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BackgroundPatients with breast cancer (BC) exhibit circadian rhythm disruptions, mainly of rest-activity rhythm (RAR), of which sleep is an essential component, and cortisol rhythm. Sleep complaints such as insomnia and cognitive impairments are prevalent in BC. In general population, sleep is known to contribute greatly to cognition. Thus, improving RAR (and particularly sleep) could help limiting cognitive impairments in BC patients. It has recently been suggested that, in addition to its essential role in spatial memory, the vestibular system contributes to RAR synchronization. Its stimulation could therefore limit both sleep disturbances and spatial memory deficits in BC.ObjectivesThe main aim of the ICANSLEEP-2 study is to assess the effects of galvanic vestibular stimulation (GVS) on circadian rhythms. The secondary aim is to assess whether GVS improves sleep and spatial memory in BC patients.MethodsTwo groups with insomnia complaints (Insomnia Severity Index > 7) will be included: a patients' group with BC (n = 50) and a healthy control group without history of cancer (n = 25). There will be two assessment sessions, before and after 2 weeks of GVS. Patients will be randomly assigned to either a GVS group or a sham group (noneffective stimulation). Controls will receive GVS. GVS effects will be quantified and compared between groups. Assessments will include actigraphy, salivary cortisol, polysomnography, a cognitive test battery (including a computer-based task for spatial memory) and validated questionnaires (for psychological functioning and sleep complaints).DiscussionCurrent methods for improving sleep in BC have had controversial outcomes regarding sleep structure. We expect GVS to offer a new mean of directly targeting RAR disruptions in BC patients, with beneficial effects on sleep structure. Given the crucial impact of sleep on cognitive functioning, notably spatial memory, improving sleep of BC patients should enhance their cognitive functioning.Ethics and disseminationThis study received ethical approval from the Ile de France IV institutional review board on 19 April 2022 (no. ID-RCB: 2022-A00437-36). The findings yielded by this protocol will be presented at various conferences and in peer-reviewed journals.Clinicaltrials.gov registration numberNCT05414357.

IntroductionThe RISKMet project aims to: (1) identify risk factors for metabolic syndrome (MetS) by comparing patients with and without MetS; (2) characterise patients treated with second-generation antipsychotics (SGAs) about MetS diagnosis; (3) study behavioural patterns, including physical activity (PA) and dietary habits, in patients and healthy individuals using a prospective cohort design.MethodThe RISKMet project investigates MetS in individuals treated with SGAs, focusing on both adult and paediatric populations. The study utilizes a case-control design to examine potential risk factors for MetS, categorizing participants as MetS+ considered as "Cases" and MetS- considered as "Controls" matched by sex and age. The evaluation of factors such as MetS, lifestyle habits, and environmental influences is conducted at two time points, T0 and T3, after 3 months. Subsequently, the project aims to assess body parameters, including physical examinations, and blood, and stool sample collection, to evaluate metabolic markers and the impact of SGAs. The analysis includes pharmacological treatment data and genetic variability. Behavioural markers related to lifestyle, eating behaviour, PA, and mood are assessed at both T0 and T3 using interviews, accelerometers, and a mobile app. The study aims to improve mental and physical well-being in SGA-treated individuals, establish a biobank for MetS research, build an evidence base for physical health programs, and develop preventive strategies for SGA-related comorbidities.ConclusionsThis project innovates MetS monitoring in psychiatry by using intensive digital phenotyping, identifying biochemical markers, assessing familial risks, and including genetically similar healthy controls.Study registration numberISRCTN18419418 at www.isrctn.com.

Background The unwillingness to share contacts is one of the least explored aspects of the COVID-19 pandemic. Here we report the factors associated with resistance to collaborate on contact tracing, based on the results of a nation-wide survey conducted in Italy in January-March 2021. Methods and findings The repeated cross-sectional on-line survey was conducted among 7,513 respondents (mean age 45.7, 50.4% women) selected to represent the Italian adult population 18–70 years old. Two groups were defined based on the direct question response expressing (1) unwillingness or (2) willingness to share the names of individuals with whom respondents had contact. We selected 70% of participants (training data set) to produce several multivariable binomial generalized linear models and estimated the proportion of variation explained by the model by McFadden R2, and the model’s discriminatory ability by the index of concordance. Then, we have validated the regression models using the remaining 30% of respondents (testing data set), and identified the best performing model by removing the variables based on their impact on the Akaike information criterion and then evaluating the model predictive accuracy. We also performed a sensitivity analysis using principal component analysis. Overall, 5.5% of the respondents indicated that in case of positive SARS-CoV-2 test they would not share contacts. Of note, this percentage varied from 0.8% to 46.5% depending on the answers to other survey questions. From the 139 questions included in the multivariable analysis, the initial model proposed 20 independent factors that were reduced to the 6 factors with only modest changes in the model performance. The 6-variables model demonstrated good performance in the training (c-index 0.85 and McFadden R2 criteria 0.25) and in the testing data set (93.3% accuracy, AUC 0.78, sensitivity 30.4% and specificity 97.4%). The most influential factors related to unwillingness to share contacts were the lack of intention to perform the test in case of contact with a COVID-19 positive individual (OR 5.60, 95% CI 4.14 to 7.58, in a fully adjusted multivariable analysis), disagreement that the government should be allowed to force people into self-isolation (OR 1.79, 95% CI 1.12 to 2.84), disagreement with the national vaccination schedule (OR 2.63, 95% CI 1.86 to 3.69), not following to the preventive anti-COVID measures (OR 3.23, 95% CI 1.85 to 5.59), the absence of people in the immediate social environment who have been infected with COVID-19 (1.66, 95% CI 1.24 to 2.21), as well as difficulties in finding or understanding the information about the infection or related recommendations. A limitation of this study is the under-representation of persons not participating in internet-based surveys and some vulnerable groups like homeless people, persons with disabilities or migrants. Conclusions Our analysis revealed several groups that expressed unwillingness to collaborate on contact tracing. The identified patterns may play a principal role not only in the COVID-19 epidemic but also be important for possible future public health threats, and appropriate interventions for their correction should be developed and ready for the implementation.

Tendinopathy is a degenerative disease in which inflammatory mediators have been found to be sometimes present. The interaction between inflammation and matrix remodeling in human tendon cells (TCs) is supported by the secretion of cytokines such as IL-1β, IL-6 and IL-33. In this context, it has been demonstrated that pulsed electromagnetic fields (PEMFs) were able to reduce inflammation and promote tendon marker synthesis. The aim of this study was to evaluate the anabolic and anti-inflammatory PEMF-mediated response on TCs in an in vitro model of inflammation. Moreover, since PEMFs enhance the anti-inflammatory efficacy of adenosine through the adenosine receptors (ARs), the study also focused on the role of A2AARs. Human TCs were exposed to PEMFs for 48 hours. After stimulation, A2AAR saturation binding experiments were performed. Along with 48 hours PEMF stimulation, TCs were treated with IL-1β and A2AAR agonist CGS-21680. IL-1Ra, IL-6, IL-8, IL-10, IL-33, VEGF, TGF-β1, PGE2 release and SCX, COL1A1, COL3A1, ADORA2A expression were quantified. PEMFs exerted A2AAR modulation on TCs and promoted COL3A1 upregulation and IL-33 secretion. In presence of IL-1β, TCs showed an upregulation of ADORA2A, SCX and COL3A1 expression and an increase of IL-6, IL-8, PGE2 and VEGF secretion. After PEMF and IL-1β exposure, IL-33 was upregulated, whereas IL-6, PGE2 and ADORA2A were downregulated. These findings demonstrated that A2AARs have a role in the promotion of the TC anabolic/reparative response to PEMFs and to IL-1β.

BackgroundThe management of mentally ill offenders in the community is one of the great challenges imposed on community psychiatry.AimThe aim of this study was to analyze the association between sociodemographic, clinical, and psychosocial factors and violent behavior in a sample of outpatients with severe mental disorders.MethodThis was a prospective cohort study with a baseline cross-sectional design used to provide a detailed analysis of patients' profiles, followed by a longitudinal design to measure aggressive and violent behavior during a 1-year follow-up. Patients with severe mental disorders, with or without a history of violence, were enrolled in four Italian Departments of Mental Health and underwent a comprehensive multidimensional assessment.ResultsThe sample included 247 outpatients, for a total of 126 cases and 121 controls. Compared to controls, patients with a history of violence had a greater frequency of lifetime domestic violence, a greater lifetime propensity to misuse substances, and a higher number of compulsory admissions. The forthnightly monitoring during the 1-year follow-up did show statistically significant differences in aggressive and violent behavior rates between the two groups. Verbal aggression was significantly associated with aggression against objects and physical aggression. Moreover, outpatients with an history of violence showed statistically significant higher MOAS scores compared to both residential patients with an history of violence, assessed in the first wave of this project, and all controls.ConclusionsPatients with a history of violence had specific characteristics and showed a greater occurrence of additional community violence during a 1-year observation period. Our results may assist clinicians in implementing standardized methods of patient assessment and violence monitoring in outpatient mental health services and may prompt improved collaboration between different community services.

Tendinopathy is a big burden in clinics and it represents 45% of musculoskeletal lesions. Despite the relevant social impact, both pathogenesis and development of the tendinopathy are still under-investigated, thus limiting the therapeutic advancement in this field. The purpose of this study was to evaluate the dose-dependent and time-related tissue-level changes occurring in a collagenase-induced tendinopathy in rat Achilles tendons, in order to establish a standardized model for future pre-clinical studies. With this purpose, 40 Sprague Dawley rats were randomly divided into two groups, treated by injecting collagenase type I within the Achilles tendon at 1 mg/mL (low dose) or 3 mg/mL (high dose). Tendon explants were histologically evaluated at 3, 7, 15, 30 and 45 days. Our results revealed that both the collagenase doses induced a disorganization of collagen fibers and increased the number of rounded resident cells. In particular, the high dose treatment determined a greater neovascularization and fatty degeneration with respect to the lower dose. These changes were found to be time-dependent and to resemble the features of human tendinopathy. Indeed, in our series, the acute phase occurred from day 3 to day 15, and then progressed towards the proliferative phase from day 30 to day 45 displaying a degenerative appearance associated with a very precocious and mild remodeling process. The model represents a good balance between similarity with histological features of human tendinopathy and feasibility, in terms of tendon size to create lesions and costs when compared to other animal models. Moreover, this model could contribute to improve the knowledge in this field, and it could be useful to properly design further pre-clinical studies to test innovative treatments for tendinopathy.

BackgroundViolence in acute psychiatric wards affects the safety of other patients and the effectiveness of treatment. However, there is a wide variation in reported rates of violence in acute psychiatric wards.ObjectivesTo use meta-analysis to estimate the pooled rate of violence in published studies, and examine the characteristics of the participants, and aspects of the studies themselves that might explain the variation in the reported rates of violence (moderators).MethodSystematic meta-analysis of studies published between January 1995 and December 2014, which reported rates of violence in acute psychiatric wards of general or psychiatric hospitals in high-income countries.ResultsOf the 23,972 inpatients described in 35 studies, the pooled proportion of patients who committed at least one act of violence was 17% (95% confidence interval (CI) 14-20%). Studies with higher proportions of male patients, involuntary patients, patients with schizophrenia and patients with alcohol use disorder reported higher rates of inpatient violence.ConclusionThe findings of this study suggest that almost 1 in 5 patients admitted to acute psychiatric units may commit an act of violence. Factors associated with levels of violence in psychiatric units are similar to factors that are associated with violence among individual patients (male gender, diagnosis of schizophrenia, substance use and lifetime history of violence).

HIV infection results in damage to the gastrointestinal (GI) tract, microbial translocation and immune activation. These are not completely normalized with combined antiretroviral therapy (cART). Moreover, increate morbidity and mortality of cART-treated HIV-infected individuals is associated with inflammation.In order to enhance GI tract immunity, we recruited and treated 20 HIV-infected humans with cART supplemented with probiotics and followed inflammation and immunological parameters (clinical trial number NCT02164344). 11 HIV seronegative subjects were included as control group. The enumeration of CD4+, CD8+, CD38+ and HLA-DR+ lymphocytes were evaluated on peripheral blood; HIV-RNA levels, sCD14, d-dimer, C-reactive protein (CRP) high sensitivity C-reactive protein (hsCRP), IL-6 and Lipopolysaccharide Binding Protein (LBP) were assayed on plasma.We observe that cART does not normalize the levels of immune activation in HIV positive patients anyway inflammation and markers of microbial translocation were significantly reduced with probiotic supplementation. Patients show a clear and statistically significant reduction in the levels of immune activation on CD4 T-lymphocytes, for both markers CD38 and HLA-DR and their simultaneous expression, LBP and hsCRP plasma levels after probiotic diet supplementation settling to values comparable to controls.Supplementing cART with probiotics in HIV-infected individuals may improve GI tract immunity and there by mitigate inflammatory sequelae, ultimately improving prognosis.ClinicalTrials.gov NCT02164344.

This study provides a general approach to the presence and possible role of orexins and their receptors in the gut (three gastric chambers and intestine) of confined environment bottlenose dolphin. The expression of prepro-orexin, orexin A and B and orexin 1 and 2 receptors were investigated by single immunostaining and western blot analysis. The co-localization of vasoactive intestinal peptide and orexin 1 receptor in the enteric nervous system was examined by double immunostaining. Also, orexin A concentration were measured in plasma samples to assess the possible diurnal variation of the plasma level of peptide in this species. Our results showed that the orexin system is widely distributed in bottlenose dolphin enteric nervous system of the all gastrointestinal tract examined. They are very peculiar and partially differs from that of terrestrial mammals. Orexin peptides and prepro-orexin were expressed in the main stomach, pyloric stomach and proximal intestine; while orexin receptors were expressed in the all examined tracts, with the exception of main stomach where found no evidence of orexin 2 receptor. Co-localization of vasoactive intestinal peptide and orexin 1 receptor were more evident in the pyloric stomach and proximal intestine. These data could suggest a possible role of orexin system on the contractility of bottlenose dolphin gastrointestinal districts. Finally, in agreement with several reports, bottlenose dolphin orexin A plasma level was higher in the morning during fasting. Our results emphasize some common features between bottlenose dolphin and terrestrial mammals. Certainly, further functional investigations may help to better explain the role of the orexin system in the energy balance of bottlenose dolphin and the complex interaction between feeding and digestive physiology.

BackgroundWe examined the extent to which disability mediates the observed associations of common mental and physical conditions with perceived health.Methods and findingsWHO World Mental Health (WMH) Surveys carried out in 22 countries worldwide (n = 51,344 respondents, 72.0% response rate). We assessed nine common mental conditions with the WHO Composite International Diagnostic Interview (CIDI), and ten chronic physical with a checklist. A visual analog scale (VAS) score (0, worst to 100, best) measured perceived health in the previous 30 days. Disability was assessed using a modified WHO Disability Assessment Schedule (WHODAS), including: cognition, mobility, self-care, getting along, role functioning (life activities), family burden, stigma, and discrimination. Path analysis was used to estimate total effects of conditions on perceived health VAS and their separate direct and indirect (through the WHODAS dimensions) effects. Twelve-month prevalence was 14.4% for any mental and 51.4% for any physical condition. 31.7% of respondents reported difficulties in role functioning, 11.4% in mobility, 8.3% in stigma, 8.1% in family burden and 6.9% in cognition. Other difficulties were much less common. Mean VAS score was 81.0 (SD = 0.1). Decrements in VAS scores were highest for neurological conditions (9.8), depression (8.2) and bipolar disorder (8.1). Across conditions, 36.8% (IQR: 31.2-51.5%) of the total decrement in perceived health associated with the condition were mediated by WHODAS disabilities (significant for 17 of 19 conditions). Role functioning was the dominant mediator for both mental and physical conditions. Stigma and family burden were also important mediators for mental conditions, and mobility for physical conditions.ConclusionsMore than a third of the decrement in perceived health associated with common conditions is mediated by disability. Although the decrement is similar for physical and mental conditions, the pattern of mediation is different. Research is needed on the benefits for perceived health of targeted interventions aimed at particular disability dimensions.

Associations between lifetime traumatic event (LTE) exposures and subsequent physical ill-health are well established but it has remained unclear whether these are explained by PTSD or other mental disorders. This study examined this question and investigated whether associations varied by type and number of LTEs, across physical condition outcomes, or across countries.Cross-sectional, face-to-face household surveys of adults (18+) were conducted in 14 countries (n = 38, 051). The Composite International Diagnostic Interview assessed lifetime LTEs and DSM-IV mental disorders. Chronic physical conditions were ascertained by self-report of physician's diagnosis and year of diagnosis or onset. Survival analyses estimated associations between the number and type of LTEs with the subsequent onset of 11 physical conditions, with and without adjustment for mental disorders.A dose-response association was found between increasing number of LTEs and odds of any physical condition onset (OR 1.5 [95% CI: 1.4-1.5] for 1 LTE; 2.1 [2.0-2.3] for 5+ LTEs), independent of all mental disorders. Associations did not vary greatly by type of LTE (except for combat and other war experience), nor across countries. A history of 1 LTE was associated with 7/11 of the physical conditions (ORs 1.3 [1.2-1.5] to 1.7 [1.4-2.0]) and a history of 5+ LTEs was associated with 9/11 physical conditions (ORs 1.8 [1.3-2.4] to 3.6 [2.0-6.5]), the exceptions being cancer and stroke.Traumatic events are associated with adverse downstream effects on physical health, independent of PTSD and other mental disorders. Although the associations are modest they have public health implications due to the high prevalence of traumatic events and the range of common physical conditions affected. The effects of traumatic stress are a concern for all medical professionals and researchers, not just mental health specialists.

BackgroundCommunity and clinical data have suggested there is an association between trauma exposure and suicidal behavior (i.e., suicide ideation, plans and attempts). However, few studies have assessed which traumas are uniquely predictive of: the first onset of suicidal behavior, the progression from suicide ideation to plans and attempts, or the persistence of each form of suicidal behavior over time. Moreover, few data are available on such associations in developing countries. The current study addresses each of these issues.Methodology/principal findingsData on trauma exposure and subsequent first onset of suicidal behavior were collected via structured interviews conducted in the households of 102,245 (age 18+) respondents from 21 countries participating in the WHO World Mental Health Surveys. Bivariate and multivariate survival models tested the relationship between the type and number of traumatic events and subsequent suicidal behavior. A range of traumatic events are associated with suicidal behavior, with sexual and interpersonal violence consistently showing the strongest effects. There is a dose-response relationship between the number of traumatic events and suicide ideation/attempt; however, there is decay in the strength of the association with more events. Although a range of traumatic events are associated with the onset of suicide ideation, fewer events predict which people with suicide ideation progress to suicide plan and attempt, or the persistence of suicidal behavior over time. Associations generally are consistent across high-, middle-, and low-income countries.Conclusions/significanceThis study provides more detailed information than previously available on the relationship between traumatic events and suicidal behavior and indicates that this association is fairly consistent across developed and developing countries. These data reinforce the importance of psychological trauma as a major public health problem, and highlight the significance of screening for the presence and accumulation of traumatic exposures as a risk factor for suicide ideation and attempt.

This study provides a general approach to the presence and possible role of orexins and their receptors in the gut (three gastric chambers and intestine) of confined environment bottlenose dolphin. The expression of prepro-orexin, orexin A and B and orexin 1 and 2 receptors were investigated by single immunostaining and western blot analysis. The co-localization of vasoactive intestinal peptide and orexin 1 receptor in the enteric nervous system was examined by double immunostaining. Also, orexin A concentration were measured in plasma samples to assess the possible diurnal variation of the plasma level of peptide in this species. Our results showed that the orexin system is widely distributed in bottlenose dolphin enteric nervous system of the all gastrointestinal tract examined. They are very peculiar and partially differs from that of terrestrial mammals. Orexin peptides and prepro-orexin were expressed in the main stomach, pyloric stomach and proximal intestine; while orexin receptors were expressed in the all examined tracts, with the exception of main stomach where found no evidence of orexin 2 receptor. Co-localization of vasoactive intestinal peptide and orexin 1 receptor were more evident in the pyloric stomach and proximal intestine. These data could suggest a possible role of orexin system on the contractility of bottlenose dolphin gastrointestinal districts. Finally, in agreement with several reports, bottlenose dolphin orexin A plasma level was higher in the morning during fasting. Our results emphasize some common features between bottlenose dolphin and terrestrial mammals. Certainly, further functional investigations may help to better explain the role of the orexin system in the energy balance of bottlenose dolphin and the complex interaction between feeding and digestive physiology.