screening, diagnostic, and prevalence-estimated cutoff points of the Chen Internet Addiction Scale-Gaming Version (CIAS-G) for IGD in the DSM-5; and (2) the differences in the CIAS-G and subscale scores among individuals with IGD, regular gamers (RGs), and other control subjects. Methods: We recruited 69 participants with IGD, 69 RGs, and 69 healthy participants based on diagnostic interviews conducted by a psychiatrist according to DSM-5 IGD criteria. All participants completed the CIAS-G and were assessed using the clinical global impression scale. Results: The optimal screening and diagnostic cutoff points were 68 or more (sensitivity, 97.1%; specificity, 76.8%) and 72 or more (sensitivity, 85.5%; specificity, 87.0%) for IGD based on DSM-5 criteria, respectively. The 76 or more cutoff point had the highest number needed to misdiagnose and was the optimal prevalence estimated cutoff point. Conclusions: The screening cutoff point could be used to identify individuals with IGD for further diagnostic interviewing to confirm the diagnosis in the clinical setting or for two-stage epidemiological evaluation. The diagnostic cutoff point provides a provisional diagnosis of IGD when diagnostic interviewing is unavailable. The prevalence-estimated cutoff point could be used to estimate the prevalence of IGD in large-scale epidemiological investigations when further diagnostic interviewing is impractical. The clinical and epidemiological utility of CIAS-G warrants further study.

Phosphodiesterase 1b (PDE1B) Regulates Spatial and Contextual Memory in Hippocampus.

Augmentation of cyclic nucleotide signaling through inhibition of phosphodiesterase (PDE) activity has long been understood to enhance memory. Efforts in this domain have focused predominantly on PDE4, a cAMP-specific phosphodiesterase implicated in consolidation. But less is known about the function of other PDEs expressed in neuroanatomical regions critical to memory. The PDE1 isoforms are the only PDEs to regulate neuronal cAMP and cGMP levels in a Ca2+/Calmodulin (CaM) dependent manner. Here, we show that knock-down of PDE1B in hippocampus of adult mice enhances contextual and spatial memory without effect on non-cognitive behaviors. Pharmacological augmentation of memory in rats was observed with a selective inhibitor of PDE1 dosed before and immediately after training, but not with drug dosed either 1 h after training or before recall. Our data clearly demonstrate a role for the PDE1B isoforms as negative regulators of memory, and they implicate PDE1 in an early phase of consolidation, but not retrieval. Inhibition of PDE1B is a promising therapeutic mechanism for treating memory impairment.

Detection of a novel mutation in NLRP3/CIAS1 gene in an Indian child with Neonatal-Onset Multisystem Inflammatory Disease (NOMID).

Neonatal-Onset Multisystem Inflammatory Disease (NOMID) or Chronic Infantile Neurologic Cutaneous Articular (CINCA) syndrome is a monogenic autoinflammatory disorder characterized by urticarial skin rash, fever, chronic meningitis and joint manifestations. Here we report a case of an Indian male child who presented at the age of 9 months with fever, respiratory distress, urticarial skin rash, arthritis, and neuroregression. Suspecting NOMID/CINCA syndrome, the child's blood was sent to the Jaslok Hospital and Research Centre for mutation analysis of the CIAS1/NLRP3 gene. The DNA was screened for mutations in exon 3 of CIAS1/NLRP3 gene by automated Sanger sequencing. DNA sequencing showed a novel heterozygous c.1813A➔G, p.R605G mutation in exon 3 of CIAS1/NLRP3 gene (ref no NM_001243133.1). His parents tested negative for this mutation. We therefore identified a novel de novo mutation in this family in the CIAS1/NLRP3 gene responsible for the child's clinical features.

First phenotypic and genotypic description of Fasciola hepatica infecting highland cattle in the state of Mexico, Mexico.

Fascioliasis is a plantborne and zoonotic parasitic disease caused by fasciolid liver flukes. Fasciola hepatica is the only fasciolid species described in the Americas. Human fascioliasis endemic areas are mainly located in high altitude areas of the Americas. Given the necessity to characterize F. hepatica populations involved, the phenotypic and genotypic features of fasciolid adults infecting cattle in the highland area of Toluca, State of Mexico, Mexico, were analyzed and compared to fasciolid materials from the Northern Bolivian Altiplano, representing the altiplanic transmission pattern in a hyperendemic scenario. A computer image analysis system (CIAS) was applied on the basis of standardized measurements. The aforementioned F. hepatica highland populations were compared to standard lowland natural populations of European origin (Spain and France) and F. gigantica of African origin (Burkina Faso). Liver-fluke size was studied by principal component analysis (PCA). Two phenotypic patterns could be distinguished in the F. hepatica material analyzed from the Americas: the valley pattern (Toluca, Mexico) and the altiplanic pattern (Northern Altiplano, Bolivia). PCA showed that the Altiplano population presented a large body size range with a pronouncedly lower minimum size. Mahalanobis distances demonstrated that American populations are very close to European populations. Genetic haplotyping was performed using the ribosomal DNA intergenic region, including ITS-1, 5.8S and ITS-2. The intergenic region was 951 bp-long, providing 2 combined haplotypes due to one mutation appearing in the ITS-2 sequence. Molecular results showed that Fh-1A and Fh-2A, the most frequent haplotypes of F. hepatica from southern Europe, are present in Mexican cattle. Nuclear rDNA biomarkers correlated with adult fluke phenotypic characteristics. Results showed that the Mexican population analyzed and European standard populations presented a phenotypic and genotypic homogeneity, suggesting an introduction with livestock transported during the early colonization period. Results are moreover analyzed in terms of altitude and permanent/seasonal transmission characteristics.

Measurement invariance across Genders on the Childhood Illness Attitude Scales (CIAS).

OBJECTIVE: The Childhood Illness Attitude Scales (CIAS) were created as a developmentally appropriate measure for symptoms of health anxiety (HA) in school-aged children. Despite overall sound psychometric properties reported in previous studies, more comprehensive examination of the latent structure and potential response bias in the CIAS is needed. The purpose of the present study was to cross-validate the latent structure of the CIAS across genders and to examine gender-specific variations in CIAS scores. METHODS: The sample comprised data from 602 Canadian and Danish school-aged children (Mage=10.54, SD=0.99; 52.5% girls). Confirmatory factor analyses were conducted to test 3-, modified 3-, and 4-factor models in both samples. Multigroup confirmatory factor analysis was performed to test factor structure invariance across boys and girls in a combined sample. Differential Item Functioning (DIF) was assessed using test characteristic curves. RESULTS: A modified 3-factor solution (i.e., fears=11 items, help-seeking=6 items, and symptom effects=4 items) provided the best fit to the data (χ2 (364, N=602)=681.7, p<0.001; χ2/df=1.803; RMSEA=0.037; CFI=0.926). The factor structure was stable, well-fitting, and indicated measurement invariance across groups. DIF analyses revealed no gender-based response bias at the scale level. CONCLUSION: Results support a revised 3-factor version of the CIAS that can be used with confidence to assess symptoms of HA in school-aged boys and girls.

Macrophages Play a Key Role in the Obesity-Induced Periodontal Innate Immune Dysfunction via Nucleotide-Binding Oligomerization Domain-Like Receptor Protein 3 Pathway.

BACKGROUND: Obesity is associated with infiltration of macrophages into adipose tissue. However, effects of obesity on macrophage infiltration and activation in periodontal tissues with periodontitis are still to be elucidated. METHODS: A diet-induced obesity 16-week mouse model was constructed, and periodontitis was induced by periodontal ligation for 10 days. The model consisted of periodontitis (P) and control (C) groups, with high fat (HF) and normal (N) diet conditions. Bone loss (BL) was analyzed by microcomputed tomography. In periodontal tissues, immunohistochemical staining and quantitative polymerase chain reaction (qPCR) detected expressions of: 1) nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) pathway; 2) macrophage-specific marker (F4/80); and 3) macrophage chemotactic protein 1 (MCP1). Bone marrow-derived macrophages (BMDMs) from the mouse model were stimulated by Porphyromonas gingivalis lipopolysaccharide (LPS) in vitro (NC/NC + LPS: BMDMs from NC group without/with LPS stimulation; HFC/HFC + LPS: BMDMs from HFC group without/with LPS stimulation). Expressions of NLRP3 pathway in BMDMs were detected by immunocytochemical staining and qPCR. RESULTS: BL increased significantly with periodontitis (NC versus NP; HFC versus HFP) and obesity (NP versus HFP). Expressions of NLRP3 pathway were significantly elevated in gingival tissues with periodontitis (NC versus NP; HFC versus HFP), but not with obesity (NC versus HFC; NP versus HFP). F4/80 and MCP1 expressions were significantly upregulated in gingival tissues with periodontitis (NC versus NP; HFC versus HFP) but significantly downregulated in the context of obesity (NP versus HFP). In vitro, NLRP3 pathway expressions were significantly upregulated in BMDMs after LPS stimulation (NC + LPS versus NC; HFC + LPS versus HFC), but significantly downregulated in HFC groups (HFC versus NC; HFC + LPS versus NC + LPS). CONCLUSION: Obesity may paralyze innate immune response of periodontium via attenuating infiltration and activation of macrophages and further aggravate periodontal disease.

Modafinil combined with cognitive training: pharmacological augmentation of cognitive training in schizophrenia.

Several efforts to develop pharmacological treatments with a beneficial effect on cognition in schizophrenia are underway, while cognitive remediation has shown modest effects on cognitive performance. Our goal was to test if pharmacological augmentation of cognitive training would result in enhancement of training-induced learning. We chose modafinil as the pharmacological augmenting agent, as it is known to have beneficial effects on learning and cognition. 49 participants with chronic schizophrenia were enroled in a double-blind, placebo-controlled study across two sites and were randomised to either modafinil (200mg/day) or placebo. All participants engaged in a cognitive training program for 10 consecutive weekdays. The primary outcome measure was the performance on the trained tasks and secondary outcome measures included MATRICS cognitive battery, proxy measures of everyday functioning and symptom measures. 84% of the participants completed all study visits. Both groups showed significant improvement in the performance of the trained tasks suggesting potential for further learning. Modafinil did not induce differential enhancement on the performance of the trained tasks or any differential enhancement of the neuropsychological and functional measures compared to placebo. Modafinil showed no significant effects on symptom severity. Our study demonstrated that combining pharmacological compounds with cognitive training is acceptable to patients and can be implemented in large double-blind randomised controlled trials. The lack of differential enhancement of training-induced learning raises questions, such as choice and optimal dose of drug, cognitive domains to be trained, type of cognitive training, intervention duration and chronicity of illness that require systematic investigation in future studies.

Anakinra and related drugs targeting interleukin-1 in the treatment of cryopyrin-associated periodic syndromes.

Anakinra is an interleukin (IL) receptor antagonist that works by blocking the biological activity of IL-1 by competitively inhibiting binding of IL-1 to the type 1 interleukin receptor. IL-1 production is induced in response to inflammatory stimuli and mediates various physiological mechanisms, including inflammation and immunological reactions. Patients with neonatal onset multisystem inflammatory disease (NOMID) produce excess IL-1ß, a major proinflammatory cytokine that regulates innate immune responses. Anakinra binds competitively and this results in a rapid reduction in disease severity. NOMID, also known as chronic infantile neurologic, cutaneous, articular syndrome, is the most severe clinical phenotype in the spectrum of cryopyrin-associated periodic syndromes. It is characterized by cutaneous symptoms, arthropathy, and central nervous system involvement. Extensive studies in patients with NOMID have led to advances in characterizing the extent of organ-specific involvement and damage that occurs with chronic overproduction of IL-1ß. NOMID is caused predominantly by mutations in the NLRP3/CIAS1 gene that encodes for the protein cryopyrin, leading to activation of the "NLRP3 inflammasome complex". This in turn regulates the maturation and secretion of the inflammatory cytokine, IL-1ß. The clinical value of IL-1ß has been demonstrated by the positive response of patients after treatment with anakinra, with rapid improvement in clinical symptoms, markers of inflammation, and a significant decrease in major organ manifestations.

Improving cognition in schizophrenia with antipsychotics that elicit neurogenesis through 5-HT(1A) receptor activation.

Atypical antipsychotics fail to substantially improve cognitive impairment associated with schizophrenia (CIAS) and one strategy to improve it is to stimulate adult neurogenesis in hippocampus, because this structure is part of an altered circuitry that underlies aspects of CIAS. Deficits in hippocampal adult neurogenesis may disrupt cognitive processes that are dependent on newborn neurons, such as pattern separation (the formation of distinct representations of similar inputs). Mechanisms by which hippocampal adult neurogenesis can be increased are therefore of therapeutic interest and a promising molecular target is the activation of serotonin 5-HT(1A) receptors because agonists at this site increase adult neuronal proliferation in the dentate gyrus. We hypothesize that use of antipsychotics possessing 5-HT(1A) receptor agonist properties may protect against or attenuate CIAS by a dual mechanism: a favorable influence on adult neurogenesis that develops upon sustained drug treatment, and an increase in dopamine levels in the prefrontal cortex that starts upon acute treatment. This hypothesis is consistent with the beneficial properties of 5-HT(1A) activation reported from pilot clinical studies using 5-HT(1A) agonists as adjunct to antipsychotic treatments. Recent antipsychotics, including clozapine and aripiprazole, exhibit different levels of 5-HT(1A) receptor partial agonism and may, therefore, differentially elicit hippocampal adult neurogenesis and increases in prefrontal cortex dopamine. We suggest that comparative studies should elucidate correlations between effects of antipsychotics on adult neurogenesis and prefrontal cortex dopamine with effects on performance in translational cognitive tasks known to involve new born neurons, such as tasks involving pattern separation, and working memory tasks sensitive to prefrontal cortex dopamine levels.