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Epstein-Barr virus (EBV) uses latency programs to colonize the memory B-cell reservoir, and each program is associated with human malignancies. However, knowledge remains incomplete of epigenetic mechanisms that maintain the highly restricted latency I program, present in memory and Burkitt lymphoma cells, in which EBNA1 is the only EBV-encoded protein expressed. Given increasing appreciation that higher order chromatin architecture is an important determinant of viral and host gene expression, we investigated roles of Wings Apart-Like Protein Homolog (WAPL), a host factor that unloads cohesin to control DNA loop size and that was discovered as an EBNA2-associated protein. WAPL knockout (KO) in Burkitt cells de-repressed LMP1 and LMP2A expression, but not other EBV oncogenes, to yield a viral program reminiscent of EBV latency II, which is rarely observed in B-cells. WAPL KO also increased LMP1/2A levels in latency III lymphoblastoid cells. WAPL KO altered EBV genome architecture, triggering formation of DNA loops between the LMP promoter region and the EBV origins of lytic replication (oriLyt). Hi-C analysis further demonstrated that WAPL KO reprogrammed EBV genomic DNA looping. LMP1 and LMP2A de-repression correlated with decreased histone repressive marks at their promoters. We propose that EBV coopts WAPL to negatively regulate latent membrane protein expression to maintain Burkitt latency I. Author summary: EBV is a highly prevalent herpesvirus etiologically linked to multiple lymphomas, gastric and nasopharyngeal carcinomas, and multiple sclerosis. EBV persists in the human host in B-cells that express a series of latency programs, each of which is observed in a distinct type of human lymphoma. The most restricted form of EBV latency, called latency I, is observed in memory cells and in most Burkitt lymphomas. In this state, EBNA1 is the only EBV-encoded protein expressed to facilitate infected cell immunoevasion. However, epigenetic mechanisms that repress expression of the other eight EBV-encoded latency proteins remain to be fully elucidated. We hypothesized that the host factor WAPL might have a role in restriction of EBV genes, as it is a major regulator of long-range DNA interactions by negatively regulating cohesin proteins that stabilize DNA loops, and WAPL was found in a yeast 2-hybrid screen for EBNA2-interacting host factors. Using CRISPR together with Hi-ChIP and Hi-C DNA architecture analyses, we uncovered WAPL roles in suppressing expression of LMP1 and LMP2A, which mimic signaling by CD40 and B-cell immunoglobulin receptors, respectively. These proteins are expressed together with EBNA1 in the latency II program. We demonstrate that WAPL KO changes EBV genomic architecture, including allowing the formation of DNA loops between the oriLyt enhancers and the LMP promoter regions. Collectively, our study suggests that WAPL reinforces Burkitt latency I by preventing the formation of DNA loops that may instead support the latency II program. [ABSTRACT FROM AUTHOR]

Persistent Negative Symptoms (PNS) affect real-world functioning already at the onset of schizophrenia. Longitudinal studies on beneficial effects of psychosocial treatments for PNS in First Episode Schizophrenia (FES) are still relatively scarce. The aim of the current study was to evaluate the longitudinal persistence of PNS in young FES individuals treated according to the multimodal "Early Intervention in Psychosis" (EIP) program over a 2-year follow-up period. 133 FES subjects (aged 12–35 years) were recruited within the Italian EIP program and completed the Positive And Negative Syndrome Scale (PANSS) and the Global Assessment of Functioning (GAF). In accordance with the PNS criteria, we dichotomized FES individuals with and without PNS. In the FES group with PNS, a multiple linear regression analysis was conducted to examine relevant associations between longitudinal PNS levels and the specialized treatment components of our EIP protocol. Twenty (15%) FES participants met the PNS criteria. At baseline, PNS levels had relevant positive correlations with functioning decline and PANSS total score. At the end, the 2-years follow-up period, FES subjects with PNS showed a significant decrease in PNS levels. In our linear regression analysis, this reduction was associated with a higher number of individual psychotherapy and case management sessions delivered during our follow-up (together with a shorter DUP [Duration of Untreated Psychosis]). PNS are clinically relevant in a minority of FES individuals. Our results suggest that patient-tailored psychosocial interventions can reduce clinical severity of PNS over a 2-year period. [ABSTRACT FROM AUTHOR]

Introduction: Suicidal thinking is relevant in patients with First Episode Psychosis (FEP). However, longitudinal studies specifically examining treatment response for suicidal ideation in FEP are still relatively scarce, especially with long‐term design and in real‐world clinical settings. The aims of this research were (A) to longitudinally assess suicidal thoughts in people with FEP along a 2‐year follow‐up period and (B) to overtime investigate any significant association of suicidal ideation levels with the specific treatment components of an 'Early Intervention in Psychosis' (EIP) protocol along the 2 years of follow‐up. Methods: At entry, 232 FEP participants (aged 12–35 years) completed the Brief Psychiatric Rating Scale (BPRS), including a 'Suicidality' item subscore. Multiple linear regression analysis was then performed. Results: Across the follow‐up, FEP subjects showed a relevant decrease in suicidal thinking levels overtime. This was specifically predicted by the total number of individual psychotherapy sessions offered within the 2‐year EIP protocol and antidepressant dose (at least as regards the first year of our intervention). Conclusion: Suicidal ideation is clinically relevant in FEP but seems to improve overtime together with the provision of specific, patient‐tailored and integrated EIP treatments, especially individual psychotherapy. [ABSTRACT FROM AUTHOR]

Aim: Disorganization has been considered as a clinical domain close to the core of psychosis. However, it has received poor attention, especially at the illness onset. Moreover, most of the studies examining disorganized symptoms have been conducted in patients with chronic psychosis and research in the early stages of illness is still relatively scarce. Thus, the aims of this study were (a) to longitudinally monitor the stability of disorganization in patients with first episode psychosis (FEP) across a 1‐year follow‐up period, and (b) to investigate any relevant association of disorganized symptoms with functioning, psychopathology and the specific treatment components of an 'early intervention in psychosis' (EIP) program along the 1 year of follow‐up. Methods: At baseline, 312 FEP participants (aged 12–35 years) completed the positive and negative syndrome scale (PANSS) and the global assessment of functioning (GAF). Spearman's correlations and multiple linear regression analysis were used. Results: At baseline, disorganization showed significant associations with all PANSS subscores, and a relevant negative correlation with GAF score. Across the follow‐up, FEP individuals showed a significant improvement in disorganization severity. This decrease was specifically related to both baseline antipsychotic dosage and the number of individual cognitive‐behavioural therapy sessions offered across the 1‐year follow‐up period. Conclusions: Disorganization is clinically relevant in FEP patients, already ate the enrollment in an EIP program. However, it tends to improve over time together with the delivery of specialized, person‐tailored FEP interventions within a specific EIP protocol. [ABSTRACT FROM AUTHOR]

Aim: Recently, there has been increasing interest in providing Personal Health Budgets (PHBs) to patients with severe mental illness. However, information on implementing PHB initiatives is still limited. Aim of this observational study was to evaluate the applicability of a PHB intervention model in a sample of Italian adults with first‐episode psychosis (FEP) across a 2‐year follow‐up period. Methods: Participants (n = 104; 18–50 years) were recruited within the 'Parma‐Early Psychosis' program and completed the brief psychiatric rating scale (BPRS), the health of nation outcome scale (HoNOS) and the global assessment of functioning (GAF). Mixed‐design analysis of variance (ANOVA) and Kaplan‐Maier survival analysis (as drop‐out measure) were performed. Results: A significant effect of time on all BPRS, HoNOS and GAF scores along the follow‐up was observed in both the FEP subgroups (i.e., with [n = 49] and without [n = 55] PHB intervention). Mixed‐design ANOVA results showed a significant 'time x group' interaction effects on BPRS 'Disorganization', HoNOS 'Psychiatric Symptoms' and GAF scores in FEP participants with PHB. Kaplan‐Meyer survival analysis showed a longer survival mean for FEP patients with PHB. Conclusions: Our results support the applicability of a PHB model within an 'Early Intervention in Psychosis' program in public community mental health services. [ABSTRACT FROM AUTHOR]

Purpose: In‐beam positron emission tomography (PET) is one of the modalities that can be used for in vivo noninvasive treatment monitoring in proton therapy. Although PET monitoring has been frequently applied for this purpose, there is still no straightforward method to translate the information obtained from the PET images into easy‐to‐interpret information for clinical personnel. The purpose of this work is to propose a statistical method for analyzing in‐beam PET monitoring images that can be used to locate, quantify, and visualize regions with possible morphological changes occurring over the course of treatment. Methods: We selected a patient treated for squamous cell carcinoma (SCC) with proton therapy, to perform multiple Monte Carlo (MC) simulations of the expected PET signal at the start of treatment, and to study how the PET signal may change along the treatment course due to morphological changes. We performed voxel‐wise two‐tailed statistical tests of the simulated PET images, resembling the voxel‐based morphometry (VBM) method commonly used in neuroimaging data analysis, to locate regions with significant morphological changes and to quantify the change. Results: The VBM resembling method has been successfully applied to the simulated in‐beam PET images, despite the fact that such images suffer from image artifacts and limited statistics. Three dimensional probability maps were obtained, that allowed to identify interfractional morphological changes and to visualize them superimposed on the computed tomography (CT) scan. In particular, the characteristic color patterns resulting from the two‐tailed statistical tests lend themselves to trigger alarms in case of morphological changes along the course of treatment. Conclusions: The statistical method presented in this work is a promising method to apply to PET monitoring data to reveal interfractional morphological changes in patients, occurring over the course of treatment. Based on simulated in‐beam PET treatment monitoring images, we showed that with our method it was possible to correctly identify the regions that changed. Moreover we could quantify the changes, and visualize them superimposed on the CT scan. The proposed method can possibly help clinical personnel in the replanning procedure in adaptive proton therapy treatments. [ABSTRACT FROM AUTHOR]

Objective: Personal Health Budget has been provided to consumers with severe mental illness within a policy shift toward a person-tailored mental healthcare treatment based on individual unmet needs. Evidence of beneficial effects of Personal Health Budget is still scarce. The aim of this study was to provide preliminary data on clinical and social benefits of adding Personal Health Budget to a standard pharmacotherapy in patients with severe mental illness across a 24-month follow-up period. Methods: Participants (n = 137) were individuals with severe mental illness, aged 18–50 years, recruited in one of the adult mental health services of the Parma Department of Mental Health. They completed the Global Assessment of Functioning scale, the Health of the Nation Outcome Scale and the Brief Psychiatric Rating Scale. This age range was chosen to limit Personal Health Budget interventions to adults with a non-prolonged illness duration. Friedman's test for repeated measure was used to assess the longitudinal stability of functioning and clinical parameters. A linear regression analysis was also performed. Results: A significant decrease in all Global Assessment of Functioning scale, Health of the Nation Outcome Scale and Brief Psychiatric Rating Scale scores along the 24 months of follow-up was observed. Regression analysis results specifically showed a relevant association between a Personal Health Budget multiaxial intervention and the longitudinal reduction in Brief Psychiatric Rating Scale 'Negative Symptoms' and Health of the Nation Outcome Scale 'Social Problems' subscores. Conclusion: Our findings support the useful implementation of a Health of the Nation Outcome Scale approach for severe mental illness patients within the Italian mental health service network. [ABSTRACT FROM AUTHOR]