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Background and aim: Transcranial direct current stimulation (tDCS) and metacognitive therapy (MCT) can reduce depressive symptoms as monotherapies or associated with pharmacological treatment. Here, we investigated the effectiveness of combining these treatments in a group of patients with major depressive disorder (MDD). Methods: So far, fourteen participants (10 females, Mage 43 ± 12) out of N= 54 estimated sample size were recruited at the Department of Neuroscience and Mental Health – Fondazione IRRCS Ca’ Granda Ospedale Maggiore Policlinico of Milano. All participants were under pharmacological treatment. They were randomly assigned to three groups receiving (i) real tDCS + sham MCT (n= 7); (ii) sham tDCS + MCT (n = 6) (iii) real tDCS + MCT (n= 1). The treatment lasted eight weeks, in which participants had one weekly MCT (groups ii and iii) or clinical interview session (group i) following the tDCS. TDCS was combined with attentional training (20 minutes, 1.5 mA, anode over the left dorsolateral prefrontal cortex) and took place three times a week for the first three weeks and then once a week. Clinical standardized questionnaires measuring depressive symptoms, anxiety, worry, rumination, and meta-beliefs were administered before and after the treatment, two weeks, three, six, and twelve months after treatment’s end. Results: Due to sampling distribution, mixed effects models were run, including time and only two groups as fixed factors (i and ii) and participants’ random intercept. Outcome measures revealed an effect of time, showing symptoms reduction after the treatment. Crucially, our results suggested a more robust reduction of worry and negative beliefs in the group receiving MCT compared to the one receiving only tDCS. Conclusions: despite preliminary, our results suggest that MCT can effectively reduce core symptoms contributing to the development and maintenance of MDD. Completing data collection will allow disentangling whether tDCS can boost this ef

The COVID-19 pandemic and the need for additional safe, effective, and affordable vaccines gave new impetus into development of vaccine genetic platforms. Here we report the findings from the phase 1, first-in-human, dose-escalation study of COVID-eVax, a DNA vaccine encoding the receptor binding domain (RBD) of the SARS-CoV-2 spike protein. Sixty-eight healthy adults received two doses of 0.5, 1, or 2 mg 28 days apart, or a single 2-mg dose, via intramuscular injection followed by electroporation, and they were monitored for 6 months. All participants completed the primary safety and immunogenicity assessments after 8 weeks. COVID-eVax was well tolerated, with mainly mild to moderate solicited adverse events (tenderness, pain, bruising, headache, and malaise/fatigue), less frequent after the second dose, and it induced an immune response (binding antibodies and/or T cells) at all prime-boost doses tested in up to 90% of the volunteers at the highest dose. However, the vaccine did not induce neutralizing antibodies, while particularly relevant was the T cell-mediated immunity, with a robust Th1 response. This T cell-skewed immunological response adds significant information to the DNA vaccine platform and should be assessed in further studies for its protective capacity and potential usefulness also in other therapeutic areas, such as oncology.

Background: The possibility of using noninvasive brain stimulation to treat mental disorders has received considerable attention re-cently. Repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS) are considered to be effective treatments for depressive symptoms. However, no treatment recommendation is currently available for anxiety disorders, suggesting that evidence is still limited. We conducted a systematic review of the literature and a quantitative analysis of the effectiveness of rTMS and tDCS in the treatment of anxiety disorders. Methods: Following PRISMA guidelines, we screened 3 electronic databases up to the end of February 2020 for English-language, peer-reviewed articles that included the following: a clinical sample of patients with an anxiety disorder, the use of a noninvasive brain stimulation technique, the inclusion of a control condition, and pre/post scores on a validated questionnaire that measured symptoms of anxiety. Results: Eleven papers met the inclusion criteria, comprising 154 participants as-signed to a stimulation condition and 164 to a sham or control group. We calculated Hedge’s g for scores on disorder-specific and general anxiety questionnaires before and after treatment to determine effect size, and we conducted 2 independent random-effects meta-analyses. Considering the well-known comorbidity between anxiety and depression, we ran a third meta-analysis analyzing outcomes for depression scores. Results showed a significant effect of noninvasive brain stimulation in reducing scores on disorder-specific and general anxiety questionnaires, as well as depressive symptoms, in the real stimulation compared to the control condition. Limitations: Few studies met the inclusion criteria; more evidence is needed to strengthen conclusions about the effectiveness of noninvasive brain stimulation in the treatment of anxiety disorders. Conclusion: Our findings showed that noninvasive brain stimulati

Cognitive behavioral therapy (CBT) approaches use case formulation procedures based on the diathesis–stress conceptualization model, arranged in two dimensions: emotional vulnerability (present in a patient’s consciousness in terms of core beliefs) and coping strategies. Nevertheless, despite its pivotal role, there are a limited number of validation studies for this model. Life themes and semi-adaptive plans: Implications of biased beliefs, elicitation and treatment (LIBET) is a CBT case formulation method grounded on the CBT diathesis–stress model that aims to help validate the CBT case formulation model, and, in particular, its bidimensional arrangement. In LIBET, the two classic CBT dimensions are called “life themes,” which are mental states of focused attention to emotional sensitivities represented as core beliefs in consciousness, and “semi-adaptive plans,” which are the rigid management strategies of “life themes” implemented by adopting coping strategies such as anxious safety behaviors, compulsive controls and aggressive or rewarding strategies. The study uses quantitative textual analysis to validate the LIBET procedure in a clinical sample. The investigation discusses the extent to which the results can be considered a validation of the arrangement of the general CBT diathesis–stress model in the two dimensions of core beliefs and coping strategies.

Background: Using the Self-Regulatory Executive Function model as a basis, this study explored whether, in both general population and clinical samples, metacognitive beliefs and repetitive negative thinking (i.e., rumination and worry) are associated with higher levels of emotion dysregulation. Methods: 395 participants from the general population and 388 outpatients seeking psychological treatment were recruited. Emotion dysregulation, metacognitive beliefs, rumination, worry, anxiety, depression, personality disorders were assessed. ANOVA and Welch's tests, correlation and path analyses were run. Results: Repetitive negative thinking was found to play a mediating role in the relationship between metacognitive beliefs and emotion dysregulation in both general population and clinical samples. Moreover, metacognitive beliefs were found to be directly associated to emotion dysregulation. Limitations: The cross-sectional design. Conclusions: Emotion dysregulation appears to be associated with the tendency to engage in repetitive negative thinking and metacognitive beliefs. Repetitive negative thinking and metacognitive beliefs could be a suitable therapeutic target to reduce difficulties in emotion regulation.

Over the last decade, interest in the clinical field regarding the emotional area of the child has grown. Several studies have confirmed the efficacy of cognitive-behavioural treatment in childhood and adolescence (Sukhodolsky, Kassinove, & Gorman, 2004; Compton et al., 2004), and programmes for the prevention of emotional disorders, such as Rational Emotive Education (Educazione Razionale Emotiva) (Di Pietro, Morosini, & Agostini 1999), have been disseminated in schools. This is a preventive psychoeducational intervention, which derives from the principles of Ellis’s Rational Emotional Behavioural Therapy (1989) and was brought to Italy in 1991 by Mario di Pietro (1992), following its adaptation at the Institute for Rational-Emotive Therapy in New York. In recent years the Italian version has been updated and integrated with the principles of Acceptance and Commitment Therapy, making the intervention more innovative. The purpose of this article is to provide an analysis of the application of Rational Emotional Behavioural Therapy in childhood and adolescence and to deepen the practical aspects of Rational Emotive Education, providing some useful ideas for the realisation of a psychoeducational project in primary schools.

Cognitive-behavioral treatments assume that the mechanisms of change depend on the assessment and questioning of biased beliefs. In contrast, recent developments have emphasized mindful acceptance interventions, in which clients allow thoughts to come and go without questioning them. In order to discuss therapeutic efficacy difference in emotional disorders, we explored the possible normalizing effects of cognitive questioning and mindful acceptance on sympathetic reactivity aroused by recall tasks. We compared the effects of different sequencing of cognitive questioning and mindful acceptance on emotional distress in two groups in which questioning either preceded (group 1) or followed (group 2) acceptance. Thirty-five non-clinical individuals (21 males, 14 females) randomly allocated to either group 1 or 2 participated in the experimental tasks (unpleasant recall, cognitive questioning, and metacognitive acceptance). Sympathetic reactivity levels were measured using galvanic skin response. Results showed that acceptance reduced sympathetic reactivity when compared to questioning. The best sequence was that in which questioning preceded acceptance. By interpreting sympathetic reactivity as a measure of emotional distress and experimental tasks as models for therapeutic approaches, this experiment suggests that acceptance is better than questioning in reducing emotional distress especially when cognitive questioning is followed by mindful acceptance.

Glioblastoma multiforme (GBM) is the most malignant primary brain cancer. Despite aggressive treatments currently there is no cure for GBM. Many challenges should be considered for the development of new therapeutical agents for glioblastoma, including appropriate target selectivity and pharmacokinetics. Several mutations and alterations of key cellular pathways including tyrosine kinases (TKs) are involved in malignant transformation and tumor progression. Thus, the targeting of multiple pathways and the development of innovative combination drug regimens is expected to yield improved therapies. Moreover, the abilities to cross the blood-brain barrier (BBB) reaching effective concentrations in brain and to remain into this tissue avoiding the effects of efflux transporters are also critical issues in the development of new therapeutics for GBM. CR13626 is a novel brain penetrant small molecule able to potently inhibit in vitro the activity of EGFR, VEGFR2 (aka KDR), Fyn, Yes, Lck, HGK (aka MAP4K4) and RET kinases relevant for GBM development. CR13626 shows good oral bioavailability (72%) and relevant brain penetration (brain/plasma ratio of 1.4). In an orthotopic xenograft glioblastoma mouse model, oral treatment with CR13626 results in a time-dependent reduction of tumor growth, leading to a significant increase of animal survival. The unique properties of CR13626 warrant its further investigation as a potential new drug candidate in glioblastoma.

In Albert Ellis' rational emotive behavior therapy (REBT; DiGiuseppe et al., A Practioner's guide to rational emotive behavior therapy. New York, NY: Oxford University Press, 2014; Ellis, Reason and emotion in psychotherapy. New York, NY: Stuart, 1962; Ellis and Grieger, Handbook of rational-emotive therapy. New York, NY: Springer, 1986), the therapist uses three specific steps of the basic ABC DEF procedure of REBT, namely the B-C connection, D rationale and negotiation of F, to formulate the patient's problems, regulate the therapeutic process, and manage the therapeutic alliance. The negotiation of F establishes the goals of the therapy and the specific REBT contract. The B-C connection and the rationale of D help the patient to detach from his or her irrational beliefs. The healthy attitude is not to have negative thoughts but rather to tolerate them and not take seriously their demands and awfulizing aspects. This REBT attitude anticipates metacognitive procedures. It is this unceasing sharing of the rationale of the therapy that allows the REBT therapist to show empathy and respect toward the patient.

Significant reductions in mortality are reflected in strong increases in life expectancy particularly in industrialized countries. Previous analyses relate these improvements primarily to medical innovations and advances in health-related behaviors. Mostly ignored, however, is the question to what extent the gains in life expectancy are related to structural changes in the populations due to increasing education levels. We decompose changes of the total populations’ life expectancy at age 30 in Italy, Denmark, and the USA, over the 20-year period between 1990 and 2010 into the effects of education-specific mortality changes (“M effect”) and changes in the populations’ educational structure (“P effect”). We use the “replacement decomposition technique” to further subdivide the M effect into the contributions by the individual education groups. While most of the increases in life expectancy are due to the effect of changing mortality, a large proportion of improvements in longevity can indeed be attributed to the changing structure of the population by level of education in all three countries. The estimated contribution of the P effect ranges from around 15% for men in the USA to approximately 40% for women in Denmark. This study demonstrates strong associations between education and overall population health, suggesting that education policies can also be seen as indirect health policies.

Purpose: Joint pain is the cardinal symptom of OA although it poorly correlates with OA joint structure changes. Interestingly, OA pain is driven by both nociceptive and neuropathic mechanisms. The analgesic efficacy of CR4056, an I2 receptor ligand currently in phase II clinical trials, was previously reported in the OA pain model obtained by the intra-articular injection of monosodium iodoacetate (MIA) in the rat knee. Moreover, CR4056 evidenced a remarkable analgesic activity in several animal models of inflammatory, neuropathic and postoperative pain. The aim of this study was to evaluate the effect of CR4056 in a well-established model of surgically-induced OA able to mimic the structural and painful components of human OA. Methods: OA was induced in male Sprague Dawley rats (335-370 g) by transection of the medial collateral ligament and medial meniscus of the femoro-tibial right joint (MMT model). Hind paw weight bearing distribution was assessed as indirect measure of spontaneous pain by using an incapacitance tester (2Biological Instruments Snc, Besozzo, Italy), prior to surgery and 14, 28, 35 and 42 days post-surgery. Control rats were subjected to sham surgery, while treatments after MMT consisted of 6 mg/kg CR4056, or 10 mg/kg naproxen as an active control, or vehicle (9 animals/group) and they were administered orally as subacute treatment from 28 to 42 days after surgery. Statistical analysis was performed by Two-way RM ANOVA, followed by Tukey's multiple comparisons test. Results: MMT surgery resulted in a significant development of right-left hind paw weight bearing imbalance at each experimental time point, compared with the sham group (data expressed as difference of weight bearing between contralateral and ipsilateral paw). The difference in weight bearing distribution between sham and MMT rats gradually increased throughout the study, reaching its peak 42 days post-surgery in animals receiving vehicle (mean ± sem, 0.83 ± 1.87 vs. 65.92 ± 2.26, re

Introduction The present study investigated two male sexual dysfunctions: male erectile disorder (ED) and premature ejaculation (PE), respectively defined as “persistent or recurrent inability to attain, or to maintain an adequate erection until completion of the sexual activity” and “persistent or recurrent ejaculation with minimal sexual stimulation before, on, or shortly after penetration and before the person wishes it” or within two minutes of penetration. The metacognitive model is based on the idea that “it is not merely what a person thinks but how he or she thinks, that determines emotions and the control one has over them.” (Wells, 2008). In the metacognitive theory of psychological dysfunction, Wells and Matthews (1994) propose that a set of metacognitive beliefs are responsible for psychological disturbance by maintaining maladaptive attentive and cognitive coping strategies. This array of factors constitutes a Cognitive Attentional Syndrome (CAS; Wells, 2000), sustained by the presence of some metacognitive plans and beliefs that control the use of thought and attention. Some of the CAS components have been investigated in relation to male sexual dysfunctions, even if they have not been conceptualized in a specific metacognitive frame. For example, Hartmann and colleagues (2005) reported that, if compared to normal controls, “during sexual intercourse PE patients were totally preoccupied with thoughts about controlling their orgasm, while this was not a strong cognitive factor for the functional men. Other prevailing cognitions in PE patients referred to the anticipation of a possible failure and the embarrassing situation following a rapid ejaculation”. Objectives To our knowledge, no study has investigated the presence of CAS and metacognitive beliefs in the maintenance of Sexual Dysfunctions. The central aim of this study was to explore the specific role of CAS components and related metacognitive beliefs in affecting sexual performances of men with

Objective The current study examined the role of emotional competences and depression in takotsubo cardiomyopathy (TTC). Methods We compared 37 TTC patients who experienced emotion triggers (TTC-t: M (SD) age = 66.4 (12.8) years, 33 women) with 37 TTC patients who did not experience emotion triggers (TTC-nt: M (SD) age = 65.8 (11.1) years, 33 women) and 37 patients with acute myocardial infarction who experienced an emotion trigger (AMI-t: M (SD) age = 66.1 (10.1) years, 33 women). Three aspects of emotional competence (emotional intelligence, metacognitive beliefs, and emotional processing deficits) were assessed using the Trait Meta-Mood Scale (TMMS), the Meta-Cognitions Questionnaire 30, and the Emotional Processing Scale. Differences between-group means were evaluated using multivariate analysis of covariance, adjusting for depressive symptom (Hamilton Rating Scale for Depression). Results Compared with the TTC-nt and AMI-t comparison groups, TTC-t patients had low scores on emotional intelligence (TMMS Attention: F(2, 184) = 23.10, p <.001; TMMS Repair: F(2, 184) = 11.98, p <.001) and high scores in metacognitive beliefs and emotional processing deficits (e.g., Meta-Cognitions Questionnaire 30 Negative Beliefs about Thoughts: F(2, 184) = 56.93, p <.001), independent of the levels of depressive symptom. TTC-nt patients also had significantly lower scores on the Hamilton Rating Scale for Depression scale compared with AMI-t (p =.021) and TTC-t (p =.004) patients. Conclusions TTC-t patients showed a specific dysfunctional profile of emotional competence, even after adjusting for depressive symptom. These results provided a better understanding of the psychological factors that contribute to TTC.

Multivalency is widely used in nature in specific recognition processes. This paper describes an approach to multivalency in the pentameric 5-HT3 receptor, a ligand-gated ion channel, which constitutes an example of intrinsically multivalent biological receptors. Owing to the picomolar Ki value, TETRA-L represents an outstanding multivalent ligand for the neurotransmitter receptor. © The Partner Organisations 2014.

Purpose: CR4056, (2-phenyl-6-(1H-imidazol-1yl) quinazoline), an imidazoline-2 (I2) receptor ligand, is a promising analgesic drug that has been reported to be effective in several animal models of pain. The aim of this study was to evaluate the effects of CR4056 in two well-established rat models of osteoarthritis (OA), mimicking the painful and structural components of human OA. Methods: Knee OA was induced either by single intra-articular injection of monoiodoacetate (MIA) or by medial meniscal tear (MMT) in the right knee of male rats. In the MIA model, allodynia and hyperalgesia were measured as paw withdrawal threshold to mechanical stimulation. In the MMT model, pain behavior was analyzed as weight-bearing asymmetry (i.e. difference in hind paw weight distribution, HPWD) between the injured and the contralateral limbs. Results: Acute oral administration of CR4056, 14 days after MIA injection, significantly and dose-dependently reduced allodynia and hyperalgesia 90 minutes after treatment, whereas acute naproxen administration significantly reduced allodynia but not hyperalgesia. After 7 days of repeated treatment, both CR4056 and naproxen showed significant anti-allodynic and anti-hyperalgesic effects in the MIA model. Rats undergoing MMT surgery developed a significant and progressive asymmetry in HPWD compared with sham-operated animals. Repeated treatment with CR4056 significantly reduced the progression of the pain behavior, whereas naproxen had no effects. Conclusion: The data presented here show that the I2 ligand CR4056 could be a new effective treatment for OA pain. The compound is currently under Phase II clinical evaluation for this indication.

Erectile dysfunction (ED) and premature ejaculation (PE) are two forms of male sexual disorder with both psychological and physical features. While their cognitive, attentional, and affective components have been investigated separately, there is a lack of knowledge about the role played by cognitive attentional syndrome in their onset and maintenance. The aim of the present study was to investigate the possible contribution of perseverative thinking styles and thought control strategies to the development and maintenance of ED and PE. The authors hypothesized that such modes of processing might constitute a cognitive attentional syndrome specific to these disorders and sustained by particular metacognitive beliefs. A semistructured interview was administered to 11 participants with ED and 10 with PE in order to assess their metacognitive beliefs and cognitive attentional processes. The results suggest that individuals with ED and PE adopt a range of cognitive attentional strategies aimed at improving their sexual performance, and endorse both positive and negative metacognitive beliefs about these thinking responses. Overall, their cognitive and attentional patterns worsened negative internal states, reduced sexual excitement, detached them from their bodily sensations, and hindered sexual functioning. These preliminary findings suggest that perseverative thinking, thought control strategies, and metacognitive beliefs may play a key role in the onset and maintenance of male sexual dysfunction.