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IntroductionThere is debate on which are the best surrogate endpoint and metric to capture treatment effect on overall survival (OS) in RCTs testing immune-checkpoint inhibitors (ICIs).MethodsWe systematically searched for RCTs testing ICIs in patients with advanced solid tumors. Inclusion criteria were: RCTs i) assessing PD-(L)1 and CTLA-4 inhibitors either as monotherapy or in combination with another ICI, and/or targeted therapy, and/or chemotherapy, in patients with advanced solid tumors; ii) randomizing at least 100 patients. We performed a meta-analysis of RCTs to compare the surrogacy value of PFS and modified-PFS (mPFS) for OS in RCTs testing ICIs, when the treatment effect is measured by the hazard ratio (HR) for OS, and by the HR and the ratio of restricted mean survival time (rRMST) for PFS and mPFS.Results61 RCTs (67 treatment comparisons and 36,034 patients) were included in the analysis. In comparisons testing ICI plus chemotherapy, HRPFS and HRmPFS both had a strong surrogacy value (R2 = 0.74 and R2 = 0.81, respectively). In comparisons testing ICI as monotherapy, HRPFS was the best surrogate, although having a moderate correlation (R2 = 0.58). In comparisons testing ICI plus other treatment(s), the associations were very weak for all the surrogate endpoints and treatment effect measures, with R2 ranging from 0.01 to 0.22.ConclusionIn RCTs testing ICIs, the value of potential surrogates for HROS was strongly affected by the type of treatment(s) tested. The evidence available supports HRPFS as the best surrogate, and disproves the use of alternative endpoints, such as the mPFS, or treatment effect measures, such as the RMST.

BackgroundWe performed a multicenter retrospective observational study to investigate the impact of clinical–pathological features and therapeutic strategies on both the complications and survival of patients with bone metastases (BMs) from malignant melanoma.Patients and MethodsA total of 305 patients with melanoma and radiological evidence of BMs were retrospectively enrolled from 19 Italian centers. All patients received conventional treatments in accordance with each own treating physician’s practice. Both univariate and multivariate models were used to explore the impact of melanoma features, including skeletal-related events (SREs), and different treatments on both overall survival (OS) and time-to-SREs. The chi-squared test evaluated the suitability of several parameters to predict the occurrence of SREs.ResultsEighty-three percent of patients had metachronous BMs. The prevalent (90%) bone metastatic site was the spine, while 45% had involvement of the appendicular skeleton. Forty-seven percent experienced at least one SRE, including palliative radiotherapy (RT) in 37% of cases. No melanoma-associated factor was predictive of the development of SREs, although patients receiving early treatment with bone-targeted agents showed 62% lower risk and delayed time of SRE occurrence. Median OS from the diagnosis of bone metastasis was 10.7 months. The multivariate analysis revealed as independent prognostic factors the number of BMs, number of metastatic organs, baseline lactate dehydrogenase levels, and treatment with targeted therapy or immunotherapy. Subgroup analyses showed the best OS (median = 16.5 months) in the subset of patients receiving both immunotherapy and palliative RT.ConclusionBased on our results, patients undergoing immunotherapy and palliative RT showed an OS benefit suggestive of a possible additive effect. The apparent protective role of bone targeting agent use on SREs observed in our analysis should deserve prospective evaluation.

There is considerable interest in developing drugs and probes targeted to mitochondria in order to understand and treat the many pathologies associated with mitochondrial dysfunction. The large membrane potential, negative inside, across the mitochondrial inner membrane enables delivery of molecules conjugated to lipophilic phosphonium cations to the organelle. Due to their combination of charge and hydrophobicity, quaternary triarylphosphonium cations rapidly cross biological membranes without the requirement for a carrier. Their extent of uptake is determined by the magnitude of the mitochondrial membrane potential, as described by the Nernst equation. To further enhance this uptake here we explored whether incorporation of a carboxylic acid into a quaternary triarylphosphonium cation would enhance its mitochondrial uptake in response to both the membrane potential and the mitochondrial pH gradient (alkaline inside). Accumulation of arylpropionic acid derivatives depended on both the membrane potential and the pH gradient. However, acetic or benzoic derivatives did not accumulate, due to their lowered pKa. Surprisingly, despite not being taken up by mitochondria, the phenylacetic or phenylbenzoic derivatives were not retained within mitochondria when generated within the mitochondrial matrix by hydrolysis of their cognate esters. Computational studies, supported by crystallography, showed that these molecules passed through the hydrophobic core of mitochondrial inner membrane as a neutral dimer. This finding extends our understanding of the mechanisms of membrane permeation of lipophilic cations and suggests future strategies to enhance drug and probe delivery to mitochondria.

IntroductionConducted under the auspices of the Italian Society of Consultation Liaison Psychiatry (SIPC) the aim of this study was to describe the characteristics of Consultation Liaison Psychiatry (CLP) activity in Italy (SIPC-2—2018) over the past 20 years by comparing with data from the first Italian nation-wide study (SIPC-1—1998).MethodsWe collected data on CLP visits of 3,943 patients from 10 Italian hospitals over a period of 1 year. Data were compared with those from the SIPC-1 1998 study (4,183 participants). Patients were assessed with the same ad hoc 60-item Patient Registration Form recording information from five different areas: Sociodemographic, hospitalization-related, consultation-related, interventions and outcome.ResultsCompared with participants from the previous study, SIPC-2-2018 participants were significantly older (d = 0.54) and hospitalized for a longer duration (d = 0.20). The current study detected an increase in the proportion of referrals from surgical wards and for individuals affected by onco-hematologic diseases. Depressive disorders still represented the most frequent psychiatric diagnosis, followed by adjustment and stress disorders and delirium/dementia. Also, CLP psychiatrists prescribed more often antidepressants (Φ = 0.13), antipsychotics (Φ = 0.09), mood stabilizers (Φ = 0.24), and less often benzodiazepines (Φ = 0.07).ConclusionCLP workload has increased considerably in the past 20 years in Italy, with changes in patient demographic and clinical characteristics. A trend toward increase in medication-based patient management was observed. These findings suggest that the psychiatric needs of patients admitted to the general hospital are more frequently addressed by referring physicians, although Italian CLP services still deserve better organization and autonomy.

IntroductionInsomnia is a stress-related sleep disorder, may favor a state of allostatic overload impairing brain neuroplasticity, stress immune and endocrine pathways, and may contribute to mental and physical disorders. In this framework, assessing and targeting insomnia is of importance.AimSince maladaptive neuroplasticity and allostatic overload are hypothesized to be related to GABAergic alterations, compounds targeting GABA may play a key role. Accordingly, the aim of this review was to discuss the effect of GABAA receptor agonists, short-medium acting hypnotic benzodiazepines and the so called Z-drugs, at a molecular level.MethodLiterature searches were done according to PRISMA guidelines. Several combinations of terms were used such as “hypnotic benzodiazepines” or “brotizolam,” or “lormetazepam” or “temazepam” or “triazolam” or “zolpidem” or “zopiclone” or “zaleplon” or “eszopiclone” and “insomnia” and “effects on sleep” and “effect on brain plasticity” and “effect on stress system”. Given the complexity and heterogeneity of existing literature, we ended up with a narrative review.ResultsAmong short-medium acting compounds, triazolam has been the most studied and may regulate the stress system at central and peripheral levels. Among Z-drugs eszopiclone may regulate the stress system. Some compounds may produce more “physiological” sleep such as brotizolam, triazolam, and eszopiclone and probably may not impair sleep processes and related neural plasticity. In particular, triazolam, eszopiclone, and zaleplon studied in vivo in animal models did not alter neuroplasticity.ConclusionCurrent models of insomnia may lead us to revise the way in which we use hypnotic compounds in clinical practice. Specifically, compounds should target sleep processes, the stress system, and sustain neural plasticity. In this framework, among the short/medium acting hypnotic benzodiazepines, triazolam has been the most studied compound while among the Z-drugs eszopiclone has demonstrated interesting effects. Both offer potential new insight for treating insomnia.

Background: Several data suggest that coronavirus disease 2019 (COVID-19) pandemic may exacerbate or trigger eating disorders (EDs). The aim of this paper was to summarize current literature studies on COVID pandemic and EDs.Methods: Literature search, study selection, methods, and quality evaluation were performed according to the preferred reporting items for systematic review and meta-analyses (PRISMA) guidelines.Results: A systematic search allowed the initial selection of 172 papers; 21 (12.2%) papers were eligible and included in the review. In selected studies, a total number of 29,108 subjects were enrolled (range: 10–11,391; mean/SD: 1,386 ± 2,800), 6,216 were men (21.4%), 22,703 were women (77.9%), and 189 (0.7%) were gender fluid or not declared. The mean age/SD of subjects was 30.2 ± 7.7. About 12 studies (57.1%) were online surveys, 4 (19.0%) were retrospective studies, 2 (9.5%) were qualitative studies, 2 (9.5%) were longitudinal cohort studies, and 1 was a social media survey (4.8%). Their analysis revealed five main findings: (1) changes in the routines of physical activities were related to the worsening of preoccupation on weight/body shape; (2) food access limitation during pandemic represented the risk factors for both triggering and exacerbating EDs; (3) restriction in healthcare facilities contributed to increase anxiety levels and to modify treatment compliance; (4) social isolation was related to the exacerbation of symptoms in patients with EDs who are home-confined with family members; and (5) conflicts and difficulties in relationships with “no way out” were the maintenance factors for ED symptoms, especially in adolescents and young adults.Conclusion: The COVID-19 pandemic had a negative impact on EDs that might be triggered by the exceptional conditions derived from COVID-19-related stress in predisposed subjects. Patients who were already affected by EDs experienced the worsening of their clinical conditions and related quality of life (QoL).

Artificial Intelligence (AI) has the potential to greatly improve the delivery of healthcare and other services that advance population health and wellbeing. However, the use of AI in healthcare also brings potential risks that may cause unintended harm. To guide future developments in AI, the High-Level Expert Group on AI set up by the European Commission (EC), recently published ethics guidelines for what it terms “trustworthy” AI. These guidelines are aimed at a variety of stakeholders, especially guiding practitioners toward more ethical and more robust applications of AI. In line with efforts of the EC, AI ethics scholarship focuses increasingly on converting abstract principles into actionable recommendations. However, the interpretation, relevance, and implementation of trustworthy AI depend on the domain and the context in which the AI system is used. The main contribution of this paper is to demonstrate how to use the general AI HLEG trustworthy AI guidelines in practice in the healthcare domain. To this end, we present a best practice of assessing the use of machine learning as a supportive tool to recognize cardiac arrest in emergency calls. The AI system under assessment is currently in use in the city of Copenhagen in Denmark. The assessment is accomplished by an independent team composed of philosophers, policy makers, social scientists, technical, legal, and medical experts. By leveraging an interdisciplinary team, we aim to expose the complex trade-offs and the necessity for such thorough human review when tackling socio-technical applications of AI in healthcare. For the assessment, we use a process to assess trustworthy AI, called 1Z-Inspection® to identify specific challenges and potential ethical trade-offs when we consider AI in practice.

Introduction: Insomnia and circadian rhythm disorders, such as the delayed sleep phase syndrome, are frequent in psychiatric disorders and their evaluation and management in early stages should be a priority. The aim of this paper was to express recommendations on the use of exogenous melatonin, which exhibits both chronobiotic and sleep-promoting actions, for the treatment of these sleep disturbances in psychiatric disorders.Methods: To this aim, we conducted a systematic review according to PRISMA on the use of melatonin for the treatment of insomnia and circadian sleep disorders in neuropsychiatry. We expressed recommendations for the use of melatonin in psychiatric clinical practice for each disorder using the RAND/UCLA appropriateness method.Results: We selected 41 studies, which included mood disorders, schizophrenia, substance use disorders, attention deficit hyperactivity disorders, autism spectrum disorders, neurocognitive disorders, and delirium; no studies were found for both anxiety and eating disorders.Conclusion: The administration of prolonged release melatonin at 2–10 mg, 1–2 h before bedtime, might be used in the treatment of insomnia symptoms or comorbid insomnia in mood disorders, schizophrenia, in adults with autism spectrum disorders, neurocognitive disorders and during sedative-hypnotics discontinuation. Immediate release melatonin at

BackgroundCoronavirus disease 2019 (COVID-19) seriously affected the whole of Italy. The extreme virulence and the speed of propagation resulted in restrictions and home confinement. This change was immediately perceived by people who found themselves exposed to feelings of uncertainty, fear, anger, stress, and a drastic change in the diurnal but above all nocturnal lifestyle. For these reasons, we aimed to study the quality of sleep and its connection to distress levels and to evaluate how lifestyle changed in the Italian population during the lockdown.MethodsBy means of an Internet survey we recruited 6,519 adults during the whole of the COVID-19 lockdown (from March 10–1st phase to May 4–2nd phase). We investigated the sociodemographic and COVID-19-related information and assessed sleep quality using the Medical Outcomes Study–sleep scale (MOS-SS) and mental health with the short form of Depression, Anxiety, and Stress Scales–21 Items (DASS-21). Multiple logistic regression model was used to evaluate the multivariate association between the dependent variable (good sleeper vs. poor sleeper) and all the variables that were significant in the univariate analysis.ResultsA total of 3,562 (55.32%) participants reported poor sleep quality according to the MOS-Sleep Index II score. The multiple binary logistic regression results of poor sleepers revealed several risk factors during the outbreak restrictions: female gender, living in Central Italy, having someone close who died because of COVID-19, markedly changed sleep–wake rhythms characterized by earlier or postponed habitual bedtime, earlier habitual awakening time and reduced number of afternoon naps, and extremely severe levels of stress, anxiety, and depression.ConclusionThis is the first study designed to understand sleep quality and sleep habits during the whole of the lockdown period in the Italian population that provides more than 6,000 participants in a survey developed specifically for the health emergency related to COVID-19. Our study found that more than half of the Italian population had impaired sleep quality and sleep habits due to elevated psychological distress during the COVID-19 lockdown containment measures. A multidisciplinary action should be undertaken in order to plan appropriate responses to the current crisis caused by the lockdown for the COVID-19 outbreak.

Subsets of non-acute promyelocytic leukemia (APL) acute myelogenous leukemia (AML) exhibit aberrant retinoid signaling and demonstrate sensitivity to retinoids in vitro. We present the results of a phase 1 dose-escalation study that evaluated the safety, pharmacodynamics, and efficacy of IRX195183, a novel retinoic acid receptor α agonist, in patients with relapsed or refractory myelodysplastic syndrome (MDS) or AML. In this single center, single arm study, eleven patients with relapsed or refractory MDS/AML were enrolled and treated. Oral IRX195183 was administered at two dose levels: 50 mg daily or 75 mg daily for a total of two 28-day cycles. Patients with stable disease or better were allowed to continue on the drug for four additional 28-day cycles. Common adverse events included hypertriglyceridemia, fatigue, dyspnea, and edema. Three patients at the first dose level developed asymptomatic Grade 3 hypertriglyceridemia. The maximally tolerated dose was not reached. Four of the eleven patients had (36%) stable disease or better. One had a morphological complete remission with incomplete hematologic recovery while on the study drug. Two patients had evidence of in vivo leukemic blast maturation, as reflected by increased CD38 expression. In a pharmacodynamics study, plasma samples from four patients treated at the lowest dose level demonstrated the capacity to differentiate leukemic cells from the NB4 cell line in vitro. These results suggest that IRX195183 is safe, achieves biologically meaningful plasma concentrations and may be efficacious in a subset of patients with MDS/AML. Clinical Trial Registration:clinicaltrials.gov, identifier NCT02749708.

BackgroundInsomnia is the most commonly reported sleep problem in industrialized countries worldwide being present in about 36.8% of the general population. In Italy, such a percentage seems to be even higher. Although insomnia can be an independent disorder, it is most frequently observed as a comorbid condition and may precipitate, exacerbate, or prolong a broad range of comorbid conditions including physical and mental illnesses. Evaluating and targeting insomnia in the Italian clinical practice should be a priority.MethodsThe present expert options and recommendations development process was based on the RAND/UCLA Appropriateness Method for conceptualizing, designing, and carrying out the appropriateness of procedures for the diagnosis and treatment. Only available options in Italy were taken into considerations.ResultsWe evaluated 12 international guidelines and 12 most recent systematic reviews for insomnia evaluation and treatment produced in the last 10 years.ConclusionsOur findings suggested that symptoms of insomnia must always be assessed in the Italian clinical practice by evaluating nocturnal and daytime symptoms, comorbid conditions and lifestyle. In a patient with chronic insomnia with and without comorbidity, insomnia treatment should be always initiated. CBT-Insomnia therapy should be the first option accordingly to availability. The choice of the drug should be based on different factors such as type of insomnia, age, comorbidities, and potential side effects. Melatonin 2 mg prolonged release should be the first choice in subjects >55 years. If the choice would be a Z-drug or a short-acting benzodiazepine (in subjects

The Mediterranean Basin is frequently affected by desert dust outbreaks coming from the north of Africa. The presence of this type of particulate matter (PM) joint to others (in particular, anthropogenic pollution from the intense human activities) makes the air quality over this region a worrying issue. In this sense, an accurate characterization of the dust transport is essential. This study tries to shed some light on the sensitivity of dust modeling to the spatial resolution by using the online integrated meteorological-chemical model (WRF-Chem). Three simulations only differing on spatial resolution (D1 at 1.32°, D2 at 0.44° and D3 at 0.11°), during a representative omega-blocking situation over Europe causing Saharan dust transport over the Mediterranean and central Europe were evaluated against MODIS and AERONET. This evaluation revealed an improvement in the model AOD representation when resolution becomes finer, specially over the Saharan desert dust affected area. These discrepancies between resolutions could be attributed to changes both in thermodynamics and dynamics, since AOD is sensitive to aerosol mass, size distribution and water uptake. Relative humidity (RH) and PM-ratio (PM2.5/PM10) present non-local differences due to the increase of the resolution as a consequence of changes in the long-range transport spatial pattern. Henceforth, the comparison of wind speed and direction, geopotencial height and sea level pressure (SLP) against ERA5 data shows a better representation of the dynamical patterns when decreasing spatial resolution.

Background: A compelling number of studies, conducted in both children and adults, have reported an association between sleep disturbances/circadian sleep alterations and autism spectrum disorder (ASD); however, the data are sparse and the nature of this link is still unclear. The present review aimed to systematically collect the literature data relevant on sleep disturbances and circadian sleep dysrhythmicity related to ASD across all ages and to provide an integrative theoretical framework of their association.Methods: A systematic review of the MEDLINE, PubMed, and Cochrane databases was conducted from November 2018 to February 2019. The search strategies used were MeSH headings and keywords for “sleep–wake circadian rhythms” OR “circadian sleep disorders” OR “sleep–wake pattern” OR “sleep disorders” OR “melatonin” AND “autism spectrum disorder” OR “autism”.Results: One hundred and three studies were identified, 15 regarded circadian sleep dysrhythmicity, 74 regarded sleep disturbances, and 17 regarded melatonin alterations in children and adults with ASD. Our findings suggested that autistic subjects frequently present sleep disturbances in particular short sleep duration, low sleep quality/efficiency, and circadian sleep desynchronization such as delayed phases and/or eveningness. Sleep disturbances and circadian sleep alterations have been related to the severity of autistic symptoms. Genetic studies have shown polymorphisms in circadian CLOCK genes and in genes involved in melatonin pathways in subjects with ASD.Conclusions: Sleep disturbances and circadian sleep alterations are frequent in subjects with autistic symptoms. These subjects have shown polymorphisms in clock genes expression and in genes involved in melatonin production. The impairment of circadian sleep regulation may increase the individual’s vulnerability to develop symptoms of ASD by altering the sleep regulation in toto, which plays a key role in normal brain development. Even though controversies and “research gaps” are present in literature at this point, we may hypothesize a bidirectional relation between circadian sleep dysfunction and ASD. In particular, circadian sleep dysrhythmicity may predispose to develop ASD symptoms and vice versa within a self-reinforcing feedback loop. By targeting sleep disturbances and circadian sleep dysrhythmicity, we may improve treatment strategies for both children and adults with ASD.

The main goal of this study was to delve deeper into the relationship between transformational leadership and better general health status among employees. Based on the Job Demands-Resources model of occupational well-being, the current research investigated the role of transformational leadership, as a job resource, in fostering individual hardiness, as a personal resource, which may in turn result in higher levels of work engagement and, consequently, better general health status among employees. Data were collected from 358 white-collar employees in an Italian company. Most of them were women (52.9%) with a mean age of 44.42 years (SD = 9.22). To evaluate the hypothesis of a mediating role of employees’ hardiness and work engagement within the relationship between transformational leadership and workers’ general health, a bootstrapping approach was tested using a serial mediation model. In the current sample, enhanced levels of hardiness and work engagement among employees mediated the association between perceived levels of transformational leadership and individual general health conditions. These findings corroborated the role of transformational leadership as a strategic job resource in enhancing employees’ hardiness and engagement with their work, which may in turn protect their general health status. Organizations willing to rely on a healthy workforce should implement human resource management strategies focused on leadership training capable of boosting employees’ hardiness.