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Abstract DNA damage resulting from genotoxic injury can initiate cellular senescence, a state characterized by alterations in cellular metabolism, lysosomal activity, and the secretion of factors collectively known as the senescence-associated secretory phenotype (SASP). Senescence can have beneficial effects on our bodies, such as anti-cancer properties, wound healing, and tissue development, which are attributed to the SASP produced by senescent cells in their intermediate stages. However, senescence can also promote cancer and aging, primarily due to the pro-inflammatory activity of SASP. Studying senescence is complex due to various factors involved. Genotoxic stimuli cause random damage to cellular macromolecules, leading to variations in the senescent phenotype from cell to cell, despite a shared program. Furthermore, senescence is a dynamic process that cannot be analyzed as a static endpoint, adding further complexity. Investigating SASP is particularly intriguing as it reveals how a senescence process triggered in a few cells can spread to many others, resulting in either positive or negative consequences for health. In our study, we conducted a meta-analysis of the protein content of SASP obtained from different research groups, including our own. We categorized the collected omic data based on: i) cell type, ii) harmful agent, and iii) senescence stage (early and late senescence). By employing Gene Ontology and Network analysis on the omic data, we identified common and specific features of different senescent phenotypes. This research has the potential to pave the way for the development of new senotherapeutic drugs aimed at combating the negative consequences associated with the senescence process. Video Abstract

Background Stakeholders worldwide increasingly acknowledge the need to address coercive practices in mental healthcare. Options have been described and evaluated in several countries, as noted recently in major policy documents from the World Health Organization (WHO) and World Psychiatric Association (WPA). The WHO's QualityRights initiative promotes human rights and quality of care for persons with mental health conditions and psychosocial disabilities. A position statement from the WPA calls for implementation of alternatives to coercion in mental healthcare. Aims We describe the engagement of both the WHO and WPA in this work. We discuss their mutual aim to support countries in improving human rights and quality of care, as well as the differences between these two organisations in their stated goals related to coercion in mental healthcare: the WHO's approach to eliminate coercion and the WPA's goal to implement alternatives to coercion. Method We outline and critically analyse the common ground between the two organisations, which endorse a similar range of rights-based approaches to promoting non-coercive practices in service provision, including early intervention in prevention and care and other policy and practice changes. Results Advocacy and action based on an agreed need to find practical solutions and advances in this area have the power to build consensus and unify key actors. Conclusions We conclude that persons with lived experience, families, mental health professionals and policy makers are now coming together in several parts of the world to work toward the common goals of improving quality, promoting human rights and addressing coercion in mental health services.

Abstract Background The conceptualization of negative symptoms (NS) in schizophrenia is still controversial. Recent confirmatory factor-analytic studies suggested that the bi-dimensional model (motivational deficit [MAP] and expressive deficit [EXP]) may not capture the complexity of NS structure, which could be better defined by a five-factor (five NS domains) or a hierarchical model (five NS domains as first-order factors, and MAP and EXP, as second-order factors). A validation of these models is needed to define the structure of NS. To evaluate the validity and temporal stability of the five-factor or the hierarchical structure of the brief negative symptom scale (BNSS) in individuals with schizophrenia (SCZ), exploring associations between these models with cognition, social cognition, functional capacity, and functioning at baseline and at 4 years follow-up. Methods Clinical variables were assessed using state-of-the-art tools in 612 SCZ at two-time points. The validity of the five-factor and the hierarchical models was analyzed through structural equation models. Results The two models had both a good fit and showed a similar pattern of associations with external validators at the two-time points, with minor variations. The five-factor solution had a slightly better fit. The associations with external validators favored the five-factor structure. Conclusions Our findings suggest that both five-factor and hierarchical models provide a valid conceptualization of NS in relation to external variables and that five-factor solution provides the best balance between parsimony and granularity to summarize the BNSS structure. This finding has important implications for the study of pathophysiological mechanisms and the development of new treatments.

IntroductionIn this study we assessed the contribution of psychopathology, including the two domains of negative symptoms (motivational deficit and expressive deficit), processing speed as an index of neurocognition, and emotion recognition, as an index of social cognition, to poor functional outcomes in people with schizophrenia.MethodsThe Positive and Negative Syndrome Scale was used to evaluate positive symptoms and disorganization and the Brief Negative Symptom Scale to assess negative symptoms. The Symbol Coding and the Trail Making Test A and B were used to rate processing speed and the Facial Emotion Identification Test to assess emotion recognition. Functional outcome was assessed with the Personal and Social Performance Scale (PSP). Regression analyses were performed to identify predictors of functional outcome. Mediation analyses was used to investigate whether social cognition and negative symptom domains fully or partially mediated the impact of processing speed on functional outcome.ResultsOne hundred and fifty subjects from 8 different European centers were recruited. Our data showed that the expressive deficit predicted global functioning and together with motivational deficit fully mediated the effects of neurocognition on it. Motivational deficit was a predictor of personal and social functioning and fully mediated neurocognitive impairment effects on the same outcome. Both motivational deficit and neurocognitive impairment predicted socially useful activities, and the emotion recognition domain of social cognition partially mediated the impact of neurocognitive deficits on this outcome.ConclusionsOur results indicate that pathways to functional outcomes are specific for different domains of real-life functioning and that negative symptoms and social cognition mediate the impact of neurocognitive deficits on different domains of functioning. Our results suggest that both negative symptoms and social cognition should be targeted by psychosocial interventions to enhance the functional impact of neurocognitive remediation.

Abstract Background Codes of ethics provide guidance to address ethical challenges encountered in clinical practice. The harmonization of global, regional, and national codes of ethics is important to avoid gaps and discrepancies. Methods We compare the European Psychiatric Association (EPA) and the World Psychiatric Association (WPA) Codes of Ethics, addressing main key points, similarities, and divergences. Results The WPA and EPA codes are inspired by similar fundamental values but do show a few differences. The two codes have a different structure. The WPA code includes 4 sections and lists 5 overarching principles as the basis of psychiatrists’ clinical practice; the EPA code is articulated in 8 sections, lists 4 ethical principles, and several fundamental values. The EPA code does not include a section on psychiatrists’ education and does not contain specific references to domestic violence and death penalty. Differences can be found in how the two codes address the principle of equity: the EPA code explicitly refers to the principle of universal health care, while the WPA code mentions the principle of equity as reflected in the promotion of distributive justice. Conclusions We recommend that both WPA and EPA periodically update their ethical codes to minimize differences, eliminate gaps, and help member societies to develop or revise national codes in line with the principles of the associations they belong to. Minimizing differences between national and international codes and fostering a continuous dialogue on ethical issues will provide guidance for psychiatrists and will raise awareness of the importance of ethics in our profession.

Abstract Background Cognitive impairment (CI) is one of the most prevalent and burdensome consequences of COVID-19 infection, which can persist up to months or even years after remission of the infection. Current guidelines on post-COVID CI are based on available knowledge on treatments used for improving CI in other conditions. The current review aims to provide an updated overview of the existing evidence on the efficacy of treatments for post-COVID CI. Methods A systematic literature search was conducted for studies published up to December 2023 using three databases (PubMed–Scopus–ProQuest). Controlled and noncontrolled trials, cohort studies, case series, and reports testing interventions on subjects with CI following COVID-19 infection were included. Results After screening 7790 articles, 29 studies were included. Multidisciplinary approaches, particularly those combining cognitive remediation interventions, physical exercise, and dietary and sleep support, may improve CI and address the different needs of individuals with post-COVID-19 condition. Cognitive remediation interventions can provide a safe, cost-effective option and may be tailored to deficits in specific cognitive domains. Noninvasive brain stimulation techniques and hyperbaric oxygen therapy showed mixed and preliminary results. Evidence for other interventions, including pharmacological ones, remains sparse. Challenges in interpreting existing evidence include heterogeneity in study designs, assessment tools, and recruitment criteria; lack of long-term follow-up; and under-characterization of samples in relation to confounding factors. Conclusions Further research, grounded on shared definitions of the post-COVID condition and on the accurate assessment of COVID-related CI, in well-defined study samples and with longer follow-ups, is crucial to address this significant unmet need.

The current management of patients with primary psychosis worldwide is often remarkably stereotyped. In almost all cases an antipsychotic medica-tion is prescribed, with second-generation antipsychotics usually preferred to first-generation ones. Cognitive behavioral therapy is rarely used in the vast majority of countries, although there is evidence to support its efficacy. Psychosocial interventions are often provided, especially in chronic cases, but those applied are frequently not validated by research. Evidence-based family interventions and supported employment programs are seldom implemented in ordinary practice. Although the notion that patients with primary psychosis are at increased risk for cardiovascular diseases and diabetes mellitus is widely shared, it is not frequent that appropriate measures be implemented to address this problem. The view that the management of the patient with primary psychosis should be personalized is endorsed by the vast majority of clinicians, but this personalization is lacking or inadequate in most clinical contexts. Although many mental health services would declare themselves recovery-oriented, it is not common that a focus on empowerment, identity, meaning and resilience is ensured in ordinary practice. The present paper aims to address this situation. It describes systematically the salient domains that should be considered in the characterization of the individual patient with primary psychosis aimed at personalization of management. These include positive and negative symptom dimensions, other psychopathological components, onset and course, neurocognition and social cognition, neurodevelopmental indicators; social functioning, quality of life and unmet needs; clinical staging, antecedent and concomitant psychiatric conditions, physical comorbidities, family history, history of obstetric complications, early and recent environmental exposures, protective factors and resilience, and internalized stigma. For each domain, simple assessment instruments are identified that could be considered for use in clinical practice and included in standardized decision tools. A management of primary psychosis is encouraged which takes into account all the available treatment modalities whose efficacy is supported by research evidence, selects and modulates them in the individual patient on the basis of the clinical characterization, addresses the patients needs in terms of employment, housing, self-care, social relationships and education, and offers a focus on identity, meaning and resilience.

Abstract Early treatment of neonatal diabetes with sulfonylureas has been proven to produce marked improvements of neurodevelopment, beside the demonstrated efficacy on glycemic control. Several barriers still prevent an early treatment in preterm babies including the limited availability of suitable galenic form of glibenclamide. We adopted oral glibenclamide suspension (Amglidia) for the early treatment of neonatal diabetes due to an homozygous variant of KCNJ11 gene c.10C>T [p.Arg4Cys] in an extremely preterm infant born at 26 + 2 weeks' of gestational age. After ~6 weeks of insulin treatment with a low glucose intake (4.5 g/kg/day), the infant was switched to Amglidia 6 mg/ml diluted in maternal milk, via nasogastric tube (0.2 mg/kg/day) progressively reduced to 0.01 mg/kg/day (after ~3 months). While on glibenclamide, the patient exhibited a mean daily growth of 11 g/kg/day. The treatment was suspended at month 6 of birth (weight 4.9 kg [5th–10th centile], M3 of c.a.) for normalization of glucose profile. During the treatment, the patient exhibited a stable glucose profile within the range of 4–8 mmol/L in the absence of hypo or hyperglycemic episodes with 2–3 blood glucose tests per day. The patient was diagnosed with retinopathy of prematurity Stade II in Zone II without plus disease at 32 weeks, with progressive regression and complete retinal vascularization at 6 months of birth. Amglidia could be regarded as the specific treatment for neonatal diabetes even in preterm babies due to its beneficial effect on the metabolic and neurodevelopmental side.

In youths with obesity, the gut hormone potentiation of insulin secretion — the incretin effect — is blunted. We explored the longitudinal impact of the incretin effect during pubertal transition on β cell function and insulin sensitivity. Youths with obesity and 2-hour glucose level ≥ 120 mg/dL underwent a 3-hour oral glucose-tolerance test (OGTT) and an isoglycemic i.v. glucose infusion to quantify the incretin effect. After 2 years, 30 of 39 participants had a repeated OGTT and were stratified into 3 tertiles according to the baseline incretin effect. The high–incretin effect group demonstrated a longitudinal increase in β cell function (disposition index, minimal model [DIMM]), with greater insulin sensitivity at follow-up and stable insulin secretion (φtotal). A lower incretin effect at baseline was associated with higher 1-hour and 2-hour glucose level at follow-up. The high–incretin effect group displayed a greater increase of GLP-17–36 than the moderate- and low-incretin group at baseline, while such a difference did not persist after 2 years. Glucagon suppression was reduced at follow-up in those with low-baseline incretin in respect to the high-incretin group. The incretin effect during pubertal transition affected the longitudinal trajectory of β cell function and weight in youths with obesity.

The abandonment of inland areas has become a major demographical challenge, causing a condition of local fragility in terms of spatial marginalization. To deal with this issue in Italy, a number of policy actions have been implemented over the time, namely the National Strategy for Inland Areas, established a decade ago, and more recently the Next Generation EU (NGEU) to foster local economic recovery and employment. In this context, RI.P.R.O.VA.RE., a project funded by the former Italian Ministry of the Environment and Protection of Land and Sea (MATTM), was aimed at strengthening the resilience features of communities and territories, focusing on areas within the Matese and Ufita in the Campania region and the Medio Agri in the Basilicata region (southern Italy). Besides the ability to respond to different pressure factors (e.g., of demographic and economic origin), the project also addressed issues concerning seismic and flood risks. This paper synthesizes the methods and tools provided for their analysis and mitigation as a prerequisite for regenerating inland areas. After presenting the developed methods and tools, the results obtained for the Matese study area are presented and discussed. While, on the one hand, the retrieved risk zoning maps allow individuating those municipalities requiring priority structural interventions, on the other hand, the latter are properly individuated based on the peculiar characteristics of urban fabrics.

Background The structure of negative symptoms of schizophrenia is still a matter of controversy. Although a two-dimensional model (comprising the expressive deficit dimension and the motivation and pleasure dimension) has gained a large consensus, it has been questioned by recent investigations. Aims To investigate the latent structure of negative symptoms and its stability over time in people with schizophrenia using network analysis. Method Negative symptoms were assessed in 612 people with schizophrenia using the Brief Negative Symptom Scale (BNSS) at baseline and at 4-year follow-up. A network invariance analysis was conducted to investigate changes in the network structure and strength of connections between the two time points. Results The network analysis carried out at baseline and follow-up, supported by community detection analysis, indicated that the BNSS's items aggregate to form four or five distinct domains (avolition/asociality, anhedonia, blunted affect and alogia). The network invariance test indicated that the network structure remained unchanged over time (network invariance test score 0.13; P = 0.169), although its overall strength decreased (6.28 at baseline, 5.79 at follow-up; global strength invariance test score 0.48; P = 0.016). Conclusions The results lend support to a four- or five-factor model of negative symptoms and indicate overall stability over time. These data have implications for the study of pathophysiological mechanisms and the development of targeted treatments for negative symptoms.

Many large-magnitude faults (6.5≤ Mw ≤7.2) of the Italian Apennines are characterized by multi-century return times, so historical sources may have missed their last earthquake or other predecessors. Hence, even in Italy, where seismic catalogs are among the most comprehensive and time-extensive worldwide, there is a need for complementary studies that might fill the lack of historical information and enhance the knowledge concerning the recurrence times of destructive earthquakes. As paleoseismology is the discipline that can do this, in this study, we present results collected in five new trenches opened along the 33-km-long Norcia fault system (central Apennines) where, in addition to the historically known 1703 earthquake (Mw 6.9), we uncovered indications of four Holocene predecessor, with a recurrence time of 1,825 ± 420 years. Considering also the paleoseismic results already published on the nearby Mt Vettore fault system (2016 earthquake of Mw 6.6), we guess that now the seismic hazard of this region could be assessed more robustly.

Background: In several countries, the growing emphasis on human rights and the ratification of the Convention on the Rights of Persons with Disabilities (CRPD) have highlighted the need for changes in culture, attitudes and practices of mental health services. New approaches, such as recovery-oriented care (ROC) and trauma-informed care (TIC) emphasize the users' needs and experiences and promote autonomy and human rights. Aims: To provide an overview of the literature on recovery-oriented care (ROC) and trauma-informed care (TIC) and their relevance to the promotion of human rights and quality of mental health care. Method: We conducted a scoping review by searching the following databases: PubMed, Scopus, PsycINFO. We performed a qualitative synthesis of the literature aimed at reviewing: (1) current conceptualisations of recovery in mental health care; (2) recovery-oriented practices in mental health care; (3) current conceptualizations of trauma and TIC in mental health care; (4) trauma-informed practices in mental health care; (5) the relationship between ROC and TIC, with a particular focus on their shared goal of promoting alternatives to coercion, and on trauma-informed and/or recovery oriented alternatives to coercion. Results: According to prevailing conceptual frameworks, ROC and TIC share many underlying principles and should be regarded as complementary. Both approaches affirm the conceptualization of service users as persons, foster their autonomy and rely on their involvement in designing and monitoring mental health services. Both approaches promote human rights. A wider consensus on conceptual frameworks, tools and methodologies is needed to support ROC and TIC implementation and allow comparison among practices. Recovery-oriented and trauma-informed models of care can contribute to the implementation of non-coercive practices, which show promising results but warrant further empirical study. Conclusions: Recovery-oriented and trauma-informed practices and principles may contribute to the shift towards rights-based mental health care and to the implementation and successful uptake of alternatives to coercion. Local and international work aimed to promote and test these approaches may provide a contribution to improving mental health care world-wide. Future research should focus on the outcomes of all involved stakeholders' and include the perspectives of both staff members and service users in different contexts. [ABSTRACT FROM AUTHOR]

Objective: Pediatric obesity is associated with insulin resistance, which, in turn, impacts glucose and lipid metabolism. This study sought to assess how glucose variability relates to intrahepatic fat content, β cell insulin sensitivity, and glycolysis in youth with obesity. Methods: A total of 27 youth with obesity (11 girls, BMI percentile, median [25th–75th percentiles]: 99.0 [97.9–99.0]) wore a continuous glucose monitoring device for 10 days and underwent a 3‐h oral glucose tolerance test. β cell function was assessed using the oral minimal model, and liver proton density fat fraction was measured by magnetic resonance imaging. Results: Average sensor‐derived glucose and glucose standard deviation (STDEV) and coefficient of variation (CV) were associated with liver proton density fat fraction (p = 0.0130, p = 0.0005, and p = 0.0028, respectively). First‐phase insulin secretion, basal insulin secretion, and insulin sensitivity were associated with STDEV (p = 0.0344, p = 0.0091, and p = 0.0031, respectively) and CV (p = 0.0128, p = 0.0012, and p = 0.0022, respectively). STDEV and CV were also associated with 2‐h glucose (p = 0.0067 and p = 0.0324, respectively) and plasma lactate (p = 0.0030 and p = 0.0123, respectively). Conclusions: Daily glucose variability is associated with the degree of intrahepatic fat content, postprandial glucose, and plasma lactate concentrations. [ABSTRACT FROM AUTHOR]

Background Negative symptoms of schizophrenia are correlated with reduction of normal function and lower quality of life. They were newly defined by the NIMH-MATRICS Consensus in 2005, dividing the rating tools to assess them into first-generation scales, developed before the Consensus, and second-generation scales, based on the recently introduced definitions. Methods The COnsensus-based Standards for the selection of health Measurement Instrument (COSMIN) guidelines for systematic reviews were used to evaluate the quality of psychometric data of the first-generation scales that cover the 5 negative symptom domains of the NIMHS Consensus: the Scale for the Assessment of Negative Symptoms (SANS), the High Royds Evaluation of Negativity Scale (HEN), and the Negative Symptom Assessment-16 (NSA-16). Results The search strategy resulted in the inclusion of a total of 13 articles, 7 for the SANS, 4 for the NSA-16, and 2 for the HEN. For the SANS and the NSA-16, the overall results of the scales' measurement properties are mostly insufficient or indeterminate. The quality of evidence for the HEN is poor, due to a small number of validation studies/included patients. Conclusions After applying the COSMIN guidelines, we do not recommend the usage of these first-generation scales to rate negative symptoms. At the minimum they require further validation. [ABSTRACT FROM AUTHOR]

The assessment of negative symptoms in schizophrenia has advanced since the 2006 NIMH-MATRICS Consensus Statement, leading to the development of second-generation rating scales like the Brief Negative Symptom Scale and the Clinical Assessment Interview for Negative Symptoms. These scales address the limitations of first-generation tools, such as the inclusion of aspects that are not negative symptoms and the lack of assessment of the subject's internal experience. However, psychometric validation of these scales is still in progress, and they are not yet recommended by regulatory agencies, thus limiting their use in clinical trials and settings. Complementing these traditional methods, remote digital phenotyping offers a novel approach by leveraging smartphones and wearable technology to capture real-time, high-resolution clinical data. Despite the potential to overcome traditional assessment barriers, challenges remain in aligning these digital measures with clinical ratings and ensuring data security. Equally important is patient acceptance, as the success of remote digital phenotyping relies on the willingness of patients to use these technologies. This review provides a critical overview of both second-generation scales and remote digital phenotyping for assessing negative symptoms, highlighting future research needs. [ABSTRACT FROM AUTHOR]

Objective. Low-Level Laser Therapy encourages the healing process, reduces inflammation and pain. The aim of this study is to identify the impact of Low-Level Laser Therapy on tissue regeneration with special attention to hard tissues and to compare the effect of several wave lengths in the proliferation and differentiation of cells. Methods. The keywords used were “bone regeneration”, “laser therapy”, “photobiomodulation” OR “bio-stimulation”, “Low-Level Laser therapy” OR “LLLT”, “osteoblast proliferation” AND “differentiation”. Results. The bio-stimulation with Low-Level Laser Therapy also seems to interfere with the osseous integration of implants, by increasing its adherence on the bone-implant surfaces. Evidence has shown that LowLevel Laser Therapy influences the cellular proliferation and differentiation. Conclusions. Low-Level Laser Therapy is a promising therapy in the field of regeneration, but further studies are needed in order to define the standard protocol.

Type 1 diabetes (T1D) is a chronic autoimmune disease featured by the loss of beta cell function and the need for lifetime insulin replacement. Over the recent decade, the use of automated insulin delivery systems (AID) has shifted the paradigm of treatment: the availability of continuous subcutaneous (SC) glucose sensors to guide SC insulin delivery through a control algorithm has allowed, for the first time, to reduce the daily burden of the disease as well as to abate the risk for hypoglycemia. AID use is still limited by individual acceptance, local availability, coverage, and expertise. A major drawback of SC insulin delivery is the need for meal announcement and the peripheral hyperinsulinemia that, over time, contributes to macrovascular complications. Inpatient trials using intraperitoneal (IP) insulin pumps have demonstrated that glycemic control can be improved without meal announcement due to the faster insulin delivery through the peritoneal space. This calls for novel control algorithms able to account for the specificities of IP insulin kinetics. Recently, our group described a two-compartment model of IP insulin kinetics demonstrating that the peritoneal space acts as a virtual compartment and IP insulin delivery is virtually intraportal (intrahepatic), thus closely mimicking the physiology of insulin secretion. The FDA-accepted T1D simulator for SC insulin delivery and sensing has been updated for IP insulin delivery and sensing. Herein, we design and validate—in silico—a time-varying proportional integrative derivative controller to guide IP insulin delivery in a fully closed-loop mode without meal announcement.

Mesenchymal stromal cells (MSCs) are a heterogeneous population containing multipotent adult stem cells with a multi-lineage differentiation capacity, which differentiated into mesodermal derivatives. MSCs are employed for therapeutic purposes and several investigations have demonstrated that the positive effects of MSC transplants are due to the capacity of MSCs to modulate tissue homeostasis and repair via the activity of their secretome. Indeed, the MSC-derived secretomes are now an alternative strategy to cell transplantation due to their anti-inflammatory, anti-apoptotic, and regenerative effects. The cellular senescence is a dynamic process that leads to permanent cell cycle arrest, loss of healthy cells’ physiological functions and acquiring new activities, which are mainly accrued through the release of many factors, indicated as senescence-associated secretory phenotype (SASP). The senescence occurring in stem cells, such as those present in MSCs, may have detrimental effects on health since it can undermine tissue homeostasis and repair. The analysis of MSC secretome is important either for the MSC transplants and for the therapeutic use of secretome. Indeed, the secretome of MSCs, which is the main mechanism of their therapeutic activity, loses its beneficial functions and acquire negative pro-inflammatory and pro-aging activities when MSCs become senescent. When MSCs or their derivatives are planned to be used for therapeutic purposes, great attention must be paid to these changes. In this review, we analyzed changes occurring in MSC secretome following the switch from healthy to senescence status.