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Context The oral minimal model is a widely accepted noninvasive tool to quantify both β-cell responsiveness and insulin sensitivity (SI) from glucose, C-peptide, and insulin concentrations during a 3-hour 9-point oral glucose tolerance test (OGTT). Objective Here, we aimed to validate a 2-hour 7-point protocol against the 3-hour OGTT and to test how variation in early sampling frequency impacts estimates of β-cell responsiveness and SI. Methods We conducted a secondary analysis on 15 lean youth with stage 1 type 1 diabetes (T1D; ≥ 2 islet autoantibodies with no dysglycemia) who underwent a 3-hour 9-point OGTT. The oral minimal model was used to quantitate β-cell responsiveness (φtotal) and insulin sensitivity (SI), allowing assessment of β-cell function by the disposition index (DI = φtotal × SI). Seven- and 5-point 2-hour OGTT protocols were tested against the 3-hour 9-point gold standard to determine agreement between estimates of φtotal and its dynamic and static components, SI, and DI across different sampling strategies. Results The 2-hour estimates for the disposition index exhibited a strong correlation with 3-hour measures (r = 0.975; P < .001) with similar results for β-cell responsiveness and SI (r = 0.997 and r = 0.982; P < .001, respectively). The agreement of the 3 estimates between the 7-point 2-hour and 9-point 3-hour protocols fell within the 95% CI on the Bland-Altman grid with a median difference of 16.9% (−35.3 to 32.5), 0.2% (−0.6 to 1.3), and 14.9% (−1.4 to 28.3) for DI, φtotal, and SI. Conversely, the 5-point protocol did not provide reliable estimates of φ dynamic and static components. Conclusion The 2-hour 7-point OGTT is reliable in individuals with stage 1 T1D for assessment of β-cell responsiveness, SI, and DI. Incorporation of these analyses into current 2-hour diabetes staging and monitoring OGTTs offers the potential to more accurately quantify risk of progression in the early stages of T1D.

Context The “carbohydrate-insulin model” claims that adipose tissue insulin sensitivity explains development of obesity via adipocyte energy storage and/or low postprandial metabolic fuel levels. Objective We tested whether adipose tissue insulin sensitivity predicts changes in the degree of obesity over time. Methods This secondary analysis of an observational study of youth with obesity included 213 youths at a pediatric weight management clinic. Adipose tissue insulin sensitivity/resistance and whole-body insulin sensitivity were evaluated using oral glucose tolerance test (OGTT)-derived surrogates in the face of changes in the degree of obesity over time. The main outcome measure was change in body mass index (BMI) z score. Results Mean BMI z change was 0.05 ± 0.28 (range, −1.15 to 1.19), representing a broad distribution of changes in the degree of obesity over a follow-up period of 1.88 ± 1.27 years. Adipose tissue insulin resistance was not associated with changes in the degree of obesity in univariate or multivariate analyses (adjusted for baseline age, BMI z score, sex, ethnicity, and time of follow-up). Low postprandial free fatty acid concentrations or their suppression during the OGTT were not associated with changes in the degree of obesity in univariate or multivariate analyses. Whole-body insulin sensitivity was not associated with changes in the degree of obesity in univariate or multivariate analyses. Conclusion In this secondary analysis, in youth with obesity, adipose tissue insulin resistance is not protective from increases of the degree of obesity and skeletal muscle insulin resistance is not associated with increases of the degree of obesity. The analysis was performed using data derived from NCT00000112 and NCT00536250.

Il saggio propone una riflessione critica sui criteri adottati dalla SNAI per la perimetrazione delle aree interne e la selezione di ambiti pilota. Il percorso metodologico, testato su Campania e Basilicata e replicabile sull'intero territorio nazionale, definisce criteri e indicatori in grado di disvelare, oltre alle ben note dinamiche di declino, il potenziale dei territori interni, a supporto di una più adeguata definizione degli ambiti di intervento e delle strategie di sviluppo.

Genotoxic injuries converge on senescence-executive program that promotes production of a senescence-specific secretome (SASP). The study of SASP is particularly intriguing, since through it a senescence process, triggered in a few cells, can spread to many other cells and produce either beneficial or negative consequences for health. We analysed the SASP of quiescent mesenchymal stromal cells (MSCs) following stress induced premature senescence (SIPS) by ionizing radiation exposure. We performed a proteome analysis of SASP content obtained from early and late senescent cells. The bioinformatics studies evidenced that early and late SASPs, besides some common ontologies and signalling pathways, contain specific factors. In spite of these differences, we evidenced that SASPs can block in vitro proliferation of cancer cells and promote senescence/apoptosis. It is possible to imagine that SASP always contains core components that have an anti-tumour activity, the progression from early to late senescence enriches the SASP of factors that may promote SASP tumorigenic activity only by interacting and instructing cells of the immune system. Our results on Caco-2 cancer cells incubated with late SASP in presence of peripheral white blood cells strongly support this hypothesis. We evidenced that quiescent MSCs following SIPS produced SASP that, while progressively changed its composition, preserved the capacity to block cancer growth by inducing senescence and/or apoptosis only in an autonomous manner.

To date, the role of family members in caring for relatives affected by schizophrenia has focused largely on the negative aspects of impact of the illness. The present study aimed to: (1) assess family functioning and burden of care in caregivers living in Northern, Central, and Southern Italy who looked after subjects affected by chronic schizophrenia; (2) evaluate the relationship between aspects of family functioning and burden of care, in particular personal growth (PG) of caregivers; and (3) identify variables capable of affecting PG of caregivers. A total of 136 caregivers (mean length of illness of family member more than 20 years) were recruited from 9 Italian research sites and evaluated in terms of “positive” family functioning–problem-solving, communication skills and personal goals Family Functioning Questionnaire (FFQ), burden of care, and PG Family Problems Questionnaire (FPQ). Caregivers reported an overall good family functioning with a relatively low objective and subjective burden of care. The latter was positively correlated with length of illness, with women showing a higher subjective burden than men. Reduced problem-solving skills and ability of each family member to pursue personal goals were both associated with reduced objective and subjective burden which, conversely, were both increased by inadequate support and scarce positive comments from relatives and friends. Approximately 50% of caregivers stated that “they had learned something positive from the situation,” highlighting a statistically higher proportion of caregivers in southern Italy than in northern and central Italy. Caregivers’ PG was associated with good family functioning, adequate professional support, and positive comments. PG also seemed to be positively influenced by support from relatives and friends (O.R. 14.306). The numerous challenges and positive aspects associated with caregiving should be duly acknowledged by mental health services and integrated into routine clinical assessment and intervention framework.

Background: Schizophrenia is a severe psychiatric disorder with periods of remission and relapse. As discontinuation of antipsychotic medication is the most important reason for relapse, long-term maintenance treatment is key. Whether intramuscular long-acting (depot) antipsychotics are more efficacious than oral medication in preventing medication discontinuation is still unresolved. We aimed to compare time to all-cause discontinuation in patients randomly allocated to long-acting injectable (LAI) versus oral medication. Methods: EULAST was a pragmatic, randomised, open-label trial conducted at 50 general hospitals and psychiatric specialty clinics in 15 European countries and Israel. Patients aged 18 years and older, with DSM-IV schizophrenia (as confirmed by the Mini International Neuropsychiatric Interview 5 plus) and having experienced their first psychotic episode from 6 months to 7 years before screening, were randomly allocated (1:1:1:1) using block randomisation to LAI paliperidone, LAI aripiprazole, or the respective oral formulations of these antipsychotics. Randomisation was stratified by country and duration of illness (6 months up to 3 years vs 4 to 7 years). Patients were followed up for up to 19 months. The primary endpoint was discontinuation, regardless of the reason, during 19 months of treatment. We used survival analysis to assess the time until all-cause discontinuation in the intention-to-treat (ITT) group, and per protocol analyses were also done. This trial is registered with ClinicalTrials.gov, NCT02146547, and is complete. Findings: Between Feb 24, 2015, and Dec 15, 2018, 533 individuals were recruited and assessed for eligibility. The ITT population included 511 participants, with 171 (33%) women and 340 (67%) men, and a mean age of 30·5 (SD 9·6) years. 410 (80%) of 511 participants were White, 35 (7%) were Black, 20 (4%) were Asian, and 46 (9%) were other ethnicity. In the combined oral antipsychotics treatment group of 247 patients, 72 (29%) patients completed the study and 175 (71%) met all-cause discontinuation criteria. In the combined LAI treatment arm of 264 patients, 95 (36%) completed the study and 169 (64%) met the all-cause discontinuation criteria. Cox regression analyses showed that treatment discontinuation for any cause did not differ between the two combined treatment groups (hazard ration [HR] 1·16, 95% CI 0·94–1·43, p=0·18). No significant difference was found in the time to all-cause discontinuation between the combined oral and combined LAI treatment groups (log rank test χ 2=1·87 [df 1]; p=0·17). During the study, 121 psychiatric hospitalisations occurred in 103 patients, and one patient from each of the LAI groups died; the death of the patient assigned to paliperidone was assessed to be unrelated to the medication, but the cause of other patient's death was not shared with the study team. 86 (25%) of 350 participants with available data met akathisia criteria and 70 (20%) met parkinsonism criteria at some point during the study. Interpretation: We found no substantial advantage for LAI antipsychotic treatment over oral treatment regarding time to discontinuation in patients with early-phase schizophrenia, indicating that there is no reason to prescribe LAIs instead of oral antipsychotics if the goal is to prevent discontinuation of antipsychotic medication in daily clinical practice. Funding: Lundbeck and Otsuka.

Summary Important developments in the conceptualisation and classification of negative symptoms have contributed to refining hypotheses on their pathophysiology. The uptake of recent progress is still only partial and the whole field might make a leap forward once relevant studies fully make use of assessment tools based on current conceptualisations.

Background The main purpose of the study is to assess the association between obstructive sleep apnea (OSA) and insulin secretion in children with obesity. Methods We enrolled children and adolescents who attended our pediatric clinic because of obesity and OSA. Glucose homeostasis was assessed through standard 2-h oral glucose tolerance test (OGTT). Nocturnal cardio-respiratory polygraphy was performed for OSA diagnosis. Twenty-two patients underwent a 3-h OGTT to investigate insulin secretion and sensitivity through the oral-minimal model. Results seventy-seven children and adolescents were included in the study. Based on OSA severity, the cohort was divided into three groups (29 mild, 29 moderate, and 19 severe OSA). The group with mild OSA showed lower levels of 30-min glucose (p = 0.01) and 60-min glucose (p = 0.03), and lower prevalence of elevated 1-h glucose (10.4% versus 44.8% in moderate and 31.6% in severe OSA, p = 0.01). The odds for elevated 1-h plasma glucose was 6.2-fold (95%CI 1.6–23.4) higher in subjects with moderate and severe OSA compared to mild OSA (p = 0.007) independent of confounders. Spearman correlation test revealed a positive correlation between 30-min plasma glucose and apnea-hypopnea index (AHI, r = 0.31, p = 0.01), oxygen desaturation index (ODI, r = 0.31, p = 0.009), and mean desaturation (r = 0.25, p = 0.04). The 3-h OGTT study included 22 participants (7 mild, 9 moderate, and 6 severe OSA). The group with mild OSA showed a higher dynamic, static, and total insulin secretion compared to those with moderate and severe OSA (p p = 0.007, p = 0.007, respectively). AHI was significantly correlated to dynamic insulin secretion (r = −0.48, p = 0.02). Conclusions OSA might impair beta-cell function reducing the pool of promptly releasable insulin in children and adolescents with obesity, in the absence of an effect on insulin sensitivity.

Background Deficits in social cognition (SC) are significantly related to community functioning in schizophrenia (SZ). Few studies investigated longitudinal changes in SC and its impact on recovery. In the present study, we aimed: (a) to estimate the magnitude and clinical significance of SC change in outpatients with stable SZ who were assessed at baseline and after 4 years, (b) to identify predictors of reliable and clinically significant change (RCSC), and (c) to determine whether changes in SC over 4 years predicted patient recovery at follow-up. Methods The reliable change index was used to estimate the proportion of true change in SC, not attributable to measurement error. Stepwise multiple logistic regression models were used to identify the predictors of RCSC in a SC domain (The Awareness of Social Inference Test [TASIT]) and the effect of change in TASIT on recovery at follow-up. Results In 548 participants, statistically significant improvements were found for the simple and paradoxical sarcasm of TASIT scale, and for the total score of section 2. The reliable change index was 9.8. A cut-off of 45 identified patients showing clinically significant change. Reliable change was achieved by 12.6% and RCSC by 8% of participants. Lower baseline TASIT sect. 2 score predicted reliable improvement on TASIT sect. 2. Improvement in TASIT sect. 2 scores predicted functional recovery, with a 10-point change predicting 40% increase in the probability of recovery. Conclusions The RCSC index provides a conservative way to assess the improvement in the ability to grasp sarcasm in SZ, and is associated with recovery.

Research on negative symptoms of schizophrenia has received renewed interest since the 1980s. A scientometric analysis that objectively maps scientific knowledge, with changes in recent trends, is currently lacking. We searched the Web of Science Core Collection (WOSCC) on December 17, 2021 using relevant keywords. R-bibliometrix and CiteSpace were used to perform the analysis. We retrieved 27,568 references published between 1966 and 2022. An exponential rise in scientific interest was observed, with an average annual growth rate in publications of 16.56% from 1990 to 2010. The co-cited reference network that was retrieved presented 24 different clusters with a well-structured network (Q=0.7921; S=0.9016). Two distinct major research trends were identified: research on the conceptualization and treatment of negative symptoms. The latest trends in research on negative symptoms include evidence synthesis, nonpharmacological treatments, and computational psychiatry. Scientometric analyses provide a useful summary of changes in negative symptom research across time by identifying intellectual turning point papers and emerging trends. These results will be informative for systematic reviews, meta-analyses, and generating novel hypotheses.

Definition of an appropriate and personalized treatment plan focused on long-term outcomes is crucial in the management of schizophrenia. Following review of the literature, a panel of six leading psychiatrists discussed the importance of clear and shared long-term goals when initiating antipsychotic treatment in light of their clinical experience. The importance of establishing shared and progressive treatment objectives was stressed, which should be tailored based on the patient’s characteristics, goals, and preferences. Consensus emerged on the key role that therapeutic alliance and patient empowerment play throughout the course of treatment. Reduction in symptoms in the acute phase along with good efficacy and tolerability in the maintenance phase emerged as essential features of a therapy that can favor achievement of long-term outcomes. Long-acting injectable (LAI) antipsychotics enhance adherence to treatment compared to oral formulations and have been shown to be effective in the maintenance phase. Currently available LAIs are characterized by a delayed onset of action and require a loading dose or oral supplementation to achieve therapeutic concentrations. Risperidone ISM® is a novel LAI antipsychotic with fast and sustained release of antipsychotic, reaching therapeutic plasma levels within a few hours after administration without oral supplementation or loading doses. Risperidone ISM® has been shown to rapidly control symptoms in patients with an acute exacerbation of schizophrenia and to be effective and well tolerated as maintenance treatment irrespective of the severity of initial symptoms. It thus represents a valuable and novel therapeutic option in management of schizophrenia.

My research has focused on unmet needs in caring for people with schizophrenia. In particular, I focused on negative symptoms, a complex psychopathological dimension of the disorder, with a significant impact on the disease outcome, and not effectively addressed by existing treatments. In the present commentary, I summarize the trajectory of my research activity. I start with the description of my initial attempts to define the role of the dorsolateral prefrontal cortex in the pathogenesis of broadly defined negative symptoms. Then, I report on the evidence that led me to realize that no progress in research on schizophrenia negative symptoms could occur without considering the heterogeneity and complexity of the construct. Finally, I illustrate my attempts to succeed in this direction and the most pressing unsolved issues in this research field.

Gender differences in clinical and psychosocial aspects of schizophrenia have been widely reported. Findings have not always been consistent, and some of them need further research. In a large sample of community dwelling persons with schizophrenia, we investigated gender differences in clinical, cognitive and functional indices, as well as their changes over a 4-year follow-up and their impact on real-life functioning. Gender differences in personal resources, cognitive and functional indices were explored also in a sample of healthy controls. Men with respect to women had an earlier age of illness onset, a worse premorbid adjustment in the academic domain, more severe avolition, expressive deficit and positive symptoms, lower prevalence of comorbidity for affective disorders, less frequent use of two coping strategies ('religion' and 'use of emotional support') and more frequent positive history of substance and alcohol abuse. In addition, men were more impaired in verbal learning, while women in reasoning/problem solving. Some patterns of gender differences observed in healthy controls were not confirmed in patients. Men's disadvantages in the clinical picture did not translate into a worse outcome. This finding may be related to the complex interplay of several factors acting as predictors or mediators of outcome.

Minimally invasive surgery (MIS) is a widespread approach in general surgery. Computer guiding software, such as the augmented reality (AR), the virtual reality (VR) and mixed reality (MR), has been proposed to help surgeons during MIS. This study aims to report these technologies' current knowledge and diffusion during surgical training in Italy. A web-based survey was developed under the aegis of the Italian Society of Endoscopic Surgery (SICE). Two hundred and seventeen medical doctors' answers were analyzed. Participants were surgeons (138, 63.6%) and residents in surgery (79, 36.4%). The mean knowledge of the role of the VR, AR and MR in surgery was 4.9 ± 2.4 (range 1-10). Most of the participants (122, 56.2%) did not have experience with any proposed technologies. However, although the lack of experience in this field, the answers about the functioning of the technologies were correct in most cases. Most of the participants answered that VR, AR and MR should be used more frequently for the teaching and training and during the clinical activity (170, 80.3%) and that such technologies would make a significant contribution, especially in training (183, 84.3%) and didactic (156, 71.9%). Finally, the main limitations to the diffusion of these technologies were the insufficient knowledge (182, 83.9%) and costs (175, 80.6%). Based on the present study, in Italy, the knowledge and dissemination of these technologies are still limited. Further studies are required to establish the usefulness of AR, VR and MR in surgical training.

Il contributo affronta una delle fasi fondamentali del ciclo di gestione del post-disastro: la fase del recupero, collocata tra la fine dell'emergenza e l'inizio della ricostruzione e finora scarsamente esplorata e regolamentata, soprattutto nel contesto nazionale. Più specificamente, si esamina l'evoluzione del significato e del ruolo di tale fase in relazione all'evolversi del concetto di resilienza; quindi, sulla base della letteratura scientifica e di alcune esperienze pregresse, si evidenziano caratteristiche ed esigenze proprie di questa fase e si delineano alcune raccomandazioni e proposte operative per accrescerne l'efficacia. Raccomandazioni e proposte fanno principalmente riferimento alle modalità per garantire un'efficace pianificazione preventiva del recupero post-evento, ai criteri per innovare i modelli di governance e ai principali strumenti da mettere in campo per consentire la rapida transizione verso la ricostruzione.

AIM: Evidence from mouse models suggests that brain serotonergic pathways control blood glucose. We hypothesized that sumatriptan (5HT1B -receptor agonist) would alter glucose homeostasis in humans. MATERIALS AND METHODS: We conducted a two-visit random-order double-blinded placebo-controlled cross-over trial in 10 overweight adults that were otherwise healthy. Participants received sumatriptan (single dose, 100 mg) or placebo before undergoing a 60-min intravenous glucose tolerance test, followed by a 120-min hyperinsulinaemic euglycaemic clamp. RESULTS: Glucose excursion was greater during intravenous glucose tolerance test with sumatriptan compared with placebo [iAUC0-60 min 316 (268-333) vs. 251 (197-319) min/mmol/L p = .047]. This was probably explained by a combination of reduced circulating insulin levels [iAUC0-10 min 1626 (1103-2733) vs. 2336 (1702-3269) min/pmol/L, p = .005], reduced insulin sensitivity [M/I-value 2.11 (1.15, 4.05) vs. 3.03 (1.14, 4.90) mg/kg/min per pmol/L, p = .010] and glucose effectiveness [SG 0.17 (0.12, 0.21) vs. 0.22 (0.18, 0.65)/min, p = .027]. CONCLUSIONS: 5HT1B receptors have a glucoregulatory role in humans, probably acting on insulin secretion, insulin sensitivity and glucose effectiveness.

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.

To examine the determinants and metabolic impact of the reduction in fasting and postload insulin levels after a low n-6 to n-3 polyunsaturated fatty acid (PUFA) ratio diet in obese youth.Insulin secretion and clearance were assessed by measuring and modelling plasma insulin and C-peptide in 17 obese youth who underwent a nine-point, 180-minute oral glucose tolerance test (OGTT) before and after a 12-week, eucaloric low n-6:n-3 polyunsaturated fatty acid (PUFA) ratio diet. Hepatic fat content was assessed by repeated abdominal magnetic resonance imaging.Insulin clearance at fasting and during the OGTT was significantly increased after the diet, while body weight, glucose levels, absolute and glucose-dependent insulin secretion, and model-derived variables of β-cell function were not affected. Dietary-induced changes in insulin clearance positively correlated with changes in whole-body insulin sensitivity and β-cell glucose sensitivity, but not with changes in hepatic fat. Subjects with greater increases in insulin clearance showed a worse metabolic profile at enrolment, characterized by impaired insulin clearance, β-cell glucose sensitivity, and glucose tolerance, and benefitted the most from the diet, achieving greater improvements in glucose-stimulated hyperinsulinaemia, insulin resistance, and β-cell function.We showed that a 12-week low n-6:n-3 PUFA ratio diet improves hyperinsulinaemia by increasing fasting and postload insulin clearance in obese youth, independently of weight loss, glucose concentrations, and insulin secretion.

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 Low-Level 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.

Background The European impact of the clinical high risk for psychosis (CHR-P) paradigm is constrained by the lack of critical mass (detection) to power prognostic and preventive interventions. Methods An ITAlian partnership for psychosis prevention (ITAPP) was created across CHR-P centers, which were surveyed to describe: (a) service, catchment area, and outreach; (b) service users; and (c) interventions and outcomes. Descriptive statistics and Kaplan-Meier failure function complemented the analyses. Results The ITAPP included five CHR-P clinical academic centers established from 2007 to 2018, serving about 13 million inhabitants, with a recruitment capacity of 277 CHR-P individuals (mean age: 18.7 years, SD: 4.8, range: 12-39 years; 53.1% females; 85.7% meeting attenuated psychotic symptoms; 85.8% without any substance abuse). All centers were multidisciplinary and included adolescents and young adults (transitional) primarily recruited through healthcare services. The comprehensive assessment of at-risk mental state was the most widely used instrument, while the duration of follow-up, type of outreach, and preventive interventions were heterogeneous. Across 205 CHR-P individuals with follow up (663.7 days ± 551.7), the cumulative risk of psychosis increased from 8.7% (95% CI 5.3-14.1) at 1 year to 15.9% (95% CI 10.6-23.3) at 2 years, 21.8% (95% CI 14.9-31.3) at 3 years, 34.8% (95% CI 24.5-47.9) at 4 years, and 51.9% (95% CI 36.3-69.6) at 5 years. Conclusions The ITAPP is one of the few CHR-P clinical research partnerships in Europe for fostering detection, prognosis, and preventive care, as well as for translating research innovations into practice.

This contribution discusses the need for a substantial reform of recovery, intended as the disaster phase stretching between the end of the emergency and the beginning of reconstruction. First, the main features and emerging needs of this phase have been explored on the base of both literature review and reports on extensively investigated recent disasters, such as the recovery after Katrina in New Orleans or the Christchurch earthquake in 2010-2011. Then, two recovery case studies have been in-depth analyzed: the ongoing recovery after the Central Italy seismic swarm 2016-2017, and the past successful recovery following the Gujarat earthquake in India in 2001. Finally, a set of recommendations – aimed at improving practices and tools that should be prepared and dedicated to this rather neglected, albeit crucial, disaster phase – has been outlined. An innovative governance model oriented towards a more participatory approach, capable of involving all stakeholders that should have a say on the recovery and reconstruction pathways, is proposed. Pre-disaster planning is then recommended as a set of tools that should oversee the entire process, allowing a rapid and smooth shift into reconstruction. Such tools should include guidance and rules for building back better and for rehabilitating cultural heritage that can be saved or at least partially restored; urban and spatial planning that are essential for example to identify the most suitable sheltering solutions so that they will be coherent and aligned with visions for the future development of the hit areas. Last but not least, post disaster damage and loss assessment is proposed as a key activity that permits not only to establish priorities for immediate recovery, but also to learn lessons about vulnerabilities, both physical and systemic, that should be reduced for a resilient recovery.

Introduction: The Cognitive Assessment Interview (CAI) is an interview-based scale developed to measure cognitive impairment and its impact on functioning in subjects with schizophrenia (SCZ). Previous studies demonstrated good psychometric properties of the CAI. However, only relatively small samples of SCZ were investigated. This study aimed to determine in a large sample of SCZ (N = 580) the relationships of the Italian Version of the CAI with measures of cognitive performance and functional capacity and real-life functioning, using state-of-the-art instruments. Methods: Intraclass correlation coefficients (ICCs) and Cronbach's alpha were calculated to examine the CAI's inter-rater reliability and internal consistency. Pearson's correlation coefficients were used to evaluate relationships between CAI global and domain composite scores with neurocognition, social cognition, functional capacity, and functioning. Results: The inter-rater reliability and internal consistency were good to excellent. The CAI global composite score showed a strong correlation with the MATRICS Consensus Cognitive Battery (MCCB) composite score (r = −0.50) and moderate/strong associations with measures of functional capacity (−0.46 < r < −0.52) and real-life functioning (−0.30 < r < −0.51). Finally, CAI composite social cognition score correlated moderately with the Facial Emotion Identification Test (r = −0.31) and two subscales of the Awareness of Social Inference Test (−0.32 < r < −0.34). Conclusions: The study suggests that CAI is a valid co-primary measure for clinical trials and a suitable instrument to screen impairment in neurocognitive and social cognitive domains and its impact on functioning in SCZ in everyday clinical practice.

© 2022 The Authors. Cell Proliferation published by Beijing Institute for Stem Cell and Regenerative Medicine and John Wiley & Sons Ltd.Objectives: Multilineage differentiating Stress Enduring (MUSE) cells are endogenous, stress-resistant stem cells, expressing pluripotency master genes and able to differentiate in cells of the three embryonic sheets. Stage-Specific Embryonic Antigen 3 (SSEA-3), a glycosphingolipid (GSL), is the marker for identifying MUSE cells and is used to isolate this population from mesenchymal stromal cells. GSLs modulate signal transduction by interacting with plasma membrane components. The growth factor FGF2, important for MUSE cells biology, may interact with GSLs. Specific cell surface markers represent an invaluable tool for stem cell isolation. Nonetheless their role, if any, in stem cell biology is poorly investigated. Functions of stem cells, however, depend on niche external cues, which reach cells through surface markers. We addressed the role of SSEA-3 in MUSE cell behaviour, trying to define whether SSEA-3 is just a marker or if it plays a functional role in this cell population by determining if it has any relationship with FGF2 activity. Results: We evidenced how the SSEA-3 and FGF2 cooperation affected the self-renewal and clonogenic capacity of MUSE cells. The block of SSEA-3 significantly reduced the multilineage potential of MUSE cells with production of nullipotent clones. Conclusions: We contributed to dissecting the mechanisms underlying MUSE cell properties for establishing successful stem-cell-based therapies and the promotion of MUSE cells as a tool for the in vitro disease model.

To evaluate whether short-term treatment with a selective 11β-Hydroxysteroid dehydrogenase-1 (11β-HSD1) inhibitor, AZD4017, would block hepatic cortisol production and thereby decrease hepatic fat in patients with nonalcoholic fatty liver disease (NAFLD)/nonalcoholic steatohepatitis (NASH), with or without type 2 diabetes (T2D).This was a randomized, double-blind, placebo-controlled, phase 2 study conducted at two sites. Key inclusion criteria were the presence of NAFLD or NASH on magnetic resonance imaging (MRI) or recent biopsy positive for NASH. Enrolled patients were randomly assigned (1:1) to AZD4017 or placebo for 12 weeks. Primary outcomes were between-group differences in mean change from baseline to week 12 in liver fat fraction (LFF) and conversion ofA total of 93 patients were randomized; 85 patients completed treatment. The mean (standard deviation [SD]) change in LFF was -0.667 (5.246) and 0.139 (4.323) in the AZD4017 and placebo groups (P = 0.441). For patients with NASH and T2D, the mean (SD) change in LFF was significantly improved in the AZD4017 versus the placebo group (-1.087 [5.374] vs. 1.675 [3.318]; P = 0.033). Conversion ofAlthough the study did not meet one of the primary outcomes, AZD4017 blocked the conversion of

Although adult stem cells may be useful for studying tissue-specific diseases, they cannot be used as a general model for investigating human illnesses given their limited differentiation potential. Multilineage-differentiating stress-enduring (Muse) stem cells, a SSEA3(+) cell population isolated from mesenchymal stromal cells, fat, and skin fibroblasts, may be able to overcome that restriction. The Muse cells present in fibroblast cultures obtained from biopsies of patients’ skin may be differentiated into cells of interest for analyzing diseases. We isolated Muse stem cells from patients with an intellectual disability (ID) and mutations in the IQSEC2 gene (i.e., BRAG1 gene) and induced in vitro neuroglial differentiation to study cell commitment and the differentiation of neural lineages. The neuroglial differentiation of Muse cells revealed that IQSEC2 mutations may alter the self-renewal and lineage specification of stem cells. We observed a decrease in the percentage of SOX2 (+) neural stem cells and neural progenitors (i.e., SOX2+ and NESTIN+) in cultures obtained from Muse cells with the mutated IQSEC2 gene. The alteration in the number of stem cells and progenitors produced a bias toward the astrocytes’ differentiation. Our research demonstrates that Muse stem cells may represent a new cell-based disease model.

The current study aimed to investigate alterations of event-related potentials (ERPs) microstate during reward anticipation in subjects with schizophrenia (SCZ), and their association with hedonic experience and negative symptoms. EEG data were recorded in thirty SCZ and twenty-three healthy controls (HC) during the monetary incentive delay task in which reward, loss and neutral cues were presented. Microstate analysis and standardized low-resolution electromagnetic tomography (sLORETA) were applied to EEG data. Furthermore, analyses correlating a topographic index (the ERPs score), calculated to quantify brain activation in relationship to the microstate maps, and scales assessing hedonic experience and negative symptoms were performed. Alterations in the first (125.0-187.5 ms) and second (261.7-414.1 ms) anticipatory cue-related microstate classes were observed. In SCZ, reward cues were associated to shorter duration and earlier offset of the first microstate class as compared to the neutral condition. In the second microstate class, the area under the curve was smaller for both reward and loss anticipation cues in SCZ as compared to HC. Furthermore, significant correlations between ERPs scores and the anticipation of pleasure scores were detected, while no significant association was found with negative symptoms. sLORETA analysis showed that hypo-activation of the cingulate cortex, insula, orbitofrontal and parietal cortex was detected in SCZ as compared to HC. Abnormalities in ERPs could be traced already during the early stages of reward processing and were associated with the anticipation of pleasure, suggesting that these dysfunctions might impair effective evaluation of incoming pleasant experiences. Negative symptoms and anhedonia are partially independent results.

Individuals with psychoses have brain alterations, particularly in frontal and temporal cortices, that may be particularly prominent, already at illness onset, in those more likely to have poorer symptom remission following treatment with the first antipsychotic. The identification of strong neuroanatomical markers of symptom remission could thus facilitate stratification and individualized treatment of patients with schizophrenia. We used magnetic resonance imaging at baseline to examine brain regional and network correlates of subsequent symptomatic remission in 167 medication-naïve or minimally treated patients with first-episode schizophrenia, schizophreniform disorder, or schizoaffective disorder entering a three-phase trial, at seven sites. Patients in remission at the end of each phase were randomized to treatment as usual, with or without an adjunctive psycho-social intervention for medication adherence. The final follow-up visit was at 74 weeks. A total of 108 patients (70%) were in remission at Week 4, 85 (55%) at Week 22, and 97 (63%) at Week 74. We found no baseline regional differences in volumes, cortical thickness, surface area, or local gyrification between patients who did or did not achieved remission at any time point. However, patients not in remission at Week 74, at baseline showed reduced structural connectivity across frontal, anterior cingulate, and insular cortices. A similar pattern was evident in patients not in remission at Week 4 and Week 22, although not significantly. Lack of symptom remission in first-episode psychosis is not associated with regional brain alterations at illness onset. Instead, when the illness becomes a stable entity, its association with the altered organization of cortical gyrification becomes more defined.

The current management of patients with primary psychosis worldwide is often remarkably stereotyped. In almost all cases an antipsychotic medica­tion 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 patient’s needs in terms of employment, housing, self-care, social relationships and education, and offers a focus on identity, meaning and resilience.

Introduction: Negative symptoms in schizophrenia are associated with poor response to available treatments, poor quality of life, and functional outcome. Therefore, they represent a substantial burden for people with schizophrenia, their families, and health-care systems. Areas covered: In this manuscript, we will provide an update on the conceptualization, assessment, and treatment of this complex psychopathological dimension of schizophrenia. Expert opinion: Despite the progress in the conceptualization of negative symptoms and in the development of state-of-the-art assessment instruments made in the last decades, these symptoms are still poorly recognized, and not always assessed in line with current conceptualization. Every effort should be made to disseminate the current knowledge on negative symptoms, on their assessment instruments and available treatments whose efficacy is supported by research evidence. Longitudinal studies should be promoted to evaluate the natural course of negative symptoms, improve our ability to identify the different sources of secondary negative symptoms, provide effective interventions, and target primary and persistent negative symptoms with innovative treatment strategies. Further research is needed to identify pathophysiological mechanisms of primary negative symptoms and foster the development of new treatments.

ImportanceThe Padova Chart for Health in Children (PCHC) aims to gather the evidence of healthcare promotion and protection for chidren and adolescents (i.e., aged ObservationsThe PCHC is divided into four sections: nutrition, cardiovascular health, respiratory health, and mental and social health. Each section is structured in an ALICE approach (assessment, lobbying, intervention, call-for-action, evaluation): assessment of necessity, describing relevance to healthcare; lobbying to identify those who can effect the proposed interventions; interventions involving family, school and peers; a call-for-action to define priorities among the proposed interventions; and objective evaluation measures that can be applied on a population basis.Conclusions and RelevanceInterventions promoting health in childhood require joint action from multiple institutional, local and family representatives, with the shared goal of promoting health across the entire age group. These lifestyle interventions have the potential to change the lifetime risk trajectory for NCDs.

Introduction. The current treatment and prevention of oral disorders, dental caries, periodontal and gum diseases, follow a very non-specific control of plaque as the main causative factor. The main therapeutically approach is carried out on the sole perspective to keep the levels of oral bacteria in an acceptable range compatible with one-way vision of oral-mouth health, as something completely separated from a systemic microbial homeostasis (dysbiosis) concomitant present in the gut. A sealed compartmental view which sees separate and incommunicable responses to a specific condition without considering the presence of interacting confounding factors can negatively influence the diagnosis a diseases and of course its progression. A general non-specific antimicrobial with more general antiplaque therapy based mainly on oral care products together with surgery interventions represent at the moment the only mechanical responses in treating oral diseases. Material and method. The present paper is a narrative review concening interractions between oral and gut microbiota, with a focus on the interdisciplinary approach in antimicrobial treatment. Pubmed, Cochrane Library database were used for searching engines. Key words used were as follows: “inflammatory bowel syndrome (IBS)”, “ulcerative colitis”, “oral dysbiosis”, “gut dysbiosis”, “probiotics”, “periodontitis”. Results and discussions. Literature research showed that there are few issues to be discussed the ever increasing resistance to antibiotics, the high consumption of industrial food and sugars and their negatively effect on gut and oral microbiota. There is a need to highlight and develop a novel philosophical approach in the treatments for oral diseases that will necessarily involve non-conventional antimicrobial solutions. Such approaches should preferably reduce the consumption of both intestinal and oral microbiota, that are intimately connected and host approximately well over 1000 different species of bacteria at 108–109 bacteria per mL of mucous and saliva. Preventive approaches based upon the restoration of the microbial ecological balance, rather than elimination of the disease associated species, have been proposed. Conclusions. Having both oral-gut microbiota screened is an essential moment that influence the healthy immune modulatory and regenerative capacity of the body and, the new proposed formula integrates a wider screen on the patients where oral condition is strictly evaluated together with gut screen; therefore any proposed treatment will be inevitably sustained by the use of prebiotics and probiotics to promote health-associated bacterial growth. Keywords: inflammatory bowel syndrome (IBS), ulcerative colitis, oral dysbiosis, gut dysbiosis, probiotics, periodontitis

Introduction. Burning mouth syndrome (BMS) is a clinical condition characterized by the presence of chronic pain in absence of clinically visible lesions of the oral mucosa. The etiology is uncertain and the therapeutic strategies still controversial. The objective of this prospective study is to analyze the efficacy of essential oils-based mouthwashes in the therapy of BMS. Material and method. This study included 16 patients affected by BMS who were treated with essential oils-based mouthwashes and glucose solution on alternated days for 30 days. Symptomatology was evaluated after 15, 30 and 90 days. Results and discussions. A the end of the treatment, most of the patients (67%) referred an improvement of symptoms up to complete remission in 90 days. Conclusions. Based on this study, essential oils-based mouthwashes could represent a valid aid in the treatment of BMS. Further studies are necessary in order to identify effective and standardized therapeutic protocols. Keywords: Burning Mouth Syndrome; oral rinse; essential oils; therapeutic strategies

Nearly half of all patients with heart failure (HF) have a normal left ventricular (LV) ejection fraction (EF) and the condition is termed heart failure with preserved ejection fraction (HFpEF). It is assumed that in these patients HF is due primarily to LV diastolic dysfunction. The prognosis in HFpEF is almost as severe as in HF with reduced EF (HFrEF). In contrast to HFrEF where drugs and devices are proven to reduce mortality, in HFpEF there has been limited therapy available with documented effects on prognosis. This may reflect that HFpEF encompasses a wide range of different pathological processes, which multimodality imaging is well placed to differentiate. Progress in developing therapies for HFpEF has been hampered by a lack of uniform diagnostic criteria. The present expert consensus document from the European Association of Cardiovascular Imaging (EACVI) provides recommendations regarding how to determine elevated LV filling pressure in the setting of suspected HFpEF and how to use multimodality imaging to determine specific aetiologies in patients with HFpEF.

International audience; Abstract Ki67 has potential clinical importance in breast cancer but has yet to see broad acceptance due to inter-laboratory variability. Here we tested an open source and calibrated automated digital image analysis (DIA) platform to: (i) investigate the comparability of Ki67 measurement across corresponding core biopsy and resection specimen cases, and (ii) assess section to section differences in Ki67 scoring. Two sets of 60 previously stained slides containing 30 core-cut biopsy and 30 corresponding resection specimens from 30 estrogen receptor-positive breast cancer patients were sent to 17 participating labs for automated assessment of average Ki67 expression. The blocks were centrally cut and immunohistochemically (IHC) stained for Ki67 (MIB-1 antibody). The QuPath platform was used to evaluate tumoral Ki67 expression. Calibration of the DIA method was performed as in published studies. A guideline for building an automated Ki67 scoring algorithm was sent to participating labs. Very high correlation and no systematic error ( p = 0.08) was found between consecutive Ki67 IHC sections. Ki67 scores were higher for core biopsy slides compared to paired whole sections from resections ( p ≤ 0.001; median difference: 5.31%). The systematic discrepancy between core biopsy and corresponding whole sections was likely due to pre-analytical factors (tissue handling, fixation). Therefore, Ki67 IHC should be tested on core biopsy samples to best reflect the biological status of the tumor.; v2.5, 25 March 2021.