Search

Introduction: Cyberchondria (CYB) represents a poorly characterized syndrome involving the urge-driven tendency to excessively seek health-related information on the Internet. Intended to provide reassurance, the searching results in increased anxiety and distress, uncertainty and reinforcing CYB. CYB may represent a trans-diagnostic digital compulsive syndrome. However, the extent to which CYB contributes to the psychopathology of compulsive psychiatric disorders, such as illness anxiety disorder (hypochondriasis), obsessive-compulsive and related disorders (OCRD) or other online disorders of behavioral addiction, is not understood. Objectives: We describe one of the first reported cases of a treatment-seeking patient with DSM-5 illness anxiety disorder and disabling CYB. We review the available peer-reviewed published knowledge on CYB. Methods: Updated search of PubMed, PsycINFO, Cochrane Library. Search terms: "cyberchondria", "cyberchondriasis". Results: 58 original research studies were found. No consensus definition of CYB was established. Existing studies were exclusively cross-sectional, recruited from general population samples, with no descriptions of CYB in clinical samples. Data on the epidemiology, sociodemographic and clinical characteristics and associated comorbidities were scarce. A scale has been developed to quantify CYB severity in the general population. CYB was variously found to correlate with the presence of health anxiety broadly defined, obsessivecompulsive symptoms, problematic use of the internet, and other psychological constructs. Only cognitive behavioral therapy and psychoeducation were suggested as a possible therapeutic approach. Conclusions: Research on CYB remains in its infancy. Further studies are warranted to understand CYB in terms of definition, clinical features, measurement, relationship with hypochondriasis and other compulsive disorders, and therapeutic interventions. [ABSTRACT FROM AUTHOR]

Background/objectives: In the past two decades, significant advancements in neuromodulation techniques have occurred, such as transcranial magnetic stimulation (TMS) for treatment-resistant depression (TRD). According to the assumption that repeated stimulation within a condensed timeframe can yield sustained efficacy, an accelerated protocol may be more effective in reducing time to response. With those premises, this study aimed to evaluate a sample of TRD patients treated with standard repetitive TMS (rTMS) and accelerated rTMS (arTMS)., Methods: Nine subjects were treated with standard rTMS and 19 with arTMS. Psychometric assessment was made at the baseline and one week, one month, and three months after the treatment. A linear mixed-effect regression was performed along with other appropriate statistical analyses., Results: A significant improvement over time was observed for both depressive and cognitive symptoms. Moreover, considering the reduction in the Montgomery-Asberg Depression Rating Scale scores, a better treatment response was observed in subjects treated with arTMS ( p < 0.05)., Conclusions: Our findings showed a significant difference between the two protocols in terms of clinical response. Although further studies are needed to confirm the superiority of arTMS, the better cost-effectiveness of this technique should be considered.

Despite millennia of therapeutic plant use, deliberate exploitation of Cannabis 's diverse biomedical potential has only recently gained attention. Bioactivity studies focus mainly on cannabidiol (CBD) and tetrahydrocannabinol (THC) with limited information about the broader cannabinome's "minor phytocannabinoids". In this context, our research targeted the synthesis of minor cannabinoids containing a lateral chain with 3 or 4 carbon atoms, focusing on cannabigerol (CBG) and cannabichromene (CBC) analogues. Using known and innovative strategies, we achieved the synthesis of 11 C3 and C4 analogues, five of which were inhibitors of skin inflammation, with the CBG-C4 ester derivative emerging as the most potent compound.

Approximately 50% of patients with psychiatric disorders do not fully adhere to the prescribed psychopharmacological therapy, significantly impacting the progression of the disorder and the patient's quality of life. The present study aimed to assess potential differences in terms of rates and clinical features of treatment adherence in a large cohort of psychiatric patients with different diagnoses attending various psychiatric services. The study included 307 psychiatric patients diagnosed with a primary major depressive disorder, bipolar disorder, anxiety disorder, schizophrenic spectrum disorder, or personality disorder. Patient's adherence to treatment was evaluated using the Clinician Rating Scale, with a cutoff of at least five defining adherence subgroups. One-third of the sample reported poor medication adherence. A lower rate of adherence emerged among patients with schizophrenic spectrum disorder and bipolar disorder. Subjects with poor adherence were more frequently inpatients and showed higher current substance use, a greater number of previous hospitalizations, and more severe scores at psychopathological assessment compared with patients with positive adherence. Poor adherence was associated with symptom severity and increased rates of relapses and rehospitalizations. In addition, substance use appears to be an unfavorable transdiagnostic factor for treatment adherence., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Introduction: Obsessive-compulsive disorder (OCD) is a prevalent and disabling condition characterized by a wide variety of phenotypic expressions. Several studies have reinforced the hypothesis of OCD heterogeneity by proposing subtypes based on predominant symptomatology, course, and comorbidities. Early-onset OCD (EO) could be considered a neurodevelopmental subtype of OCD, with evidence of distinct neurocircuits supporting disease progression. To deepen the heterogeneous nature of the disorder, we analyzed sociodemographic and clinical differences between the EO and late-onset (LO) subtypes in a large outpatient cohort., Methods: Two hundred and eighty-four patients diagnosed with OCD were consecutively recruited from the OCD Tertiary Clinic at Luigi Sacco University Hospital in Milan. Sociodemographic and clinical variables were analyzed for the entire sample and compared between the two subgroups (EO, age <18 years [n = 117,41.2 %]; LO: late-onset, age ≥18 years [n = 167, 58.8 %])., Results: The EO group showed a higher frequency of male gender (65 % vs 42.5 %, p < .001), and a higher prevalence of Tic and Tourette disorders (9.4 % vs 0 %, p < .001) compared to the LO group. Additionally, in the EO subgroup, a longer duration of untreated illness was observed (9.01 ± 9.88 vs 4.81 ± 7.12; p < .001), along with a lower presence of insight (13.8 % vs. 7.5 %, p < .05)., Conclusions: The early-onset OCD subtype highlights a more severe clinical profile compared to the LO group. Exploring distinct manifestations and developmental trajectories of OCD can contribute to a better definition of homogeneous subtypes, useful for defining targeted therapeutic strategies for treatment., Competing Interests: Declaration of competing interest In the last three years, Prof. Dell’Osso has received lecture honoraria and grants from Angelini, Lundbeck, Janssen, Pfizer, Otzuka, Neuraxpharm, and Livanova. In the last three years, Dr Benatti has received lecture honoraria from Angelini, Lundbeck, Janssen, Rovi. The other authors have no conflicts to declare., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Obsessive Compulsive Disorder (OCD) is listed as one of the top 10 most disabling neuropsychiatric conditions in the world. The neurobiology of OCD has not been completely understood and efforts are needed in order to develop new treatments. Beside the classical neurotransmitter systems and signalling pathways implicated in OCD, the possible involvement of the endocannabinoid system (ECS) has emerged in pathophysiology of OCD. We report here selective downregulation of the genes coding for enzymes allowing the synthesis of the endocannabinoids. We found reduced DAGLα and NAPE-PLD in blood samples of individuals with OCD (when compared to healthy controls) as well as in the amygdala complex and prefrontal cortex of dopamine transporter (DAT) heterozygous rats, manifesting compulsive behaviours. Also mRNA levels of the genes coding for cannabinoid receptors type 1 and type 2 resulted downregulated, respectively in the rat amygdala and in human blood. Moreover, NAPE-PLD changes in gene expression resulted to be associated with an increase in DNA methylation at gene promoter, and the modulation of this gene in OCD appears to be correlated to the progression of the disease. Finally, the alterations observed in ECS genes expression appears to be correlated with the modulation in oxytocin receptor gene expression, consistently with what recently reported. Overall, we confirm here a role for ECS in OCD at both preclinical and clinical level. Many potential biomarkers are suggested among its components, in particular NAPE-PLD, that might be of help for a prompt and clear diagnosis., (© 2024. The Author(s).)

Obsessive-compulsive disorder (OCD) is a prevalent and highly disabling condition, characterized by a range of phenotypic expressions, potentially associated with geo-cultural differences. This article aims to provide an overview of the published studies by the International College of Obsessive-Compulsive Spectrum Disorders, in relation to the Snapshot database which has, over the past 10 years, gathered clinical naturalistic data from over 500 patients with OCD attending various research centers/clinics worldwide. This collaborative effort has provided a multi-cultural worldwide perspective of different socio-demographic and clinical features of patients with OCD. Data on age, gender, smoking habits, age at onset, duration of illness, comorbidity, suicidal behaviors, and pharmacological treatment strategies are presented here, showing peculiar differences across countries.

Background:  The C-type lectin receptor CD93 is a single pass type I transmembrane glycoprotein involved in inflammation, immunity, and angiogenesis. This study investigates the role of CD93 in platelet function. CD93 knockout (KO) mice and wild-type (WT) controls were compared in this study., Methods:  Platelet activation and aggregation were investigated by flow cytometry and light transmission aggregometry, respectively. Protein expression and phosphorylation were analyzed by immunoblotting. Subcellular localization of membrane receptors was investigated by wide-field and confocal microscopy., Results:  The lack of CD93 in mice was not associated to any evident bleeding defect and no alterations of platelet activation were observed upon stimulation with thromboxane A2 analogue and convulxin. Conversely, platelet aggregation induced by stimulation of the thrombin receptor PAR4 was significantly reduced in the absence of CD93. This defect was associated with a significant reduction of α-granule secretion, integrin αIIbβ3 activation, and protein kinase C (PKC) stimulation. Resting WT and CD93-deficient platelets expressed comparable amounts of PAR4. However, upon stimulation with a PAR4 activating peptide, a more pronounced clearance of PAR4 from the platelet surface was observed in CD93-deficient platelets compared with WT controls. Confocal microscopy analysis revealed a massive movement of PAR4 in cytosolic compartments of activated platelets lacking CD93. Accordingly, platelet desensitization following PAR4 stimulation was more pronounced in CD93 KO platelets compared with WT controls., Conclusion:  These results demonstrate that CD93 supports platelet activation triggered by PAR4 stimulation and is required to stabilize the expression of the thrombin receptor on the cell surface., Competing Interests: None declared., (Thieme. All rights reserved.)

The role of circulating tumor cell (CTC) clusters in the metastatic dissemination process is gaining increased attention. Besides homotypic clusters, heterotypic clusters that contain tumor cells admixed with normal cells are frequently observed in patients with solid tumors. Current methods used for cluster detection and enumeration do not allow an accurate estimation of the relative fractions of tumor cells. Here we describe a method for estimating tumor fraction of clusters including isolation and collection of single clusters, assessment of copy number alterations of single clusters by low-pass whole genome sequencing, and bioinformatic analysis of sequencing data., (© 2024. Springer Science+Business Media, LLC, part of Springer Nature.)

The potentially problematic use of the Internet is a growing concern worldwide, which causes and consequences are not completely understood yet. The neurobiology of Internet addiction (IA) has attracted much attention in scientific research, which is now focusing on identifying measurable biological markers. Aim of this study was to investigate epigenetic and genetic regulation of oxytocin receptor (OXTR), dopamine transporter (DAT1) and serotonin transporter (SERT) genes using DNA obtained from saliva samples of young university students: the Internet Addiction Test (IAT) was administered to evaluate the potential existence and intensity of IA. Significant changes in DNA methylation levels at OXTR, DAT1 and SERT genes were observed in the 30 < IAT < 49 group (mild-risk internet users) compared to the IAT < 29 subjects (complete control of internet use) and IAT > 50 subjects (considered as moderately addicted). Moreover, epigenetic markers were significantly correlated, either directly (for OXTR and DAT1) or inversely (OXTR and DAT1 versus SERT), to the psychometric properties. Our data confirmed the association of OXTR, DAT1 and SERT genes in processes related to behavioural addictions and might be of relevance to suggest possible biological predictors of altered behaviours and the eventual vulnerability to develop an IA. Different other genetic pathways have been suggested to play a role in IA and research is ongoing to better define them, in order to help in the early diagnosis as well as in the development of new potential treatments., (© 2023. The Author(s).)

The second messenger cyclic AMP regulates many nuclear processes including transcription, pre-mRNA splicing and mitosis. While most functions are attributed to protein kinase A, accumulating evidence suggests that not all nuclear cyclic AMP-dependent effects are mediated by this kinase, implying that other effectors may be involved. Here we explore the nuclear roles of Exchange Protein Activated by cyclic AMP 1. We find that it enters the nucleus where forms reversible biomolecular condensates in response to cyclic AMP. This phenomenon depends on intrinsically disordered regions present at its amino-terminus and is independent of protein kinase A. Finally, we demonstrate that nuclear Exchange Protein Activated by cyclic AMP 1 condensates assemble at genomic loci on chromosome 6 in the proximity of Histone Locus Bodies and promote the transcription of a histone gene cluster. Collectively, our data reveal an unexpected mechanism through which cyclic AMP contributes to nuclear spatial compartmentalization and promotes the transcription of specific genes., (© 2023. Springer Nature Limited.)

Objective: Limited studies have investigated cannabis use in patients with obsessive-compulsive disorder (OCD), despite its widespread use by patients with psychiatric illnesses. The aim of this study was to assess the frequency, correlates, and clinical impact of cannabis use in an Italian sample of patients with OCD., Methods: Seventy consecutive outpatients with OCD were recruited from a tertiary specialized clinic. To assess cannabis-related variables, patients completed a questionnaire developed for the purpose of this study, investigating cannabis use-related habits and the influence of cannabis use on OCD symptoms and treatments. A set of clinician and self-reported questionnaires was administered to measure disease severity. The sample was then divided into three subgroups according to the pattern of cannabis use: "current users" (CUs), "past-users" (PUs), and "non-users" (NUs)., Results: Approximately 42.8% of patients reported lifetime cannabis use and 14.3% reported current use. Approximately 10% of cannabis users reported an improvement in OCD symptoms secondary to cannabis use, while 23.3% reported an exacerbation of anxiety symptoms. CUs showed specific unfavorable clinical variables compared to PUs and NUs: a significant higher rate of lifetime use of tobacco, alcohol, and other substances, and a higher rate of pre-OCD onset comorbidities. Conversely, the three subgroups showed a similar severity of illness., Conclusion: A considerable subgroup of patients with OCD showed a predisposition towards cannabis use and was associated with some specific clinical characteristics, suggesting the need for targeted consideration and interventions in this population.

Obsessive Compulsive Disorder (OCD) is a mental health condition still classified and diagnosed with subjective interview-based assessments and which molecular clues have not completely been elucidated. We have recently identified a new regulator of anxiety and OCD-like behavior called Immuno-moodulin (IMOOD) and, here, we report that IMOOD gene promoter is differentially methylated in OCD subjects when compared to genomic material collected from healthy controls and this alteration is significantly correlated with the increased expression of the gene in OCD. We also demonstrated that IMOOD promoter can form G-quadruplexes and we suggest that, in homeostatic conditions, these structures could evoke DNA-methylation silencing the gene, whereas in pathological conditions, like OCD, could induce gene expression making the promoter more accessible to transcriptional factors. We here thus further suggest IMOOD as a new biomarker for OCD and also hypothesize new mechanisms of gene regulation., Competing Interests: Declaration of competing interest We wish to confirm that there are no known conflicts of interest associated with this publication and there has been no significant financial support for this work that could have influenced its outcome., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Colorectal carcinoma (CRC) represents the fourth most common cancer worldwide and is the third most common cause of malignancy-associated mortality. Distant metastases to the liver and lungs are the main drivers of CRC-dependent death. Pro-oxidant therapies, which halt disease progression by exacerbating oxidative stress, represent an antitumour strategy that is currently exploited by chemotherapy and ionizing radiation. A more selective strategy to therapeutically exploit reactive oxygen species (ROS) signaling would consist in targeting a redox sensor that is up-regulated in metastatic cells and is tightly coupled to the stimulation of cancer cell death programs. The non-selective cation channel, Transient Receptor Potential Ankyrin 1 (TRPA1), serves as a sensor of the cellular redox state, being activated to promote extracellular Ca 2+ entry by an increase in oxidative stress. Recent work demonstrated that TRPA1 channel protein is up-regulated in several cancer types and that TRPA1-mediated Ca 2+ signals can either engage an antiapoptotic pro-survival signaling pathway or to promote mitochondrial Ca 2+ dysfunction and apoptosis. Herein, we sought to assess for the first time the outcome of TRPA1 activation by ROS on primary cultures of metastatic colorectal carcinoma (mCRC cells). We found that TRPA1 channel protein is up-regulated and mediates enhanced hydrogen peroxide (H 2 O 2 )-induced Ca 2+ entry in mCRC cells as compared to non-neoplastic control cells. The lipid peroxidation product 4-hydroxynonenal (4-HNE) is the main ROS responsible for TRPA1 activation upon mCRC cell exposure to oxidative stress. TRPA1-mediated Ca 2+ entry in response to H 2 O 2 and 4-HNE results in mitochondrial Ca 2+ overload, followed by mitochondrial depolarization and caspase-3/7 activation. Therefore, targeting TRPA1 could represent an alternative strategy to eradicate metastatic CRC by enhancing its sensitivity to oxidative stress., (© 2023. The Author(s).)

The present cross-sectional, retrospective study aimed to assess the prevalence of cardiovascular disease (CVD) risk factors and metabolic syndrome in a sample of psychiatric patients treated with long-acting injectable antipsychotics (LAIs). The clinical charts of 120 patients, mainly diagnosed with schizophrenia (30.0%), schizoaffective disorder (15.0%), and bipolar disorder (13.3%) on LAIs therapy - initiated in the period from 2013 to 2019 and lasting at least one year - were retrospectively reviewed and related socio-demographic, clinical and laboratory variables were collected. The 70.8% of patients were treated with first-generation LAIs, and the remaining 29.2% with second-generation LAIs. The overall sample showed low compliance in performing the required exams and evaluations related to CVD risk factors. The prevalence of metabolic syndrome was 30.8%, and, considering specific CVD risk factors, 55% of the total sample reported abdominal obesity, 43.3% arterial hypertension, 41.7% low HDL-cholesterol, 25.8% hypertriglyceridemia, and 20.8% fasting hyperglycemia. Lastly, 6.7% showed prolonged corrected QT (QTc) interval at the ECG. Patients treated with LAIs should be regularly monitored for metabolic changes and CVD risk factors. Metabolic changes rapidly develop after initiating an antipsychotic therapy and these often involve parameters, that can be easily recorded in an outpatient setting (e.g. abdominal obesity and hypertension)., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: health care workers (HCWs) represent a vulnerable group in the COVID-19 pandemic, given the exposure to greater risk and higher levels of work-related stress. Neurofeedback (NF) has shown to be effective in the treatment of stress-related symptoms. We aimed to assess the effectiveness of an alpha-increase NF protocol for the treatment of acute stress symptoms in HCWs exposed to the COVID-19 pandemic., Method: eighteen medical doctors on duty during the COVID-19 health emergency underwent an intensive NF alpha-increase protocol. The mean alpha wave values were recorded at the beginning (T0) and at the last day of stimulation (T1). Rapid Stress Assessment: Italian version; Copenhagen Burnout Inventory (CBI); Pittsburgh Sleep Quality Index (PSQI), and Brief-COPE were administered as psychometric assessment., Results: a significant increase in alpha wave values and a significant reduction of the PSQI scores from T0 to T1 were found., Conclusions: NF alpha-increase protocol showed promising results in terms of stress modulation, sleep quality improvement, and safety in a pilot sample of HCWs., Competing Interests: Competing interests: BB has received lecture honoraria from Lundbeck and Janssen. BDO has received lecture honoraria from Angelini, Janssen, Lundbeck, Livanova, Arcapharma, and Neuraxpharm., (© 2023 Giovanni Fioriti Editore s.r.l.)

Numerous studies recently showed that the inhibitory neurotransmitter, γ-aminobutyric acid (GABA), can stimulate cerebral angiogenesis and promote neurovascular coupling by activating the ionotropic GABA A receptors on cerebrovascular endothelial cells, whereas the endothelial role of the metabotropic GABA B receptors is still unknown. Preliminary evidence showed that GABA A receptor stimulation can induce an increase in endothelial Ca 2+ levels, but the underlying signaling pathway remains to be fully unraveled. In the present investigation, we found that GABA evoked a biphasic elevation in [Ca 2+ ] i that was initiated by inositol-1,4,5-trisphosphate- and nicotinic acid adenine dinucleotide phosphate-dependent Ca 2+ release from neutral and acidic Ca 2+ stores, respectively, and sustained by store-operated Ca 2+ entry. GABA A and GABA B receptors were both required to trigger the endothelial Ca 2+ response. Unexpectedly, we found that the GABA A receptors signal in a flux-independent manner via the metabotropic GABA B receptors. Likewise, the full Ca 2+ response to GABA B receptors requires functional GABA A receptors. This study, therefore, sheds novel light on the molecular mechanisms by which GABA controls endothelial signaling at the neurovascular unit.

During hemostasis, thrombosis, and inflammation, activated blood platelets release extracellular vesicles (PEVs) that represent biological mediators of physiological and pathological processes. We have recently demonstrated that the activation of platelets by breast cancer cells is accompanied by a massive release of PEVs, evidence that matches with the observation that breast cancer patients display increased levels of circulating PEVs. A core concept in PEVs biology is that their nature, composition and biological function are strongly influenced by the conditions that induced their release. In this study we have performed a comparative characterization of PEVs released by platelets upon activation with thrombin, a potent thrombotic stimulus, and upon exposure to the breast cancer cell line MDA-MB-231. By nanoparticle tracking analysis and tandem mass spectrometry we have characterized the two populations of PEVs, showing that the thrombotic and tumoral stimuli produced vesicles that largely differ in protein composition. The bioinformatic analysis of the proteomic data led to the identification of signaling pathways that can be differently affected by the two PEVs population in target cells. Specifically, we have demonstrated that both thrombin- and cancer-cell-induced PEVs reduce the migration and potentiate Ca 2+ -induced apoptosis of Jurkat cells, but only thrombin-derived PEVs also potentiate cell necrosis. Our results demonstrate that stimulation of platelets by thrombotic or tumoral stimuli induces the release of PEVs with different protein composition that, in turn, may elicit selective biological responses in target cells., (© 2022. The Author(s).)

Background: Platelets can support cancer progression via the release of microparticles and microvesicles that enhance the migratory behaviour of recipient cancer cells. We recently showed that platelet-derived extracellular vesicles (PEVs) stimulate migration and invasiveness in highly metastatic MDA-MB-231 cells by stimulating the phosphorylation of p38 MAPK and the myosin light chain 2 (MLC2). Herein, we assessed whether the pro-migratory effect of PEVs involves the remodelling of the Ca 2+ handling machinery, which drives MDA-MB-231 cell motility., Methods: PEVs were isolated from human blood platelets, and Fura-2/AM Ca 2+ imaging, RT-qPCR, and immunoblotting were exploited to assess their effect on intracellular Ca 2+ dynamics and Ca 2+ -dependent migratory processes in MDA-MB-231 cells., Results: Pretreating MDA-MB-231 cells with PEVs for 24 h caused an increase in Ca 2+ release from the endoplasmic reticulum (ER) due to the up-regulation of SERCA2B and InsP 3 R1/InsP 3 R2 mRNAs and proteins. The consequent enhancement of ER Ca 2+ depletion led to a significant increase in store-operated Ca 2+ entry. The larger Ca 2+ mobilization from the ER was required to potentiate serum-induced migration by recruiting p38 MAPK and MLC2., Conclusions: PEVs stimulate migration in the highly metastatic MDA-MB-231 breast cancer cell line by inducing a partial remodelling of the Ca 2+ handling machinery.

Global concern about problematic usage of the internet (PUI), and its public health and societal costs, continues to grow, sharpened in focus under the privations of the COVID-19 pandemic. This narrative review reports the expert opinions of members of the largest international network of researchers on PUI in the framework of the European Cooperation in Science and Technology (COST) Action (CA 16207), on the scientific progress made and the critical knowledge gaps remaining to be filled as the term of the Action reaches its conclusion. A key advance has been achieving consensus on the clinical definition of various forms of PUI. Based on the overarching public health principles of protecting individuals and the public from harm and promoting the highest attainable standard of health, the World Health Organisation has introduced several new structured diagnoses into the ICD-11, including gambling disorder, gaming disorder, compulsive sexual behaviour disorder, and other unspecified or specified disorders due to addictive behaviours, alongside naming online activity as a diagnostic specifier. These definitions provide for the first time a sound platform for developing systematic networked research into various forms of PUI at global scale. Progress has also been made in areas such as refining and simplifying some of the available assessment instruments, clarifying the underpinning brain-based and social determinants, and building more empirically based etiological models, as a basis for therapeutic intervention, alongside public engagement initiatives. However, important gaps in our knowledge remain to be tackled. Principal among these include a better understanding of the course and evolution of the PUI-related problems, across different age groups, genders and other specific vulnerable groups, reliable methods for early identification of individuals at risk (before PUI becomes disordered), efficacious preventative and therapeutic interventions and ethical health and social policy changes that adequately safeguard human digital rights. The paper concludes with recommendations for achievable research goals, based on longitudinal analysis of a large multinational cohort co-designed with public stakeholders., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Store-operated Ca2+-entry is a cellular mechanism that governs the replenishment of intracellular stores of Ca2+ upon depletion caused by the opening of intracellular Ca2+-channels. Gain-of-function mutations of the 2 key proteins of store-operated Ca2+-entry, STIM1 and ORAI1, are associated with several ultra-rare diseases clustered as tubular aggregate myopathies. Our group has previously demonstrated that a mouse model bearing the STIM1 p.I115F mutation recapitulates the main features of the STIM1 gain-of-function disorders: muscle weakness and thrombocytopenia. Similar findings have been found in other mice bearing different mutations on STIM1. At present, no valid treatment is available for these patients. In the present contribution, we report that CIC-39Na, a store-operated Ca2+-entry inhibitor, restores platelet number and counteracts the abnormal bleeding that characterizes these mice. Subtle differences in thrombopoiesis were observed in STIM1 p.I115F mice, but the main difference between wild-type and STIM1 p.I115F mice was in platelet clearance and in the levels of platelet cytosolic basal Ca2+. Both were restored on treatment of animals with CIC-39Na. This finding paves the way to a pharmacological treatment strategy for thrombocytopenia in tubular aggregate myopathy patients., (© 2022 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Cyberchondria (CYB) is characterized by excessive online searching for medical information and is associated with increasing levels of distress, anxiety, and interference with daily activities. As the use of digital devices and the Internet as a source of everyday information has increased, particularly during the current coronavirus disease (COVID-19) pandemic, so has CYB, becoming an object of interest to clinicians and researchers. The present review will provide an overview of the latest updates in CYB research. Emerging evidence draws attention to various vulnerability factors for developing CYB, including personal characteristics such as female gender, younger age, or a history of mental disorder, as well as engagement in particular forms of online behavior, such as increased use of social media, increased acceptance of online information, and information overload. Additionally, recent studies suggest that CYB may itself act as a mediating factor for increased COVID-19-related psychological burden. However, the data are still very sparse. Knowledge gaps include a universally accepted definition of CYB, severity thresholds to help differentiate nonpathological online health searches from CYB, as well as robustly evidence-based interventions., (© 2022 Elsevier Ltd. All rights reserved.)

Introduction: Obsessive-compulsive disorder (OCD) is characterized by a range of phenotypic expressions. Gender may be a relevant factor in mediating the disorder's heterogeneity. The aim of the present report was to explore a large multisite clinical sample of OCD patients, hypothesizing existing demographic, geographical and clinical differences between male and female patients with OCD., Methods: Socio-demographic and clinical variables of 491 adult OCD outpatients recruited in the International College of Obsessive-Compulsive Spectrum Disorders (ICOCS) network were investigated with a retrospective analysis on a previously gathered set of data from eleven countries worldwide. Patients were assessed through structured clinical interviews, the Yale- Brown Obsessive-Compulsive Scale (Y-BOCS), the Montgomery-Asberg Depression Rating Scale (MADRS) and the Self-rating Depression Scale (SDS)., Results: Among females, adult onset (>18 years old) was significantly over-represented (67% vs. 33%, p < 0.005), and females showed a significantly older age at illness onset compared with males (20.85 ± 10.76 vs. 17.71 ± 8.96 years, p < 0.005). Females also had a significantly lower education level than males (13.09 ± 4.02 vs. 13.98 ± 3.85 years; p < 0.05), a significantly higher rate of being married (50.8% vs. 33.5%; p < 0.001) and a higher rate of living with a partner (47.5% vs. 37.6%; p < 0.001) than males. Nonetheless, no significant gender differences emerged in terms of the severity of OCD symptoms nor in the severity of comorbid depressive symptoms. No predictive effect of gender was found for Y-BOCS, MADRS and SDS severity., Discussion/conclusions: Our findings showed significant differences between genders in OCD. A sexually dimorphic pattern of genetic susceptibility may have a crucial role to OCD clinical heterogeneity, potentially requiring different specific therapeutic strategies. Further research is warranted to validate gender as an important determinant of the heterogeneity in OCD., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Objectives. This cross-sectional study aimed to investigate the frequency and presentation of cyberchondria (CYB) in patients with obsessive-compulsive disorder (OCD), anxiety disorders (ADs), and major depression disorder (MDD). Methods. Seventy-seven patients (OCD:25, ADs:26, MDD:26) referred to a tertiary psychiatry outpatient clinic and 27 healthy controls (HCs) were included. A 'working' definition of CYB was used to measure CYB frequency. CYB severity was measured with the Cyberchondria Severity Scale (CSS). Results. CYB as currently defined was present in just 1.3% of the combined patients' sample. Using a broader definition (omitting the disability criterion), we found a higher distribution (OCD:12%, ADs:19.2%, MDD:15.4%, HCs:3.7%) and greater CYB symptom severity. Patients with OCD (63.3 ± 18.9) and ADs (63.3 ± 25.9) showed a higher CYB severity, compared with HCs (48.4 ± 9.9, p <.05). In the combined patients' sample, a positive correlation was found between the CSS scores and measures of health anxiety or hypochondriasis. Higher CYB symptom severity emerged in patients with a positive family history of psychiatric disorders and in those prescribed benzodiazepines or mood-stabilisers. Conclusion. CYB represents a common transdiagnostic syndrome in patients with OCD, ADs, and MDD with a spectrum of severity and indicates a variable burden of illness, supporting the need for specific clinical considerations and interventions.Key pointsCyberchondria (CYB) represents a common transdiagnostic syndrome in patients with obsessive-compulsive disorder, anxiety, and depressive disorders.CYB's frequency as a syndrome of compulsive online health searches associated with an increased anxiety and distress was reported in 10-20% patients.Health anxiety/hypochondriasis showed a strong correlation with CYB.Patients with a positive family history of psychiatric disorders and those prescribed benzodiazepines or mood-stabilisers showed higher CYB symptom severity.Considering the spread of Internet use for health-related information, additional studies investigating CYB in clinical samples are encouraged.

Deep vein thrombosis results from the cooperative action of leukocytes, platelets, and endothelial cells. The proline-rich tyrosine kinase Pyk2 regulates platelet activation and supports arterial thrombosis. In this study, we combined pharmacological and genetic approaches to unravel the role of Pyk2 in venous thrombosis. We found that mice lacking Pyk2 almost completely failed to develop deep venous thrombi upon partial ligation of the inferior vena cava. Pyk2-deficient platelets displayed impaired exposure of phosphatidylserine and tissue factor expression by endothelial cells and monocytes was completely prevented by inhibition of Pyk2. In human umbilical vein endothelial cells (HUVEC), inhibition of Pyk2 hampered IL-1b-induced expression of VCAM and P-selectin, and von Willebrand factor release. Pyk2-deficient platelets showed defective adhesion on von Willebrand factor and reduced ability to bind activated HUVEC under flow. Moreover, inhibition of Pyk2 in HUVEC strongly reduced platelet adhesion. Similarly, Pyk2-deficient neutrophils were unable to efficiently roll and adhere to immobilized endothelial cells under venous flow conditions. Moreover, platelets and neutrophils from Pyk2- knockout mice showed defective ability to form heterogeneous aggregates upon stimulation, while platelet monocyte interaction occurred normally. Consequently, platelet neutrophil aggregates, abundant in blood of wild-type mice upon inferior vena cava ligation, were virtually undetectable in Pyk2-knockout mice. Finally, we found that expression of Pyk2 was required for NETosis induced by activated platelets. Altogether our results demonstrate a critical role of Pyk2 in the regulation of the coordinated thromboinflammatory responses of endothelial cells, leukocytes and platelets leading to venous thrombosis. Pyk2 may represent a novel promising target in the treatment of deep vein thrombosis.

Background: The mental health (MH) burden on healthcare practitioners (HCPs) is emerging as a significant cost of the pandemic, although few studies have compared the MH of HCPs in different countries., Methods: A link to an online survey was posted in the Spring of 2020 which included questions regarding perceived impact of the pandemic; current MH symptom severity and impairment was evaluated using validated scales., Results: Overall, 1315 individuals (74% female, mean age: 42.9 + 16.4) in Canada, the United States, Brazil and Italy completed the survey. Nearly 26% met diagnostic thresholds for GAD and MDD; Italian respondents reported the lowest rates of disorder. Except for Canada, non-HCPs in each country reported higher symptom severity than HCPs. Amongst the HCPs, Canadian HCPs reported the highest rates of anxiety and depression as well as increases in alcohol and cannabis use, lower levels of perceived emotional support and more worry about themselves or their loved ones contracting COVID-19., Conclusion: Despite key infrastructural and COVID-19 mortality differences between the countries, the MH effects appeared to be quite similar. HCPs, with the exception of Canada, reported less impact on their mental health compared to the general population, suggesting resilience in the face of adversity.Key pointsRates of current mental health disorders were similar across Canada, the USA and Brazil but lower in Italy, yet much higher than pre-pandemic ratesNon-Healthcare Practitioners (HCPs) reported significantly higher severity on all MH scales in the overall sample. This was consistent within the USA, Brazil and Italy, however in Canada, HCPs reported higher anxiety, depression and stress symptom severity compared to Canadian non-HCPs.Canadian HCPs reported significantly higher anxiety and depression symptom severity than all other countriesCanadian HCPs also reported significantly greater increases in alcohol and cannabis use, lower levels of perceived emotional support and more worry about themselves or their loved ones contracting COVID-19 compared to HCPs in the other countries.

Background: Platelet-derived extracellular vesicles (PEVs) are small vesicles released by activated platelets that are gaining growing interest in the field of vascular biology. The mode of platelet activation is a critical determinant of PEVs release, phenotype and function. However, only very limited information is available concerning the impact of the platelet purification procedure on PEVs release., Methods: Washed or isolated platelets were separated by differential centrifugations. For washed platelets, the platelet pellet was washed by resuspension in PIPES buffer and finally resuspended in HEPES buffer. Isolated platelets were obtained by directly resuspending the platelet pellet in HEPES, skipping the washing steps in PIPES buffer. PEVs release was induced in washed or isolated platelets by stimulation with different agonist and analysed by Nanoparticle Tracking Analysis., Results: Isolated platelets showed a higher release of PEVs upon adenosine diphosphate (ADP) stimulation compared to washed platelets, whereas PEVs released upon stimulation with strong agonists (thrombin, collagen, A23187, U46619) were similar in the two groups. This different responsiveness to ADP was also observed as a higher α-granules release and protein kinase C activation in isolated platelets compared to washed ones. Residual plasma contamination appeared to be essential for the ability of platelets to release PEVs in response to ADP., Conclusions: In conclusion, our study strongly suggests that procedure adopted for platelets preparation is a critical determinant of PEVs release upon ADP stimulation., Competing Interests: The authors declare no conflict of interest. MZ and SSB are serving as the Guest Editors of this journal. We declare that MZ and SSB had no involvement in the peer review of this article and have no access to information regarding its peer review. Full responsibility for the editorial process for this article was delegated to GP., (© 2022 The Author(s). Published by IMR Press.)

Background: The isolation of circulating tumor cells (CTCs) requires rapid processing of the collected blood due to their inherent fragility. The ability to recover CTCs from peripheral blood mononuclear cells (PBMCs) preserved from cancer patients could allow for retrospective analyses or multicenter CTC studies., Methods: We compared the efficacy of CTC recovery and characterization using cryopreserved PMBCs vs fresh whole blood from patients with non-small cell lung cancer (NSCLC; n = 8) and sarcoma (n = 6). Two epithelial cellular adhesion molecule (EpCAM)-independent strategies for CTC enrichment, based on Parsortix® technology or immunomagnetic depletion of blood cells (AutoMACS®) were tested, followed by DEPArray™ single-cell isolation. Phenotype and genotype, assessed by copy number alterations analysis, were evaluated at a single-cell level. Detection of target mutations in CTC-enriched samples from frozen NSCLC PBMCs was also evaluated by digital PCR (dPCR)., Results: The use of cryopreserved PBMCs from cancer patients allowed for the retrospective enumeration of CTCs and their molecular characterization, using both EpCAM-independent strategies that performed equally in capturing CTC. Cells isolated from frozen PBMCs were representative of whole blood-derived CTCs in terms of number, phenotype, and copy number aberration profile/target mutations. Long-term storage (≥3 years) did not affect the efficacy of CTC recovery. Detection of target mutations was also feasible by dPCR in CTC-enriched samples derived from stored PBMCs., Conclusions: Isolating CTCs from longitudinally collected PBMCs using an unbiased selection strategy can offer a wider range of retrospective genomic/phenotypic analyses to guide patients' personalized therapy, paving the way for sample sharing in multicenter studies., (© American Association for Clinical Chemistry 2022. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Since the global pandemic of the coronavirus disease 2019 (COVID-19), online health information-seeking behaviors have notably increased. Cyberchondria can be a vulnerability factor for the worsening of anxiety-depressive symptoms and quality of life. The current study aims to understand the predictive effect of cyberchondria on health anxiety, anxiety, depression and quality of life considering the mediating effect of obsessive-compulsive symptoms and Internet addiction and the moderating effect of COVID anxiety. 572 Italian participants (66% female; Mean age = 34; SD = 15) took part in a cross-sectional online survey involving CSS-12, MOCQ-R, IAT, SHAI, HADS, WHOQoL-BREF and CAS. Mediation and moderation analyses were conducted. Obsessive-compulsive symptoms and Internet addiction were found to partially mediate the cyberchondria-health anxiety and the cyberchondria-anxiety links and to totally mediate the cyberchondria-depression and the cyberchondria-quality of life links. COVID anxiety was found to moderate the relationship between cyberchondria and anxiety. The findings suggest that compulsivity may have a key role in the explanation of the underlying mechanisms of cyberchondria. Healthcare practitioners should provide additional support for individuals with cyberchondria. As such, cyberchondria is a contributing factor to the exacerbation of anxiety-depressive disorders and may impact on the quality of life., Competing Interests: The authors declare no conflict of interest., (© 2022 The Authors.)

Nowadays, the use of social networks (SNs) is pervasive and ubiquitous. Among other things, SNs have become a key resource for establishing and maintaining personal relationships, as further demonstrated by the emergence of the pandemic. However, easy access to SNs may be a source of addictive behaviour, especially among the younger population. The literature highlights various psychological and physiological factors as possible predictors of vulnerability to SN addiction. This paper explores the joint effects of stress level and cognitive absorption, in the form of temporal dissociation while on SNs, on the addiction of university students to SNs. Here, 312 participants were involved in an online survey. About 14% of the sample presented a risk for SN addiction. Moreover, it was found that stress level predicted SN addiction both directly and indirectly through the effect of individual temporal dissociation, as experienced during SN usage. These results suggest a significant role of perceived stress level on addiction risk, while also pointing out additional vulnerability to SN addiction for cognitive profiles that are relatively more prone to temporal dissociation while online.

Objective: Bupropion, an antidepressant inhibiting the reuptake of dopamine and noradrenaline, should be useful to treat depressive symptoms in patients with Parkinson's disease (PD). Limited and conflicting literature data questioned its effectiveness and safety in depressed PD patients and extended its use to other neuropsychiatric symptoms associated with this disorder., Design: The databases PubMed, Embase, Web of Sciences, Cochrane Library, and the grey literature were searched. Following a scoping review methodology, articles focusing on Bupropion uses in PD patients who manifested depressive or other neuropsychiatric alterations were reviewed., Results: Twenty-three articles were selected, including 7 original articles, 3 systematic reviews or meta-analyses, 11 case reports, 1 clinical guideline, and 1 expert opinion. Bupropion showed considerable effectiveness in reducing depressive symptoms, particularly in relation to apathy. Solitary findings showed a restorative effect on compulsive behaviour secondary to treatment with dopamine as well as on anxiety symptoms. The effect on motor symptoms remains controversial. The safety profile of this medication seems positive, but additional precautions should be used in subjects with psychotic symptoms., Conclusion: The available literature lacks good evidence to support the use of Bupropion in PD patients presenting depressive symptoms. Further investigations are needed to extend and confirm reported findings and to produce accurate clinical guidelines., (© 2022. The Author(s).)

Background: Obsessive-compulsive disorder (OCD) is a prevalent and severe clinical condition. Robust evidence suggests a gene-environment interplay in its etiopathogenesis, yet the underlying molecular clues remain only partially understood. In order to further deepen our understanding of OCD, it is essential to ascertain how genes interact with environmental risk factors, a cross-talk that is thought to be mediated by epigenetic mechanisms. The human microbiota may be a key player, because bacterial metabolites can act as epigenetic modulators. We analyzed, in the blood and saliva of OCD subjects and healthy controls, the transcriptional regulation of the oxytocin receptor gene and, in saliva, also the different levels of major phyla. We also investigated the same molecular mechanisms in specific brain regions of socially isolated rats showing stereotyped behaviors reminiscent of OCD as well as short chain fatty acid levels in the feces of rats., Results: Higher levels of oxytocin receptor gene DNA methylation, inversely correlated with gene expression, were observed in the blood as well as saliva of OCD subjects when compared to controls. Moreover, Actinobacteria also resulted higher in OCD and directly correlated with oxytocin receptor gene epigenetic alterations. The same pattern of changes was present in the prefrontal cortex of socially-isolated rats, where also altered levels of fecal butyrate were observed at the beginning of the isolation procedure., Conclusions: This is the first demonstration of an interplay between microbiota modulation and epigenetic regulation of gene expression in OCD, opening new avenues for the understanding of disease trajectories and for the development of new therapeutic strategies., (© 2022. The Author(s).)

Competing Interests: Monica NigerConsulting or Advisory Role: Incyte, Basilea Pharmaceutica, EMD Serono, MSD/AstraZenecaTravel, Accommodations, Expenses: Celgene Sherrie BhooriHonoraria: Eisai, Ipsen, Boston ScientificConsulting or Advisory Role: Eisai Maria Di BartolomeoHonoraria: Lilly, MSD Oncology, ServierConsulting or Advisory Role: Lilly, MSD OncologyResearch Funding: LillyTravel, Accommodations, Expenses: Roche, Sanofi Filippo PietrantonioHonoraria: Servier, Bayer, AstraZeneca/MedImmune, Lilly, Sanofi, MSD Oncology, AmgenConsulting or Advisory Role: Amgen, Servier, MSD Oncology, MerckResearch Funding: Bristol Myers Squibb (Inst), AstraZeneca (Inst) Filippo de BraudHonoraria: Roche, Pfizer, BMS, Merck, MSD, Servier, Sanofi, Amgen Astellas BioPharma, IncyteConsulting or Advisory Role: Roche, Incyte, EMD SERONO, Bristol Myers Squibb, Nerviano Medical Sciences, Sanofi, Novartis Italy, NMS Medical Science, MenariniResearch Funding: Novartis (Inst), Roche (Inst), Merck Serono (Inst), Pfizer (Inst), Servier (Inst), Philogen (Inst), Loxo (Inst), Tesaro (Inst), Nerviano Medical Sciences (Inst), Kymab (Inst), Bristol Myers Squibb/Medarex, Merck KGaA, Ignyta, MedImmune, Exelixis, Bayer Health, Daiichi Sankyo Europe GmbH, Incyte, Basilea Pharmaceutical, Janssen Oncology Giancarlo PruneriHonoraria: Novartis, Roche, Genomic HealthConsulting or Advisory Role: ADS BiotecResearch Funding: Roche, Roche Molecular DiagnosticsNo other potential conflicts of interest were reported.

Triple negative breast cancer (TNBC) is characterized by clinical aggressiveness, lack of recognized target therapy, and a dismal patient prognosis. Several studies addressed genomic changes occurring during neoadjuvant chemotherapy (NAC) focusing on somatic variants, but without including copy number alterations (CNAs). We analyzed CNA profiles of 31 TNBC primary tumor samples before and after NAC and of 35 single circulating tumor cells (CTCs) collected prior, during and after treatment by using next-generation sequencing targeted profile and low-pass whole genome sequencing, respectively. In pre-treatment tissue samples, the most common gains occurred on chromosomes 1, 2 and 8, and SOX11 and MYC resulted the most altered genes. Notably, amplification of MSH2 (4/4 versus 0/12, p < 0.01) and PRDM1 and deletion of PAX3 (4/4 versus 1/12, p < 0.01) significantly characterized primary tumors of patients with pathological complete response. All patients with paired pre- and post-NAC samples reported a change in post-treatment CNAs compared to baseline, despite they showed at least one common alteration. CNAs detected after treatment involved genes within druggable pathways such as EGFR, cell cycle process and Ras signaling. In two patients, CTCs shared more alterations with residual rather than primary tumor involving genes such as MYC, BCL6, SOX2, FGFR4. The phylogenetic analysis of CTCs within a single patient revealed NAC impact on tumor evolution, suggesting a selection of driver events under treatment pressure. In conclusion, our data showed how chemoresistance might arise early from treatment-induced selection of clones already present in the primary tumor, and that the characterization of CNAs on single CTCs informs on cancer evolution and potential druggable targets., (© 2022. The Author(s).)

Background: Brain-Derived Neurotrophic Factor (BDNF) is a promising candidate biomarker in both the development and aetiology of different neuropsychiatric conditions, including obsessive-compulsive disorder (OCD). Most of the studies in the field have been carried out in blood cells, including peripheral blood mononucleated cells (PBMCs), although DNA of high quality can be easily isolated from saliva., Objective: The objective of this study was to evaluate the epigenetic regulation of the BDNF gene in the saliva of a clinical sample of OCD patients in order to assess this source as an alternative to blood., Methods: We first analyzed DNA methylation levels at BDNF in the saliva of subjects suffering from OCD (n= 50) and healthy controls (n=50). Then, we compared these data with the results previously obtained for the same genomic region in blood samples from the same patients and controls (CTRL)., Results: Our preliminary data showed a significant reduction of 5mC levels at BDNF gene (OCD: 1.23 ± 0.45; CTRL: 1.85 ± 0.64; p < 0.0001) and a significant correlation between DNA methylation in PBMCs and saliva (Spearman r = 0.2788)., Conclusion: We support the perspective that saliva could be a possible, reliable source, and a substitute for blood, in search of epigenetic biomarkers in OCD., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Endothelial colony forming cells (ECFCs) represent the most suitable cellular substrate to induce revascularization of ischemic tissues. Recently, optical excitation of the light-sensitive conjugated polymer, regioregular Poly (3-hexyl-thiophene), rr-P3HT, was found to stimulate ECFC proliferation and tube formation by activating the non-selective cation channel, Transient Receptor Potential Vanilloid 1 (TRPV1). Herein, we adopted a multidisciplinary approach, ranging from intracellular Ca 2+ imaging to pharmacological manipulation and genetic suppression of TRPV1 expression, to investigate the effects of photoexcitation on intracellular Ca 2+ concentration ([Ca 2+ ] i ) in circulating ECFCs plated on rr-P3HT thin films. Polymer-mediated optical excitation induced a long-lasting increase in [Ca 2+ ] i that could display an oscillatory pattern at shorter light stimuli. Pharmacological and genetic manipulation revealed that the Ca 2+ response to light was triggered by extracellular Ca 2+ entry through TRPV1, whose activation required the production of reactive oxygen species at the interface between rr-P3HT and the cell membrane. Light-induced TRPV1-mediated Ca 2+ entry was able to evoke intracellular Ca 2+ release from the endoplasmic reticulum through inositol-1,4,5-trisphosphate receptors, followed by store-operated Ca 2+ entry on the plasma membrane. These data show that TRPV1 may serve as a decoder at the interface between rr-P3HT thin films and ECFCs to translate optical excitation in pro-angiogenic Ca 2+ signals., (Copyright © 2021. Published by Elsevier Ltd.)

Objectives: The Internet has become one of the most common sources people use to search for health-related information, a behavior rapidly increased during the novel Coronavirus disease 2019 (COVID-19). The present study aimed to investigate behavioral patterns in the online health-related searches and Cyberchondria (CYB) during the COVID-19 pandemic time, in order to explore socio-demographic and psychopathological factors related to CYB. Methods: During the third wave of the COVID-19 pandemic in Italy, a cross-sectional online survey collected the main socio-demographic variables and habits related to Internet use of 572 participants. CYB was measured by the Cyberchondria Severity Scale-Short Version and different psychopathological factors were measured by specific questionnaires: the Coronavirus Anxiety Scale, the Hospital Anxiety and Depression Scale, the Short Health Anxiety Inventory, the Meta-Cognitions about Health Questionnaire, the Internet Addiction Test, the Maudsley Obsessional-Compulsive Questionnaire-Short Version, the Rosenberg's Self-Esteem Scale, and the WHO Quality of Life-BREF. Descriptives, non-parametric ANOVAs, and Spearman correlations were performed. Results: In the present sample, the Internet was the main source participants used to search for health-related information and nearly one-third increased this habit during the pandemic. Higher expression of CYB emerged in females, in younger participants, in students, and in those suffering from a physical/psychiatric illness. CYB showed a positive correlation with different phenomenology of anxiety (i.e., anxiety about COVID-19, health anxiety, general anxiety, metacognitive believes about anxiety) and with depression, obsessive-compulsive symptoms, and problematic usage of the Internet. Conversely, quality of life and self-esteem showed a negative correlation with CYB. Conclusion: During the COVID-19 pandemic, the use of the Internet for health-related information and CYB contribute to the psychological stress affecting individuals and society. Delineating subjects more vulnerable to CYB and associated psychopathological factors will help to elaborate operational indications for prevention and psychological support., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Vismara, Vitella, Biolcati, Ambrosini, Pirola, Dell'Osso and Truzoli.)

Background: Clinical therapeutic approaches to Bipolar Disorders (BDs) include diverse pharmacotherapies, targeting different symptomatic BD presentations. To date, guidelines about pharmacological treatment of BDs have focused on short-term treatment of mood episodes, at the expense of longer-term treatment, especially for (the most common) predominantly depressive polarity patients., Methods: A database of BD-I and BD-II patients was collected between 2013 and 2019 at the University Psychiatric Clinic of Ospedale Policlinico and Ospedale Luigi Sacco of Milan. Only patients in euthymic phases (no current mood episode) were included in the study. We then analyzed socio-demographic and clinical characteristic overall and in the subgroup BD-I and BD-II, comparing patients taking vs. not taking ADs., Results: Our results showed that approximately 1/3 of BD patients between acute episodes took ADs, also among patients from the subgroup with BD-I, especially those first presenting with a depressive episodes, and those with a most recent depressive (as opposed to elevated, irritable, or mixed) polarity episode., Limitations: Although patients included in our study were primarily in follow up for Bipolar Disorder, use of ADs could be explained by other comorbidities, such as Anxiety or Eating Disorders., Conclusions: These data shed light on how managing depressive symptoms is a very important aspect of treating BDs, highlighting the need for wider and more specific studies on the use of ADs in BDs., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Introduction: Problematic Usage of the Internet (PUI) refers to a broad and likely heterogeneous group of Internet-related conditions associated with behavioural disturbances and functional impairment., Methods: Within PUI several conditions have been reported, including Gaming Disorder, Shopping Addiction, Cyberchondria, Gambling Disorder, Cyberpornography Addiction and Cyberbullying. While increasing reports in the field try to define the epidemiologic and clinical boundaries of these conditions, the rapid and continuous evolution of Internet related behaviours as well as their problematic/pathological expressions are often difficult to diagnose, assess, approach with treatment interventions and follow-up., Results: In addition, some of the PUI-related conditions show characteristics of addiction to the Internet as a preferential tool to engage in specific behaviours, while some others exclusively manifest on the Internet, making it necessary to find distinct assessment and treatment pathways., Conclusion: The inclusion of Internet Gaming Disorder in Section III by the DSM-5 and the recognition of Gaming Disorder by the ICD-11 opened the way for a systematic clinical investigation of this and other PUI-related conditions, particularly in terms of preventive and therapeutic strategies. The present article is aimed at offering an updated clinical overview on the main expressions of PUI, focussing on the latest acquisitions in this evolving field., (© 2021 Dell’Osso et al.)

The clinical relevance of circulating tumor cell clusters (CTC-clusters) in breast cancer (BC) has been mostly studied using the CellSearch ® , a marker-dependent method detecting only epithelial-enriched clusters. However, due to epithelial-to-mesenchymal transition, resorting to marker-independent approaches can improve CTC-cluster detection. Blood samples collected from healthy donors and spiked-in with tumor mammospheres, or from BC patients, were processed for CTC-cluster detection with 3 technologies: CellSearch ® , CellSieve™ filters, and ScreenCell ® filters. In spiked-in samples, the 3 technologies showed similar recovery capability, whereas, in 19 clinical samples processed in parallel with CellSearch ® and CellSieve™ filters, filtration allowed us to detect more CTC-clusters than CellSearch ® (median number = 7 versus 1, p = 0.0038). Next, samples from 37 early BC (EBC) and 23 metastatic BC (MBC) patients were processed using ScreenCell ® filters for attaining both unbiased enrichment and marker-independent identification (based on cytomorphological criteria). At baseline, CTC-clusters were detected in 70% of EBC cases and in 20% of MBC patients (median number = 2, range 0-20, versus 0, range 0-15, p = 0.0015). Marker-independent approaches for CTC-cluster assessment improve detection and show that CTC-clusters are more frequent in EBC than in MBC patients, a novel finding suggesting that dissemination of CTC-clusters is an early event in BC natural history.

Obsessive-Compulsive Disorder (OCD) is a prevalent and severe clinical condition whose hallmarks are excessive, unwanted thoughts (obsessions) and repetitive behaviors (compulsions). The onset of symptoms generally occurs during pre-adult life and typically affects subjects in different aspects of their life's, compromising social and professional relationships. Although robust evidence suggests a genetic component in the etiopathogenesis of OCD, the causes of the disorder are still not completely understood. It is thus of relevance to take into account how genes interact with environmental risk factors, thought to be mediated by epigenetic mechanisms. We here provide an overview of genetic and epigenetic mechanisms of OCD, focusing on the modulation of key central nervous system genes, in the attempt to suggest possible disease biomarkers., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: Cognitive behavioural therapy (CBT), incorporating exposure and response prevention (ERP) is widely recognised as the psychological treatment of choice for obsessive-compulsive disorder (OCD). Uncertainty remains however about the magnitude of the effect of CBT with ERP and the impact of moderating factors in patients with OCD., Method: This systematic review and meta-analysis assessed randomised-controlled trials of CBT with ERP in patients of all ages with OCD. The study was preregistered in PROSPERO (CRD42019122311). The primary outcome was end-of-trial OCD symptom scores. The moderating effects of patient-related and study-related factors including type of control intervention and risk of bias were examined. Additional exploratory analyses assessed the effects of treatment fidelity and impact of researcher allegiance., Results: Thirty-six studies were included, involving 2020 patients (537 children/adolescents and 1483 adults) with 1005 assigned to CBT with ERP and 1015 to control conditions. When compared against all control conditions, a large pooled effect size (ES) emerged in favour of CBT with ERP (g = 0.74: 95% CI = 0.51 to 0.97 k = 36), which appeared to diminish with increasing age. While CBT with ERP was more effective than psychological placebo (g = 1.13 95% CI 0.71 to 1.55, k = 10), it was no more effective than other active forms of psychological therapy (g = -0.05: 95% CI -0.27 to 0.16, k = 8). Similarly, whereas CBT with ERP was significantly superior when compared to all forms of pharmacological treatment (g = 0.36: 95% CI 0.7 to 0.64, k = 7), the effect became marginal when compared with adequate dosages of pharmacotherapy for OCD (g = 0.32: 95% CI -0.00 to 0.64, k = 6).A minority of studies (k = 8) were deemed to be at low risk of bias. Moreover, three quarters of studies (k = 28) demonstrated suspected researcher allegiance and these studies reported a large ES (g = 0.95: 95% CI 0.69 to 1.2), while those without suspected researcher allegiance (k = 8) indicated that CBT with ERP was not efficacious (g = 0.02: 95% CI -0.29 to 0.33)., Conclusions: A large effect size was found for CBT with ERP in reducing the symptoms of OCD, but depends upon the choice of comparator control. This meta-analysis also highlights concerns about the methodological rigor and reporting of published studies of CBT with ERP in OCD. In particular, efficacy was strongly linked to researcher allegiance and this requires further future investigation., Competing Interests: Declaration of Competing Interest Prof. Naomi A. Fineberg declares that in the past 3 years she has held research or networking grants from the ECNP, UK NIHR, EU H2020, MRC, University of Hertfordshire; she has accepted travel and/or hospitality expenses from the BAP, ECNP, RCPsych, CINP, International Forum of Mood and Anxiety Disorders, World Psychiatric Association, Indian Association for Biological Psychiatry, Sun; she has received payment from Taylor and Francis and Elsevier for editorial duties. In the past 3 years, she has accepted a paid speaking engagement in a webinar sponsored by Abbott. Previously, she has accepted paid speaking engagements in various industry supported symposia and has recruited patients for various industry-sponsored studies in the field of OCD treatment. She leads an NHS treatment service for OCD. She holds Board membership for various registered charities linked to OCD. She gives expert advice on psychopharmacology to the UK MHRA. Dr. Jemma Reid, Prof. Keith Laws, Dr. Matteo Vismara and Dr. Benedetta Grancini report no financial relationships with commercial interests., (Copyright © 2021. Published by Elsevier Inc.)