Borderline personality disorder and aggressive behavior: A study based on the DSM-5 alternative model.

INTRODUCTION: Unplanned reactive aggressive acts are a clinical feature of particular interest in patients with borderline personality disorder (BPD). The early identification of personality traits correlated to aggressive behavior is certainly desirable in BDP populations. This study analyzes a clinical sample of 122 adult outpatients with BPD referred to Adult Mental Health Services of the Department of Mental Health of Bologna, in Italy. METHODS: The study examines the relationship with personality facets of the DSM-5 alternative model for personality disorders (AMPD), Personality Inventory for DSM (PID-5), with respect to the four main components of aggression measured by the Aggression Questionnaire (AQ): hostility, anger, verbal and physical aggression. Using robust regression models, the relationships between PID-5 facets and domains and the aggression components under consideration were identified. RESULTS: Verbal and physical aggression in our sample of BPD outpatients is mainly associated to PID-5 antagonism domain. Physically aggressive behavior is also related to callousness facet. CONCLUSIONS: The traits most consistently associated with aggression were the domain of Antagonism and the facet of Hostility. The study findings highlight the need for clinicians working with individuals with BPD to pay particular attention to traits of hostility, callousness, and hostility to understand aggression.

Differential effects of sertraline and cognitive behavioural therapy on behavioural inhibition in patients with obsessive compulsive disorder.

Patients with obsessive compulsive disorder (OCD) randomised to sertraline, manualised cognitive behavioural therapy (CBT), or combination (sertraline + CBT), underwent cognitive assessment. Cognitive testing was conducted at baseline and at week 16. The stop signal reaction time task (SSRT) was used to evaluate motor impulsivity and attentional flexibility was evaluated using the intra/extra-dimensional set shifting task. Paired-samples t -tests or nonparametric variants were used to compare baseline and posttreatment scores within each treatment group. Forty-five patients were tested at baseline (sertraline n  = 14; CBT n  = 14; sertraline + CBT n  = 17) and 23 patients at week 16 (sertraline n  = 6; CBT n  = 7; sertraline + CBT n  = 10). The mean dosage of sertraline was numerically higher in those taking sertraline as a monotherapy (166.67 mg) compared with those taking sertraline in combination with CBT (100 mg). Analysis of pre-post treatment scores using an intent-to-treat-analysis found a significant reduction in the SSRT in those treated with sertraline, whilst there was no significant change on this task for those treated with CBT or the combination. This study found that motor inhibition improved significantly following sertraline monotherapy. Suboptimal sertraline dosing might explain the failure to detect an effect on motor inhibition in the group receiving combination of sertraline + CBT. Higher dose sertraline may have broader cognitive effects than CBT for OCD, motor impulsivity may have value as a measure of treatment outcome and, by extension, the SSRT could serve as a biomarker for personalising care.

CryoEM insights into RNA primer synthesis by the human primosome.

Eukaryotic DNA replication depends on the primosome - a complex of DNA polymerase alpha (Pol α) and primase - to initiate DNA synthesis by polymerisation of an RNA-DNA primer. Primer synthesis requires the tight coordination of primase and polymerase activities. Recent cryo-electron microscopy (cryoEM) analyses have elucidated the extensive conformational transitions required for RNA primer handover between primase and Pol α and primer elongation by Pol α. Because of the intrinsic flexibility of the primosome, however, structural information about the initiation of RNA primer synthesis is still lacking. Here, we capture cryoEM snapshots of the priming reaction to reveal the conformational trajectory of the human primosome that brings DNA primase subunits 1 and 2 (PRIM1 and PRIM2, respectively) together, poised for RNA synthesis. Furthermore, we provide experimental evidence for the continuous association of primase subunit PRIM2 with the RNA primer during primer synthesis, and for how both initiation and termination of RNA primer polymerisation are licenced by specific rearrangements of DNA polymerase alpha catalytic subunit (POLA1), the polymerase subunit of Pol α. Our findings fill a critical gap in our understanding of the conformational changes that underpin the synthesis of the RNA primer by the primosome. Together with existing evidence, they provide a complete description of the structural dynamics of the human primosome during DNA replication initiation.

Structural basis for stabilisation of the RAD51 nucleoprotein filament by BRCA2.

The BRCA2 tumour suppressor protein preserves genomic integrity via interactions with the DNA-strand exchange RAD51 protein in homology-directed repair. The RAD51-binding TR2 motif at the BRCA2 C-terminus is essential for protection and restart of stalled replication forks. Biochemical evidence shows that TR2 recognises filamentous RAD51, but existing models of TR2 binding to RAD51 lack a structural basis. Here we used cryo-electron microscopy and structure-guided mutagenesis to elucidate the mechanism of TR2 binding to nucleoprotein filaments of human RAD51. We find that TR2 binds across the protomer interface in the filament, acting as a brace for adjacent RAD51 molecules. TR2 targets an acidic-patch motif on human RAD51 that serves as a recruitment hub in fission yeast Rad51 for recombination mediators Rad52 and Rad55-Rad57. Our findings provide a structural rationale for RAD51 filament stabilisation by BRCA2 and reveal a common recruitment mechanism of recombination mediators to the RAD51 filament.

Healthcare Service Quality Evaluation in a Community-Oriented Primary Care Center, Italy.

Community-oriented primary care (COPC) is an inclusive healthcare approach that combines individual care with a population-based outlook, striving to offer effective and equitable services. This study concentrates on assessing the perceived quality of a "Casa della Comunità" (CdC) implemented by the Romagna Local Health Authority, which embraces the COPC model. Through the examination of user experiences, the study aims to comprehend the influence of the CdC's care delivery model on the community's perception of service quality. From 13-18 March 2023, paper questionnaires were distributed by trained healthcare professionals and volunteers. The cross-sectional study enrolled participants aged 18 or older, capable of understanding written Italian, and willing to take part voluntarily. A total of 741 questionnaires were collected, resulting in an overall acceptance rate of 85.6%. Among the respondents, 37.9% were female, with an average age of 55.4 ± 16.2 years. While the respondents generally held a positive view of the quality, the results displayed varying levels of satisfaction across the different areas. Multivariate analysis revealed significant associations between factors such as gender, employment status, financial resources, education level, and distance from the healthcare center with the perceived quality of the facility in terms of accessibility, environment, staff, continuity of care, and overall satisfaction. The study yielded valuable insights, identifying strengths and areas for improvement and underscoring the importance of ongoing monitoring studies to enhance patient satisfaction continuously.

Problematic internet use during the COVID-19 pandemic: A systematic review and meta-analysis of prevalence data.

AIMS: This study sought to synthesize prevalence rates of problematic internet use (PIU) during the COVID-19 pandemic in the general adult (age over 18 years old) population and to investigate its possible moderators. METHODS: A preregistered systematic literature review using the PubMed/MEDLINE, EBSCOhost/PsycINFO, Web of Science, Cochrane Library, GSK Clinical Study Register, and ClinicalTrials.gov databases was conducted. Research was completed in accordance with the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols 2015 checklist. RESULTS: A total of 22 publications were identified, fulfilling inclusion criteria from a total of 595 studies. The analysis revealed that the prevalence of PIU during the COVID-19 pandemic period was 25%, however applying a stringent threshold for the PIU, resulted in a much lower prevalence of 7.9%. CONCLUSION: The PIU prevalence rate during the COVID-19 pandemic in the general population was 7.9%. Measuring the prevalence of PIU remains complicated due to the large methodological and cultural diversity that exists, so global prevalence estimates of PIU vary substantially. More methodologically sound research on psychodiagnostic assessment and cultural variances is required. (Neuropsychopharmacol Hung 2023; 25(3): 131-141) Keywords: COVID-19; internet addiction; problematic usage of the internet; prevalence; systematic review, meta-analysis Systematic review registration: PROSPERO registration number: CRD42021284619.

Liver inter-organelle membrane contact sites revealed by serial section electron tomography.

Inter-organelle membrane contact sites (MCSs) are defined as areas of close proximity between the membranes of two organelles (10-80nm). They have been implicated in many physiological processes such as Ca++, lipids or small molecules transfer, organelles biogenesis or dynamic and have an important role in many cellular processes such as apoptosis, autophagy, and signaling. Since the distance and the extent of these contacts are in the nanometer range, high resolution techniques are ideal for imaging these structures. It is for this reason that transmission electron microscopy (TEM) has been considered the gold standard for MCSs visualization and the first technique that described them. However, often TEM analysis is limited to 2D lacking information on the 3D association between the organelles involved in MCSs. To fully describe the complex architecture of MSCs and to unveil their role in cellular physiology a 3D analysis is required. This chapter provides a method for the analysis of MCSs using serial section electron tomography (ssET), a technique able to reconstruct in 3D at nanometer resolution cellular and subcellular structures. By applying this procedure, it was possible to elucidate the role of the contacts between Endoplasmic Reticulum (ER) and other organelles in liver lipid metabolism.

Episodic obsessive-compulsive disorder and bipolar spectrum disorder: new evidence from a large Italian OCD sample.

OBJECTIVES: Obsessive-Compulsive Disorder (OCD) has been considered to be a chronic illness; however, some authors described a subtype of OCD characterised by symptom-free periods of time: Episodic-OCD (E-OCD). Only few studies focussed on this subtype of the disorder. The objectives of this research were to study the association between the episodic course of the disorder and lifetime psychiatric comorbidities and to investigate socio-demographic and other clinical features correlated to the episodic course. METHODS: The sample is composed of adult OCD patients. The course was defined episodic when at least one circumscribed symptom-free interval of at least 6 months was present. The sample was divided into two subgroups: Episodic-OCD and Chronic-OCD. Differences between groups were analysed with Student's t-test, χ2 tests, Fisher test and multivariate logistic regression. RESULTS: Data regarding 585 individuals were collected. 14.2% (N = 83) of our sample had an episodic course. Bipolar I comorbid disorder, abrupt onset, lower severity of illness and lower rates of repeating compulsions were associated with the likelihood of having an E-OCD. CONCLUSIONS: Our findings confirm that a significant proportion of OCD patients have an episodic course and that E-OCD could represent a specific endophenotype.

A significant proportion of OCD patients has an episodic course;Episodic OCD was related to comorbid Bipolar I Disorder;Episodic course was associated with an abrupt onset of OCD;Lower rates of repeating compulsions were associated with Episodic OCD.

A metal ion-dependent mechanism of RAD51 nucleoprotein filament disassembly.

The RAD51 ATPase polymerizes on single-stranded DNA to form nucleoprotein filaments (NPFs) that are critical intermediates in the reaction of homologous recombination. ATP binding maintains the NPF in a competent conformation for strand pairing and exchange. Once strand exchange is completed, ATP hydrolysis licenses the filament for disassembly. Here we show that the ATP-binding site of the RAD51 NPF contains a second metal ion. In the presence of ATP, the metal ion promotes the local folding of RAD51 into the conformation required for DNA binding. The metal ion is absent in the ADP-bound RAD51 filament, that rearranges in a conformation incompatible with DNA binding. The presence of the second metal ion explains how RAD51 couples the nucleotide state of the filament to DNA binding. We propose that loss of the second metal ion upon ATP hydrolysis drives RAD51 dissociation from the DNA and weakens filament stability, contributing to NPF disassembly.

The CMG DNA helicase and the core replisome.

Eukaryotic DNA replication is performed by the replisome, a large and dynamic multi-protein machine endowed with the required enzymatic components for the synthesis of new DNA. Recent cryo-electron microscopy (cryoEM) analyses have revealed the conserved architecture of the core eukaryotic replisome, comprising the CMG (Cdc45-MCM-GINS) DNA helicase, the leading-strand DNA polymerase epsilon, the Timeless-Tipin heterodimer, the hub protein AND-1 and the checkpoint protein Claspin. These results bid well for arriving soon at an integrated understanding of the structural basis of semi-discontinuous DNA replication. They further set the scene for the characterisation of the mechanisms that interface DNA synthesis with concurrent processes such as DNA repair, propagation of chromatin structure and establishment of sister chromatid cohesion.

Feasibility, acceptability and practicality of transcranial stimulation in obsessive compulsive symptoms (FEATSOCS): A randomised controlled crossover trial.

BACKGROUND: Transcranial direct current stimulation (tDCS) is a non-invasive form of neurostimulation with potential for development as a self-administered intervention. It has shown promise as a safe and effective treatment for obsessive compulsive disorder (OCD) in a small number of studies. The two most favourable stimulation targets appear to be the left orbitofrontal cortex (L-OFC) and the supplementary motor area (SMA). We report the first study to test these targets head-to-head within a randomised sham-controlled trial. Our aim was to inform the design of future clinical research studies, by focussing on the acceptability and safety of the intervention, feasibility of recruitment, adherence to and tolerability of tDCS, and the size of any treatment-effect. METHODS: FEATSOCS was a randomised, double-blind, sham-controlled, cross-over, multicentre study. Twenty adults with DSM-5-defined OCD were randomised to treatment, comprising three courses of clinic-based tDCS (SMA, L-OFC, Sham), randomly allocated and delivered in counterbalanced order. Each course comprised four 20-min 2 mA stimulations, delivered over two consecutive days, separated by a 'washout' period of at least four weeks. Assessments were carried out by raters who were blind to stimulation-type. Clinical outcomes were assessed before, during, and up to four weeks after stimulation. Patient representatives with lived experience of OCD were actively involved at all stages. RESULTS: Clinicians showed willingness to recruit participants and recruitment to target was achieved. Adherence to treatment and study interventions was generally good, with only two dropouts. There were no serious adverse events, and adverse effects which did occur were transient and mostly mild in intensity. Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) scores were numerically improved from baseline to 24 h after the final stimulation across all intervention groups but tended to worsen thereafter. The greatest effect size was seen in the L-OFC arm, (Cohen's d = -0.5 [95% CI -1.2 to 0.2] versus Sham), suggesting this stimulation site should be pursued in further studies. Additional significant sham referenced improvements in secondary outcomes occurred in the L-OFC arm, and to a lesser extent with SMA stimulation. CONCLUSIONS: tDCS was acceptable, practicable to apply, well-tolerated and appears a promising potential treatment for OCD. The L-OFC represents the most promising target based on clinical changes, though the effects on OCD symptoms were not statistically significant compared to sham. SMA stimulation showed lesser signs of promise. Further investigation of tDCS in OCD is warranted, to determine the optimal stimulation protocol (current, frequency, duration), longer-term effectiveness and brain-based mechanisms of effect. If efficacy is substantiated, consideration of home-based approaches represents a rational next step. TRIAL REGISTRATION: ISRCTN17937049. https://doi.org/10.1186/ISRCTN17937049.

Assessing suicide risk in patients with obsessive-compulsive disorder: a dimensional approach

Objectives: Although an association has been found recently between obsessive-compulsive disorder and an increased risk of suicide, the prevalence of both suicidal ideation and attempts vary considerably and are generally assessed categorically. Our aims were to evaluate the prevalence of suicidal ideation and behaviors using a dimensional approach. Methods: The sample included 129 patients with obsessive-compulsive disorder. Suicidality was assessed by administering the Columbia-Suicide Severity Rating Scale. Logistic and linear regressions were used to examine predictors of suicidal ideation, severe suicidal ideation, and suicidal behavior. Results: The lifetime prevalence of suicidal ideation and behaviors were 64.3% and 16.3%, respectively. Lifetime suicidal ideation was associated with the number of stressful life events, duration of illness, Hamilton Rating Scale for Depression scores, and family history of mood disorders. A family history of obsessive-compulsive disorder was associated with a lower probability of lifetime suicidal ideation. Severe suicidal ideation was related to greater severity of the most stressful life event, Hamilton Rating Scale for Depression scores, and longer duration of untreated illness. The probability of lifetime suicidal behavior was related to Hamilton Rating Scale for Anxiety scores, symmetry obsessions, and washing and checking compulsions. The probability of lifetime non-suicidal self-injurious behaviors was related to Hamilton Rating Scale for Anxiety scores. Conclusions: Recognizing predictors of suicidal ideation/behavior is crucial to identifying patients at greater risk.

Assessing suicide risk in patients with obsessive-compulsive disorder: a dimensional approach.

OBJECTIVES: Although an association has been found recently between obsessive-compulsive disorder and an increased risk of suicide, the prevalence of both suicidal ideation and attempts vary considerably and are generally assessed categorically. Our aims were to evaluate the prevalence of suicidal ideation and behaviors using a dimensional approach. METHODS: The sample included 129 patients with obsessive-compulsive disorder. Suicidality was assessed by administering the Columbia-Suicide Severity Rating Scale. Logistic and linear regressions were used to examine predictors of suicidal ideation, severe suicidal ideation, and suicidal behavior. RESULTS: The lifetime prevalence of suicidal ideation and behaviors were 64.3% and 16.3%, respectively. Lifetime suicidal ideation was associated with the number of stressful life events, duration of illness, Hamilton Rating Scale for Depression scores, and family history of mood disorders. A family history of obsessive-compulsive disorder was associated with a lower probability of lifetime suicidal ideation. Severe suicidal ideation was related to greater severity of the most stressful life event, Hamilton Rating Scale for Depression scores, and longer duration of untreated illness. The probability of lifetime suicidal behavior was related to Hamilton Rating Scale for Anxiety scores, symmetry obsessions, and washing and checking compulsions. The probability of lifetime non-suicidal self-injurious behaviors was related to Hamilton Rating Scale for Anxiety scores. CONCLUSIONS: Recognizing predictors of suicidal ideation/behavior is crucial to identifying patients at greater risk.

Effects of exercise on obsessive-compulsive disorder symptoms: a systematic review and meta-analysis.

OBJECTIVE: This systematic review and meta-analysis assessed the efficacy of exercise in reducing OCD symptoms. METHODS: We searched PubMed, Cochrane Central Register of Controlled Trials, MEDLINE, Scopus and grey literature until March 2022. The study was preregistered at Prospero (CRD42021283931). We included randomised controlled and pre-post trials assessing physical activity as an intervention for OCD. Risk of bias was assessed using the Cochrane ROBINS-I tool and the RoB2 tool. RESULTS: The analysis included 6 trials (N = 92); 2 were RCTS and 4 were pre-post design studies. A random-effects meta-analysis of pre-post data identified a large reduction of OCD symptoms following exercise (g = 1.33 [95%CI 1.06-1.61]; k = 6). Exercise was also associated with significant pre-post reductions in anxiety (g = 0.71 [95%CI 0.37-1.05; k = 4) and depression (g = 0.57 [95%CI 0.26-0.89]; k = 2). Risk of bias was moderate-high in uncontrolled trials on the ROBINS-I and RCTs showed 'some concerns' on the RoB2. CONCLUSION: Exercise was associated with a large pre-post reduction of OCD symptoms; however, few trials were of robust quality and all were at risk of bias. Further well-powered and better quality RCTs are required to assess the role of exercise as an intervention for OCD.KEY POINTSStudies exploring exercise as an adjunct therapy for OCD have small participant numbers, therefore a systematic review and meta-analysis is needed to estimate potential efficacy.Pre-post analysis shows that exercise was associated with a large reduction of OCD symptomsThe current systematic review and meta-analysis points to the potential for exercise to be beneficial for the treatment for OCD symptoms. However, more well-powered and better controlled RCTs are required to fully assess the benefit of exercise for the treatment of OCD symptoms.

Behavioral excess and disruptive conduct: A historical and taxonomic approach to the origin of the 'impulse control disorders' diagnostic construct.

AIMS: Impulse control disorders (ICDs) are iatrogenic and idiopathic conditions with psychosocial and economic consequences for the affected individuals and their families (e.g. bankruptcy and divorce). However, the definition of ICDs has changed over time, and ICDs are not consistently included within existing taxonomies. We discuss the origins of the ICD diagnostic construct and its unsolved tensions. METHODS: To contextualize the ICD diagnostic construct, we provided an overview of its origins in past centuries and followed its development across multiple editions of the Diagnostic and Statistical Manual and the International Classification of Diseases, as well as its definition within emerging ontologies. RESULTS: Two independent roots of the ICD construct emerged: (a) the interest in behavioral excess as expressed in encyclopedic compilations (18th century) and (b) the juridical debate on disruptive conduct and responsibility (19th-20th centuries). These roots underlie the repeated taxonomic remodeling observed throughout the 20th and 21st centuries and three critical issues persisting in both clinical practice and research. First, the number of ICDs keeps increasing across the spectrum of human behaviors, disregarding common pathogenetic and phenomenological grounds. Secondly, ICDs substantially overlap with other mental conditions. Impulsivity is often neglected as a minor inconvenience or side effect when co-occurring with major diagnoses (e.g. depression) and therefore inadequately managed. Finally, ICDs' definitions display an unsolved tension between being conceived as hobby, moral fault or pathological drive, which may be responsible for stigma and delayed intervention. CONCLUSION: The reasons that made impulse control disorders (ICDs) difficult to define from their first conceptualization are the same reasons that now complicate taxonomic efforts and diagnosis. Tracing back ICDs' roots and criticalities can help to define a common and less ambiguous theoretical framework, which may also result in the demise of the ICD construct and a move towards more clearly defined and more useful ontologies.

Expression of Synj2bp in mouse liver regulates the extent of wrappER-mitochondria contact to maintain hepatic lipid homeostasis.

BACKGROUND: In mouse liver hepatocytes, nearly half of the surface area of every mitochondrion is covered by wrappER, a wrapping-type of ER that is rich in fatty acids and synthesizes lipoproteins (VLDL) (Anastasia et al. in Cell Rep 34:108873, 2021; Hurtley in Science (80- ) 372:142-143, 2021; Ilacqua et al. in J Cell Sci 135:1-11, 2021). A disruption of the ultrastructure of the wrappER-mitochondria contact results in altered fatty acid flux, leading to hepatic dyslipidemia (Anastasia et al. 2021). The molecular mechanism that regulates the extent of wrappER-mitochondria contacts is unknown. METHODS: We evaluated the expression level of the mitochondrial protein Synj2bp in the liver of normal and obese (ob/ob) mice. In addition, we silenced its expression in the liver using an AAV8 vector. We coupled quantitative EM morphometric analysis to proteomics and lipid analyses on these livers. RESULTS: The expression level of Synj2bp in the liver positively correlates with the extent of wrappER-mitochondria contacts. A 50% reduction in wrappER-mitochondria contacts causes hepatic dyslipidemia, characterized by a gross accumulation of lipid droplets in the liver, an increased hepatic secretion of VLDL and triglycerides, a curtailed ApoE expression, and an increased capacity of mitochondrial fatty acid respiration. CONCLUSION: Synj2bp regulates the extent of wrappER-mitochondria contacts in the liver, thus contributing to the control of hepatic lipid flux.

Adverse Reactions after the Third Dose of the BNT162b2 mRNA COVID-19 Vaccine among Medical School Residents in a Regional Reference University Hospital in Italy.

The recent emergence of new variants of concern (VOCs) of SARS-CoV-2 and the uncertain duration of protection provided by the primary immunization cycle have highlighted the need for COVID-19 booster vaccinations. However, only a few studies have assessed the safety and reactogenicity profile of mRNA booster doses. Therefore, we conducted an online survey with the aim of assessing the adverse reaction profile in the 7 days following a third dose of the BNT162b2 vaccine in a population of resident physicians who had already been investigated after the primary vaccination. Among the 512 resident physicians (female = 53.2%, mean age = 29.8 years) invited to participate in the survey, 222 completed the survey (56.5% female, mean age of 29.9 years), with an average time from second to third dose of 8.6 months. The most common adverse reactions were local pain (88.3%), fatigue (58.1%), muscle/joint pain (44.1%), and headache (38.3%), all subsiding in 48-72 h. While the local reaction rate was similar to that following the first two doses, the systemic reactions were considerably less common and milder compared to the second vaccination. Nonetheless, over one third (36.1%) of participants reported interference with their normal activities. These results complement our previous findings and could aid occupational and public health professionals in the counselling of vaccinees.

Repetitive transcranial magnetic stimulation (r-TMS) and selective serotonin reuptake inhibitor-resistance in obsessive-compulsive disorder: A meta-analysis and clinical implications.

INTRODUCTION: Despite promising results from several randomized controlled trials (RCTs) and meta-analyses, the efficacy of r-TMS as a treatment for OCD remains controversial, at least in part owing to inconsistency in the trial methodologies and heterogeneity in the trial outcomes. This meta-analysis attempts to explain some of this heterogeneity by comparing the efficacy of r-TMS in patients with or without resistance to treatment with selective serotonin reuptake inhibitors (SSRI), defined using standardized criteria. METHODS: We conducted a pre-registered (PROSPERO ID: 241381) systematic review and meta-analysis. English language articles reporting blinded RCTs were retrieved from searches using MEDLINE, PsycINFO, and Cochrane Library databases. Studies were subjected to subgroup analysis based on four stages of treatment resistance, defined using an adaptation of published criteria (1 = not treatment resistant, 2 = one SSRI trial failed, 3 = two SSRI trials failed, 4 = two SSRI trials failed plus one or more CBT trial failed). Meta-regression analyses investigated patient and methodological factors (age, duration of OCD, illness severity, stage of treatment-resistance, or researcher allegiance) as possible moderators of effect size. RESULTS: Twenty-five independent comparisons (23 studies) were included. Overall, r-TMS showed a medium-sized reduction of Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) scores (Hedge's g: -0.47; 95%CI: - 0.67 to -0.27) with moderate heterogeneity (I2 = 39.8%). Assessment of publication bias using Trim and Fill analysis suggested a reduced effect size that remained significant (g: -0.29; 95%CI: -0.51 to -0.07). Subgroup analysis found that those studies including patients non-resistant to SSRI (stage 1) (g: -0.65; 95%CI: -1.05 to -0.25, k = 7) or with low SSRI-resistance (stage 2) (g:-0.47; 95%CI: -0.86 to -0.09, k = 6) produced statistically significant results with low heterogeneity, while studies including more highly resistant patients at stage 3 (g: -0.39; 95%CI: -0.90 to 0.11, k = 4) and stage 4 (g: -0.36; 95%CI: -0.75 to 0.03, k = 8) did not. Intriguingly, the only significant moderator of the effect size found by meta-regression was the severity of baseline depressive symptoms. All trials showed evidence of researcher allegiance in favour of the intervention and therefore caution is required in interpreting the reported effect sizes. CONCLUSION: This meta-analysis shows that r-TMS is an effective treatment for OCD, but largely for those not resistant to SSRI or failing to respond to only one SSRI trial. As a consequence, r-TMS may be best implemented earlier in the care pathway. These findings would have major implications for clinical service development, but further well-powered RCTs, which eliminate bias from researcher allegiance, are needed before definitive conclusions can be drawn.

Meta-analysis of cognitive behaviour therapy and selective serotonin reuptake inhibitors for the treatment of hypochondriasis: Implications for trial design.

BACKGROUND: Classification of hypochondriasis as an obsessive-compulsive and related disorder in the International Classification of Diseases 11th Revision (ICD-11) has generated new heuristics for treatment of this common, chronic and disabling disorder. Standard treatment involves cognitive behaviour therapy (CBT) or selective serotonin reuptake inhibitors (SSRIs), but no meta-analysis has so far considered hypochondriasis as a structured diagnosis or assessed the role of medication. A clearer understanding of the relative effectiveness of these interventions and identification of clinically relevant factors moderating the treatment response is needed for clinical guideline development. METHODS: The current systematic review and meta-analysis of interventions for hypochondriasis was preregistered on PROSPERO (CRD42020185768) and follows PRISMA guidelines. We searched MEDLINE, PsycINFO, and Cochrane Library databases until July 2021 for randomized controlled trials (RCTs) of interventions for patients diagnosed with hypochondriasis (or historical diagnostic equivalents). We assessed aspects of study quality using: the CONSORT Checklist for evaluation of RCTs, the Cochrane Risk of Bias 2 tool, researcher allegiance and treatment fidelity. The primary outcome was improvement in hypochondriasis symptoms, comparing intervention and control groups at trial endpoint. Moderator variables were assessed using subgroup and meta-regression analyses. RESULTS: Searches identified 13 randomised controlled trials (RCTs) (N = 1405); 12 included CBT (N = 1212) and three included SSRI (N = 193) arms as the experimental intervention. Random effects meta-analysis yielded a moderate-to-large effect size for CBT versus all controls (g = -0.70 [95% CI -0.99 to -0.41], k = 18, I2 = 81.1%). Funnel plot asymmetry indicated possible publication bias and two potentially missing trials, reducing the effect size (g = -0.60 [95% CI -0.88 to -0.32]). Subgroup analysis showed that choice of control significantly moderated effect size, with those in CBT vs. wait-list (g = -1.32 [95% CI -1.75 to -0.90], k = 7, I2 = 0%) being double those of CBT vs. psychological or pharmacological placebo controls (g = -0.58 [95% CI -0.95 to -0.22], k = 7, I2 = 82%). Analysis of studies directly comparing CBT and SSRIs found a numerical, but not statistical advantage for SSRIs (g = 0.21 [95% CI -0.46 to 0.87], k = 2, I2 = 58.34%) and a modest effect size emerged for SSRIs vs. pill placebo (g = -0.29 [95% CI -0.57 to -0.01], k = 3, I2 = 0%). Most studies (11/13) were rated as high on potential researcher allegiance bias in favour of CBT. Meta-regressions revealed that effect sizes were larger in younger participants, and smaller in better quality and more recent RCTs and those with greater CBT fidelity. CONCLUSION: CBT and SSRIs are effective in the acute treatment of hypochondriasis, with some indication that intervention at a younger age produces better outcomes for CBT. In the case of CBT, effect sizes appear to have been significantly inflated by the use of wait list controls, and researcher allegiance bias. We recommend that a definitive, adequately controlled trial, designed with respect to the methodological issues raised in this meta-analysis, is needed to determine the magnitude effects for CBT and SSRIs with confidence and the long-term effect of treatments, to inform mental health service provision for this overlooked patient group.

Advances in problematic usage of the internet research - A narrative review by experts from the European network for problematic usage of the internet.

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.