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Objective: Perampanel (PER) is indicated as adjunctive antiseizure medication (ASM) in adolescents and adults with epilepsy. Data from clinical trials show good efficacy and tolerability, while limited information is available on the routine clinical use of PER, especially when used as only add-on treatment. Methods: We performed an observational, retrospective, multicenter study on people with focal or generalized epilepsy aged >12 years, consecutively recruited from 52 Italian epilepsy centers. All patients received PER as the only add-on treatment to a background ASM according to standard clinical practice. Retention rate, seizure frequency, and adverse events were recorded at 3, 6, and 12months after PER introduction. Subanalyses by early or late use of PER and by concomitant ASM were also conducted. Results: Five hundred and three patients were included (age 36.5 ± 19.9 years). Eighty-one percent had focal epilepsy. Overall, the retention rate was very high in the whole group (89% at 12months) according with efficacy measures. No major differences were observed in the subanalyses, although patients who used PER as early add-on, as compared with late add-on, more often reached early seizure freedom at 3-month follow-up (66% vs 53%, P=.05). Treatment-emergent adverse events occurred in 25%, far less commonly than in PER randomized trials. Significance: This study confirms the good efficacy and safety of PER for focal or generalized epilepsy in real-life conditions. We provide robust data about its effectiveness as only add-on treatment even in patients with a long-standing history of epilepsy and previously treated with many ASMs.

Inositol is a natural sugar-like compound, commonly present in many plants and foods. It is involved in several biochemical pathways, most of them controlling vital cellular mechanisms, such as cell development, signaling and nuclear processes, metabolic and endocrine modulation, cell growth, signal transduction, etc. In this narrative review, we focused on the role of inositol in human brain physiology and pathology, with the aim of providing an update on both potential applications and current limits in its use in psychiatric disorders. Overall, imaging and biomolecular studies have shown the role of inositol levels in the pathogenesis of mood disorders. However, when administered as monotherapy or in addition to conventional drugs, inositol did not seem to influence clinical outcomes in both mood and psychotic disorders. Conversely, more encouraging results have emerged for the treatment of panic disorders. We concluded that, despite its multifaceted neurobiological activities and some positive findings, to date, data on the efficacy of inositol in the treatment of psychiatric disorders are still controversial, partly due to the heterogeneity of supporting studies. Therefore, systematic use of inositol in routine clinical practice cannot be recommended yet, although further basic and translational research should be encouraged.

Background: Clozapine may be considered the first-line option for treatment-resistant schizophrenia (TRS), a condition that occurs in more than 30% of patients with schizophrenia. Despite its efficacy for treating TRS, clozapine use is limited by the occurrence of several adverse effects in more than 70% of cases. Clozapine does not typically affect lung function, although a few cases have been reported in the literature. Case Presentation: To gain a better understanding of this rare event, here we report the case study of a young female with TRS, who was treated with clozapine and developed medium and bilateral pleural effusion relief with contiguous atelectasis and polyserositis. Two weeks after stopping clozapine, the follow-up chest scan showed complete remission of the pulmonary condition. We postulate that clozapine might have caused, in this case, a specific immunoinflammatory response leading to serosal complications. Conclusion: Although the underlying mechanisms of this adverse effect are not completely understood, early manifestations, such as benign eosinophilia, fever, and flu-like symptoms need to be considered a potential warning to facilitate an early diagnosis and carefully manage pulmonary complications related to clozapine treatment.

The Endocannabinoid System (ECBs) may have a crucial role in bipolar disorder (BD). Previous reports have not detected abnormalities in the expression of the cannabinoid receptor gene CNR1, encoding for CBWe recruited 44 subjects with BD type I (BD-I), in mania (n = 22) and depression (n = 22) and 25 Healthy Controls (HC). CNR1 gene expression was analyzed using a quantitative real-time polymerase chain reaction from peripheral blood mononuclear cells. Data were analyzed using frequentist non-parametric and Bayesian approaches (generalized location-scale model based on lognormal and gamma distributions).Using the frequentist non-parametric approach, the depression group had lower CNR1 expression compared to the mania group (p = 0.004). In addition, there was a negative correlation between CNR1 expression and Hamilton Depression Scale score (rho = -0.37; p = 0.007). Bayesian analyses further revealed that CNR1 expression in the mania group was higher and less variable than among HC (95% probability), while CNR1 expression in the depression group was lower and more variable than among HC (100% probability).Lack of participants with bipolar disorder in the euthymic phase, lack of toxicology screening and evaluation of CNR1 variants.CNR1 expression is higher and less variable in mania than in depression. It is highly probable that these differences also distinguish individuals in different illness phases from healthy controls. Future studies are needed to clarify the role of the endocannabinoid system in bipolar disorder.

Introduction: Status epilepticus (SE) in pregnancy represents a life-threatening medical emergency for both mother and fetus. Pregnancy-related pharmacokinetic modifications and the risks for fetus associated with the use of antiseizure medications (ASMs) and anesthetic drugs complicate SE management. No standardized treatment protocol for SE in pregnancy is available to date. Areas covered: In this review, we provide an overview of the current literature on the management of SE in pregnancy and we propose a multidisciplinary-based protocol approach. Expert opinion: Literature data are scarce (mainly anecdotal case reports or small case series). Prompt treatment of SE during pregnancy is paramount and a multidisciplinary team is needed. Benzodiazepines are the drugs of choice for SE in pregnancy. Levetiracetam and phenytoin represent the most suitable second-line agents. Valproic acid should be administered only if other ASMs failed and preferably avoided in the first trimester of pregnancy. For refractory SE, anesthetic drugs are needed, with propofol and midazolam as preferred drugs. Magnesium sulfate is the first-line treatment for SE in eclampsia. Termination of pregnancy, via delivery or abortion, is recommended in case of failure of general anesthetics. Further studies are needed to identify the safest and most effective treatment protocol.

Although international guidelines exist, the clinical heterogeneity of Lennox-Gastaut syndrome (LGS) and the increasing availability of new and repurposed drugs (e.g., fenfluramine and cannabidiol) requires a practical guide to patient management in the clinical context. We report the results of a consensus survey among 42 Italian experts in the diagnosis and treatment of LGS.The consensus procedure followed a modified Delphi approach. Statements were formulated, based on the most recent published evidence and the clinicians' personal experience, then discussed, and agreed upon by the experts through a two-round voting procedure. Approval of a statement was reached with an average score ≥7.Thirteen statements dealing with three main topics (i.e., clinical diagnosis and prognosis, impact on the Quality of Life (QoL), and treatment strategies) were generated. Six statements achieved a level of agreement sufficient for approval on the first voting round. Following the discussion and a few consequent amendments, most of the statements increased their level of agreement and all 13 were approved.Overall, the statements draw a slightly more benign picture of this rare and severe disease, highlighting the possibility of remission - albeit modest -, an apparent trend towards lower mortality, and the availability of several effective drugs, to which greater accessibility would be hoped for. Valproate remains a major therapeutic option in LGS patients although lamotrigine, rufinamide, topiramate, cannabidiol, and clobazam are popular therapeutic options in Italy, allowing for a tailor-made antiseizure therapy.

Background and purpose: Clinical outcomes of multiple sclerosis (MS) patients affected by coronavirus disease 2019 (COVID-19) have been thoroughly investigated, but a further analysis on main signs and symptoms and their risk factors still needs attention. The objective of this study was to group together and describe based on similarity the most common signs and symptoms of COVID-19 in MS patients and identify all factors associated with their manifestation. Method: Logistic and linear regression models were run to recognize factors associated with each pooled group of symptoms and their total number. Results: From March 2020 to November 2021, data were collected from 1354 MS patients with confirmed infection of COVID-19. Ageusia and anosmia was less frequent in older people (odds ratio [OR] 0.98; p=0.005) and more in smoker patients (OR 1.39; p=0.049). Smoke was also associated with an incremental number of symptoms (OR 1.24; p=0.031), substance abuse (drugs or alcohol), conjunctivitis and rash (OR 5.20; p=0.042) and the presence of at least one comorbidity with shortness of breath, tachycardia or chest pain (OR 1.24; p=0.008). Some disease-modifying therapies were associated with greater frequencies of certain COVID-19 symptoms (association between anti-CD20 therapies and increment in the number of concomitant symptoms: OR 1.29; p=0.05). Differences in frequencies between the three waves were found for flu-like symptoms (G1, p=0.024), joint or muscle pain (G2, p=0.013) and ageusia and anosmia (G5, p < 0.001). All cases should be referred to variants up to Delta. Conclusion: Several factors along with the choice of specific therapeutic approaches might have a different impact on the occurrence of some COVID-19 symptoms.

To date, the role of family members in caring for relatives affected by schizophrenia has focused largely on the negative aspects of impact of the illness. The present study aimed to: (1) assess family functioning and burden of care in caregivers living in Northern, Central, and Southern Italy who looked after subjects affected by chronic schizophrenia; (2) evaluate the relationship between aspects of family functioning and burden of care, in particular personal growth (PG) of caregivers; and (3) identify variables capable of affecting PG of caregivers. A total of 136 caregivers (mean length of illness of family member more than 20 years) were recruited from 9 Italian research sites and evaluated in terms of “positive” family functioning–problem-solving, communication skills and personal goals Family Functioning Questionnaire (FFQ), burden of care, and PG Family Problems Questionnaire (FPQ). Caregivers reported an overall good family functioning with a relatively low objective and subjective burden of care. The latter was positively correlated with length of illness, with women showing a higher subjective burden than men. Reduced problem-solving skills and ability of each family member to pursue personal goals were both associated with reduced objective and subjective burden which, conversely, were both increased by inadequate support and scarce positive comments from relatives and friends. Approximately 50% of caregivers stated that “they had learned something positive from the situation,” highlighting a statistically higher proportion of caregivers in southern Italy than in northern and central Italy. Caregivers’ PG was associated with good family functioning, adequate professional support, and positive comments. PG also seemed to be positively influenced by support from relatives and friends (O.R. 14.306). The numerous challenges and positive aspects associated with caregiving should be duly acknowledged by mental health services and integrated into routine clinical assessment and intervention framework.

Background: The Diagnostic and Statistical Manual for Mental Disorders (5th edition) introduced the specifier “with Mixed Features” to the diagnosis of Major Depressive Episode to designate the presence of (hypo) manic symptoms as part of the clinical presentation. This change has led to renewed attention on the operational definition, diagnosis, and treatment of Mixed Depression. Objective: To investigate the diagnostic and therapeutic approaches towards Mixed Depression among a representative sample of Italian psychiatrists. Methods: Between March and April 2021, 342 psychiatrists working in Italian adult mental health services were invited to participate in an anonymous online survey comprising 32 questions designed to investigate clinical and psychopathological approaches regarding the management of mixed depression in daily psychiatric practice. Results: 83.74% of participants reported having performed a diagnosis of mixed depression in the last five years, with the majority of respondents affirming that they had not used any diagnostic tool. Only 7,5% of the surveyed psychiatrists considered the DSM-5 criteria to be fully adequate in the description of this clinical entity. The most used pharmacological approach was combined therapy, in particular antipsychotics plus mood stabilizers. For monotherapy, the preferred drugs were Valproate and Quetiapine. Regarding the conceptualization of mood disorders, 199 of the participants chose the Kraepelinian unitary spectrum view; meanwhile, 101 expressed their preference for the binary model. Conclusion: Our results suggest a prominent position of mixed depression in the context of mood disorders. Univocal operational criteria and additional research on pharmacological treatment are also needed to ensure the correct recognition and management of mixed depression.

Angelman syndrome (AS) is a neurogenetic disorder due to deficient expression of the maternal copy of the UBE3A gene, which encodes ubiquitin ligase E3A protein. Severe developmental delay, seizures and other neurological disorders characterize AS.In this review, we focus on a comprehensive therapeutic approach to the most disabling neurological manifestations of AS: epilepsy, sleep disturbances, behavioral and movement disorders. Articles were identified through PubMed and Google Scholar up to October 2021.Evidence for the treatment of neurological manifestations in AS mainly derives from poor quality studies (case reports, small case series, expert opinions). Seizures can be polymorphic and includes atypical absences, myoclonic, generalized tonic-clonic, unilateral clonic, or atonic attacks. Sodium valproate, levetiracetam, and benzodiazepines are the most commonly used anti-seizure medications. Melatonin or mirtazapine seem to improve sleep quality. Antipsychotics, antidepressants, and anxiolytics have been proposed for the treatment of behavioral manifestations, but no evidence-based studies are available. Non-pharmacological approach may also be useful. Mild dystonia is common but usually does not significantly impact patients' motor performances. Well-conducted clinical trials aimed to evaluate treatment of neurological complications of AS are warranted. Gene and molecular precision therapies represent a fascinating area of research in the future.

To establish whether a slow or a rapid withdrawal of antiepileptic monotherapy influences relapse rate in seizure-free adults with epilepsy and calculates compliance and differences in the severity of relapses, based on the occurrence of status epilepticus, seizure-related injuries, and death.This is a multicentre, prospective, randomized, open label, non-inferiority trial in people aged 16 + years who were seizure-free for more than 2 years. Patients were randomized to slow withdrawal (160 days) or rapid withdrawal (60 days) and were followed for 12 months. The primary outcome was the probability of a first seizure relapse within the 12-months follow-up. The secondary outcomes included the cumulative probability of relapse at 3, 6, 9, and 12 months. A non-inferiority analysis was performed with non-inferiority margin of - 0.15 for the difference between the probabilities of seizure recurrence in slow versus rapid withdrawal.The sample comprised 48 patients, 25 randomized to slow withdrawal and 23 to rapid withdrawal. Median follow-up was 11.9 months. In the intention-to-treat population, 3 patients in the slow-withdrawal group and 1 in the rapid withdrawal group experienced seizure relapses. The corresponding probabilities of seizure recurrence were 0.12 for slow withdrawal and 0.04 for rapid withdrawal, giving a difference of 0.08 (95% CI - 0.12; 0.27), which is entirely above the non-inferiority margin. No patients developed status epilepticus and seizure-related injuries or died. Risks were similar in the Per-Protocol population.Seizure-relapse rate after drug discontinuation is lower than in other reports, without complications and unrelated to the duration of tapering.

Background and purpose Some studies have shown that air pollution, often assessed by thin particulate matter with diameter below 2.5 µg/m3 (PM2.5), may contribute to severe COVID‐19 courses, as well as play a role in the onset and evolution of multiple sclerosis (MS). However, the impact of air pollution on COVID‐19 has never been explored specifically amongst patients with MS (PwMS). This retrospective observational study aims to explore associations between PM2.5 and COVID‐19 severity amongst PwMS. Methods Data were retrieved from an Italian web‐based platform (MuSC‐19) which includes PwMS with COVID‐19. PM2.5 2016–2018 average concentrations were provided by the Copernicus Atmospheric Monitoring Service. Italian patients inserted in the platform from 15 January 2020 to 9 April 2021 with a COVID‐19 positive test were included. Ordered logistic regression models were used to study associations between PM2.5 and COVID‐19 severity. Results In all, 1087 patients, of whom 13% required hospitalization and 2% were admitted to an intensive care unit or died, were included. Based on the multivariate analysis, higher concentrations of PM2.5 increased the risk of worse COVID‐19 course (odds ratio 1.90; p = 0.009). Conclusions Even if several other factors explain the unfavourable course of COVID‐19 in PwMS, the role of air pollutants must be considered and further investigated., Air pollution, often assessed by particulate matter with diameter below 2.5 µg/m3, may contribute to severe COVID‐19 courses. 1087 patients were included, of whom 13% required hospitalization and 2% were admitted to an intensive care unit or died. Even if several other factors explain the unfavourable course of COVID‐19 in patients with multiple sclerosis, the role of air pollutants must be considered and further investigated.

Rare Disease patients manifested high concern regarding the possible increased risk of severe outcomes and worsening of disease-specific clinical manifestation due to the impact of COVID-19. Our aim was to assess the prevalence, outcomes, and impact of COVID-19 in patients with a rare disease such as Hereditary Hemorrhagic Telangiectasia (HHT) in Italian population. A nationwide, multicentric, cross-sectional observational study was conducted on patients with HHT from five Italian HHT centers by online survey. The association between COVID-19-related signs and symptoms and nosebleeds worsening, the impact of personal protective equipment on nosebleeds pattern, and the relationship between the presence of visceral AVMs and severe outcomes were analyzed. Out of 605 total survey responses and eligible for analysis, 107 cases of COVID-19 were reported. A mild-course COVID-19 disease, not requiring hospitalization, was observed in 90.7% of patients, while the remaining eight cases needed hospitalization, two of them requiring intensive-care access. No fatal outcome was recorded and 79.3% of patients reported a complete recovery. No difference in infection risk and outcome between HHT patients and general population was evidenced. No significative interference of COVID-19 on HHT-related bleeding was found. The majority of patients received COVID-19 vaccination, with relevant impact on symptoms and need for hospitalization in case of infection. COVID-19 in HHT patients had an infection profile similar to the general population. COVID-19 course and outcome were independent from any specific HHT-related clinical features. Moreover, COVID-19 and anti-SARS-CoV-2 measures did not seem to affect significantly HHT-related bleeding profile.

Background The GLA c.337T > C (p.Phe113Leu) is a known pathogenic variant associated to late-onset Fabry disease phenotype with predominant cardiac manifestations. A founder effect was demonstrated in a large cohort in the Portuguese region of Guimarães. Herein we report an in-depth phenotype description of a cluster of five Southern Italy families. Methods Family pedigrees of five index males with the p.Phe113Leu variant were obtained and all at-risk relatives underwent biochemical and genetical screening test. Carriers of GLA p.Phe113Leu variant underwent subsequent multidisciplinary clinical and instrumental evaluation. Results Thirty-one (16 M, 15 F) individuals with p.Phe113Leu pathogenic variant were identified. Sixteen out of 31 patients (51.6%) had cardiac manifestations. Notably, myocardial fibrosis was found in 7/8 patients, of whom 2 were under 40 years. Stroke occurred in 4 patients. White matter lesions were detected in 12/19 patients and occurred in 2/10 of subjects under 40 years. Seven females complained of acroparesthesias. Renal involvement occurred in 10 patients. Angiokeratomas were evident in 9 subjects. Eyes, ear, gastrointestinal and pulmonary involvement occurred in the minority of subjects. Conclusion This study demonstrates that a cluster of subjects with p.Phe113Leu pathogenic variant is also present in Southern Italy. Disease manifestations are frequent in both sexes and may occur early in life. Cardiac involvement represents the core manifestation, but neurological and renal involvement is also frequent, suggesting that extra-cardiac complications deserve clinical attention.

The aim of the present study was to identify a cut-off of c-reactive protein (c-RP) potentially predictive of high-lethality suicide attempts (SA) in an inpatient psychiatric sample. After attempting suicide, subjects were admitted to the emergency ward of the IRCCS Ospedale Policlinico San Martino and later to the section of Psychiatry from 1 August 2013 to 31 July 2018. C-reactive protein was measured. The Area Under the Receiver Operating Characteristic (ROC_AUC) was used to assess the discriminative capacity of c-RP for high- vs. low-lethality SA, and a logistic regression was performed to detect the odds ratio, adjusted for age and sex. High-lethality suicide attempters were 133 (30.8%), while low-lethality suicide attempters were 299 (69.2%). The optimal cut-off threshold (and corresponding sensitivity and specificity values) for c-RP was 4.65 mg/L (68/71%). This cut-off corresponds to an AUC of 73.5%. An odds ratio of 4.70 was generated for current high-lethality SA after a logistic regression, adjusted for age and sex. Research on social and biological factors underlying the lethality of SA is crucial for a better understanding of this complex phenomenon. Identifying potential predictors of SA, especially those at high lethality, is essential to implement personalized preventive strategies.

Although epilepsy as a comorbidity in neurodegenerative disorders is increasingly recognized, its incidence is still underestimated and the features of epilepsy in the different neurodegenerative conditions are still poorly defined. Improved health care, resulting in increased longevity, will unavoidably lead to an increment of epilepsy cases in the elderly. Thus, it is conceivable to expect that neurologists will have to deal with these comorbid conditions to a growing extent in the future. In this seminar, we provide an updated overview of the clinical features, pathophysiological mechanisms and diagnostic and treatment approaches of epilepsy in the most common neurodegenerative disorders (such as Alzheimer disease and other types of dementia, Parkinson disease, Down syndrome, prion diseases, and progressive myoclonus epilepsies), aiming to provide a tool that can help epileptologists and neurologists in the diagnosis and management of this increasingly reported comorbidity.

Background: Definitions for reliable identification of transition from relapsing-remitting multiple sclerosis (MS) to secondary progressive (SP)MS in clinical cohorts are not available. Objectives: To compare diagnostic performances of two different data-driven SPMS definitions. Methods: Data-driven SPMS definitions based on a version of Lorscheider’s algorithm (DDA) and on the EXPAND trial inclusion criteria were compared, using the neurologist’s definition (ND) as gold standard, in terms of sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), Akaike information criterion (AIC) and area under the curve (AUC). Results: A cohort of 10,240 MS patients with ⩾5 years of follow-up was extracted from the Italian MS Registry; 880 (8.5%) patients were classified as SPMS according to the neurologist definition, 1806 (17.6%) applying the DDA and 1134 (11.0%) with the EXPAND definition. The DDA showed greater discrimination power (AUC: 0.8 vs 0.6) and a higher sensitivity (77.1% vs 38.0%) than the EXPAND definition, with similar specificity (88.0% vs 91.5%). PPV and NPV were higher using the DDA than considering EXPAND definition (37.5% vs 29.5%; 97.6% vs 94.0%). Conclusion: Data-driven definitions demonstrated greater ability to capture SP transition than neurologist’s definition and the global accuracy of DDA seems to be higher than the EXPAND definition.

ObjectivesTo assess the effectiveness of tecovirimat (TPOXX) for treating mpox in terms of difference in healing time and extent of viral clearance.DesignEmulation of a target trial based on observational data.SettingItalyParticipantsForty-one men hospitalized for mpox as of September 29th, 2022.Main outcome measuresMain outcome was the time to clinical recovery. Secondary outcome was the variation in viral load in the upper respiratory tract (URT) after treatment.ResultsThe median time from symptoms onset to hospital admission and to initiation of TPOXX was 4 days (IQR 2-6) and 10 days (IQR 8-11), respectively. Fifteen patients completed a course of therapy. No deaths were observed; the overall median healing time was 21 days (IQR 17-26). We found no evidence for a significant improvement in recovery time in treated vs. untreated patients, with an estimated mean of 14.7 days for both groups. A subset of 13 patients had URT samples at T1 (median of 5 days (IQR 3-7) from symptoms onset) and T2 (median 7 days (IQR 7-9) from T1). Overall, mean viral load was 4.65 (0.30) vs. 4.91 (0.35) (log2 scale of cycle threshold) at T1 and T2, respectively. In the unadjusted analysis, variation over T1-T2 was lower in the treated 0.13 log2 (SD=0.53) vs. untreated 0.37 (0.50), although not statistically significant (unpaired t-test p=0.41). After controlling for confounding, there was no evidence for a difference in the potential changes over T1-T2 by treatment arm, and our estimate of the average treatment effect (ATE) was consistent with no difference by treatment group, although with large 95% CI around these estimates.ConclusionsOur analysis seems to exclude a clinically important effect of TPOXX in hospitalized mpox patients when compared to no treatment. These data are one of the valuable currently available sources of evidence to guide treatment decisions in patients hospitalized with TPOXX. Pending more robust data from randomized comparisons, the use of TPOXX should be restricted to the clinical trials setting.Trial registration“MpoxCohort” observational study protocol: approval number 40z, Register of Non-Covid Trials 2022.

The present study aimed to investigate the personal well-being and family distress of Italian caregivers during the lockdown. Five hundred sixty-five family caregivers and 638 age- and sex-matched noncaregivers completed a web-based survey. The following scales were administered to all participants: General Health Questionnaire-12 items (GHQ-12), Insomnia Severity Index (ISI), Brief Resilient Coping Scale (BRCS), and Family Distress Index (FDI). Caregivers were also asked to provide information about their family members with disabilities. Individual and family distress, as well as insomnia, were significantly higher in caregivers than controls. Contrariwise, caregivers reported lower resilience levels. Multiple linear regression showed that distress was higher in caregivers living in Central and Southern Italy. Individual well-being was negatively predicted by low independence measured by the activities of daily living (ADL). Family distress was higher in households of psychiatric patients. Finally, low resilience levels appeared as the strongest predictors of both individual and family distress. The lockdown caused severe distress among caregivers and families of people with disabilities. Support networks for people with disabilities and their families are fundamental to prevent severe consequences from a psychological, social, and economical point of view.

Long-acting injectable (LAI) antipsychotics are often used for the long-term management also of bipolar disorder (BD). Nonetheless, evidence on their effect on pragmatic outcomes such as hospitalization risk in BD is inconsistent. We carried out a mirror-image study comparing rates and number of days of hospitalization, one year before and after the initiation of LAI treatment, in a sample of subjects with BD. Participants were selected from the STAR Network Depot Study, a pragmatic, observational, multicenter research involving a cohort of inpatients and outpatients consecutively started on LAI treatment. Variations in rates and in total number of days of hospitalization between the 12 months before and those after treatment initiation were analyzed. Among 461 individuals screened for eligibility, we included 71 adults with BD, initiated either on first- (FGA) or second-generation (SGA) LAIs. We found a significant decrease in terms of 12-month hospitalization rates (p < 0.001) and number of days (p < 0.001) after LAI initiation, without any effect by age, gender, alcohol/substance use disorders, and symptom severity. Subgroup analyses based on antipsychotic class, history of LAI treatment, and concomitant oral medications, confirmed the decreasing trend on both hospitalization rates and number of days. However, these reductions were not significant among participants who continued this treatment for less than 6 months. Comprehensively, this study supports the role of LAIs as effective maintenance treatment options for BD. Further research is needed to identify clinical characteristics of people with BD who would most benefit from long-acting formulations of antipsychotics.

Status epilepticus (SE) is associated with high morbidity and mortality. This multicenter retrospective cohort study aims to identify the factors associated with the occurrence of SE and the predictors of its recurrence in patients with adult-onset seizures.We retrospectively analyzed data of 1115 patients with seizure onset18 years, observed from 1983 to 2020 in 7 Italian Centers (median follow-up 2.1 years). Data were collected from the databases of the Centers. Patients with SE were consecutively recruited, and patients without SE history were randomly selected in a 2:1 ratio. To assess determinants of SE, different clinical-demographic variables were evaluated and included in univariate and multivariate logistic regression model.Three hundred forty-seven patients had a SE history, whereas the remaining 768 patients had either isolated seizures or epilepsy without SE history. The occurrence of SE was independently associated with increasing age at onset of disease (OR 1.02, 95% CI 1.01--1.03, p0.001), female sex (OR 1.39, 95% CI 1.05--1.83, p=0.02) and known etiology (OR 3.58, 95% CI 2.61--4.93, p0.001). SE recurred in 21% of patients with adult-onset SE and recurrence was associated with increasing number of anti-seizure medications taken at last follow-up (OR 1.88, 95% CI 1.31--2.71, p0.001).In patients with adult-onset seizures, SE occurrence is associated with known etiologies, advanced age and female sex. Patients with recurrent SE are likely to have a refractory epilepsy, deserving careful treatment to prevent potentially fatal events.

Introduction Depression is a highly prevalent condition in the elderly, with a vast impact on quality of life, life expectancy, and medical outcomes. Selective serotonin reuptake inhibitors (SSRIs) are the most commonly prescribed agents in this condition and, although generally safe, tolerability issues cannot be overlooked. Vortioxetine is an antidepressant with a novel mechanism of action. Based on studies to date, it may have a promising tolerability profile in the elderly, as it does not adversely affect psychomotor or cognitive performance and does not alter cardiovascular and endocrine parameters. The present study aims to assess the tolerability profile of vortioxetine in comparison with the SSRIs considered as a single group in elderly participants with depression. The rate of participants withdrawing from treatment due to adverse events after 6 months of follow up will be the primary outcome. Methods and analysis This is a pragmatic, multicentre, open-label, parallel-group, superiority, randomized trial funded by the Italian Medicines Agency (AIFA - Agenzia Italiana del Farmaco). Thirteen Italian Community Psychiatric Services will consecutively enrol elderly participants suffering from an episode of major depression over a period of 12 months. Participants will be assessed at baseline and after 1, 3 and 6 months of follow up. At each time point, the following validated rating scales will be administered: Montgomery–Åsberg Depression Rating Scale (MADRS), Antidepressant Side-Effect Checklist (ASEC), EuroQual 5 Dimensions (EQ-5D), Short Blessed Test (SBT), and Charlson Age-Comorbidity Index (CACI). Outcome assessors and the statistician will be masked to treatment allocation. A total of 358 participants (179 in each group) will be enrolled. Ethics and dissemination This study will fully adhere to the ICH E6 Guideline for Good Clinical Practice. Participants’ data will be managed and safeguarded according to the European Data Protection Regulation 2016/679. An external Ethical Advisory Board will help guarantee high ethical standards. Trial registration Clinicaltrials.gov: NCT03779789, Registered on 19 December 2018. Submitted on 19 December. EudraCT number: 2018–001444-66. Trial status Protocol version 1.5; 09/06/2018. Recruitment started In February 2019 and it is ongoing. It is expected to end approximately on 30 September 2021.

Antipsychotic drugs are the mainstay treatment for schizophrenia, yet they are associated with diverse and potentially dose-related side effects which can reduce quality of life. For this reason, the lowest possible doses of antipsychotics are generally recommended, but higher doses are often used in clinical practice. It is still unclear if and how antipsychotic doses could be reduced safely in order to minimise the adverse-effect burden without increasing the risk of relapse.To assess the efficacy and safety of reducing antipsychotic dose compared to continuing the current dose for people with schizophrenia.We conducted a systematic search on 10 February 2021 at the Cochrane Schizophrenia Group's Study-Based Register of Trials, which is based on CENTRAL, MEDLINE, Embase, CINAHL, PsycINFO, PubMed, ClinicalTrials.gov, ISRCTN, and WHO ICTRP. We also inspected the reference lists of included studies and previous reviews.We included randomised controlled trials (RCTs) comparing any dose reduction against continuation in people with schizophrenia or related disorders who were stabilised on their current antipsychotic treatment. DATA COLLECTION AND ANALYSIS: At least two review authors independently screened relevant records for inclusion, extracted data from eligible studies, and assessed the risk of bias using RoB 2. We contacted study authors for missing data and additional information. Our primary outcomes were clinically important change in quality of life, rehospitalisations and dropouts due to adverse effects; key secondary outcomes were clinically important change in functioning, relapse, dropouts for any reason, and at least one adverse effect. We also examined scales measuring symptoms, quality of life, and functioning as well as a comprehensive list of specific adverse effects. We pooled outcomes at the endpoint preferably closest to one year. We evaluated the certainty of the evidence using the GRADE approach.We included 25 RCTs, of which 22 studies provided data with 2635 participants (average age 38.4 years old). The median study sample size was 60 participants (ranging from 18 to 466 participants) and length was 37 weeks (ranging from 12 weeks to 2 years). There were variations in the dose reduction strategies in terms of speed of reduction (i.e. gradual in about half of the studies (within 2 to 16 weeks) and abrupt in the other half), and in terms of degree of reduction (i.e. median planned reduction of 66% of the dose up to complete withdrawal in three studies). We assessed risk of bias across outcomes predominantly as some concerns or high risk. No study reported data on the number of participants with a clinically important change in quality of life or functioning, and only eight studies reported continuous data on scales measuring quality of life or functioning. There was no difference between dose reduction and continuation on scales measuring quality of life (standardised mean difference (SMD) -0.01, 95% confidence interval (CI) -0.17 to 0.15, 6 RCTs, n = 719, I

Depression and suicidal behavior are 2 complex psychiatric conditions of significant public health concerns due to their debilitating nature. The need to enhance contemporary treatments and preventative approaches for these illnesses not only calls for distillation of current views on their pathogenesis but also provides an impetus for further elucidation of their novel etiological determinants. In this regard, inflammation has recently been recognized as a potentially important contributor to the development of depression and suicidal behavior. This review highlights key evidence that supports the presence of dysregulated neurometabolic and immunologic signaling and abnormal interaction with microbial species as putative etiological hallmarks of inflammation in depression as well as their contribution to the development of suicidal behavior. Furthermore, therapeutic insights addressing candidate mechanisms of pathological inflammation in these disorders are proposed.

Cognitive-behavioral therapy (CBT) is a form of psychological treatment that is based on the underlying assumption that mental disorders and psychological distress are maintained by cognitive factors, that is, that general beliefs about the world, the self, and the future contribute to the maintenance of emotional distress and behavioral problems. The overall goal of CBT is to replace dysfunctional constructs with more flexible and adaptive cognitions. The most relevant cognitive-behavioral techniques in clinical practice are: i. Cognitive Restructuring (also known as the ABCDE method) is indicated to support patients dealing with negative beliefs or thoughts. The different steps in the cognitive restructuring process are summarized by the letters in the ABCDE acronym that describe the different stages of this coaching model: Activating event or situation associated with the negative thoughts, Beliefs and belief structures held by the individual that explain how they perceive the world which can facilitate negative thoughts, Consequences or feelings related to the activating event, Disputation of beliefs to allow individuals to challenge their belief system, and Effective new approach or effort to deal with the problem by facilitating individuals to replace unhelpful beliefs with more helpful ones. ii. Problem-Solving (also known as SOLVE) to raise awareness for specific triggers, and evaluate and choose more effective options. Each letter of the SOLVE acronym identifies different steps of the problem-solving process: Select a problem, generate Options, rate the Likely outcome of each option, choose the Very best option, and Evaluate how well each option worked. For example, a suicide attempt is reconceptualized as a failure in problem-solving. This treatment approach attempts to provide patients with a better sense of control over future emerging problems. iii. Re-attribution is a technique that enables patients to replace negative self-statements (eg, "it is all my fault") with different statements where responsibility is attributed more appropriately. Furthermore, decatastrophizing may help subjects, especially adolescents decide whether they may be overestimating the catastrophic nature of the precipitating event, and by allowing them to scale the event severity they learn to evaluate situations along a continuum rather than seeing them in black and white. iv. Affect Regulation techniques are often used with suicidal adolescents to teach them how to recognize stimuli that provoke negative emotions and how to mitigate the resulting emotional arousal through self-talk and relaxation.

Identifying subjects with epileptic seizures or psychogenic non-epileptic seizures from healthy subjects via interictal EEG analysis can be a very challenging issue. Indeed, at visual inspection, EEG can be normal in both cases. This paper proposes an automatic diagnosis approach based on deep learning to differentiate three classes: subjects with epileptic seizures (ES), subjects with non-epileptic psychogenic seizures (PNES) and control subjects (CS), analyzed by non-invasive low-density interictal scalp EEG recordings. The EEGs of 42 patients with new-onset ES, 42 patients with PNES video recorded and 19 patients with CS all with normal interictal EEG on visual inspection, were analyzed in the study; none of them was taking psychotropic drugs before registration. The processing pipeline applies empirical mode decomposition (EMD) to 5s EEG segments of 19 channels in order to extract enhanced features learned automatically from the customized convolutional neural network (CNN). The resulting CNN has been shown to perform well during classification, with an accuracy of 85.7%; these results encourage the use of deep processing systems to assist clinicians in difficult clinical settings.

An unprecedented global monkeypox outbreak started in May, 2022. No data are yet available about the dynamics of the immune response against monkeypox virus. The aim of this study was to describe kinetics of T-cell response, inflammatory profile, and pox-specific T-cell induction in patients with laboratory-confirmed monkeypox.17 patients with laboratory-confirmed monkeypox admitted at the Lazzaro Spallanzani National Institute for Infectious Diseases (Rome, Italy), from May 19, to July 7, 2022, were tested for differentiation and activation profile of CD4 and CD8 T (expression of CD38, PD-1, and CD57 assessed by flow cytometry), frequency of pox-specific T cells (by standard interferon-γ ELISpot), and release of interleukin (IL)-1β, IL-6, IL-8, and tumour necrosis factor (TNF) in plasma (by ELISA). All patients were tested 10-12 days after symptoms onset. In a subgroup of nine patients with a laboratory-confirmed monkeypox, the kinetics of the immune response were analysed longitudinally according to timing from symptoms onset and compared with ten healthy donors (ie, health-care workers recruited from the same institution).Among the 17 patients, ten were HIV negative and seven HIV positive, all with good viro-immunological status. On days 0-3 from symptom onset, patients with laboratory-confirmed monkeypox were characterised by a statistically significant reduction in CD4+ T cells (p=0·0011) and a concurrent increase of CD8+ T cells (p=0·0057) compared with healthy donors. A lower proportion of naive (CD45RA+CD27+) CD4+ T cells was observed in six (67%) of nine patients and a concomitant higher proportion of effector memory (CD45RA-CD27-) CD4+ T cells in all patients; this skewed immune profile tended to normalise over time. A similar differentiated profile was also observed in CD8+ T cells with a consistent expansion of terminally differentiated CD8+ T cells. Patients with monkeypox had a higher proportion of CD4+CD38+ and CD38+CD8+ T-cells than healthy donors, which normalised after 12-20 days from symptom onset. The expression of PD-1 and CD57 on CD4+ and CD8+ T-cells showed kinetics similar to that observed for CD38. Furthermore, the inflammatory cytokines (IL-1β, IL-6, IL-8, and TNF) were higher in patients with monkeypox than in healthy donors and, although they decreased over time, they remained elevated after recovery. Almost all patients (15 [94%] of 16) developed a pox-specific Th1 response. No differences in immune cells profile were observed between patients with and without HIV, whereas paucysimptomatic patients (without systemic symptoms, with less than five skin lesions, and no other mucosal localisation of monkeypox) showed a less perturbed immune profile early after symptom onset.Our data showed the immunological signature of monkeypox virus infection, characterised by an early expansion of activated effector CD4+ and CD8+ T cells that persisted over time. Almost all patients, even regardless of HIV infection, developed a poxvirus-specific Th1 cell response. These results might have implications on the expected immunogenicity of monkeypox vaccination, suggesting that it might not be necessary to vaccinate people who have already been infected.Italian Ministry of Health.For the Italian translation of the abstract see Supplementary Materials section.

Previous studies have shown, although not consistently, that first generation antipsychotics (FGA) are associated with a prevalence of extrapyramidal symptoms (EPS) higher than second generation antipsychotics (SGA). We assessed the prevalence and the incidence of antipsychotic-induced EPS in a large sample of community-dwelling Italian persons with schizophrenia before and after a 4-year naturalistic treatment, to shed light on their natural evolution and to identify possible predicting factors. EPS and psychopathology were assessed in 571 subjects with schizophrenia before (baseline) and after 4-year follow-up. Patients underwent treatment with SGA and/or FGA according to the referring clinicians' judgment. Relationships between EPS and psychopathology were assessed by network analysis, while a linear multiple regression investigated factors correlated to the presence of EPS at follow-up. EPS were significantly more frequent in the FGA- than in the SGA-treated group, and patients with EPS presented a more severe psychopathology. Parkinsonism was directly and positively connected with poor emotional expression at baseline and with poor emotional expression and disorganization at follow-up. Over the 4-year follow-up, emergent EPS were more frequent in FGA-treated patients, while relieved EPS occurred more frequently in SGA-treated persons. The presence of EPS at follow-up was significantly associated with EPS at baseline, illness duration, antipsychotic generation and the daily dose of antipsychotic medications. After a 4-year naturalistic treatment, EPS disappeared more frequently in SGA-treated patients, while they emerged more frequently in FGA-treated individuals. Therefore, although SGA did not eliminate the risk of EPS, these drugs seem to be associated to a more favorable EPS natural evolution.

Background The criteria of the Diagnostic and Statistical Manual of Mental Disorders 5th edition "with mixed features specifier" (DSM-5 MFS) are considered controversial since they include only typical manic symptoms. By contrast, Koukopoulos developed an alternative model of mixed depression (MxD) focusing primarily on the excitatory component. Objective To compareDSM-5 MFS and Koukopoulos' MxD (KMxD) in terms of prevalence, associated clinical variables and discriminative capacity for bipolar depression in patients with Major Depressive Episode (MDE). Methods 300patients with MDE -155 with major depressive disorder (MDD) and 145 with bipolar disorder (BD) - were recruited. The discriminative capacity of DSM-5 MFS and KMxD criteria for BD was estimated using the Area Under the Curves of Receiver Operating Characteristic (ROC_AUC). The clinical variables associated with these two diagnostic constructs were assessed by performing a logistic regression. Results 44 and 165 patients met the DSM-5 MFS and KMxD criteria, respectively. The ROC_AUCs and their confidence intervals for BD according to DSM-5 MFS and KMxD were 77.0% (72.0%-82.1%) and 71.9% (66.2%-77.7%) respectively. The optimal thresholds (combining sensitivity and specificity measures) for BD diagnosis were ≥1 (77%/68%) for DSM-5 MFS and ≥3 symptoms (78%/66%) for KMxD. However, considering the DSM-5 MFS cut-off (≥ 3 symptoms), the specificity (97%) increased at the expense of sensitivity (26%). Conclusions KMxD and DSM-5-MFS showed an overlapping discriminative capacity for bipolar depression. The current diagnostic threshold of DSM-5 MFS did not prove to be very inclusive, if compared to the greater diagnostic sensitivity of KMxD, which also yielded better association with clinical variables related to mixedness.

Sexual dysfunctions are common side effects reported by patients during antidepressant treatment. When they occur, patients often discontinue psychopharmacological therapy, with a negative impact on the underlying psychiatric disease. Recently, great attention has been paid to the use of nutraceuticals in the management of psychiatric disorders, although a systematic review on their effects as a treatment option for antidepressant-induced sexual dysfunctions (AISD) is lacking. Here, we conducted a systematic search in the following databases: MEDLINE (through PubMed), EMBASE, PsycINFO, Cochrane Central Register of Controlled Trials, and Web of Science. We searched eligible studies among parallel or crossover randomized controlled trials (RCTs) in adult populations. After this process, a total of 10 articles that evaluated the effect of six different nutraceuticals versus placebo were included: Maca Root, S-adenosyl-L-methionine (SAMe), Rosa Damascena, Ginkgo Biloba, Saffron, and Yohimbine. Overall, a high dose of Maca Root and the use of SAMe or Saffron may improve AISD. Additionally, the administration of Rosa Damascena seemed to be more effective in men than in women, whereas no evidence of effects emerged for Gingko Biloba and Yohimbine. Given the mixed results still available, future RCTs should consider larger samples and confounding factors, such as depressive status and individual vulnerability.

Fabry disease is a rare X-linked lysosomal storage disorder due to pathogenic variants of the galactosidase alpha (GLA) gene, leading to a deficiency of alpha-galactosidase A. The inadequate enzymatic activity leads to progressive glycosphingolipids accumulation within tissues and subsequent multi-systemic dysfunction, with predominant involvement of heart, kidney, and nervous system. Two subtypes are recognized: the classic type and the late-onset type. We here describe the clinical characteristics of a patient with late-onset Fabry disease carrying a not previously identified GLA gene variant. This 50-year-old man came to hospital because of an acute ischemic stroke. He also complained of acroparesthesia and had angiokeratomas in the nape and the back. Blood alpha-galactosidase A activity was low, plasmatic lyso-Gb3 level was borderline, cardiac MRI showed cardiac fibrosis, brain MRI documented cerebrovascular disease, and skin biopsy revealed small fiber neuropathy without globotriaosylceramide-3 skin deposits. Genetic study by means of targeted next-generation sequencing analysis disclosed a missense substitution c.1139CT (p.Pro380Leu) in the GLA gene. We suggest that this novel variant should be considered as pathogenic and associated with a late-onset variant of Fabry disease with a predominant neurological phenotype.

Background INPLASY® is an international platform for registration of systematic review and meta-analysis protocols launched in March 2020. INPLASY® provides an online database where the protocols are maintained as a permanent public record and can be accessed on the website (www.inplasy.com). Methods We described the database features and registered information of all records published since the launch of the registry up to March 31st, 2022. Additionally, the website statistics dataset was analysed to explore user experience and promote data transparency. Results A total of 3082 records were registered in INPLASY®, and more than 91% of the protocols were published within 24 hours. Most submissions were from China, followed by Portugal, Brazil, Taiwan, and Spain. INPLASY® website received a total of 240,855 page views from 37,647 visitors during the first two years. These accesses were from 139 countries worldwide. Most of the accesses were from China, followed by The United States, Brazil, and Germany. The review status ‘‘completed and published’’ was observed in 323 protocols, and these studies were published in 156 different scientific peer-reviewed journals. The INPLASY® features included: (i) INPLASY® identifier, a unique protocol number; (ii) DOI number, the URL of the protocol linked to a specific DOI; (iii) ORCID update, INPLASY® updates the authors' ORCID page including their protocol automatically; and (iv) search tools, the protocols are freely accessible on www.inplasy.com. Conclusions The INPLASY® has several practical and useful features that should be considered when planning the registration of a systematic review protocol. Furthermore, the sharp increase in the number of protocols registered in INPLASY® in the first two years and the database statistics demonstrate that INPLASY® has become an important source of systematic review protocols. Therefore, authors should access INPLASY® before planning a future review study, either to avoid unintended duplication of efforts, or to obtain registration in a timely manner.

Objectives Polypharmacy is common in maintenance treatment of bipolar illness, but proof of greater efficacy compared to monotherapy is assumed rather than well known. We systematically reviewed the evidence from the literature to provide recommendations for clinical management and future research. Method A systematic review was conducted on the use of polypharmacy in bipolar prophylaxis. Relevant papers published in English through 31 December 2019 were identified searching the electronic databases MEDLINE, Embase, PsycINFO, and the Cochrane Library. Results Twelve studies matched inclusion criteria, including 10 randomized controlled trials (RCTs). The best drug combination in prevention is represented by lithium + valproic acid which showed a significant effect on time to mood relapses (HR = 0.57) compared to valproic acid monotherapy, especially for manic episodes (HR = 0.51). The effect was significant in terms of time to new drug treatment (HR = 0.51) and time to hospitalization (HR = 0.57). A significant reduction in the frequency of mood relapses was also reported for lithium + valproic acid vs. lithium monotherapy (RR=0.12); however, the trial had a small sample size. Lamotrigine + valproic acid reported significant efficacy in prevention of depressive episodes compared to lamotrigine alone. Conclusions The literature to support a generally greater efficacy with polypharmacy in bipolar illness is scant and heterogeneous. Within that limited evidence base, the best drug combination in bipolar prevention is represented by lithium + valproic acid for manic, but not depressive episodes. Clinical practice should focus more on adequate monotherapy before considering polypharmacy.

In the popular imaginary, cocoa-derived products, like chocolate, represent a panacea for mood and affectivity. However, whether this is a myth or a fact has yet to be clarified. A systematic review and meta-analysis were conducted according to the PRISMA guidelines to investigate the effect of cocoa-derived food on depressive and anxiety symptoms, positive and negative affect. We searched Web of Knowledge

Accumulating scientific and clinical evidence highlighted pathological hyperinflammation as a cardinal feature of SARS-CoV-2 infection and acute COVID-19 disease. With the emergence of long COVID-19 syndrome, several chronic health consequences, including neuropsychiatric sequelae, have gained attention from the public and medical communities. Since inflammatory mediators have also been accredited as putative biomarkers of suicidal ideations and behaviors, hyper- and neuroinflammation might share some colliding points, overlapping and being interconnected in the context of COVID-19. This review aims to provide a summary of current knowledge on the molecular and cellular mechanisms of COVID-19-associated hyper/neuroinflammation with focus on their relevance to the inflammatory hypothesis of suicide development. Subsequently, strategies to alleviate COVID-19 hyper/neuroinflammation by immunomodulatory agents (many of which at experimental stages) as well as psychopharmacologic/psychotherapeutic approaches are also mentioned. While suicide risk in COVID-19 survivors - until now little known - needs further analysis through longitudinal studies, current observations and mechanistic postulates warrant additional attention to this possibly emerging mental health concern.

Background: Despite several attempts, the etiopathogenesis of anorexia nervosa (AN) is still unknown. However, the activation of the immune response in neuropsychiatric diseases, including AN, is increasingly evident. We aimed to explore immune response parameters in patients with AN and identify the link between the presence of specific autoantibodies for hypothalamic antigens and the inflammatory response. The relationship between inflammatory markers and the duration of the disease has been also investigated. Methods: Twenty-two patients with AN were included, and none were under psychopharmacological treatment or suffering from autoimmune conditions. Serum concentrations of interleukin (IL)-6, IL-1β, tumor necrosis factor (TNF)-α, transforming growth factor (TGF)-β, and IL-21 were determined by ELISA kits. In addition, autoantibodies against hypothalamic antigens are quantitatively evaluated. Results: IL-6, IL-1 β, TNF-α, and TGF-β are significantly increased in patients with AN. A positive correlation with body mass index and with the amount of autoantibody specific for hypothalamic antigens exists. Notably, a progressive reduction of cytokines correlates with the progression of AN. In addition, IL-21 is increased in the blood of patients with AN and negatively correlates with autoantibody concentrations. Conclusions: This study shows that the increased pro-inflammatory phenotype in patients affected by AN correlates with the concentration of autoantibody specific for hypothalamic antigens. Of interest, the pro-inflammatory state seems to be reduced with duration of AN. In addition, IL-21 could work as a stimulant of the immune response, thus possibly increasing the autoreactivity.

Background: Vancomycin-intermediate Staphylococcus aureus (VISA) emerges typically in the healthcare-associated methicillin-resistant S. aureus and more rarely in community-acquired S. aureus (CA-MRSA). VISA is a serious concern for public health due to its association with persistent infections, the failure of vancomycin treatment, and poor clinical outcomes. Currently, the burden of VISA is somewhat high, even though vancomycin is the mainstay treatment for severe MRSA infections. The molecular mechanisms of reduced glycopeptide susceptibility in S. aureus are constantly under investigation but have still not yet been fully characterized. Methods: Our goal was to investigate the reduced glycopeptide susceptibility mechanisms emerging in a VISA CA-MRSA versus its vancomycin-susceptible (VSSA) CA-MRSA parents in a hospitalized patient undergoing glycopeptide treatment. Comparative integrated omics, Illumina MiSeq whole-genome sequencing (WGS), RNA-Seq, and bioinformatics were performed. Results: Through a comparison of VISA CA-MRSA vs. its VSSA CA-MRSA parent, mutational and transcriptomic adaptations were found in a pool of genes involved, directly or indirectly, in the biosynthesis of the glycopeptide target conferring or supporting the VISA phenotype, and its cross-resistance with daptomycin. This pool included key genes responsible for the biosynthesis of the peptidoglycan precursors, i.e., D-Ala, the D-Ala-D-Ala dipeptide termini of the pentapeptide, and its incorporation in the nascent pentapeptide, as key targets of the glycopeptide resistance. Furthermore, accessory glycopeptide-target genes involved in the pathways corroborated the key adaptations, and thus, supported the acquisition of the VISA phenotype i.e., transporters, nucleotide metabolism genes, and transcriptional regulators. Finally, transcriptional changes were also found in computationally predicted cis-acting small antisense RNA triggering genes related both to the key or accessory adaptive pathways. Conclusion: Our investigation describes an adaptive resistance pathway acquired under antimicrobial therapy conferring reduced glycopeptide susceptibility in a VISA CA-MRSA due to a comprehensive network of mutational and transcriptional adaptations in genes involved in pathways responsible for the biosynthesis of glycopeptide’s target or supporters of the key resistance path.

Background: Although the antidepressant potential of repetitive transcranial magnetic stimulation (rTMS), the pleiotropic effects in geriatric depression (GD) are poorly investigated. We tested rTMS on depression, cognitive performance, growth/neurotrophic factors, cerebral blood flow (CBF) to transcranial Doppler sonography (TCD), and motor-evoked potentials (MEPs) to TMS in GD. Methods: In this case series study, six drug-resistant subjects (median age 68.0 years) underwent MEPs at baseline and after 3 weeks of 10 Hz rTMS on the left dorsolateral prefrontal cortex. The percentage change of serum nerve growth factor, vascular endothelial growth factor, brain-derived growth factor, insulin-like growth factor-1, and angiogenin was obtained. Assessments were performed at baseline, and at the end of rTMS; psychocognitive tests were also repeated after 1, 3, and 6 months. Results: Chronic cerebrovascular disease was evident in five patients. No adverse/undesirable effect was reported. An improvement in mood was observed after rTMS but not at follow-up. Electrophysiological data to TMS remained unchanged, except for an increase in the right median MEP amplitude. TCD and neurotrophic/growth factors did not change. Conclusions: We were unable to detect a relevant impact of high-frequency rTMS on mood, cognition, cortical microcircuits, neurotrophic/growth factors, and CBF. Cerebrovascular disease and exposure to multiple pharmacological treatments might have contributed.

IntroductionLanguage is usually considered the social vehicle of thought in intersubjective communications. However, the relationship between language and high-order cognition seems to evade this canonical and unidirectional description (ie, the notion of language as a simple means of thought communication). In recent years, clinical high at-risk mental state (CHARMS) criteria (evolved from the Ultra-High-Risk paradigm) and the introduction of the Clinical Staging system have been proposed to address the dynamicity of early psychopathology. At the same time, natural language processing (NLP) techniques have greatly evolved and have been successfully applied to investigate different neuropsychiatric conditions. The combination of at-risk mental state paradigm, clinical staging system and automated NLP methods, the latter applied on spoken language transcripts, could represent a useful and convenient approach to the problem of early psychopathological distress within a transdiagnostic risk paradigm.Methods and analysisHelp-seeking young people presenting psychological distress (CHARMS+/− and Clinical Stage 1a or 1b; target sample size for both groups n=90) will be assessed through several psychometric tools and multiple speech analyses during an observational period of 1-year, in the context of an Italian multicentric study. Subjects will be enrolled in different contexts: Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DINOGMI), Section of Psychiatry, University of Genoa—IRCCS Ospedale Policlinico San Martino, Genoa, Italy; Mental Health Department—territorial mental services (ASL 3—Genoa), Genoa, Italy; and Mental Health Department—territorial mental services (AUSL—Piacenza), Piacenza, Italy. The conversion rate to full-blown psychopathology (CS 2) will be evaluated over 2 years of clinical observation, to further confirm the predictive and discriminative value of CHARMS criteria and to verify the possibility of enriching them with several linguistic features, derived from a fine-grained automated linguistic analysis of speech.Ethics and disseminationThe methodology described in this study adheres to ethical principles as formulated in the Declaration of Helsinki and is compatible with International Conference on Harmonization (ICH)-good clinical practice. The research protocol was reviewed and approved by two different ethics committees (CER Liguria approval code: 591/2020—id.10993; Comitato Etico dell’Area Vasta Emilia Nord approval code: 2022/0071963). Participants will provide their written informed consent prior to study enrolment and parental consent will be needed in the case of participants aged less than 18 years old. Experimental results will be carefully shared through publication in peer-reviewed journals, to ensure proper data reproducibility.Trial registration numberDOI:10.17605/OSF.IO/BQZTN.