Under the same (Chole)sky: DNK models, timing restrictions and recursive identification of monetary policy shocks

Recent structural VAR studies of the monetary transmission mechanism have voiced concerns about the use of recursive identification schemes based on short-run exclusion restrictions. We trace out the effects on impulse propagation of informational constraints embodying classical Cholesky-timing restrictions in otherwise standard Dynamic New Keynesian (DNK) models. By reinforcing internal propagation mechanisms and enlarging a model's equilibrium state space, timing restrictions may produce a non-trivial moving average component of the equilibrium representation, making finite order VARs a poor approximation of true adjustment paths to monetary impulses, albeit correctly identified. They can even serve as an independent source of model-based nonfundamentalness, thereby hampering shock identification via VAR methods. This notwithstanding, restricted DNK models are shown to feature (i) invertible equilibrium representations for the observables and (ii) fast-converging VAR coefficient matrices under empirically tenable parameterizations. This alleviates concerns about identification and lag truncation bias: low-order Cholesky-VARs do well at uncovering the transmission of monetary impulses in a truly Cholesky world

Violence Risk Assessment and Risk Management: Case-Study of Filicide in an Italian Woman

Background: At an international level, the risk assessment and management process of violent offenders follows a standard method that implies well-defined theoretical models and the use of scientifically validated tools. In Italy, this process is still highly discretionary. The aim of this study is to highlight the advantages deriving from the use of risk assessment tools within the framework of a single case study; Methods: Recidivism risk and social dangerousness of an Italian woman perpetrator of filicide were assessed through the administration of the Level of Service/Case Management Inventory (LS/CMI) instrument supported by Historical Clinical Risk-20 Version 3 (HCR-20 V3); Results: The administration of LS/CMI showed that, in this single case, the subcomponents represent a criminogenic risk/need factor are: Family/Marital, Companions, Alcohol and Drug Problem and Leisure; while constituting strengths: employment and the absence of a Pro-criminal Orientation and an Antisocial Pattern; Conclusions: Data collected through LS/CMI indicated life areas of a single case, which should be emphasised not only to assess the risk of re-offending and social dangerousness but also for a social rehabilitation programme more suited to the subject. This study demonstrates that the LS/CMI assessment tool is suitable for the Italian context

Exploring the connection between childhood trauma, dissociation, and borderline personality disorder in forensic psychiatry: a comprehensive case study

This case study examines the complex relationship between childhood trauma, dissociation, and Borderline Personality Disorder (BPD) within the context of forensic psychiatry. It focuses on a young murder defendant named “Paul,” who has experienced various traumatic events, including childhood maltreatment and domestic violence. These experiences have led to dissociative states marked by high emotional intensity, particularly of an aggressive nature, and impaired impulse control, resulting in violent behavior during dissociative episodes. The study employs advanced assessment tools like Raven’s Standard Progressive Matrices (SPM), the Millon Clinical Multiaxial Inventory-III (MCMI-III), and the Level of Service/Case Management Inventory (LS/CMI) to gain a comprehensive understanding of Paul’s psychopathological condition, risk factors, and rehabilitation needs. The LS/CMI assessment highlights a high risk of recidivism, mainly influenced by family relationships, educational challenges, interpersonal connections, and aggressive tendencies. To address the multifaceted needs of individuals like Paul, the study emphasizes the importance of using transdiagnostic models for trauma and dissociation. This approach informs tailored treatment programs that include processing past traumatic experiences, improving self-identity, nurturing healthy relational patterns, and enhancing emotional regulation. Although this study is based on a single case, it serves as a model for integrating assessment tools and theoretical-clinical models in the field of forensic psychiatry. Understanding the intricate dynamics of childhood trauma, dissociation, and BPD is crucial for making informed decisions, conducting risk assessments, and developing rehabilitation programs within the justice system. Future research should expand the scope of cases and further validate assessment tools to advance our understanding of this complex relationship

372. Prevalence of Anti-AAV8 Neutralizing Antibodies and ARSB Cross-Reactive Immunologic Material in MPS VI Patients Candidates for a Gene Therapy Trial

Recombinant vectors based on adeno-associated virus serotype 8 (AAV8) have been successfully used in the clinic and hold great promise for liver-directed gene therapy. Pre-existing immunity against AAV8 or the development of antibodies against the therapeutic transgene product might negatively affect the outcomes of gene therapy. In the prospect of an AAV8-mediated, liver-directed gene therapy clinical trial for Mucopolysaccharidosis VI (MPS VI), a lysosomal storage disorder due to arylsulfatase B (ARSB) deficiency, we investigated in a multiethnic cohort of MPS VI patients the prevalence of neutralizing antibodies (Nab) to AAV8 and the presence of ARSB cross-reactive immunologic material (CRIM), which will either affect the efficacy of gene transfer or the duration of phenotypic correction. Thirty-six MPS VI subjects included in the study harbored 45 (62.5%) missense, 13 (18%) nonsense, 9 (12.5%) frameshift (2 insertions and 7 deletions), and 5 (7%) splicing ARSB mutations. To the best of our knowledge, four mutations had not been previously described. These include: one missense (c.1178 A>G p.H393R) and three frameshift mutations [883-884duplTT (p.F295FfsX42), c.1036delG (p.E346SfsX11), c.1475delC (pP492LfsX80)] predicted to result in truncated proteins. The detection of ARSB protein in twenty-four patients out of 34 (71%) was predicted by the type of mutations. Pre-existing Nab to AAV8 were undetectable in 19/33 (58%) analyzed patients. Twelve out of 31 patients (39%) tested were both negative for Nab to AAV8 and CRIM-positive. In conclusion, this study allows estimating the number of MPS VI patients eligible for a gene therapy trial by intravenous injections of AAV8

Mitoxantrone, pixantrone, and mitoxantrone (2-hydroxyethyl)piperazine are toll-like receptor 4 antagonists, inhibit NF-κB activation, and decrease TNF-alpha secretion in primary microglia

Toll-like receptor 4 (TLR4) recognizes various endogenous and microbial ligands and is an essential part in the innate immune system. TLR4 signaling initiates transcription factor NF-κB and production of proinflammatory cytokines. TLR4 contributes to the development or progression of various diseases including stroke, neuropathic pain, multiple sclerosis, rheumatoid arthritis and cancer, and better therapeutics are currently sought for these conditions. In this study, a library of 140 000 compounds was virtually screened and a resulting hit-list of 1000 compounds was tested using a cellular reporter system. The topoisomerase II inhibitor mitoxantrone and its analogues pixantrone and mitoxantrone (2-hydroxyethyl)piperazine were identified as inhibitors of TLR4 and NF-κB activation. Mitoxantrone was shown to bind directly to the TLR4, and pixantrone and mitoxantrone (2- hydroxyethyl)piperazine were shown to inhibit the production of proinflammatory cytokines such as tumor necrosis factor alpha (TNFα) in primary microglia. The inhibitory effect on NF-κB activation or on TNFα pro-duction was not mediated through cytotoxity at ≤ 1 μM concentration for pixantrone and mitoxantrone (2- hydroxyethyl)piperazine treated cells, as assessed by ATP counts. This study thus identifies a new mechanism of action for mitoxantrone, pixantrone, and mitoxantrone (2-hydroxyethyl)piperazine through the TLR4.Peer reviewe

Phenotype and genotype of 87 patients with Mowat-Wilson syndrome and recommendations for care

Mowat-Wilson syndrome (MWS) is a rare intellectual disability/multiple congenital anomalies syndrome caused by heterozygous mutation of the ZEB2 gene. It is generally underestimated because its rarity and phenotypic variability sometimes make it difficult to recognize. Here, we aimed to better delineate the phenotype, natural history, and genotype-phenotype correlations of MWS.MethodsIn a collaborative study, we analyzed clinical data for 87 patients with molecularly confirmed diagnosis. We described the prevalence of all clinical aspects, including attainment of neurodevelopmental milestones, and compared the data with the various types of underlying ZEB2 pathogenic variations.ResultsAll anthropometric, somatic, and behavioral features reported here outline a variable but highly consistent phenotype. By presenting the most comprehensive evaluation of MWS to date, we define its clinical evolution occurring with age and derive suggestions for patient management. Furthermore, we observe that its severity correlates with the kind of ZEB2 variation involved, ranging from ZEB2 locus deletions, associated with severe phenotypes, to rare nonmissense intragenic mutations predicted to preserve some ZEB2 protein functionality, accompanying milder clinical presentations.ConclusionKnowledge of the phenotypic spectrum of MWS and its correlation with the genotype will improve its detection rate and the prediction of its features, thus improving patient care.GENETICS in MEDICINE advance online publication, 4 January 2018; doi:10.1038/gim.2017.221

How future surgery will benefit from SARS-COV-2-related measures: a SPIGC survey conveying the perspective of Italian surgeons

COVID-19 negatively affected surgical activity, but the potential benefits resulting from adopted measures remain unclear. The aim of this study was to evaluate the change in surgical activity and potential benefit from COVID-19 measures in perspective of Italian surgeons on behalf of SPIGC. A nationwide online survey on surgical practice before, during, and after COVID-19 pandemic was conducted in March-April 2022 (NCT:05323851). Effects of COVID-19 hospital-related measures on surgical patients' management and personal professional development across surgical specialties were explored. Data on demographics, pre-operative/peri-operative/post-operative management, and professional development were collected. Outcomes were matched with the corresponding volume. Four hundred and seventy-three respondents were included in final analysis across 14 surgical specialties. Since SARS-CoV-2 pandemic, application of telematic consultations (4.1% vs. 21.6%; p < 0.0001) and diagnostic evaluations (16.4% vs. 42.2%; p < 0.0001) increased. Elective surgical activities significantly reduced and surgeons opted more frequently for conservative management with a possible indication for elective (26.3% vs. 35.7%; p < 0.0001) or urgent (20.4% vs. 38.5%; p < 0.0001) surgery. All new COVID-related measures are perceived to be maintained in the future. Surgeons' personal education online increased from 12.6% (pre-COVID) to 86.6% (post-COVID; p < 0.0001). Online educational activities are considered a beneficial effect from COVID pandemic (56.4%). COVID-19 had a great impact on surgical specialties, with significant reduction of operation volume. However, some forced changes turned out to be benefits. Isolation measures pushed the use of telemedicine and telemetric devices for outpatient practice and favored communication for educational purposes and surgeon-patient/family communication. From the Italian surgeons' perspective, COVID-related measures will continue to influence future surgical clinical practice