Unveiling the actual cost of Schizophrenia: An Activity-Based Costing (ABC) approach.

BACKGROUND: Despite its relatively low lifetime prevalence, the health, social, and economic burden of Schizophrenia is very significant. In the last 10 years, several studies have analysed the economic burden of Schizophrenia, even if there is a lack of research that has considered the actual cost for the community as the result of each event in the patient's history. OBJECTIVE: The present study aims to cover this gap by proposing a novel model to evaluate better the cost of Schizophrenia with real data from medical records. METHODS: We applied (i) a 'real life' analysis of medical database to capture each event of the clinical history and healthcare that could have an economic impact; and (ii) a novel Activity-Based Costing model to quantify the overall annual economic burden of a patient with Schizophrenia treated by public mental health services. We carried out the study with 523 patients with a diagnosis of Schizophrenia in the Department of Mental Health of Bari, in the South of Italy. RESULTS: Our results reveal an overall cost of €41.290 per patient with Schizophrenia per year. Almost half of the cost is due to rehabilitation. The second most important factor is instead related to disability and loss of productivity. CONCLUSIONS: We believe that the present approach represents the most effective method to properly estimate actual costs when real-life data are available compared with other studies mainly based on prevalence-based approaches.

Improving the mental health care process in response to Covid-19 pandemic: The case of a penitentiary mental health division.

Covid-19 outbreak led all organizations to reorganize their processes to prevent infection and contagion risk. All healthcare facilities, included penitentiary mental health services, had to redesign their processes to safely deliver care services. In this paper, the case of a Penitentiary Mental Health Division located in southern Italy is presented. Soft System Methodology and Business process management principles and techniques are adopted to analyse and redesign the detainees' mental health care process. The process, characterized by direct, close and prolonged contact with patients, exposes detainees and healthcare staff to a high Covid-19 infection risk. Through document analysis, interviews with the actors involved in the process and direct observation, the process's inefficiencies and criticalities are identified. The process is redesigned to make it compliant with Covid-19 prevention provisions and national penitentiary regulations and address the other criticalities. The proposed methodological approach-which innovatively combines Soft System Methodology and Business Process Management-constitutes a human-centered process-based redesign approach that can be used both in healthcare and other organizational settings.

Evaluating the Acceptance of Cinematic Virtual Reality-Based Applications for Rehabilitative Interventions in Schizophrenia.

Objectives: This study aims to evaluate the acceptability of Cinematic VR technology as a novel therapeutic approach supporting Social Skills Training (SST) rehabilitation interventions among patients with schizophrenia. Materials and Methods: We developed an innovative cinematic VR-based platform as a support system for SST rehabilitation of independent living skills and evaluated its acceptance among psychiatric patients in terms of usability, user experience, and use performance. Ten voluntary participants were enrolled in the study. The study inclusion criteria consisted of age 18-65 years, lack of moderate and severe intellectual disability, no substance use disorder, and schizophrenia spectrum disorder pathology according to DSM V. We administered post treatment questionnaires and developed the platform to capture relevant data automatically. Results: Patients rated usability and user experience from good to excellent. We also observed an improvement in the use performance. Conclusions: Cinematic Virtual Reality based applications showed good acceptability among patients with schizophrenia. This result supports further efforts in evaluating its effectiveness as a novel therapeutic approach supporting SST rehabilitation interventions.

Nonlinear response of the anterior cingulate and prefrontal cortex in schizophrenia as a function of variable attentional control.

Previous studies have reported abnormal prefrontal and cingulate activity during attentional control processing in schizophrenia. However, it is not clear how variation in attentional control load modulates activity within these brain regions in this brain disorder. The aim of this study in schizophrenia is to investigate the impact of increasing levels of attentional control processing on prefrontal and cingulate activity. Blood oxygen level-dependent (BOLD) responses of 16 outpatients with schizophrenia were compared with those of 21 healthy subjects while performing a task eliciting increasing levels of attentional control during event-related functional magnetic resonance imaging at 3 T. Results showed reduced behavioral performance in patients at greater attentional control levels. Imaging data indicated greater prefrontal activity at intermediate attentional control levels in patients but greater prefrontal and cingulate responses at high attentional control demands in controls. The BOLD activity profile of these regions in controls increased linearly with increasing cognitive loads, whereas in patients, it was nonlinear. Correlation analysis consistently showed differential region and load-specific relationships between brain activity and behavior in the 2 groups. These results indicate that varying attentional control load is associated in schizophrenia with load- and region-specific modification of the relationship between behavior and brain activity, possibly suggesting earlier saturation of cognitive capacity.

Improving the "real life" management of schizophrenia spectrum disorders by LAI antipsychotics: A one-year mirror-image retrospective study in community mental health services.

Schizophrenia poses a significant economic burden on the healthcare system as well as it has a significant impact on society at large. Reasons for such a high economic burden of schizophrenia include the frequent relapses and hospitalizations occurring in this disorder. We analyze the effectiveness of long-acting injectable antipsychotics (LAIs) compared to oral medications, in terms of "clinical process management" in a sample of patients with a diagnosis of schizophrenia spectrum disorder treated in community mental health centers. An observational, retrospective, mirror-image study was carried out to evaluate the effectiveness of LAIs compared to oral medications in terms of number of hospitalizations, emergency visits and planned visits on a 10-year period (from July 2007 to June 2017). Differences between first and second generation LAIs were also explored. Our findings show that hospitalization and emergency visits are significantly decreased with the use of LAIs, while planned visits are increased in patients treated with LAIs. Our results suggest that LAIs, in particular, second generation ones, reduce hospitalization rates and emergency visits, improving the economic burden of schizophrenia. Therefore, LAIs should be considered a cost-effective treatment in the management of schizophrenia under routine conditions.

Changes in prefrontal and amygdala activity during olanzapine treatment in schizophrenia.

Earlier imaging studies in schizophrenia have reported abnormal amygdala and prefrontal cortex activity during emotion processing. We investigated with functional magnetic resonance imaging (fMRI) during emotion processing changes in activity of the amygdala and of prefrontal cortex in patients with schizophrenia during 8 weeks of olanzapine treatment. Twelve previously drug-free/naive patients with schizophrenia were treated with olanzapine for 8 weeks and underwent two fMRI scans after 4 and 8 weeks of treatment during implicit and explicit emotional processing. Twelve healthy subjects were also scanned twice to control for potential repetition effects. Results showed a diagnosis by time interaction in left amygdala and a diagnosis by time by task interaction in right ventrolateral prefrontal cortex. In particular, activity in left amygdala was greater in patients than in controls at the first scan during both explicit and implicit processing, while it was lower in patients at the second relative to the first scan. Furthermore, during implicit processing, right ventrolateral prefrontal cortex activity was lower in patients than controls at the first scan, while it was greater in patients at the second relative to the first scan. These results suggest that longitudinal treatment with olanzapine may be associated with specific changes in activity of the amygdala and prefrontal cortex during emotional processing in schizophrenia.

Association of the SerCys DISC1 polymorphism with human hippocampal formation gray matter and function during memory encoding.

A common nonsynonymous single nucleotide polymorphism leading to a serine-to-cysteine substitution at amino acid 704 (Ser(704)Cys) in the DISC1 protein sequence has been recently associated with schizophrenia and with specific hippocampal abnormalities. Here, we used multimodal neuroimaging to investigate in a large sample of healthy subjects the putative association of the Ser(704)Cys DISC1 polymorphism with in vivo brain phenotypes including hippocampal formation (HF) gray matter volume and function (as assessed with functional MRI) as well as HF functional coupling with the neural network engaged during encoding of recognition memory. Individuals homozygous for DISC1 Ser allele relative to carriers of the Cys allele showed greater gray matter volume in the HF. Further, Ser/Ser subjects exhibited greater engagement of the HF together with greater HF-dorsolateral prefrontal cortex functional coupling during memory encoding, in spite of similar behavioral performance. These findings consistently support the notion that Ser(704)Cys DISC1 polymorphism is physiologically relevant. Moreover, they support the hypothesis that genetic variation in DISC1 may affect the risk for schizophrenia by modifying hippocampal gray matter and function.

Additive effects of genetic variation in dopamine regulating genes on working memory cortical activity in human brain.

Functional polymorphisms in the catechol-O-methyltransferase (COMT) and the dopamine transporter (DAT) genes modulate dopamine inactivation, which is crucial for determining neuronal signal-to-noise ratios in prefrontal cortex during working memory. We show that the COMT Met158 allele and the DAT 3' variable number of tandem repeat 10-repeat allele are independently associated in healthy humans with more focused neuronal activity (as measured with blood oxygen level-dependent functional magnetic resonance imaging) in the working memory cortical network, including the prefrontal cortex. Moreover, subjects homozygous for the COMT Met allele and the DAT 10-repeat allele have the most focused response, whereas the COMT Val and the DAT 9-repeat alleles have the least. These results demonstrate additive genetic effects of genes regulating dopamine signaling on specific neuronal networks subserving working memory.

Response to (chloro)biphenyls of the polychlorobiphenyl-degrader Burkholderia xenovorans LB400 involves stress proteins also induced by heat shock and oxidative stress.

We report the effects of 4-chlorobiphenyl and biphenyl on the physiology, morphology and proteome of the polychlorobiphenyl-degrader Burkholderia xenovorans LB400. The exposure to 4-chlorobiphenyl decreases the growth of LB400 on glucose, and cells exhibit irregular outer membranes, a larger periplasmic space and electron-dense granules in the cytoplasm. Additionally, lysis of cells was observed during incubation with 4-chlorobiphenyl or biphenyl. Proteome of B. xenovorans LB400 exposed to biphenyl and 4-chlorobiphenyl were analysed by two-dimensional gel electrophoresis. Besides induction of the Bph enzymes of biphenyl catabolic pathways, incubation with 4-chlorobiphenyl or biphenyl results in the induction of the molecular chaperones DnaK and GroEL. Induction of these chaperones, which were also induced during heat shock, strongly suggests that exposure to (chloro)biphenyls constitutes stress conditions for LB400. During growth of LB400 on biphenyl, oxidative stress was evidenced by the induction of alkyl hydroperoxide reductase AhpC, which was also induced during exposure to H(2)O(2). 4-chlorobiphenyl and biphenyl induced catechol 1,2-dioxygenase, as well as polypeptides involved in energy production, amino acid metabolism and transport.

Activity in medial prefrontal cortex during cognitive evaluation of threatening stimuli as a function of personality style.

Cognitive evaluation of emotional stimuli involves a network of brain regions including the medial prefrontal cortex (mPFC). However, threatening stimuli may be perceived with differential salience in different individuals. The goal of our study was to evaluate how different personality styles are associated with differential modulation of brain activity during explicit recognition of fearful and angry facial expressions. Twenty-eight healthy subjects underwent fMRI. Based on a cognitivist model, subjects were categorized according to how they attribute salience to emotional stimuli and how they regulate their emotional activation. We compared 14 phobic prone (PP) subjects, whose identity is more centered on the inner experience ("inward") and around control of environmental threat, and 14 eating disorders prone (EDP) subjects, whose identity is more centered on external referential contexts ("outward") and much less around control of threatening stimuli. During fMRI subjects either matched the identity of one of two angry and fearful faces to that of a simultaneously presented target face or identified the expression of a target face by choosing one of two simultaneously presented linguistic labels. The fMRI results indicated that PP subjects had greater mPFC activation when compared with EDP subjects during cognitive labeling of threatening stimuli. Activity in the mPFC also correlated with personality style scores. These results demonstrate that PP subjects recruit greater neuronal resources in mPFC whose activity is associated with cognitive aspects that are closely intertwined with emotional processing. These findings are consistent with the contention that cognitive evaluation and salience of emotional stimuli are associated with different personality styles.

Prefrontal-hippocampal coupling during memory processing is modulated by COMT val158met genotype.

BACKGROUND: Studies in humans and in animals have demonstrated that a network of brain regions is involved in performance of declarative and recognition memory tasks. This network includes the hippocampal formation (HF) as well as the ventrolateral prefrontal cortex (VLPFC). Studies in animals have suggested that the relationship between these brain regions is strongly modulated by dopamine. METHODS: Using fMRI in healthy humans matched for a series of demographic and genetic variables, we studied the effect of the COMT val158met polymorphism on function of HF and VLPFC as well as on their functional coupling during recognition memory. RESULTS: The COMT Val allele was associated with: relatively poorer performance at retrieval; reduced recruitment of neuronal resources in HF and increased recruitment in VLPFC during both encoding and retrieval; and unfavorable functional coupling between these two regions at retrieval. Moreover, functional coupling during retrieval was predictive of behavioral accuracy. CONCLUSIONS: These results shed new light on individual differences in responsivity and connectivity between HF and VLPFC related to genetic modulation of dopamine, a mechanism accounting at least in part for individual differences in recognition memory performance.

Independent component model of the default-mode brain function: Assessing the impact of active thinking.

The "default-mode" network is an ensemble of cortical regions, which are typically deactivated during demanding cognitive tasks in functional magnetic resonance imaging (fMRI) studies. Using functional connectivity, this network can be conceptualized and studied as a "stand-alone" function or system. Regardless of the task, independent component analysis (ICA) produces a picture of the "default-mode" function even when the subject is performing a simple sensori-motor task or just resting in the scanner. This has boosted the use of default-mode fMRI for non-invasive research in brain disorders. Here, we studied the effect of cognitive load modulation of fMRI responses on the ICA-based pictures of the default-mode function. In a standard graded working memory study based on the n-back task, we used group-level ICA to explore the variability of the default-mode network related to the engagement in the task, in 10 healthy volunteers. The analysis of the default-mode components highlighted similarities and differences in the layout under three different cognitive loads. We found a load-related general increase of deactivation in the cortical network. Nonetheless, a variable recruitment of the cingulate regions was evident, with greater extension of the anterior and lesser extension of the posterior clusters when switching from lower to higher working memory loads. A co-activation of the hippocampus was only found under no working memory load. As a generalization of our results, the variability of the default-mode pattern may link the default-mode system as a whole to cognition and may more directly support use of the ICA model for evaluating cognitive decline in brain disorders.

Prefrontal dysfunction in schizophrenia controlling for COMT Val158Met genotype and working memory performance.

Earlier studies with functional imaging in schizophrenia have demonstrated dysfunction of the dorsolateral prefrontal cortex during working memory. Controlling for behavioral performance and for catechol-O-methyltransferase (COMT) Val158Met genotype, we here demonstrate in a functional magnetic resonance imaging paradigm that patients recruit greater neuronal resources in prefrontal cortex during working memory, suggesting that this phenotype is a core functional trait of the disease. We also replicated earlier findings that the Val allele of the COMT polymorphism is associated with greater engagement of the prefrontal cortex.

Variation of human amygdala response during threatening stimuli as a function of 5'HTTLPR genotype and personality style.

BACKGROUND: In the brain, processing of fearful stimuli engages the amygdala, and the variability of its activity is associated with genetic factors as well as with emotional salience. The objective of this study was to explore the relevance of personality style for variability of amygdala response. METHODS: We studied two groups (n=14 in each group) of healthy subjects categorized by contrasting cognitive styles with which they attribute salience to fearful stimuli: so-called phobic prone subjects who exaggerate potential environmental threat versus so-called eating disorders prone subjects who tend to be much less centered around fear. The two groups underwent functional magnetic resonance imaging (fMRI) at 3T during performance of a perceptual task of threatening stimuli and they were also matched for the genotype of the 5' variable number tandem repeat (VNTR) polymorphism in the serotonin transporter. RESULTS: The fMRI results indicated that phobic prone subjects selectively recruit the amygdala to a larger extent than eating disorders prone subjects. Activity in the amygdala was also independently predicted by personality style and genotype of the serotonin transporter. Moreover, brain activity during a working memory task did not differentiate the two groups. CONCLUSIONS: The results of the present study suggest that aspects of personality style are rooted in biological responses of the fear circuitry associated with processing of environmental information.

Functional lateralization of the sensorimotor cortex in patients with schizophrenia: effects of treatment with olanzapine.

BACKGROUND: Earlier cross-sectional studies with functional magnetic resonance imaging (fMRI) in treated patients with schizophrenia have reported abnormalities of cortical motor processing, including reduced lateralization of primary sensory motor cortex. The objective of the present longitudinal study was to evaluate whether such cortical abnormalities represent state or trait phenomena of the disorder. METHODS: Seventeen acutely ill, previously untreated patients were studied after 4 weeks and after 8 weeks of olanzapine therapy. Seventeen matched healthy subjects served as control subjects. All subjects underwent two fMRI scans 4 weeks apart during a visually paced motor task using a simple periodic block design. Functional magnetic resonance imaging data were analyzed in Statistical Parametric Mapping (SPM99). Region of interest analyses were used to determine a laterality quotient (an index of lateralization) of motor cortical regions. RESULTS: The fMRI data indicated that patients had reduced activation of the primary sensory motor cortex at 4 weeks but not at 8 weeks; however, the laterality quotient in the primary sensory motor cortex was reduced in patients at both time points. CONCLUSIONS: These results suggest that some cortical abnormalities during motor processing represent state phenomena, whereas reduced functional lateralization of the primary sensory motor cortex represents an enduring trait of schizophrenia.

Interaction of COMT (Val(108/158)Met) genotype and olanzapine treatment on prefrontal cortical function in patients with schizophrenia.

OBJECTIVE: Deficits in working memory and in prefrontal cortical physiology are important outcome measures in schizophrenia, and both have been associated with dopamine dysregulation and with a functional polymorphism (Val(108/158)Met) in the catechol O-methyltransferase (COMT) gene that affects dopamine inactivation in the prefrontal cortex. The purpose of the present study was to evaluate in patients with schizophrenia the effect of COMT genotype on symptom variation, working memory performance, and prefrontal cortical physiology in response to treatment with an atypical antipsychotic drug. METHOD: Thirty patients with acute untreated schizophrenia were clinically evaluated with the Positive and Negative Syndrome Scale, underwent COMT Val/Met genotyping, and entered an 8-week prospective study of olanzapine treatment. Twenty patients completed two 3-T functional magnetic resonance imaging scans at 4 and 8 weeks during performance of N-back working memory tasks. RESULTS: There was a significant interaction of COMT genotype and the effects of olanzapine on prefrontal cortical function. Met allele load predicted improvement in working memory performance and prefrontal physiology after 8 weeks of treatment. A similar effect was found also for negative symptoms assessed with the Positive and Negative Syndrome Scale. CONCLUSIONS: These results suggest that a genetically determined variation in prefrontal dopamine catabolism impacts the therapeutic profile of olanzapine.

Effects of emotional contexts on cerebello-thalamo-cortical activity during action observation.

Several studies investigated the neural and functional mechanisms underlying action observation in contexts with objects. However, actions seen in everyday life are often embedded in emotional contexts. The neural systems integrating emotion cues in action observation are still poorly understood. Previous findings suggest that the processing of both action and emotion information recruits motor control areas within the cerebello-thalamo-cortical pathways. It is therefore hard to determine whether social emotional contexts influence action processing via a direct modulation of motor representations coding for the observed action or via the affective state and implicit motor preparedness elicited in observers in response to emotional contexts. Here we designed a novel fMRI task to identify neural networks engaged by the affective appraisal of a grasping action seen in two different emotional contexts, while keeping the action kinematics constant. Results confirmed that observing the same acts of grasping but in different emotional contexts modulated activity in supplementary motor area, ventrolateral thalamus, anterior cerebellum. Moreover, changes in functional connectivity between left supplementary motor area and parahippocampus in different emotional contexts suggested a direct neural pathway through which emotional contexts may drive the neural motor system. Taken together, these findings shed new light on the malleability of motor system as a function of emotional contexts.

Replication of neuroblastoma SNP association at the BARD1 locus in African-Americans.

BACKGROUND: Neuroblastoma is an often fatal pediatric cancer more frequent in European-American than African-American children. African-American children, however, are at higher risk for the more severe form of neuroblastoma and have worse overall survival than European-American children. Genome-wide association studies (GWAS) have identified several single-nucleotide polymorphisms (SNP) associated to neuroblastoma in children of European descent. Knowledge of their association to neuroblastoma in African-American children is still lacking. METHODS: We genotyped and imputed SNPs located in three gene regions reported to be associated to neuroblastoma in children of European descent, and tested them for association in 390 African-American patients with neuroblastoma compared with 2,500 healthy, ethnically matched controls. RESULTS: SNPs in the BARD1 gene region show a similar pattern of association to neuroblastoma in African-American and European-American children. The more restricted extent of linkage disequilibrium in the African-American population suggests a smaller candidate region for the putative causal variants than previously reported. Limited association was observed at the other two gene regions tested, including LMO1 in 11p15 and FLJ22536 in 6p22. CONCLUSIONS: Common BARD1 SNPs affect risk of neuroblastoma in African-Americans. The role of other SNPs associated to neuroblastoma in children of European descent could not be confirmed, possibly due to different patterns of linkage disequilibrium or limited statistical power to detect association to variants with small effect on disease risk. Extension of GWAS to populations of African descent is important to confirm their results and validity beyond the European populations and can help to refine the location of the putative causal variants.

Common variation at 6q16 within HACE1 and LIN28B influences susceptibility to neuroblastoma.

Neuroblastoma is a cancer of the sympathetic nervous system that accounts for approximately 10% of all pediatric oncology deaths. Here, we report a genome-wide association study of 2,817 neuroblastoma cases and 7,473 controls. We identified two new associations at 6q16, the first within HACE1 (rs4336470; combined P=2.7×10(-11); odds ratio 1.26, 95% confidence interval (CI) 1.18-1.35) and the second within LIN28B (rs17065417; combined P=1.2×10(-8); odds ratio 1.38, 95% CI 1.23-1.54). Expression of LIN28B and let-7 miRNA correlated with rs17065417 genotype in neuroblastoma cell lines, and we observed significant growth inhibition upon depletion of LIN28B, specifically in neuroblastoma cells that were homozygous for the risk allele. Low HACE1 and high LIN28B expression in diagnostic primary neuroblastomas were associated with worse overall survival (P=0.008 and 0.014, respectively). Taken together, these data show that common variants in HACE1 and LIN28B influence neuroblastoma susceptibility and indicate that both genes likely have a role in disease progression.

The genetic component of human longevity: analysis of the survival advantage of parents and siblings of Italian nonagenarians.

Many epidemiological studies have shown that parents, siblings and offspring of long-lived subjects have a significant survival advantage when compared with the general population. However, how much of this reported advantage is due to common genetic factors or to a shared environment remains to be resolved.We reconstructed 202 families of nonagenarians from a population of southern Italy. To estimate the familiarity of human longevity, we compared survival data of parents and siblings of long-lived subjects to that of appropriate Italian birth cohorts. Then, to estimate the genetic component of longevity while minimizing the variability due to environment factors, we compared the survival functions of nonagenarians' siblings with those of their spouses (intrafamily control group).We found that both parents and siblings of the probands had a significant survival advantage over their Italian birth cohort counterparts. On the other hand, although a substantial survival advantage was observed in male siblings of probands with respect to the male intrafamily control group, female siblings did not show a similar advantage. In addition, we observed that the presence of a male nonagenarians in a family significantly decreased the instant mortality rate throughout lifetime for all the siblings; in the case of a female nonagenarians such an advantage persisted only for her male siblings.The methodological approach used here allowed us to distinguish the effects of environmental and genetic factors on human longevity. Our results suggest that genetic factors in males have a higher impact than in females on attaining longevity.