The DNA loop release factor WAPL suppresses Epstein-Barr virus latent membrane protein expression to maintain the highly restricted latency I program.

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 cohesins 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 reprograms 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.

The three-dimensional structure of the EBV genome plays a crucial role in regulating viral gene expression in EBVaGC.

Epstein-Barr virus (EBV) establishes lifelong asymptomatic infection by replication of its chromatinized episomes with the host genome. EBV exhibits different latency-associated transcriptional repertoires, each with distinct three-dimensional structures. CTCF, Cohesin and PARP1 are involved in maintaining viral latency and establishing episome architecture. Epstein-Barr virus-associated gastric cancer (EBVaGC) represents 1.3-30.9% of all gastric cancers globally. EBV-positive gastric cancers exhibit an intermediate viral transcription profile known as 'Latency II', expressing specific viral genes and noncoding RNAs. In this study, we investigated the impact of PARP1 inhibition on CTCF/Cohesin binding in Type II latency. We observed destabilization of the binding of both factors, leading to a disrupted three-dimensional architecture of the episomes and an altered viral gene expression. Despite sharing the same CTCF binding profile, Type I, II and III latencies exhibit different 3D structures that correlate with variations in viral gene expression. Additionally, our analysis of H3K27ac-enriched interactions revealed differences between Type II latency episomes and a link to cellular transformation through docking of the EBV genome at specific sites of the Human genome, thus promoting oncogene expression. Overall, this work provides insights into the role of PARP1 in maintaining active latency and novel mechanisms of EBV-induced cellular transformation.

Decitabine disrupts EBV genomic epiallele DNA methylation patterns around CTCF binding sites to increase chromatin accessibility and lytic transcription in gastric cancer.

IMPORTANCE: Epstein-Barr virus (EBV) latency is controlled by epigenetic silencing by DNA methylation [5-methyl cytosine (5mC)], histone modifications, and chromatin looping. However, how they dictate the transcriptional program in EBV-associated gastric cancers remains incompletely understood. EBV-associated gastric cancer displays a 5mC hypermethylated phenotype. A potential treatment for this cancer subtype is the DNA hypomethylating agent, which induces EBV lytic reactivation and targets hypermethylation of the cellular DNA. In this study, we identified a heterogeneous pool of EBV epialleles within two tumor-derived gastric cancer cell lines that are disrupted with a hypomethylating agent. Stochastic DNA methylation patterning at critical regulatory regions may be an underlying mechanism for spontaneous reactivation. Our results highlight the critical role of epigenetic modulation on EBV latency and life cycle, which is maintained through the interaction between 5mC and the host protein CCCTC-binding factor.

PARP1 Inhibition Halts EBV+ Lymphoma Progression by Disrupting the EBNA2/MYC Axis.

PARP1 has been shown to regulate EBV latency. However, the therapeutic effect of PARP1 inhibitors on EBV+ lymphomagenesis has not yet been explored. Here, we show that PARPi BMN-673 has a potent anti-tumor effect on EBV-driven LCL in a mouse xenograft model. We found that PARP1 inhibition induces a dramatic transcriptional reprogramming of LCLs driven largely by the reduction of the MYC oncogene expression and dysregulation of MYC targets, both in vivo and in vitro. PARP1 inhibition also reduced the expression of viral oncoprotein EBNA2, which we previously demonstrated depends on PARP1 for activation of MYC. Further, we show that PARP1 inhibition blocks the chromatin association of MYC, EBNA2, and tumor suppressor p53. Overall, our study strengthens the central role of PARP1 in EBV malignant transformation and identifies the EBNA2/MYC pathway as a target of PARP1 inhibitors and its utility for the treatment of EBNA2-driven EBV-associated cancers.

Three-Dimensional Chromatin Structure of the EBV Genome: A Crucial Factor in Viral Infection.

Epstein-Barr Virus (EBV) is a human gamma-herpesvirus that is widespread worldwide. To this day, about 200,000 cancer cases per year are attributed to EBV infection. EBV is capable of infecting both B cells and epithelial cells. Upon entry, viral DNA reaches the nucleus and undergoes a process of circularization and chromatinization and establishes a latent lifelong infection in host cells. There are different types of latency all characterized by different expressions of latent viral genes correlated with a different three-dimensional architecture of the viral genome. There are multiple factors involved in the regulation and maintenance of this three-dimensional organization, such as CTCF, PARP1, MYC and Nuclear Lamina, emphasizing its central role in latency maintenance.

Characterization of a flat-panel detector for 2D dosimetry in scanned proton and carbon ion beams.

PURPOSE: To fully characterize the flat panel detector of the new Sphinx Compact device with scanned proton and carbon ion beams. MATERIALS AND METHODS: The Sphinx Compact is designed for daily QA in particle therapy. We tested its repeatability and dose rate dependence as well as its proportionality with an increasing number of particles and potential quenching effect. Potential radiation damage was evaluated. Finally, we compared the spot characterization (position and profile FWHM) with our radiochromic EBT3 film baseline. RESULTS: The detector showed a repeatability of 1.7% and 0.9% for single spots of protons and carbon ions, respectively, while for small scanned fields it was inferior to 0.2% for both particles. The response was independent from the dose rate (difference from nominal value < 1.5%). We observed an under-response due to quenching effect for both particles, mostly for carbon ions. No radiation damage effects were observed after two months of weekly use and approximately 1350 Gy delivered to the detector. Good agreement was found between the Sphinx and EBT3 films for the spot position (central-axis deviation within 1 mm). The spot size measured with the Sphinx was larger compared to films. For protons, the average and maximum differences over different energies were 0.4 mm (3%) and 1 mm (7%); for carbon ions they were 0.2 mm (4%) and 0.4 mm (6%). CONCLUSIONS: Despite the quenching effect the Sphinx Compact fulfills the requirements needed for constancy checks and could represent a time-saving tool for daily QA in scanned particle beams.

Disorganization in first episode affective psychosis: Treatment response and clinical considerations from a 2-year follow-up study in a "real world" setting.

INTRODUCTION: Disorganization is a crucial domain in affective psychoses. However, it has received poor research attention, especially at the illness onset. The aims of this study were: (a) to monitor the longitudinal course of disorganization in young people with first episode affective psychosis (FEAP) across 2 years of follow-up, and (b) to investigate any relevant correlation of disorganized symptoms with psychopathology, functioning and the specific treatment elements of an "Early Intervention in Psychosis" (EIP) protocol along the follow-up period. MATERIALS AND METHODS: Seventy-five FEAP participants (aged 12-35 years) completed the Positive And Negative Syndrome Scale (PANSS) and the Global Assessment of Functioning (GAF). Spearman's rank correlation coefficients were calculated. RESULTS: During the follow-up, disorganized symptoms showed significant enduring positive correlations with PANSS items representing delusional thought content and uncooperativeness, as well as a persistent negative association with the GAF score. Across the 2-year follow-up period, FEAP individuals also had a relevant reduction in disorganization levels. This symptom decrease was specifically related with the combination of antipsychotic medication with the specific psychosocial components of our EIP intervention offered to FEAP patients during the first 12 months of treatment. CONCLUSIONS: Disorganization is relevant in FEAP subjects already at their enrollment in specialized EIP protocols. However, it decreases over time, together with the delivery of specific, combined (person-tailored) EIP interventions.

In-vivo range verification analysis with in-beam PET data for patients treated with proton therapy at CNAO.

Morphological changes that may arise through a treatment course are probably one of the most significant sources of range uncertainty in proton therapy. Non-invasive in-vivo treatment monitoring is useful to increase treatment quality. The INSIDE in-beam Positron Emission Tomography (PET) scanner performs in-vivo range monitoring in proton and carbon therapy treatments at the National Center of Oncological Hadrontherapy (CNAO). It is currently in a clinical trial (ID: NCT03662373) and has acquired in-beam PET data during the treatment of various patients. In this work we analyze the in-beam PET (IB-PET) data of eight patients treated with proton therapy at CNAO. The goal of the analysis is twofold. First, we assess the level of experimental fluctuations in inter-fractional range differences (sensitivity) of the INSIDE PET system by studying patients without morphological changes. Second, we use the obtained results to see whether we can observe anomalously large range variations in patients where morphological changes have occurred. The sensitivity of the INSIDE IB-PET scanner was quantified as the standard deviation of the range difference distributions observed for six patients that did not show morphological changes. Inter-fractional range variations with respect to a reference distribution were estimated using the Most-Likely-Shift (MLS) method. To establish the efficacy of this method, we made a comparison with the Beam's Eye View (BEV) method. For patients showing no morphological changes in the control CT the average range variation standard deviation was found to be 2.5 mm with the MLS method and 2.3 mm with the BEV method. On the other hand, for patients where some small anatomical changes occurred, we found larger standard deviation values. In these patients we evaluated where anomalous range differences were found and compared them with the CT. We found that the identified regions were mostly in agreement with the morphological changes seen in the CT scan.

Psychometric properties of the Parma Scale for the treatment evaluation of offenders with mental disorder: A new instrument for routine outcome monitoring in forensic psychiatric settings.

PURPOSE: Routine Outcome Monitoring (ROM) is still poorly implemented in the routine forensic psychiatric practice. As reliable ROM instruments are lacking, the aims of this research was to assess the psychometric properties of the Parma Scale (Pr-Scale) and its sensitivity to measure scores' longitudinal changes. METHODS: Interrater and test-retest reliability, internal consistency and concurrent validity were investigated in offenders with mental disorder. Scores' longitudinal changeability was examined after a 3-month period using the Wilcoxon test for repeated measure. RESULTS: Sixty male adult patients were recruited in this study. Our findings showed good to excellent interrater and test-retest reliability, concurrent validity and internal consistency for the Pr-Scale. Pr-Scale scores also display a moderate to large changeability over time. CONCLUSIONS: Our results support the clinical use of the Pr-Scale in forensic psychiatric settings as reliable ROM instrument.

Validation of the Italian version of the Davos Assessment of Cognitive Biases Scale (DACOBS) in a sample of schizophrenia spectrum disorder patients and healthy controls.

PURPOSE: Recently two instruments were developed to address the study of the cognitive biases in schizophrenia spectrum disorders (SSD): the Cognitive Biases Questionnaire for Psychosis (CBQ-P) and the Davos Assessment of Cognitive Biases Scale (DACOBS). Aim of this study was to validate the Italian version of the DACOBS. METHODS: We investigated factor structure, reliability, discriminative and convergent validity of the instrument by comparing to the CBQ-P in an Italian sample of 102 patients diagnosed with SSD and 330 healthy controls (HC), matched by age, education and gender. RESULTS: The second-order seven-factor solution provided the best results among the four models tested. Reliability proved to be very satisfactory, with ω coefficient ranged from 0.75 for Jumping to conclusions to 0.89 for Safety Behavior. The Italian version of DACOBS could discriminate psychosis from HC (Wilks' Lambda=0.64, F=34.284, p<0.001; h2=0.364). All seven DACOBS subscales were significantly correlated with the CBQ-P subscales (total sample: r=0.331-0.707; SSD group: r=0.424-0.735; HC group: r=0.177-0.460). CONCLUSIONS: The Italian version of DACOBS is a valid instrument for measuring cognitive biases for patients with psychosis, confirming previous results regarding the psychometric properties of the tool.

The nuclear lamina binds the EBV genome during latency and regulates viral gene expression.

The Epstein Barr virus (EBV) infects almost 95% of the population worldwide. While typically asymptomatic, EBV latent infection is associated with several malignancies of epithelial and lymphoid origin in immunocompromised individuals. In latently infected cells, the EBV genome persists as a chromatinized episome that expresses a limited set of viral genes in different patterns, referred to as latency types, which coincide with varying stages of infection and various malignancies. We have previously demonstrated that latency types correlate with differences in the composition and structure of the EBV episome. Several cellular factors, including the nuclear lamina, regulate chromatin composition and architecture. While the interaction of the viral genome with the nuclear lamina has been studied in the context of EBV lytic reactivation, the role of the nuclear lamina in controlling EBV latency has not been investigated. Here, we report that the nuclear lamina is an essential epigenetic regulator of the EBV episome. We observed that in B cells, EBV infection affects the composition of the nuclear lamina by inducing the expression of lamin A/C, but only in EBV+ cells expressing the Type III latency program. Using ChIP-Seq, we determined that lamin B1 and lamin A/C bind the EBV genome, and their binding correlates with deposition of the histone repressive mark H3K9me2. By RNA-Seq, we observed that knock-out of lamin A/C in B cells alters EBV gene expression. Our data indicate that the interaction between lamins and the EBV episome contributes to the epigenetic control of viral gene expression during latency, suggesting a restrictive function of the nuclear lamina as part of the host response against viral DNA entry into the nucleus.

Association between case management and longitudinal decrease in negative symptoms in patients with first episode psychosis: A 2-year follow-up.

AIM: Negative symptoms (NS) severely affect daily functioning already at the psychosis onset. However, most studies investigating beneficial effects of specific treatments for NS mainly included individuals with prolonged psychotic disorders. Furthermore, evidence on psychosocial rehabilitation for NS in early psychosis is still relatively poor. The aims of this study therefore were (A) to longitudinally examine NS stability in people with first episode psychosis (FEP) along a 2-year follow-up period, and (B) to overtime explore any relevant association of NS levels with the specific intervention components of an 'early intervention in psychosis' (EIP) protocol during the follow-up. METHODS: At baseline, 266 FEP subjects (aged 12-35 years) completed the positive and negative syndrome scale (PANSS). Multiple linear regression analyses were then performed. RESULTS: Along the follow-up, FEP participants had a relevant improvement in NS levels. This was specifically predicted by the total number of case management sessions offered within our 2-year EIP protocol, as well as by shorter duration of untreated psychosis at entry and by longitudinal reduction in PANSS depressive and positive symptom dimension levels. No association with antipsychotic medication was found. CONCLUSIONS: NS are clinically relevant in FEP, already at the recruitment time in specialized EIP services. However, their severity appears to improve over time together with the delivery of patient-tailored, integrated EIP case management.

Negative symptoms in first episode schizophrenia: treatment response across the 2-year follow-up of the "Parma Early Psychosis" program.

Negative symptoms (NS) severely interfere with real-world performance, already at the onset of schizophrenia and in "clinical high risk" mental states. However, most of the empirical studies specifically examining treatment effectiveness on NS included patients with stable, prolonged schizophrenia. Moreover, research on psychosocial interventions for NS in early schizophrenia is still relatively scarce. Thus, the aims of this study were (1) to longitudinally monitor the NS stability in young individuals with First Episode Schizophrenia (FES) across a 2-year follow-up period, and (2) to investigate any significant association of NS with functioning, other aspects of FES psychopathology and the specific treatment component effects on NS of an "Early Intervention in Psychosis" (EIP) program during the 2 years of follow-up. At entry, 159 FES 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 analyses were performed. NS had relevant enduring associations with PANSS disorganization scores and GAF functioning decline. Across the follow-up, FES individuals showed a significant improvement in NS levels. This was specifically associated with the number of individual psychotherapy and intensive case management sessions provided during the 2 years of our EIP program, as well as with the antipsychotic dosage at entry. NS are clinically relevant in FES, already at the enrollment in specialized EIP services. However, their clinical severity seems to decrease over time, together with the delivery of specific, patient-tailored EIP interventions.

Investigating the use of virtual 4DCT from 4DMRI in gated carbon ion radiation therapy of abdominal tumors.

PURPOSE: To generate virtual 4DCT from 4DMRI with field of view (FOV) extended to the entire involved patient anatomy, in order to evaluate its use in carbon ion radiation therapy (CIRT) of the abdominal site in a clinical scenario. MATERIALS AND METHODS: The virtual 4DCT was generated by deforming a reference CT in order to (1) match the anatomy depicted in the 4DMRI within its FOV, by calculating deformation fields with deformable image registration to describe inter-fractional and breathing motion, and (2) obtain physically plausible deformation outside of the 4DMRI FOV, by propagating and modulating the previously obtained deformation fields. The implemented method was validated on a digital anthropomorphic phantom, for which a ground truth (GT) 4DCT was available. A CIRT treatment plan was optimized at the end-exhale reference CT and the RBE-weighted dose distribution was recalculated on both the virtual and GT 4DCTs. The method estimation error was quantified by comparing the virtual and GT 4DCTs and the corresponding recomputed doses. The method was then evaluated on 8 patients with pancreas or liver tumors treated with CIRT using respiratory gating at end-exhale. The clinical treatment plans adopted at the National Center for Oncological Hadrontherapy (CNAO, Pavia, Italy) were considered and the dose distribution was recomputed on all respiratory phases of the planning and virtual 4DCTs. By comparing the two datasets and the corresponding dose distributions, the geometrical and dosimetric impact of organ motion was assessed. RESULTS: For the phantom, the error outside of the 4DMRI FOV was up to 4.5mm, but it remained sub-millimetric in correspondence to the target within the 4DMRI FOV. Although the impact of motion on the target D95% resulted in variations ranging from 22% to 90% between the planned dose and the doses recomputed on the GT 4DCT phases, the corresponding estimation error was ≤2.2%. In the patient cases, the variation of the baseline tumor position between the planning and the virtual end-exhale CTs presented a median (interquartile range) value of 6.0 (4.9) mm. For baseline variations larger than 5mm, the tumor D95% variation between the plan and the dose recomputed on the end-exhale virtual CT resulted larger than 10%. Median variations higher than 10% in the target D95% and gastro-intestinal OARs D2% were quantified at the end-inhale, whereas close to the end-exhale phase, limited variations of relevant dose metrics were found for both tumor and OARs. CONCLUSIONS: The negligible impact of the geometrical inaccuracy in the estimated anatomy outside of the 4DMRI FOV on the overall dosimetric accuracy suggests the feasibility of virtual 4DCT with extended FOV in CIRT of the abdominal site. In the analyzed patient group, inter-fractional variations such as baseline variation and breathing variability were quantified, demonstrating the method capability to support treatment planning in gated CIRT of the abdominal site.

Individual psychotherapy can reduce suicidal ideation in first episode psychosis: Further findings from the 2-year follow-up of the 'Parma Early Psychosis' programme.

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.

Examining disorganization in patients with first episode psychosis: Findings from a 1-year follow-up of the 'Parma early psychosis' program.

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.

Ultrahypofractionated radiotherapy for localized prostate cancer with simultaneous boost to the dominant intraprostatic lesion: a plan comparison.

OBJECTIVE: To compare different stereotactic body techniques-intensity-modulated radiotherapy with photons and protons, applied to radiotherapy of prostatic cancer-with simultaneous integrated boost (SIB) on the dominant intraprostatic lesion (DIL). METHODS: Ten patients were selected for this planning study. Dosimetric results were compared between volumetric modulated arc therapy, intensity-modulated radiation therapy (IMRT), and intensity-modulated proton therapy both with two (IMPT 2F) and five fields (IMPT 5F) planning while applying the prescription schemes of 7.25 Gy/fraction to the prostate gland and 7.5 Gy/fraction to the DIL in 5 fractions. RESULTS: Comparison of the coverages of the planning target volumes showed that small differences exist. The IMPT-2F-5F techniques allowed higher doses in the targets; conformal indexes resulted similar; homogeneity was better in the photon techniques (2%-5%). Regarding the organs at risk, all the techniques were able to maintain the dose well below the prescribed constraints: in the rectum, the IMPT-2F-5F and IMRT were more efficient in lowering the intermediate doses; in the bladder, the median dose was significantly better in the case of IMPT (2F-5F). In the urethra, the best sparing was achieved only by IMPT-5F. CONCLUSIONS: Stereotactic radiotherapy with SIB for localized prostate cancer is feasible with all the investigated techniques. Concerning IMPT, the two-beam technique does not seem to have a greater advantage compared to the standard techniques; the 5-beam technique seems more promising also accounting for the range uncertainty.

Personal health budget in patients with first episode psychosis: A new rehabilitation model based on a community care system in Italy.

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.

Localization of anatomical changes in patients during proton therapy with in-beam PET monitoring: A voxel-based morphometry approach exploiting Monte Carlo simulations.

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.

Prevalence and Appropriateness of Antipsychotic Prescribing in an Italian Prison: Is Everything Always Really Overprescribed?

PURPOSE/BACKGROUND: Although the prevalence of mental disorders in prisoners is known to be higher than in the general population, less is known about the antipsychotic (AP) prescribing rate in jail. The aim of this research was to investigate prevalence and appropriateness of AP prescription in an Italian prison to expand our understanding on this crucial area of clinical-forensic practice. METHODS/PROCEDURES: A cross-sectional (census day) design was used among male adults in the Parma Penitentiary Institutes (PPI). Sociodemographic, clinical and prescription data were collected from the PPI electronic clinical database management system. The AP prescribing appropriateness was examined in accordance with the therapeutic indications included in the Italian National Formulary. A descriptive statistical analysis was performed. FINDINGS/RESULTS: A total of 98 (14.1%) of 696 PPI prisoners were taking AP medications. Moreover, 90 (91.8%) of the 98 PPI participants were also taking other psychotropic medications concurrently. Quetiapine and olanzapine were the most common prescribed APs. Antipsychotic medications were most likely to be prescribed for off-label indications (74.4%). Less than one fifth of all AP prescriptions were for psychotic disorders. IMPLICATIONS/CONCLUSIONS: Antipsychotic medications are widely used in prison, often together with other psychotropic drugs. Considering their common adverse effects, it is crucial to longitudinally monitor their potential risk of metabolic, cardiovascular, and extrapyramidal symptoms and signs, as well as their early risk of mortality. Given the high prevalence of AP off-label prescription, the rationale for AP prescribing should be clearly documented and regularly reviewed within the prison by mental health professionals.