Search

Background: Sleep is a complex phenomenon that affects several aspects of life, including cognitive functioning, emotional regulation, and overall well-being. Sleep disturbances, especially during adolescence, can negatively impact emotional regulation, making it a critical factor in targeting psychopathology., Methods: This study explores the interplay between emotional dysregulation (ED) and sleep patterns in a sample of 90 adolescent patients by means of self- and parent-rated clinical measures., Results: Our findings reveal a bidirectional relationship between ED and sleep problems. Adolescents with higher affective instability experience poorer sleep quality, while those with worse sleep quality exhibit higher internalizing problems. Additionally, emotional reactivity is associated with disrupted circadian rhythms., Conclusions: These results emphasize the significance of addressing sleep problems in the context of psychopathology treatment, potentially leading to improved outcomes. Further research is needed to determine the most effective treatment strategies, including nonpharmacological and pharmacological interventions. Understanding the intricate relationship between sleep problems and emotion regulation offers insights for more targeted and effective treatment approaches for youths struggling with ED.

Several genes are implicated in spermatogenesis and fertility regulation, and these genes are presently being analysed in clinical practice due to their involvement in male factor infertility (MFI). However, there are still few genetic analyses that are currently recommended for use in clinical practice. In this manuscript, we reviewed the genetic causes of qualitative sperm defects. We distinguished between alterations causing reduced sperm motility (asthenozoospermia) and alterations causing changes in the typical morphology of sperm (teratozoospermia). In detail, the genetic causes of reduced sperm motility may be found in the alteration of genes associated with sperm mitochondrial DNA, mitochondrial proteins, ion transport and channels, and flagellar proteins. On the other hand, the genetic causes of changes in typical sperm morphology are related to conditions with a strong genetic basis, such as macrozoospermia, globozoospermia, and acephalic spermatozoa syndrome. We tried to distinguish alterations approved for routine clinical application from those still unsupported by adequate clinical studies. The most important aspect of the study was related to the correct identification of subjects to be tested and the correct application of genetic tests based on clear clinical data. The correct application of available genetic tests in a scenario where reduced sperm motility and changes in sperm morphology have been observed enables the delivery of a defined diagnosis and plays an important role in clinical decision-making. Finally, clarifying the genetic causes of MFI might, in future, contribute to reducing the proportion of so-called idiopathic MFI, which might indeed be defined as a subtype of MFI whose cause has not yet been revealed.

Attention deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) have been related to an increased risk for behavioral addictions including online gaming. However, the relationship between these two conditions and Internet gaming disorder (IGD) is still debated. The aim of this study is to address this topic by exploring the prevalence of IGD in a consecutive sample of ASD youth and ADHD youth, compared with a normal control group, and by assessing selected psychopathological and neuropsychological features in ASD and ADHD patients with and without IGD. This study included 77 ASD patients (67 males, mean age 13.58 ± 2.75 years), 94 ADHD patients (79 males, mean age 11.46 ± 2.47 years), and 147 normal controls (NC) (mean age 13.9 ± 3.0 years, 114 males) that received structured measures for IGD (IAT, IGDS9-SF, and UADI). In the ADHD group, 72.34% of the sample were above the IGD cut-off, compared with 45.45% in the ASD group and 9.5% in the NC group. ASD patients with IGD presented with greater severity and more severe attention problems, with no difference in the ASD core symptoms between patients with and without IGD. In the comparison between the ASD and ADHD groups according to the presence of IGD, ASD patients with IGD were the most severe group according to the CGI (Clinical Global Impression) scale. The follow-up, conducted on 45 patients affected by ASD, showed an improvement in CGI and CGAS (Children's Global Assessment Scale) scores, but not in the IGD symptoms. These findings could place the diagnosis of ASD as a negative prognostic factor in the follow-up of aspects of video game addiction compared with ADHD.

Background: The decision to resect or not the primary tumor in asymptomatic patients with synchronous metastatic colorectal cancer (mCRC) is a complex and challenging issue for oncologists, especially when an antiangiogenic-based therapy is planned., Methods: Patients enrolled in the phase III TRIBE and TRIBE2 studies that compared upfront FOLFOXIRI + bevacizumab to FOLFIRI or FOLFOX + bevacizumab, respectively, were included. We assessed the association of primary tumor resection (PTR) with progression-free survival (PFS), overall survival (OS), response rate (ORR), rate of grade > 2 adverse events (AEs), and serious gastrointestinal and surgical AEs in the overall population and according to the treatment arm., Results: Of the 999 patients included, 513 (51%) underwent PTR at baseline. Longer PFS and OS were observed in resected patients compared to those with unresected primary tumors: 11.2 vs. 10.0 months ( p < 0.001) and 26.6 vs. 22.5 ( p < 0.001), respectively. In multivariate models, PTR was confirmed as an independent prognostic factor for better PFS ( p = 0.032) and OS ( p = 0.018). Patients with PTR experienced a higher incidence of grade 3 or 4 diarrhea ( p = 0.055) and lower incidence of anemia ( p = 0.053), perforation ( p = 0.015), and serious gastrointestinal and surgical AEs ( p < 0.001). No statistically significant differences were noted in incidence of bleeding ( p = 0.39). The benefit of FOLFOXIRI + bevacizumab in terms of PFS ( p for interaction: 0.46), OS ( p for interaction: 0.80), ORR ( p for interaction: 0.36), and incidence of grade 3 or 4 AEs was independent of PTR., Conclusions: PTR at baseline was independently associated with good prognosis in synchronous mCRC patients and with lower incidence of serious gastrointestinal and surgical AEs during upfront chemotherapy plus bevacizumab. The benefit and toxicity profile of FOLFOXIRI plus bevacizumab was independent of PTR.

Prognosis in advanced gastric cancer (aGC) is predicted by clinical factors, such as stage, performance status, metastasis location, and the neutrophil-to-lymphocyte ratio. However, the role of body composition and sarcopenia in aGC survival remains debated. This study aimed to evaluate how abdominal visceral and subcutaneous fat volumes, psoas muscle volume, and the visceral-to-subcutaneous (VF/SF) volume ratio impact overall survival (OS) and progression-free survival (PFS) in aGC patients receiving first-line palliative chemotherapy. We retrospectively examined CT scans of 65 aGC patients, quantifying body composition parameters (BCPs) in 2D and 3D. Normalized 3D BCP volumes were determined, and the VF/SF ratio was computed. Survival outcomes were analyzed using the Cox Proportional Hazard model between the upper and lower halves of the distribution. Additionally, response to first-line chemotherapy was compared using the χ 2 test. Patients with a higher VF/SF ratio ( N = 33) exhibited significantly poorer OS ( p = 0.02) and PFS ( p < 0.005) and had a less favorable response to first-line chemotherapy ( p = 0.033), with a lower Disease Control Rate ( p = 0.016). Notably, absolute BCP measures and sarcopenia did not predict survival. In conclusion, radiologically assessed VF/SF volume ratio emerged as a robust and independent predictor of both survival and treatment response in aGC patients.

Background . R0 minor parenchyma-sparing hepatectomy (PSH) is feasible for colorectal liver metastases (CRLM) in contact with hepatic veins (HV) at hepatocaval confluence since HV can be reconstructed, but in the case of contact with the first-order glissonean pedicle (GP), major hepatectomy is mandatory. To pursue an R0 parenchyma-sparing policy, we proposed vessel-guided mesohepatectomy for liver partition (MLP) and eventually combination with liver augmentation techniques for staged major PSH. Methods . We analyzed 15 consecutive vessel-guided MLPs for CRLM at the hepatocaval confluence. Patients had a median of 11 (range: 0-67) lesions with a median diameter of 3.5 cm (range: 0.0-8.0), bilateral in 73% of cases. Results . Grade IIIb or more complications occurred in 13%, median hospital stay was 14 (range: 6-62) days, 90-day mortality was 0%. After a median follow-up of 17.5 months, 1-year OS and RFS were 92% and 62%. In nine (64%) patients, MLP was combined with portal vein embolization (PVE) or ALPPS to perform staged R0 major PSH. Future liver remnant (FLR) volume increased from a median of 15% (range: 7-20%) up to 41% (range: 37-69%). Super-selective PVE was performed in three (33%) patients and enhanced ALPPS (e-ALPPS) in six (66%). In two e-ALPPS an intermediate stage of deportalized liver PSH was necessary to achieve adequate FLR volume. Conclusions . Vessel-guided MLP may transform the liver in a paired organ. In selected cases of multiple bilobar CRLM, to guarantee oncological radicality (R0), major PSH is feasible combining advanced surgical parenchyma sparing with liver augmentation techniques when FLR volume is insufficient.

Non-suicidal self-injury (NSSI) is deliberate harm to the body surface without suicidal intent, though it may be a predictor of suicide attempts. Our aim was to test the hypothesis that persisting and recovering NSSI may have a different longitudinal risk for suicidal ideation and behavior and that the intensity of Cyclothymic Hypersensitive Temperament (CHT) may increase this risk. Fifty-five patients (mean age 14.64 ± 1.77 years) referred for mood disorders according to the DSM-5 were consecutively recruited and followed-up for a mean of 19.79 ± 11.67 months and grouped according to the presence/absence of NSSI at baseline and follow-up into three groups: without NSSI (non-NSSI; n = 22), with NSSI recovered at follow-up (past-NSSI; n = 19), and with persistent NSSI at follow-up (pers-NSSI; n = 14). At follow-up, both NSSI groups were more severely impaired and failed to improve internalizing problems and dysregulation symptoms. Both NSSI groups reported higher scores in suicidal ideation compared to non-NSSI, but only pers-NSSI presented higher scores in suicidal behavior. CHT was higher in pers-NSSI, followed by past-NSSI and then by non-NSSI. Our data support a continuity between NSSI and suicidality, and they suggest the prognostic validity of persistent NSSI, associated with highest CHT scores.

Providing energy from fusion and finding ways to scale up the fusion process to commercial proportions in an efficient, economical, and environmentally benign way is one of the grand challenges for engineering. Controlling the burning plasma in real-time is one of the critical issues that need to be addressed. Plasma Position Reflectometry (PPR) is expected to have an important role in next-generation fusion machines, such as DEMO, as a diagnostic to monitor the position and shape of the plasma continuously, complementing magnetic diagnostics. The reflectometry diagnostic uses radar science methods in the microwave and millimetre wave frequency ranges and is envisaged to measure the radial edge density profile at several poloidal angles providing data for the feedback control of the plasma position and shape. While significant steps have already been given to accomplish that goal, with proof of concept tested first in ASDEX-Upgrade and afterward in COMPASS, important, ground-breaking work is still ongoing. The Divertor Test Tokamak (DTT) facility presents itself as the appropriate future fusion device to implement, develop, and test a PPR system, thus contributing to building a knowledge database in plasma position reflectometry required for its application in DEMO. At DEMO, the PPR diagnostic's in-vessel antennas and waveguides, as well as the magnetic diagnostics, may be exposed to neutron irradiation fluences 5 to 50 times greater than those experienced by ITER. In the event of failure of either the magnetic or microwave diagnostics, the equilibrium control of the DEMO plasma may be jeopardized. It is, therefore, imperative to ensure that these systems are designed in such a way that they can be replaced if necessary. To perform reflectometry measurements at the 16 envisaged poloidal locations in DEMO, plasma-facing antennas and waveguides are needed to route the microwaves between the plasma through the DEMO upper ports (UPs) to the diagnostic hall. The main integration approach for this diagnostic is to incorporate these groups of antennas and waveguides into a diagnostics slim cassette (DSC), which is a dedicated complete poloidal segment specifically designed to be integrated with the water-cooled lithium lead (WCLL) breeding blanket system. This contribution presents the multiple engineering and physics challenges addressed while designing reflectometry diagnostics using radio science techniques. Namely, short-range dedicated radars for plasma position and shape control in future fusion experiments, the advances enabled by the designs for ITER and DEMO, and the future perspectives. One key development is in electronics, aiming at an advanced compact coherent fast frequency sweeping RF back-end [23-100 GHz in few μs] that is being developed at IPFN-IST using commercial Monolithic Microwave Integrated Circuits (MMIC). The compactness of this back-end design is crucial for the successful integration of many measurement channels in the reduced space available in future fusion machines. Prototype tests of these devices are foreseen to be performed in current nuclear fusion machines.

We aimed to evaluate the outcome of the disappearance or small remnants of colorectal liver metastases during first-line chemotherapy assessed by hepatobiliary contrast-enhanced and diffusion-weighted MR imaging (DW-MRI). Consecutive patients with at least one disappearing liver metastasis (DLM) or small residual liver metastases (≤10 mm) assessed by hepatobiliary contrast-enhanced and DW-MRI during first-line chemotherapy were included. Liver lesions were categorized into three groups: DLM; residual tiny liver metastases (RTLM) when ≤5 mm; small residual liver metastases (SRLM) when >5mm and ≤10 mm. The outcome of resected liver metastases was assessed in terms of pathological response, whereas lesions left in situ were evaluated in terms of local relapse or progression. Fifty-two outpatients with 265 liver lesions were radiologically reviewed; 185 metastases fulfilled the inclusion criteria: 40 DLM, 82 RTLM and 60 SRLM. We observed a pCR rate of 75% (3/4) in resected DLM and 33% (12/36) of local relapse for DLM left in situ. We observed a risk of relapse of 29% and 57% for RTLM and SRLM left in situ, respectively, and a pCR rate of about 40% overall for resected lesions. DLM assessed via hepatobiliary contrast-enhanced and DW-MRI very probably indicates a complete response. The surgical removal of small remnants of liver metastases should always be advocated whenever technically possible.

In aviation, any detail can have massive consequences. Among the potential sources of failure, human error is still the most troublesome to handle. Therefore, research concerning the management of mental workload, attention, and stress is of special interest in aviation. Recognizing conditions in which a pilot is over-challenged or cannot act lucidly could avoid serious outcomes. Furthermore, knowing in depth a pilot's neurophysiological and cognitive-behavioral responses could allow for the optimization of equipment and procedures to minimize risk and increase safety. In addition, it could translate into a general enhancement of both the physical and mental well-being of pilots, producing a healthier and more ergonomic work environment. This review brings together literature on the study of stress and workload in the specific case of pilots of both civil and military aircraft. The most common approaches for studying these phenomena in the avionic context are explored in this review, with a focus on objective methodologies (e.g., the collection and analysis of neurophysiological signals). This review aims to identify the pros, cons, and applicability of the various approaches, to enable the design of an optimal protocol for a comprehensive study of these issues.

The management of the primary tumor in metastatic colorectal, gastric and pancreatic cancer patients may be challenging. Indeed, primary tumor progression could be associated with severe symptoms, compromising the quality of life and the feasibility of effective systemic therapy, and might result in life-threatening complications. While retrospective series have suggested that surgery on the primary tumor may confer a survival advantage even in asymptomatic patients, randomized trials seem not to definitively support this hypothesis. We discuss the evidence for and against primary tumor resection for patients with metastatic gastrointestinal (colorectal, gastric and pancreatic) cancers treated with systemic therapies and put in context the pros and cons of the onco-surgical approach in the time of precision oncology. We also evaluate current ongoing trials on this topic, anticipating how these will influence both research and everyday practice.

Background: Whether the etiology of underlying liver disease represents a prognostic factor in patients with hepatocellular carcinoma (HCC) treated with lenvatinib is still a matter of debate. This study investigates whether the viral etiology of HCC plays a prognostic role in overall survival (OS). Methods: Data derived from a multicenter series of 313 HCC patients treated with lenvatinib between 2019 and 2022 were analyzed. Actuarial survival estimates were computed using the Kaplan−Meier method and compared with the log-rank test. We performed an event-based counterfactual mediation analysis to estimate direct (chronic inflammation and immunosuppression), indirect (tobacco smoking, alcohol use, illicit drug abuse with injections), and the total effect of viral etiology on OS. Results were expressed as hazard ratio (HR) and 95% CI. Results: Median OS was 21 months (95% CI: 20−23) in the group with other etiologies and 15 months (14−16) in the group with viral etiology (p < 0.0001). The total effect of viral etiology was associated with OS (HR 2.76, 1.32−5.21), and it was mainly explained by the pure direct effect of viral etiology (HR 2.74, 1.15−4.45). By contrast, its total indirect effect was not associated with poorer survival (HR 1.05, 0.82−2.13). These results were confirmed when considering tobacco, alcohol consumption, or injection drug abuse as potential mediators. Median progression-free survival was 9 months (8−10) in patients with other etiologies and 6 months (5−7) in patients with viral etiology (p < 0.0001). No difference in terms of adverse event rate was observed between the two groups. Conclusions: Patients affected by HCC with nonviral etiology treated with lenvatinib exhibit longer survival than those with viral etiology. This finding may have relevance in the treatment decision-making process.

Multiple studies support the relationship between ADHD and overweight/obesity in youth. Different mechanisms may be involved, such as temperamental and psychopathological factors. The aim of this study was to test the hypothesis that specific temperamental and psychopathological dimensions could mediate the relationship between ADHD and obesity. The sample included 100 children and adolescents (78 males and 22 females; age range 6 to 18 years; mean age 9.90 ± 2.5 years). The assessment procedure included Conners' Parent Rating Scale-Long (CPRS-R:L) as the inclusion criterion for ADHD diagnosis, the Child Behavior Checklist (CBCL), a dimensional measure for psychopathology, and the Junior Temperament and Character Inventory, which describes four temperamental dimensions: novelty seeking (NS), harm avoidance (HA), reward dependence (RD), and persistence (P). While in the whole ADHD sample, the highest scores were found in NS and the lowest in P, ADHD with overweight/obesity, compared to ADHD with normal weight, showed higher HA and RD, lower NS, and higher CBCL Internalizing scores. These findings suggest that ADHD youth with overweight/obesity present specific temperamental and psychopathological features compared to those without overweight/obesity. If confirmed in larger samples, using a control group without ADHD, these temperamental and psychological features may be helpful for an earlier recognition of ADHD patients at higher risk for obesity, and may represent possible targets for temperament-based preventive interventions and tailored treatment programs. These features should be included in the routine assessment of children and adolescents with ADHD and/or are overweight/obese.

Systemic inflammation is a key risk factor for hepatocellular carcinoma (HCC) progression and poor outcomes. Inflammatory markers such as the neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) may have prognostic value in HCC treated with standard of care atezolizumab plus bevacizumab (Atezo-Bev). We conducted a multicenter, international retrospective cohort study of patients with unresectable HCC treated with Atezo-Bev to assess the association of NLR and PLR with overall survival (OS), progression-free survival (PFS), and objective response rates. Patients with NLR ≥ 5 had a significantly shorter OS (9.38 vs. 16.79 months, p < 0.001) and PFS (4.90 vs. 7.58 months, p = 0.03) compared to patients with NLR < 5. NLR ≥ 5 was an independent prognosticator of worse OS (HR 2.01, 95% CI 1.22−3.56, p = 0.007) but not PFS. PLR ≥ 300 was also significantly associated with decreased OS (9.38 vs. 15.72 months, p = 0.007) and PFS (3.45 vs. 7.11 months, p = 0.04) compared to PLR < 300, but it was not an independent prognosticator of OS or PFS. NLR and PLR were not associated with objective response or disease control rates. NLR ≥ 5 independently prognosticated worse survival outcomes and is worthy of further study and validation.

Motor impairments are among the most relevant, evident, and disabling symptoms of Parkinson’s disease that adversely affect quality of life, resulting in limited autonomy, independence, and safety. Recent studies have demonstrated the benefits of physiotherapy and rehabilitation programs specifically targeted to the needs of Parkinsonian patients in supporting drug treatments and improving motor control and coordination. However, due to the expected increase in patients in the coming years, traditional rehabilitation pathways in healthcare facilities could become unsustainable. Consequently, new strategies are needed, in which technologies play a key role in enabling more frequent, comprehensive, and out-of-hospital follow-up. The paper proposes a vision-based solution using the new Azure Kinect DK sensor to implement an integrated approach for remote assessment, monitoring, and rehabilitation of Parkinsonian patients, exploiting non-invasive 3D tracking of body movements to objectively and automatically characterize both standard evaluative motor tasks and virtual exergames. An experimental test involving 20 parkinsonian subjects and 15 healthy controls was organized. Preliminary results show the system’s ability to quantify specific and statistically significant (p < 0.05) features of motor performance, easily monitor changes as the disease progresses over time, and at the same time permit the use of exergames in virtual reality both for training and as a support for motor condition assessment (for example, detecting an average reduction in arm swing asymmetry of about 14% after arm training). The main innovation relies precisely on the integration of evaluative and rehabilitative aspects, which could be used as a closed loop to design new protocols for remote management of patients tailored to their actual conditions., Competing Interests: The authors declare no conflict of interest.

Immune-checkpoint inhibitors (ICIs) showed impressive results in terms of activity and efficacy in metastatic colorectal cancer (mCRC) patients bearing tumors with deficient mismatch repair (dMMR) or high microsatellite instability (MSI-H). Despite that microsatellite status is the major predictive biomarker for the efficacy of ICIs, a proportion of dMMR/MSI-H mCRC tumors do not achieve benefit from immunotherapy due to the primary resistance. Deeper knowledge of biological mechanisms regulating dMMR/MSI-H CRC tumors and immune response may be useful to find new predictive biomarkers of ICIs benefit and tailor the use of immunotherapy even in dMMR/MSI-H mCRC patients. Moreover, several issues are still open, such as the secondary resection of metastases and the optimal duration of ICIs therapy in dMMR/MSI-H mCRC patients. Looking beyond microsatellite status, in a future perspective, several tools (i.e., Tumor Mutational Burden and PD-L1 expression) have been investigated to clarify their possible role as predictive biomarkers. Furthermore, a small subgroup of pMMR/MSS CRC tumors with a POLE mutation of the proofreading domain is characterized by hypermutated phenotype and might derive benefit from immune checkpoint inhibition. In the present work, we aim to review the most recent literature regarding treatment with ICIs in mCRC, focusing on dMMR/MSI-H and special subgroups of CRC patients. Hence, we summarize possible future targets and the most promising predictive biomarkers.

Immune checkpoint inhibitors (ICIs) are a key component of different stages of hepatocellular carcinoma (HCC) treatment, particularly in the first line of treatment. A lesson on the primary resistance which hampers their efficacy and activity was learned from the failure of the trials which tested them as first-line mono-therapies. Despite the combination of anti-PD(L)1 agents with anti-VEGF, anti CTLA4, or TKIs demonstrating relevant improvements in efficacy, the "doublets strategy" still shows room for improvement, due to a limited overall survival benefit and a high rate of progressive disease as best response. In this review, we discuss the results from the currently tested doublet strategies (i.e., atezolizumab+bevacizumab, durvalumab+tremelimumab with a mention to the newly presented ICIs/TKIs combinations), which highlight the need for therapeutic improvement. Furthermore, we examine the rationale and provide an overview of the ongoing trials testing the treatment intensification strategy with triplet drugs: anti-PD1+anti-CTLA4+anti-VEGF/TKIs and anti-PD1+anti-VEGF+alternative immunity targets. Lastly, we report on the alternative strategy to integrate ICIs into the new paradigm of immune therapeutics constituted by CAR-T and anti-cancer vaccines. This review provides up-to-date knowledge of ongoing clinical trials of the aforementioned strategies and critical insight into their mechanistic premises.

The paper proposes an ecological and portable protocol for the large-scale collection of reading data in high-functioning autism spectrum disorder (ASD) children based on recording the finger movements of a subject reading a text displayed on a tablet touchscreen. By capitalizing on recent evidence that movements of a finger that points to a scene or text during visual exploration or reading may approximate eye fixations, we focus on recognition of written content and function words, pace of reading, and accuracy in reading comprehension. The analysis showed significant differences between typically developing and ASD children, with the latter group exhibiting greater variation in levels of reading ability, slower developmental pace in reading speed, less accurate comprehension, greater dependency on word length and word frequency, less significant prediction-based processing, as well as a monotonous, steady reading pace with reduced attention to weak punctuation. Finger-tracking patterns provides evidence that ASD readers may fail to integrate single word processing into major syntactic structures and lends support to the hypothesis of an impaired use of contextual information to predict upcoming stimuli, suggesting that difficulties in perception may arise as difficulties in prediction.

Standard treatments of localized rectal cancer are surgery or the multimodal approach with neoadjuvant treatments (chemo-radiotherapy, short-course radiotherapy, induction, or consolidation chemotherapy) followed by surgery. In metastatic colorectal cancer (mCRC), immune checkpoint inhibitors (ICIs) are now the first choice in patients with a deficient mismatch repair system/microsatellite instability (dMMR/MSI-H) and are being explored in combination with chemotherapy to rewire the immune system against malignant cells in subjects with proficient mismatch repair system/microsatellite low (pMMR/MSI-L) cancers, with promising signals of efficacy. Recently, some efforts have been made to translate ICIs in earlier stages of CRC, including localized rectal cancer, with breakthrough efficacy and an organ preservation rate of mono-immunotherapy in dMMR/MSI-H patients and promising anti-tumor activity of immunotherapy plus neoadjuvant (chemo)radiotherapy in pMMR/MSI-L subjects. Here, we present the rationale, results, and limitations of the most remarkable trials assessing ICIs in dMMR/MSI-H and pMMR/MSI-L localized rectal cancer patients, at the same time highlighting the most promising research perspectives that have followed these studies.

Arm swinging is a typical feature of human walking: Continuous and rhythmic movement of the upper limbs is important to ensure postural stability and walking efficiency. However, several factors can interfere with arm swings, making walking more risky and unstable: These include aging, neurological diseases, hemiplegia, and other comorbidities that affect motor control and coordination. Objective assessment of arm swings during walking could play a role in preventing adverse consequences, allowing appropriate treatments and rehabilitation protocols to be activated for recovery and improvement. This paper presents a system for gait analysis based on Microsoft Azure Kinect DK sensor and its body-tracking algorithm: It allows noninvasive full-body tracking, thus enabling simultaneous analysis of different aspects of walking, including arm swing characteristics. Sixteen subjects with Parkinson's disease and 13 healthy controls were recruited with the aim of evaluating differences in arm swing features and correlating them with traditional gait parameters. Preliminary results show significant differences between the two groups and a strong correlation between the parameters. The study thus highlights the ability of the proposed system to quantify arm swing features, thus offering a simple tool to provide a more comprehensive gait assessment., Competing Interests: The authors declare no conflict of interest.

Disruption in routine may be related to experiencing negative emotional states and to aggressive behaviors in individuals with Autism Spectrum Disorder (ASD). The lockdown because of COVID-19 contributed to the disruption of individuals’ routines, including the sleep−wake cycle. The current study tested a relationship between the adherence to the sleep−wake routine and aggressive behaviors via the mediation role of negative emotional states (i.e., anxiety and anger). Forty-three parents of adults with ASD completed a web-based questionnaire about their life condition during the first lockdown (April−May 2020). Preliminary analyses showed a worsening in the adults’ aggressive behaviors during the lockdown in comparison to before it (Z = −3.130; p = 0.002). In the mediation models, the relationship between the adherence to the sleep−wake routines and aggressive behaviors was significant. The models showed the hypothesized mediated relationships among the adherence to the sleep−wake routines, negative emotional states, and aggressive behaviors (Model 1: F (1, 41) = 10.478, p < 0.001; Model 2: F(1, 41) = 9.826, p = 0.003). The findings confirmed the potential protective role of the adherence to the sleep−wake routines for the emotional and behavioral adjustment of adults with autism. Theoretical and practical contributions of the study were discussed; indeed, our results may inform parent-coaching as well as intervention programs for individuals with ASD given that adequate sleep hygiene may contribute to improvements in internalizing/externalizing behaviors.

Aggressive behaviors and disruptive/conduct disorders are some of the commonest reasons for referral to youth mental health services; nevertheless, the efficacy of therapeutic interventions in real-world clinical practice remains unclear. In order to define more appropriate targets for innovative pharmacological therapies for disruptive/conduct disorders, the European Commission within the Seventh Framework Programme (FP7) funded the MATRICS project (Multidisciplinary Approaches to Translational Research in Conduct Syndromes) to identify neural, genetic, and molecular factors underpinning the pathogenesis of aggression/antisocial behavior in preclinical models and clinical samples. Within the program, a multicentre case-control study, followed by a single-blind, placebo-controlled, cross-over, randomized acute single-dose medication challenge, was conducted at two Italian sites. Aggressive children and adolescents with conduct disorder (CD) or oppositional defiant disorder (ODD) were compared to the same age (10-17 y) typically developing controls (TDC) on a neuropsychological tasks battery that included both "cold" (e.g., inhibitory control, decision making) and "hot" executive functions (e.g., moral judgment, emotion processing, risk assessment). Selected autonomic measures (heart rate variability, skin conductance, salivary cortisol) were recorded before/during/after neuropsychological testing sessions. The acute response to different drugs (methylphenidate/atomoxetine, risperidone/aripiprazole, or placebo) was also examined in the ODD/CD cohort in order to identify potential neuropsychological/physiological mechanisms underlying aggression. The paper describes the protocol of the clinical MATRICS WP6-1 study, its rationale, the specific outcome measures, and their implications for a precision medicine approach.

In recent years, there has been growing interest in investigating the effect of specific pharmacological treatments for ADHD not only on its core symptoms, but also on social skills in youths. This stands especially true for ADHD patients displaying impulsive aggressiveness and antisocial behaviors, being the comorbidity with Disruptive Behavior Disorders, one of the most frequently observed in clinical settings. This systematic review aimed to synthesize research findings on this topic following PRISMA guidelines and to identify gaps in current knowledge, future directions, and treatment implications. Search strategies included the following terms: ADHD; methylphenidate and other ADHD drugs; empathy, theory of mind and emotion recognition. Full-text articles were retrieved and data from individual studies were collected. Thirteen studies were finally included in our systematic review. Ten studies assessing changes in empathy and/or theory of mind in patients with ADHD treated after pharmacological interventions were identified. Similarly, seven partially overlapping studies assessing changes in emotion recognition were retrieved. Despite a great heterogeneity in the methodological characteristics of the included studies, most of them reported an improvement in emphatic and theory of mind abilities in youths with ADHD treated with psychostimulants and nonstimulant drugs, as well as positive but less consistent results about emotion recognition performances.

The lockdown due to the COVID-19 pandemic has had adverse psychological effects on children and parents. While parenting is essential for positive development, increased parental distress has interfered with children's wellbeing. In our study, we aimed to identify the predictors of parental distress in families of children with neuropsychiatric disorders during lockdown. Seventy-seven parents of children with neuropsychiatric disorders were asked to fill three online questionnaires (a socio-demographic questionnaire, the Child Behavior Checklist (CBCL) and Parental-Stress-Index (PSI-4-SF) to explore the relationship between parental distress, emotional/behavioral problems in children and quarantine-related factors through univariate analyses and multiple mediation models. Significant positive associations between CBCL-internalizing-problems and all PSI-4-SF subscales, and between CBCL-externalizing-problems and "Difficult Child" subscales were found. "Parent-Child Dysfunctional Interaction" subscale and teachers-child relationship quality resulted negatively associated, as well as the "Difficult Child" subscale and peers-child relationship quality. The effect of teachers-child relationship quality on "Parent-Child Dysfunctional Interaction" was mediated by children internalizing problems, while the effect of peers-child relationship quality on "Difficult Child" by the child internalizing/externalizing problems. Internalizing problems in children with neuropsychiatric disorders were among the strongest predictors of parental stress during lockdown, mediating the indirect effects of quarantine-related factors, thus suggesting the importance of their detection during and after emergency situations to provide assistance and reduce parenting pressure.

Background: When COVID-19 was declared as a pandemic, many countries imposed severe lockdowns that changed families' routines and negatively impacted on parents' and children's mental health. Several studies on families with children with autism spectrum disorder (ASD) revealed that lockdown increased the difficulties faced by individuals with ASD, as well as parental distress. No studies have analyzed the interplay between parental distress, children's emotional responses, and adaptive behaviors in children with ASD considering the period of the mandatory lockdown. Furthermore, we compared families with children on the spectrum and families with typically developing (TD) children in terms of their distress, children's emotional responses, and behavioral adaptation., Methods: In this study, 120 parents of children aged 5-10 years (53 with ASD) participated., Results: In the four tested models, children's positive and negative emotional responses mediated the impact of parental distress on children's playing activities. In the ASD group, parents reported that their children expressed more positive emotions, but fewer playing activities, than TD children. Families with children on the spectrum reported greater behavioral problems during the lockdown and more parental distress., Conclusions: Our findings inform the interventions designed for parents to reduce distress and to develop coping strategies to better manage the caregiver-child relationship.

Background: Severe suicide ideation or attempts and non-suicidal self-injury (NSSI) present both differences and relevant overlaps, including frequent co-occurrence and shared risk factors. Specific categorical diagnoses, namely bipolar disorder (BD), may affect clinical features and natural histories of suicidal or not suicidal self-harm behaviour. Our study aimed to compare suicidality (severe suicidal ideation or suicidal attempts) and NSSI in referred bipolar adolescents., Methods: The sample included 95 bipolar adolescents (32 males, 63 females) aged 11 to 18 years. Thirty adolescents with suicide attempts/suicidal ideation and BD (SASIB) were compared with structured measures to 35 adolescents with NSSI and BD, without suicidal ideation or attempts (NSSIB), and to 30 adolescents with BD, without suicidal ideation or attempts or NSSI (CB)., Results: Compared to CB, suicidality and NSSI were both associated with female sex, borderline personality disorder and self-reported internalizing disorders, anxiety/depression and thought disorders. The NSSI were specifically associated with somatic problems. Severe suicidal ideation and suicide attempts were associated with adverse life events, immigration, bullying, eating disorders, social problems, depressive feelings, performance and social anxiety, and feelings of rejection., Conclusions: Both shared and differential features between suicidal and not suicidal adolescents may represent possible targets for diagnostic and preventative interventions.

LEGO ® -based therapy is a social skills development program aimed at children with autism spectrum disorder (ASD). A systematic review of the literature was conducted using PRISMA guidelines. PubMed, Scopus and Web of Science bibliographic databases were searched from their date of inception to August 2020. The review included 19 studies. Studies were classified according to experimental designs (e.g., Randomized Control Trial, Non-Randomized Studies of Interventions and case report and series) and a narrative synthesis of each was provided, along with a critical discussion of the strengths and weaknesses of the available literature on the topic. Although LEGO ® -based therapy appears a promising treatment for social interaction in ASD, the findings of LEGO ® -based therapy studies should be interpreted and generalized with caution, due to the low quality of the studies and the small sample sizes.

Plasma Electrolytic Oxidation (PEO) was applied to extruded ZM21 Mg alloys to improve their corrosion resistance in a chloride-containing environment. PEO was carried out in DC mode and voltage control in a fluoride-free electrolyte. Potentiodynamic polarization tests in 3.5 wt.% NaCl aqueous solution and neutral salt spray (NSS) tests were carried out. Microstructural and profilometric characterization, as well as NSS tests were performed in different conditions: (i) bare ZM21, (ii) PEO-treated ZM21, (iii) powder-coated ZM21 (without PEO interlayer), and (iv) PEO-treated ZM21 with powder coating top layer (carboxyl-functionalized polyester resin). The PEO + powder coating double layer was identified as the best-performing corrosion protection.

In the last decades, the conceptualization of schizophrenia has dramatically changed, moving from a neurodegenerative process occurring in early adult life to a neurodevelopmental disorder starting be-fore birth, showing a variety of premorbid and prodromal symptoms and, in relatively few cases, evolving in the full-blown psychotic syndrome. High rates of co-occurring different neurodevelopmental disorders such as Autism spectrum disorder and ADHD, predating the onset of SCZ, and neurobio-logical underpinning with significant similarities, support the notion of a pan-developmental disturbance consisting of impairments in neuromotor, receptive language, social and cognitive development. Con-sidering that many SCZ risk factors may be similar to symptoms of other neurodevelopmental psychi-atric disorders, transition processes from child & adolescent to adult systems of care should include both high risk people as well as subject with other neurodevelopmental psychiatric disorders with different levels of severity. This descriptive mini-review discuss the need of innovative clinical approaches, re-considering specific diagnostic categories, stimulating a careful analysis of risk factors and promoting the appropriate use of new and safer medications.

On 11 March 2020, a national lockdown was imposed by the Italian government to contain the spread of COVID19 disease. This is an observational longitudinal study conducted at Fondazione Stella Maris (FSM), Italy to investigate lockdown-related emotional and behavioural changes in paediatric neuropsychiatric population. Families having children (1.5-18 years) with neuropsychiatric disorders referred to FSM have been contacted and proposed to fulfil two online questionnaires (General questionnaire and Child Behaviour Check List (CBCL)) to (i) compare (paired two-sample t -tests) the CBCL scores during lockdown with previous ones, and (ii) investigate the influence (multiple linear regression models) of variables such as age, diagnosis grouping (neurological, neurodevelopmental, emotional, and behavioural disorders) and financial hardship. One hundred and forty-one parents fulfilled the questionnaires. Anxiety and somatic problems increased in 1.5-5 years subpopulation, while obsessive-compulsive, post-traumatic and thought problems increased in 6-18 years subpopulation. In the regression models, younger age in the 1.5-5 years subpopulation resulted as "protective" while financial hardship experienced by families during lockdown was related to psychiatric symptoms increasing in the 6-18 years subpopulation. Some considerations, based on first clinical impressions, are provided in text together with comments in relation to previous and emerging literature on the topic.

Suicidal ideation and attempts in adolescents are closely associated to bipolar disorders (BD). Growing evidence also suggests that high functioning autism spectrum disorders (HF-ASD) are at increased risk for suicidal ideation and behaviors. Although BD and HF-ASD are frequently comorbid, no studies explored suicidality in these individuals. This exploratory study addressed this issue in a clinical group of inpatient adolescents referred to a psychiatric emergency unit. Seventeen adolescents with BD and HF-ASD and severe suicidal ideation or attempts (BD-ASD-S), were compared to 17 adolescents with BD and HF-ASD without suicidal ideation or attempts (BD-ASD-noS), and to 18 adolescents with BD and suicidal ideation or attempts without ASD (BD-noASD-S), using a structured assessment methodology. Individuals with BD-ASD-S had a higher intelligence quotient, more severe clinical impairment, more lethality in suicide attempts, more internalizing symptoms, less impulsiveness, and lower social competence. Severity of ASD traits in individuals and parents did not correlate with suicidal risk. Some dimensions of resilience were protective in terms of repulsion by life and attraction to death. Main limitations are the small sample size, the lack of a control group of typically developing adolescents. However, a better understanding of the specificities of bipolar HF-ASD individuals with suicidality may improve prevention and treatment strategies.

Background: Bipolar Disorders (BD) in youth are a heterogeneous condition with different phenomenology, patterns of comorbidity and outcomes. Our aim was to explore the effects of gender; age at onset (prepubertal- vs. adolescent-onset) of BD; and elements associated with attention deficit hyperactivity disorder (ADHD) and Substance Use Disorder (SUD) comorbidities, severe suicidal ideation or attempts, and poorer response to pharmacological treatments., Method: 117 youth (69 males and 57 females, age range 7 to 18 years, mean age 14.5 ± 2.6 years) consecutively referred for (hypo)manic episodes according to the Diagnostic and Statistical Manual of Mental Disorders , 54th ed (DSM 5) were included., Results: Gender differences were not evident for any of the selected features. Prepubertal-onset BD was associated with higher rates of ADHD and externalizing disorders. SUD was higher in adolescent-onset BD and was associated with externalizing comorbidities and lower response to treatments. None of the selected measures differentiated patients with or without suicidality. At a 6-month follow up, 51.3% of the patients were responders to treatments, without difference between those receiving and not receiving a psychotherapy. Clinical severity at baseline and comorbidity with Conduct Disorder (CD) and SUD were associated with poorer response. Logistic regression indicated that baseline severity and number of externalizing disorders were associated with a poorer outcome., Conclusions: Disentangling broader clinical conditions in more specific phenotypes can help timely and focused preventative and therapeutic interventions.

This study contributes to the literature on the parental correlates of children's narcissism. It addresses whether parental overvaluation may drive the putative link between parents' narcissism and children's narcissism and self-esteem. The cross-sectional design involved a community sample of 519 school-age children (age ranging from 9 to 11 years old) and their parents from an Italian urban context. Child-reported measures included narcissistic traits and self-esteem, while parent-reported measures included narcissistic traits and overvaluation, as well as parenting styles. A series of structural equation models, run separately for mothers and fathers, showed that both parents' narcissism was directly and positively related to overvaluation and the children's narcissistic traits; overvaluation partially mediated the indirect link between the fathers' and children's narcissistic traits. None of the parenting-style dimensions were related to the children's outcomes, with the exception of the mothers' positive parenting being directly and positively related to children's self-esteem. These findings shed new light upon the parental correlates of child narcissism by suggesting that mothers and fathers convey their narcissism to their offspring through differential pathways. Our findings may be understood from universal as well as cultural specifics regarding the parenting roles of mothers and fathers. Clinical implications for the treatment of youth narcissism suggest the potential of targeting not only children but also their parents.

Executive functions have been previously shown to correlate with empathic attitudes and prosocial behaviors. People with higher levels of executive functions, as a whole, may better regulate their emotions and reduce perceived distress during the empathetic processes. Our goal was to explore the relationship between empathy and executive functioning in a sample of children and adolescents diagnosed with Attention Deficit and Hyperactivity Disorder alone or associated with comorbid Disruptive Behavior Disorders and/or Autism Spectrum Disorder. We also aimed to examine the role of empathic dimensions and executive skills in regulating externalizing behaviors. The 151 participants with ADHD were assigned to four groups according to their psychiatric comorbidity (either "pure" or with ASD and/or ODD/CD) and assessed by means of either parent- or self-reported questionnaires, namely the BRIEF-2, the BES, and the IRI. No questionnaire was found to discriminate between the four groups. Affective Empathy was found to positively correlate with Emotional and Behavioral Regulation competences. Furthermore, Aggressiveness and Oppositional Defiant Problems were positively associated with Executive Emotional and Behavioral Regulation competences. On the other hand, Rule-Breaking Behaviors and Conduct Problems were negatively associated with Affective Empathy and with Behavioral skills. Our study provides an additional contribution for a better understanding of the complex relationship between empathic competence and executive functions, showing that executive functioning and empathic attitudes interact with each other to regulate aggressive behaviors. This study further corroborates developmental models of empathy and their clinical implications, for which externalizing behaviors could be attenuated by enhancing executive functioning skills.

Background . FOLFOXIRI plus Bevacizumab is one of the most frequently used first-line treatments for patients with BRAF -mutant colorectal cancer (CRC), while second-line treatment requires extensive further research. In this pooled analysis, we evaluate the impact of anti-angiogenics in patients with pre-treated BRAF -mutant CRC. Methods. We monitored patients in randomized, controlled studies who had advanced CRC and were undergoing second-line chemotherapy in addition to utilizing Bevacizumab, Ramucirumab or Aflibercept treatments. These data were pooled together with the data and results of BRAF -mutant patients enrolled in two phase III trials (TRIBE and TRIBE-2 study), who had been treated with second-line treatment both with or without Bevacizumab. Overall survival (OS), in relation to BRAF mutational status, was the primary focus. Results . Pooled analysis included 129 patients. Anti-angiogenics were found to have a significant advantage over the placebo in terms of OS (HR 0.50, 95%CI 0.29-0.85) ( p = 0.01). Conclusions . Our pooled analysis confirms the efficacy of anti-angiogenics in pre-treated BRAF -mutant CRC, establishing the combination of chemotherapy plus Bevacizumab or Ramucirumab or Aflibercept as a valid treatment option.

Generation of human induced pluripotent stem cells (hiPSCs) and their differentiation into a variety of cells and organoids have allowed setting up versatile, non-invasive, ethically sustainable, and patient-specific models for the investigation of the mechanisms of human diseases, including viral infections and host-pathogen interactions. In this study, we investigated and compared the infectivity and replication kinetics in hiPSCs, hiPSC-derived neural stem cells (NSCs) and undifferentiated neurons, and the effect of viral infection on host innate antiviral responses of representative flaviviruses associated with diverse neurological diseases, i.e., Zika virus (ZIKV), West Nile virus (WNV), and dengue virus (DENV). In addition, we exploited hiPSCs to model ZIKV infection in the embryo and during neurogenesis. The results of this study confirmed the tropism of ZIKV for NSCs, but showed that WNV replicated in these cells with much higher efficiency than ZIKV and DENV, inducing massive cell death. Although with lower efficiency, all flaviviruses could also infect pluripotent stem cells and neurons, inducing similar patterns of antiviral innate immune response gene expression. While showing the usefulness of hiPSC-based infection models, these findings suggest that additional virus-specific mechanisms, beyond neural tropism, are responsible for the peculiarities of disease phenotype in humans.

Different human papillomavirus (HPV) types are characterized by differences in tissue tropism and ability to promote cell proliferation and transformation. In addition, clinical and experimental studies have shown that some genetic variants/lineages of high-risk HPV (HR-HPV) types are characterized by increased oncogenic activity and probability to induce cancer. In this study, we designed and validated a new method based on multiplex PCR-deep sequencing of the E6/E7 region of HR-HPV types to characterize HPV intra-type variants in clinical specimens. Validation experiments demonstrated that this method allowed reliable identification of the different lineages of oncogenic HPV types. Advantages of this method over other published methods were represented by its ability to detect variants of all HR-HPV types in a single reaction, to detect variants of HR-HPV types in clinical specimens with multiple infections, and, being based on sequencing of the full E6/E7 region, to detect amino acid changes in these oncogenes potentially associated with increased transforming activity.

A West Nile Virus (WNV) lineage 2 strain, named Nea Santa-Greece-2010, has been demonstrated to be responsible for the large outbreaks of neuroinvasive disease (WNND) that have been occurring in Greece since 2010, based on sequence similarities of viral isolates identified between 2010-2012. However, knowledge on the evolution of this strain is scarce because only partial WNV genome sequences are available from Greece. The aim of this study was to get the complete genome sequence of WNV from patients with infection. To this aim, plasma and urine samples collected during the 2012 Greek outbreak were retrospectively investigated. Full WNV genome sequence was obtained from a patient with WNND. The genome had 99.7% sequence identity to Nea Santa, higher than to other related WNV lineage 2 strains, and five amino acid changes apparently not relevant for viral pathogenicity or fitness. In addition, infection by WNV lineage 2 was confirmed in additional nine patients with WNND; in three of them the infection with WNV Nea Santa was demonstrated by sequencing. In conclusion, this study characterized for the first time a WNV full genome from a patient with WNND from Greece, demonstrated the persistence of the Nea Santa strain, and suggested that the virus might have locally evolved.