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Marlana M Ray,1 Jennifer Yeung,1 Jonathan Hoehn,2 Matthew Valenti,3 Kelsey E Lewis,1 Rachel N Pauls,1 Catrina C Crisp1 1Urogynecology Division, TriHealth, Cincinnati, OH, USA; 2Hatton Research Institute, TriHealth, Cincinnati, OH, USA; 3OB/GYN Department, University of Cincinnati, Cincinnati, OH, USACorrespondence: Marlana M Ray, TriHealth, Urogynecology Division, 3219 Clifton Ave, Medical Office Building Suite 100, Cincinnati, OH, 45220, USA, Email marlana_ray@trihealth.comPurpose: Studies involving minimally invasive hysterectomy and robotic sacrocolpopexy have demonstrated safety and feasibility of same-day discharge. There are limited data, however, on same-day discharge outcomes for vaginal hysterectomy and pelvic reconstruction. This study aimed to compare 30 and 90-day surgical outcomes between same-day discharge versus overnight stay following vaginal hysterectomy and apical suspension.Patients and Methods: This retrospective study evaluated surgeries performed over two time periods. Overnight stay was standard between December 2018 and February 2020. Same-day discharge was standard from December 2020 to February 2022. All patients who underwent vaginal hysterectomy with apical suspension were included. The primary outcome was to determine if there was an increase in 30-day readmission rates. Secondary outcomes included emergency department visits and reoperations within 30 days, the previous variables at 90 days, and the rate for successful same-day discharge.Results: A total of 324 patients were analyzed over the 30 months: 149 (46%) in the overnight stay group and 175 (54%) in the same-day discharge group. At 30 days, no difference was found between groups for readmissions (2.7% vs 4.0%, p = 0.56), emergency department visits (14.8% vs 14.9%, p = 1.0), or reoperations (2.0% vs.1.7%, p = 1.0). At 90 days, outcomes were also similar. Same-day discharge as standard practice was successful in 80% of patients.Conclusion: In this retrospective two cohort study, the safety of same-day discharge following vaginal hysterectomy with apical suspension was demonstrated with no increased risk of 30 or 90-day readmissions, emergency visits, or reoperation rates. The majority (80%) of patients were discharged on the day of surgery, suggesting feasibility of this model.Keywords: female pelvic reconstructive surgery, urogynecology, vaginal prolapse repair, pelvic floor surgery

Luciano Ibba,1,2 Luigi Gargiulo,1,2 Carlo Alberto Vignoli,1,2 Giovanni Fiorillo,1,2 Mario Valenti,1,2 Antonio Costanzo,1,2 Alessandra Narcisi1 1Dermatology Unit, IRCCS Humanitas Research Hospital, Milan, Italy; 2Department of Biomedical Sciences, Humanitas University, Milan, ItalyCorrespondence: Luciano Ibba, Department of Biomedical Sciences, Humanitas University, Rozzano, Milan, 20089, Italy, Email luciano.ibba@humanitas.itAbstract: Upadacitinib is a selective Janus kinase inhibitor approved for the treatment of severe atopic dermatitis (AD). This systematic review aims to summarize the most recent data in terms of effectiveness and safety of upadacitinib in the treatment of severe AD in a real-world setting. The review included a comprehensive search of databases, including PubMed, Google Scholar and Web of Science, according to Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) guidelines. The literature search initially identified 242 studies. Of these, 214 were excluded after reviewing their titles and abstracts. We then conducted a full-text review of 25 studies, of which 17 met our inclusion criteria and were therefore included in our systematic review. The analysis of real-world studies showed high effectiveness of upadacitinib, in terms of both clinical signs and subjective symptoms, in different patient populations, including those resistant to other treatments. No new significant safety concerns have emerged as compared to randomized clinical trials.Keywords: JAKi, real-life, upadacitinib, atopic dermatitis, systematic review

Objectives: Fibromyalgia syndrome (FMS) is a chronic clinical condition characterized by pain, fatigue, altered sleep, and cognitive disturbances. The purpose of this study was to compare two alternative treatments (nutraceutical and acupuncture) in FMS patients through a randomized clinical trial. Research Methods: A total of 60 FMS female patients were randomized for treatment with a nutritional combination containing coenzyme Q10, vitamin D, alpha-lipoic acid, magnesium, and tryptophan (Migratens® Group) or acupuncture treatment (Acupuncture Group) performed according the principles of traditional Chinese medicine (TCM), both for 3 months. Changes in pain and in quality of life (QoL) measured with a Fibromyalgia Impact Questionnaire Score-Revised (FIQ-R) and the Fibromyalgia Severity Scale (FSS) were performed at 1, 3, and 6 months after the start of treatments. Results: A total of 55 patient completed the study (21 in the Migratens® Group and 34 in the Acupuncture Group). Migratens® treatment shows a statistically significant reduction of pain 1 month after the start of therapy (T1, p = 0.025), strengthened after 3 months with maintenance of treatment (p = 0.012). The efficacy in reducing pain was apparent in the Acupuncture Group at all post-treatment determinations and at follow-up (T1 and T2 p = ® seems to be an effective option to for patients with FMS. Our experience confirmed also the validity of acupuncture in these patients. Considering the complexity of the management of FMS patients, our results suggest a cyclical and sequential, or even concurrent treatment with different approaches, to improve the efficacy and the compliance of patients to long-term treatment

Background and Objectives: An imbalance in cytokine production may be involved in the pathogenesis of chronic C hepatitis. The aim of the study was to investigate circulating levels of interleukin-10 (IL-10) in a selected cohort of patients affected by chronic C hepatitis. Design and Setting: Retrospective study based on consecutive hepatitis C virus patients, affected by chronic active hepatitis, attending the general hospital of hepatology unit from June to September 2009 Patients and Methods: A total of 49 patients with chronic C hepatitis and 20 healthy control subjects similar in gender and age were examined. Circulating IL-10 was assessed by ELISA commercial kit (R and D Systems) in all investigated subjects. Results: There was no significant difference in IL-10 values between controls and overall patients (P>.05). Nevertheless, among patients, subjects with more severe necroinflammation had higher values than others (PPConclusions: These findings suggest that IL-10 may be a useful additional marker to assess necroinflammation and to monitor the evolution of liver damage. They also argue for a potential pathophysiological role for IL-10 in the persistence and progression of hepatitis.

Abstract Background Previous studies have shown favourable results with intensive behavioural treatment for children with autism: evidence has emerged that treatment can be successfully implemented in a community setting and in adolescent participants. The aim of this study was to describe the 2-year adaptive functioning outcome of children and adolescents with autism treated intensively within the context of special autism centres, as well as to evaluate family satisfaction with the activity of the centres. Methods Sixty participants with autism (20 females and 40 males, aged between 4 and 18 years) attending the semi-residential rehabilitation centres for autism located in the Abruzzo region (Central Italy) were followed up and their adaptive functioning was evaluated both at baseline and after one and two years using the Vineland Adaptive Behaviour Scales (VABS). Parents' satisfaction with the service was evaluated using the Orbetello Satisfaction Scale for Children and Adolescent Mental Health. Results The increase in VABS scores was significant on several domains in the different gender and age categories. It is worth noting that male children had improved a great deal (roughly, an effect size >0.20) in the domains of communication, daily living and motor skills (effect sizes 0.34, 0.45 and 0.27 respectively) whereas in male adolescents, a notable increase in VABS scores was recorded in the domain of socialization only (effect size 0.23). On the other hand, adaptive behaviour in female children increased in the domains of socialization and motor skills (effect sizes 0.27 and 0.42 respectively) whereas in female adolescents, good results were achieved in the domains of daily living, socialization and motor skills (effect sizes 0.22, 0.26 and 0.20 respectively). The level of satisfaction of users of the service over time was found to be substantial, even when they had recently started the program. Conclusions Our results support the implementation of special autism treatment community centres, based on a parent co-directed rehabilitative, intensive and early intervention. Further experimental research designed to document the effectiveness of services provided to children and adolescents with autism in the community is recommended.

Abstract Objective Different sources are available for the surveillance of Road Traffic injuries (RTI), but studied individually they present several limits. In this paper we present the results of a surveillance integrating healthcare data with the data gathered by the municipal police in the southeastern area of Rome (630,000 inhabitants) during the year 2003. Methods The Municipal police RTI reports, which list the exact location, circumstances and some risk factor of the crash, were searched in the emergency visit, hospitalization and mortality databases, to integrate them with the information on health consequences. A multivariate analysis was conducted to evaluate risk factors (crash circumstances, age ad gender of the casualty) associated with hospital admission following a RTI. Mapping of RTI locations was created. The locations with higher risk of accidents with severe health consequences and at higher risk for pedestrians were identified. Results According to police records 4571 RTI occurred in 2003, 75% of which led to emergency department admissions. Sixteen percent of these emergency visits ended in hospitalization, and 44 deaths were reported within 30 days of the event, most of which occurred in young men. The people with the highest risk of hospitalization after an RTI were the cyclists, pedestrians and followed by people on two-wheeled vehicles. The type of crash with the highest risk of hospitalization was head-on collision. Geographical analyses showed four clusters with higher severity of RTI. Specific attention was paid to pedestrian injuries. Analyzing the locations of RTIs involving pedestrians permitted us to rank the most dangerous streets. The roads at high risk for pedestrians identified problems in the bus stop constructions and in the placement of the zebra pedestrian crossings. Conclusion This study proves the feasibility of an integrated surveillance system of RTI by using routinely collected local data. The high-risk locations identified with the geographic analyses method in this study highlighted infrastructural problems, suggesting immediate preventive interventions.

Abstract Background Manic-depression or bipolar disorder (BD) is a multi-faceted illness with an inevitably complex treatment. Methods This article summarizes the current status of our knowledge and practice of its treatment. Results It is widely accepted that lithium is moderately useful during all phases of bipolar illness and it might possess a specific effectiveness on suicidal prevention. Both first and second generation antipsychotics are widely used and the FDA has approved olanzapine, risperidone, quetiapine, ziprasidone and aripiprazole for the treatment of acute mania. These could also be useful in the treatment of bipolar depression, but only limited data exists so far to support the use of quetiapine monotherapy or the olanzapine-fluoxetine combination. Some, but not all, anticonvulsants possess a broad spectrum of effectiveness, including mixed dysphoric and rapid-cycling forms. Lamotrigine may be effective in the treatment of depression but not mania. Antidepressant use is controversial. Guidelines suggest their cautious use in combination with an antimanic agent, because they are supposed to induce switching to mania or hypomania, mixed episodes and rapid cycling. Conclusion The first-line psychosocial intervention in BD is psychoeducation, followed by cognitive-behavioral therapy. Other treatment options include Electroconvulsive therapy and transcranial magnetic stimulation. There is a gap between the evidence base, which comes mostly from monotherapy trials, and clinical practice, where complex treatment regimens are the rule.

Abstract Background RT-PCR has been widely used for the analysis of gene expression in many systems, including tumor samples. GAPDH (Glyceraldehyde-3-phosphate dehydrogenase) has been frequently considered as a constitutive housekeeping gene and used to normalize changes in specific gene expression. However, GAPDH has been shown to be up-regulated in many cancers and down-regulated by chemotherapic drugs. Bisphosphonates, potent inhibitors of bone resorption, have recently shown a direct and indirect antitumor effect in vitro and in animal models. They exert their effects mainly by inhibiting the mevalonate pathway but also by modulating the expression of many genes not only in osteoclasts but also in cancer cells. Methods We evaluated GAPDH gene expression by real time RT PCR in breast (MCF-7 and T47D) and prostate (PC3 and DU-145) cancer cell lines treated with amino and non-amino bisphosphonates. Results Our results showed that amino-bisphosphonates significantly decrease in a dose-dependent manner the expression of GAPDH gene. Conclusion Therefore, GAPDH is inaccurate to normalize mRNA levels in studies investigating the effect of bisphosphonates on gene expression and it should be avoided. On the other hand, this gene could be considered a potential target to observe the effects of bisphosphonates on cancer cells.

This paper presents and analyzes an integrated, cross-layer protocol for wireless ad hoc networking that utilizes position location (e.g., through an onboard GPS receiver) and jointly performs the operations of network-layer relaying and link-layer ARQ-based error control. The protocol is a modified version of the hybrid-ARQ-based intra-cluster geographically-informed relaying (HARBINGER) protocol (2005) and unifies the concepts of geographic random forwarding (GeRaF) (2003), point-to-point hybrid-ARQ (2001), and cooperative diversity (2004). The modification makes the protocol especially suitable for sensor networks whose nodes cycle in and out of sleep states and permits a closed-form analysis. Performance bounds and simulations indicate the potential for a dramatic improvement in the tradeoff between active node density and end-to-end message delay as compared with the GeRaF protocol and are used to motivate further study of practical implementation issues.

Bipolar disorder (BD) involves autonomic nervous system dysfunction, detectable through heart rate variability (HRV). HRV is a promising biomarker, but its dynamics during acute mania or depression episodes are poorly understood. Using a Bayesian approach, we developed a probabilistic model of HRV changes in BD, measured by the natural logarithm of the Root Mean Square of Successive RR interval Differences (lnRMSSD). Patients were assessed three to four times from episode onset to euthymia. Unlike previous studies, which used only two assessments, our model allowed for more accurate tracking of changes. Results showed strong evidence for a positive lnRMSSD change during symptom resolution (95.175% probability of positive direction), though the sample size limited the precision of this effect (95% Highest Density Interval [-0.0366, 0.4706], with a Region of Practical Equivalence: [-0.05; 0.05]). Episode polarity did not significantly influence lnRMSSD changes., (© 2024. The Author(s).)

Importance: Poststroke cognitive impairment is common, but the cognitive trajectory following a first stroke, relative to prestroke cognitive function, remains unclear., Objective: To map the trajectory of cognitive function before any stroke and after stroke in global cognition and in 4 cognitive domains, as well as to compare the cognitive trajectory prestroke in stroke survivors with the trajectory of individuals without incident stroke over follow-up., Design, Setting, and Participants: The study used harmonized and pooled data from 14 population-based cohort studies included in the Cohort Studies of Memory in an International Consortium collaboration. These studies were conducted from 1993 to 2019 across 11 countries among community-dwelling older adults without a history of stroke or dementia. For this study, linear mixed-effects models were used to estimate trajectories of cognitive function poststroke relative to a stroke-free cognitive trajectory. The full model adjusted for demographic and vascular risk factors. Data were analyzed from July 2022 to March 2024., Exposure: Incident stroke., Main Outcomes and Measures: The primary outcome was global cognition, defined as the standardized average of 4 cognitive domains (language, memory, processing speed, and executive function). Cognitive domain scores were formed by selecting the most commonly administered test within each domain and standardizing the scores., Results: The study included 20 860 participants (12 261 [58.8%] female) with a mean (SD) age of 72.9 (8.0) years and follow-up of 7.51 (4.2) years. Incident stroke was associated with a substantial acute decline in global cognition (-0.25 SD; 95% CI, -0.33 to -0.17 SD), the Mini-Mental State Examination, and all cognitive domains (ranging from -0.17 SD to -0.22 SD), as well as accelerated decline in global cognition (-0.038 SD per year; 95% CI, -0.057 to -0.019 SD per year) and all domains except memory (ranging from -0.020 to -0.055 SD per year), relative to a stroke-free cognitive trajectory. There was no significant difference in prestroke slope in stroke survivors compared with the rate of decline in individuals without stroke in all cognitive measures. The mean rate of decline without a previous stroke was -0.049 SD per year (95% CI, -0.051 to -0.047 SD) in global cognition., Conclusions and Relevance: In this cohort study using pooled data from 14 cohorts, incident stroke was associated with acute and accelerated long-term cognitive decline in older stroke survivors.

Background and Hypothesis: This umbrella review aims to comprehensively synthesize the evidence of association between peripheral, electrophysiological, neuroimaging, neuropathological, and other biomarkers and diagnosis of psychotic disorders., Study Design: We selected systematic reviews and meta-analyses of observational studies on diagnostic biomarkers for psychotic disorders, published until February 1, 2018. Data extraction was conducted according to the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines. Evidence of association between biomarkers and psychotic disorders was classified as convincing, highly suggestive, suggestive, weak, or non-significant, using a standardized classification. Quality analyses used the Assessment of Multiple Systematic Reviews (AMSTAR) tool., Study Results: The umbrella review included 110 meta-analyses or systematic reviews corresponding to 3892 individual studies, 1478 biomarkers, and 392 210 participants. No factor showed a convincing level of evidence. Highly suggestive evidence was observed for transglutaminase autoantibodies levels (odds ratio [OR] = 7.32; 95% CI: 3.36, 15.94), mismatch negativity in auditory event-related potentials (standardized mean difference [SMD] = 0.73; 95% CI: 0.5, 0.96), P300 component latency (SMD = -0.6; 95% CI: -0.83, -0.38), ventricle-brain ratio (SMD = 0.61; 95% CI: 0.5, 0.71), and minor physical anomalies (SMD = 0.99; 95% CI: 0.64, 1.34). Suggestive evidence was observed for folate, malondialdehyde, brain-derived neurotrophic factor, homocysteine, P50 sensory gating (P50 S2/S1 ratio), frontal N -acetyl-aspartate, and high-frequency heart rate variability. Among the remaining biomarkers, weak evidence was found for 626 and a non-significant association for 833 factors., Conclusions: While several biomarkers present highly suggestive or suggestive evidence of association with psychotic disorders, methodological biases, and underpowered studies call for future higher-quality research., (© The Author(s) 2024. Published by Oxford University Press on behalf of the University of Maryland's school of medicine, Maryland Psychiatric Research Center.)

Background : Bipolar disorder (BD) involves significant mood and energy shifts reflected in speech patterns. Detecting these patterns is crucial for diagnosis and monitoring, currently assessed subjectively. Advances in natural language processing offer opportunities to objectively analyze them. Aims : To (i) correlate speech features with manic-depressive symptom severity in BD, (ii) develop predictive models for diagnostic and treatment outcomes, and (iii) determine the most relevant speech features and tasks for these analyses. Methods : This naturalistic, observational study involved longitudinal audio recordings of BD patients at euthymia, during acute manic/depressive phases, and after-response. Patients participated in clinical evaluations, cognitive tasks, standard text readings, and storytelling. After automatic diarization and transcription, speech features, including acoustics, content, formal aspects, and emotionality, will be extracted. Statistical analyses will (i) correlate speech features with clinical scales, (ii) use lasso logistic regression to develop predictive models, and (iii) identify relevant speech features. Results : Audio recordings from 76 patients (24 manic, 21 depressed, 31 euthymic) were collected. The mean age was 46.0 ± 14.4 years, with 63.2% female. The mean YMRS score for manic patients was 22.9 ± 7.1, reducing to 5.3 ± 5.3 post-response. Depressed patients had a mean HDRS-17 score of 17.1 ± 4.4, decreasing to 3.3 ± 2.8 post-response. Euthymic patients had mean YMRS and HDRS-17 scores of 0.97 ± 1.4 and 3.9 ± 2.9, respectively. Following data pre-processing, including noise reduction and feature extraction, comprehensive statistical analyses will be conducted to explore correlations and develop predictive models. Conclusions : Automated speech analysis in BD could provide objective markers for psychopathological alterations, improving diagnosis, monitoring, and response prediction. This technology could identify subtle alterations, signaling early signs of relapse. Establishing standardized protocols is crucial for creating a global speech cohort, fostering collaboration, and advancing BD understanding.

Background: Bipolar disorder is highly prevalent and consists of biphasic recurrent mood episodes of mania and depression, which translate into altered mood, sleep and activity alongside their physiological expressions., Aims: The IdenTifying dIgital bioMarkers of illnEss activity and treatment response in BipolAr diSordEr with a novel wearable device (TIMEBASE) project aims to identify digital biomarkers of illness activity and treatment response in bipolar disorder., Method: We designed a longitudinal observational study including 84 individuals. Group A comprises people with acute episode of mania ( n = 12), depression ( n = 12 with bipolar disorder and n = 12 with major depressive disorder (MDD)) and bipolar disorder with mixed features ( n = 12). Physiological data will be recorded during 48 h with a research-grade wearable (Empatica E4) across four consecutive time points (acute, response, remission and episode recovery). Group B comprises 12 people with euthymic bipolar disorder and 12 with MDD, and group C comprises 12 healthy controls who will be recorded cross-sectionally. Psychopathological symptoms, disease severity, functioning and physical activity will be assessed with standardised psychometric scales. Physiological data will include acceleration, temperature, blood volume pulse, heart rate and electrodermal activity. Machine learning models will be developed to link physiological data to illness activity and treatment response. Generalisation performance will be tested in data from unseen patients., Results: Recruitment is ongoing., Conclusions: This project should contribute to understanding the pathophysiology of affective disorders. The potential digital biomarkers of illness activity and treatment response in bipolar disorder could be implemented in a real-world clinical setting for clinical monitoring and identification of prodromal symptoms. This would allow early intervention and prevention of affective relapses, as well as personalisation of treatment.

Background: Personal sensing, leveraging data passively and near-continuously collected with wearables from patients in their ecological environment, is a promising paradigm to monitor mood disorders (MDs), a major determinant of the worldwide disease burden. However, collecting and annotating wearable data is resource intensive. Studies of this kind can thus typically afford to recruit only a few dozen patients. This constitutes one of the major obstacles to applying modern supervised machine learning techniques to MD detection., Objective: In this paper, we overcame this data bottleneck and advanced the detection of acute MD episodes from wearables' data on the back of recent advances in self-supervised learning (SSL). This approach leverages unlabeled data to learn representations during pretraining, subsequently exploited for a supervised task., Methods: We collected open access data sets recording with the Empatica E4 wristband spanning different, unrelated to MD monitoring, personal sensing tasks-from emotion recognition in Super Mario players to stress detection in undergraduates-and devised a preprocessing pipeline performing on-/off-body detection, sleep/wake detection, segmentation, and (optionally) feature extraction. With 161 E4-recorded subjects, we introduced E4SelfLearning, the largest-to-date open access collection, and its preprocessing pipeline. We developed a novel E4-tailored transformer (E4mer) architecture, serving as the blueprint for both SSL and fully supervised learning; we assessed whether and under which conditions self-supervised pretraining led to an improvement over fully supervised baselines (ie, the fully supervised E4mer and pre-deep learning algorithms) in detecting acute MD episodes from recording segments taken in 64 (n=32, 50%, acute, n=32, 50%, stable) patients., Results: SSL significantly outperformed fully supervised pipelines using either our novel E4mer or extreme gradient boosting (XGBoost): n=3353 (81.23%) against n=3110 (75.35%; E4mer) and n=2973 (72.02%; XGBoost) correctly classified recording segments from a total of 4128 segments. SSL performance was strongly associated with the specific surrogate task used for pretraining, as well as with unlabeled data availability., Conclusions: We showed that SSL, a paradigm where a model is pretrained on unlabeled data with no need for human annotations before deployment on the supervised target task of interest, helps overcome the annotation bottleneck; the choice of the pretraining surrogate task and the size of unlabeled data for pretraining are key determinants of SSL success. We introduced E4mer, which can be used for SSL, and shared the E4SelfLearning collection, along with its preprocessing pipeline, which can foster and expedite future research into SSL for personal sensing., (©Filippo Corponi, Bryan M Li, Gerard Anmella, Clàudia Valenzuela-Pascual, Ariadna Mas, Isabella Pacchiarotti, Marc Valentí, Iria Grande, Antoni Benabarre, Marina Garriga, Eduard Vieta, Allan H Young, Stephen M Lawrie, Heather C Whalley, Diego Hidalgo-Mazzei, Antonio Vergari. Originally published in JMIR mHealth and uHealth (https://mhealth.jmir.org), 17.07.2024.)

Background: Aerobic capacity has shown to predict physical and mental health-related quality of life in bipolar disorder (BD). However, the correlation between exercise respiratory capacity and mitochondrial function remains understudied. We aimed to assess longitudinally intra-individual differences in these factors during mood episodes and remission in BD., Methods: This study included eight BD patients admitted to an acute psychiatric unit. Incremental cardiopulmonary exercise test (CPET) was conducted during acute episodes (T0), followed by constant work rate cycle ergometry (CWRCE) to evaluate endurance time, oxygen uptake at peak exercise (VO 2peak ) and at the anaerobic threshold. The second test was repeated during remission (T1). Mitochondrial respiration rates were assessed at T0 and T1 in peripheral blood mononuclear cells., Results: Endurance time, VO 2peak , and anaerobic threshold oxygen consumption showed no significant variations between T0 and T1. Basal oxygen consumption at T1 tended to inversely correlate with maximal mitochondrial respiratory capacity (r=-0.690, p=0.058), and VO 2peak during exercise at T1 inversely correlated with basal and minimum mitochondrial respiration (r=-0.810, p=0.015; r=-0.786, p=0.021, respectively)., Conclusions: Our preliminary data showed that lower basal oxygen consumption may be linked to greater mitochondrial respiratory capacity, and maximum oxygen uptake during the exercise task was associated with lower basal mitochondrial respiration, suggesting that lower oxygen requirements could be associated with greater mitochondrial capacity. These findings should be replicated in larger samples stratified for manic and depressive states., Competing Interests: AG-P has received CME-related honoraria, or consulting fees from Janssen-Cilag, Lundbeck, Casen Recordati, LCN, Rovi and Angelini. GA has received CME-related honoraria, or consulting fees from Angelini, Casen Recordati, Janssen-Cilag, Lundbeck, Lundbeck/Otsuka, and Rovi, with no financial or other relationship relevant to the subject of this article. EV has received grants and served as consultant, advisor, or CME speaker for the following entities: AB-Biotics, AbbVie, Angelini, Biogen, Biohaven, Boehringer-Ingelheim, Celon Pharma, Compass, Dainippon Sumitomo Pharma, Ethypharm, Ferrer, Gedeon Richter, GH Research, Glaxo-Smith Kline, Idorsia, Janssen, Lundbeck, Medincell, Novartis, Orion Corporation, Organon, Otsuka, Rovi, Sage, Sanofi-Aventis, Sunovion, Takeda, and Viatris, outside the submitted work. IP has received CME-related honoraria, or consulting fees from ADAMED, Janssen-Cilag, and Lundbeck. IG has received grants and served as consultant, advisor or CME speaker for the following identities: Angelini, Casen Recordati, Ferrer, Janssen Cilag, and Lundbeck, Lundbeck-Otsuka, Luye, SEI Healthcare. MB Grant/Research Support: MRFF, NHMRC, Congressionally Directed Medical Research Programs CDMRP USA, AEDRTC Australian Eating Disorders Research and Translation Centre, Patient-Centered Outcomes Research Institute PCORI, Baszucki Brain Research Fund, Danmarks Frie Forskningsfond. Psykiatrisk Center Kobenhavn, Stanley Medical Research Institute, Victorian Government Department of Jobs, Precincts and Regions, Wellcome Trust, Victorian Medical Research Acceleration Fund, Controversias Psiquiatria Barcelona, CRE, Victorian COVID-19 Research Fund, Consultancies: Lundbeck, Sandoz, Servier, Medisquire, HealthEd, ANZJP, EPA, Janssen, Medplan, RANZCP, Abbott India, ASCP, International Society of Bipolar Disorder, Precision Psychiatry, Penn State College of Medicine, Shanghai Mental Health Centre. Last 3 years – all unrelated to this work. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Giménez-Palomo, Guitart-Mampel, Roqué, Sánchez, Borràs, Meseguer, García-García, Tobías, Valls-Roca, Anmella, Valentí, Olivier, de Juan, Ochandiano, Andreu, Radua, Verdolini, Berk, Vieta, Garrabou, Roca, Alsina-Restoy and Pacchiarotti.)

Mood disorders (MDs) are among the leading causes of disease burden worldwide. Limited specialized care availability remains a major bottleneck thus hindering pre-emptive interventions. MDs manifest with changes in mood, sleep, and motor activity, observable in ecological physiological recordings thanks to recent advances in wearable technology. Therefore, near-continuous and passive collection of physiological data from wearables in daily life, analyzable with machine learning (ML), could mitigate this problem, bringing MDs monitoring outside the clinician's office. Previous works predict a single label, either the disease state or a psychometric scale total score. However, clinical practice suggests that the same label may underlie different symptom profiles, requiring specific treatments. Here we bridge this gap by proposing a new task: inferring all items in HDRS and YMRS, the two most widely used standardized scales for assessing MDs symptoms, using physiological data from wearables. To that end, we develop a deep learning pipeline to score the symptoms of a large cohort of MD patients and show that agreement between predictions and assessments by an expert clinician is clinically significant (quadratic Cohen's κ and macro-average F1 score both of 0.609). While doing so, we investigate several solutions to the ML challenges associated with this task, including multi-task learning, class imbalance, ordinal target variables, and subject-invariant representations. Lastly, we illustrate the importance of testing on out-of-distribution samples., (© 2024. The Author(s).)

Background: The relative importance of different components of cognitive reserve (CR), as well as their differences by gender, are poorly established., Objective: To explore several dimensions of CR, their differences by gender, and their effects on cognitive performance and trajectory in a cohort of older people without relevant psychiatric, neurologic, or systemic conditions., Methods: Twenty-one variables related to the education, occupation, social activities, and life habits of 1,093 home-dwelling and cognitively healthy individuals, between 68 and 86 years old, were explored using factorial analyses to delineate several dimensions of CR. These dimensions were contrasted with baseline cognitive performance, follow-up over 5 years of participants' cognitive trajectory, conversion to mild cognitive impairment (MCI), and brain volumes using regression and growth curve models, controlling for gender, age, marital status, number of medications, trait anxiety, depression, and ApoE genotype., Results: Five highly intercorrelated dimensions of CR were identified, with some differences in their structure and effects based on gender. Three of them, education/occupation, midlife cognitive activities, and leisure activities, were significantly associated with late-life cognitive performance, accounting for more than 20% of its variance. The education/occupation had positive effect on the rate of cognitive decline during the 5-year follow up in individuals with final diagnosis of MCI but showed a reduced risk for MCI in men. None of these dimensions showed significant relationships with gray or white matter volumes., Conclusion: Proxy markers of CR can be represented by five interrelated dimensions. Education/occupation, midlife cognitive activities, and leisure activities are associated with better cognitive performance in old age and provide a buffer against cognitive impairment. Education/occupation may delay the clinical onset of MCI and is also associated with the rate of change in cognitive performance., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 del Ser, Valeriano-Lorenzo, Jáñez-Escalada, Ávila-Villanueva, Frades, Zea, Valentí, Zhang and Fernández-Blázquez.)

Background: Depressive and manic episodes within bipolar disorder (BD) and major depressive disorder (MDD) involve altered mood, sleep, and activity, alongside physiological alterations wearables can capture., Objective: Firstly, we explored whether physiological wearable data could predict (aim 1) the severity of an acute affective episode at the intra-individual level and (aim 2) the polarity of an acute affective episode and euthymia among different individuals. Secondarily, we explored which physiological data were related to prior predictions, generalization across patients, and associations between affective symptoms and physiological data., Methods: We conducted a prospective exploratory observational study including patients with BD and MDD on acute affective episodes (manic, depressed, and mixed) whose physiological data were recorded using a research-grade wearable (Empatica E4) across 3 consecutive time points (acute, response, and remission of episode). Euthymic patients and healthy controls were recorded during a single session (approximately 48 h). Manic and depressive symptoms were assessed using standardized psychometric scales. Physiological wearable data included the following channels: acceleration (ACC), skin temperature, blood volume pulse, heart rate (HR), and electrodermal activity (EDA). Invalid physiological data were removed using a rule-based filter, and channels were time aligned at 1-second time units and segmented at window lengths of 32 seconds, as best-performing parameters. We developed deep learning predictive models, assessed the channels' individual contribution using permutation feature importance analysis, and computed physiological data to psychometric scales' items normalized mutual information (NMI). We present a novel, fully automated method for the preprocessing and analysis of physiological data from a research-grade wearable device, including a viable supervised learning pipeline for time-series analyses., Results: Overall, 35 sessions (1512 hours) from 12 patients (manic, depressed, mixed, and euthymic) and 7 healthy controls (mean age 39.7, SD 12.6 years; 6/19, 32% female) were analyzed. The severity of mood episodes was predicted with moderate (62%-85%) accuracies (aim 1), and their polarity with moderate (70%) accuracy (aim 2). The most relevant features for the former tasks were ACC, EDA, and HR. There was a fair agreement in feature importance across classification tasks (Kendall W=0.383). Generalization of the former models on unseen patients was of overall low accuracy, except for the intra-individual models. ACC was associated with "increased motor activity" (NMI>0.55), "insomnia" (NMI=0.6), and "motor inhibition" (NMI=0.75). EDA was associated with "aggressive behavior" (NMI=1.0) and "psychic anxiety" (NMI=0.52)., Conclusions: Physiological data from wearables show potential to identify mood episodes and specific symptoms of mania and depression quantitatively, both in BD and MDD. Motor activity and stress-related physiological data (EDA and HR) stand out as potential digital biomarkers for predicting mania and depression, respectively. These findings represent a promising pathway toward personalized psychiatry, in which physiological wearable data could allow the early identification and intervention of mood episodes., (©Gerard Anmella, Filippo Corponi, Bryan M Li, Ariadna Mas, Miriam Sanabra, Isabella Pacchiarotti, Marc Valentí, Iria Grande, Antoni Benabarre, Anna Giménez-Palomo, Marina Garriga, Isabel Agasi, Anna Bastidas, Myriam Cavero, Tabatha Fernández-Plaza, Néstor Arbelo, Miquel Bioque, Clemente García-Rizo, Norma Verdolini, Santiago Madero, Andrea Murru, Silvia Amoretti, Anabel Martínez-Aran, Victoria Ruiz, Giovanna Fico, Michele De Prisco, Vincenzo Oliva, Aleix Solanes, Joaquim Radua, Ludovic Samalin, Allan H Young, Eduard Vieta, Antonio Vergari, Diego Hidalgo-Mazzei. Originally published in JMIR mHealth and uHealth (https://mhealth.jmir.org), 04.05.2023.)

Background: In mental health, comorbidities are the norm rather than the exception. However, current meta-analytic methods for summarizing the neural correlates of mental disorders do not consider comorbidities, reducing them to a source of noise and bias rather than benefitting from their valuable information., Objectives: We describe and validate a novel neuroimaging meta-analytic approach that focuses on comorbidities. In addition, we present the protocol for a meta-analysis of all major mental disorders and their comorbidities., Methods: The novel approach consists of a modification of Seed-based d Mapping-with Permutation of Subject Images (SDM-PSI) in which the linear models have no intercept. As in previous SDM meta-analyses, the dependent variable is the brain anatomical difference between patients and controls in a voxel. However, there is no primary disorder, and the independent variables are the percentages of patients with each disorder and each pair of potentially comorbid disorders. We use simulations to validate and provide an example of this novel approach, which correctly disentangled the abnormalities associated with each disorder and comorbidity. We then describe a protocol for conducting the new meta-analysis of all major mental disorders and their comorbidities. Specifically, we will include all voxel-based morphometry (VBM) studies of mental disorders for which a meta-analysis has already been published, including at least 10 studies. We will use the novel approach to analyze all included studies in two separate single linear models, one for children/adolescents and one for adults., Discussion: The novel approach is a valid method to focus on comorbidities. The meta-analysis will yield a comprehensive atlas of the neuroanatomy of all major mental disorders and their comorbidities, which we hope might help develop potential diagnostic and therapeutic tools., Competing Interests: NV has received financial support for CME activities and travel funds from the following entities (unrelated to the present work): Angelini, Janssen-Cilag, Lundbeck, Otsuka. EVia is a co-investigator in a Janssen-Cilag, S.A., clinical trial with the esketamine molecule (unrelated to the present work). KR received a grant from TAKEDA pharmaceutical for another project and consulting fees from Lundbeck and Supernus (unrelated to the present work). The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Fortea, Albajes-Eizagirre, Yao, Soler, Verdolini, Hauson, Fortea, Madero, Solanes, Wollman, Serra-Blasco, Wise, Lukito, Picó-Pérez, Carlisi, Zhang, Pan, Farré-Colomés, Arnone, Kempton, Soriano-Mas, Rubia, Norman, Fusar-Poli, Mataix-Cols, Valentí, Via, Cardoner, Solmi, Shin, Vieta and Radua.)

Background: Brain structural and functional changes in bipolar disorder (BD) are well-established findings, but it is uncertain whether these changes are already present in first episode mania (FEM)., Methods: We compared 31 FEM subjects, with 31 healthy individuals matched for age, sex, and premorbid IQ. Whole-brain voxel-wise morphometry, functional magnetic resonance imaging during the n-back task, and a functional connectivity analysis were performed., Results: There were no volumetric differences between the 2 groups. During the 2-back task, FEM patients did not perform differently from controls and activated similar regions, but they showed less deactivation in the ventromedial prefrontal cortex (vmPFC), the anterior hub of the default mode network (DMN). They showed preserved functional connectivity between the vmPFC and other regions of the DMN, but increased connectivity with the superior frontal gyrus., Conclusions: The absence of volumetric changes in FEM patients suggests that these changes could be related to progression of the illness. On the other hand, the failure of deactivation of the anterior hub of the DMN is present from the onset of the illness and may represent a core pathophysiological feature of BD., (© The Author(s) 2018. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Introduction : Subjective memory complaints (SMC) in the elderly have been suggested as an early sign of dementia. This study aims at investigating whether specific cognitive complaints are more useful than others to discriminate Mild Cognitive Impairment (MCI) by examining the dimensional structure of the Everyday Memory Questionnaire (EMQ). Materials and Methods : A sample of community-dwelling elderly individuals was recruited (766 controls and 78 MCI). The EMQ was administered to measure self-perception of cognitive complaints. All participants also underwent a comprehensive clinical and neuropsychological battery. Combined exploratory factor analysis (EFA) and Item Response Theory (IRT) were performed to identify the underlying structure of the EMQ. Furthermore, logistic regression analyses were conducted to study whether single cognitive complaints were able to predict MCI. Results : A suitable five-factor solution was found. Each factor focused on a different cognitive domain. Interestingly, just three of them, namely Forgetfulness of Immediate Information (FII), Executive Functions (EF) and Prospective Memory (PM) proved to be effective in distinguishing between cognitively healthy individuals and MCI. Based on these results we propose a shortened EMQ version comprising 10 items (EMQ-10). Discussion : Not all cognitive complaints have the same clinical relevance. Only subjective complaints on specific cognitive domains are able to discriminate MCI. We encourage clinicians to use the EMQ-10 as a useful tool to quantify and monitor the progression of individuals who report cognitive complaints.

Introduction: Alzheimer's disease (AD) is a major threat for the well-being of an increasingly aged world population. The physiopathological mechanisms of late-onset AD are multiple, possibly heterogeneous, and not well understood. Different combinations of variables from several domains (i.e., clinical, neuropsychological, structural, and biochemical markers) may predict dementia conversion, according to distinct physiopathological pathways, in different groups of subjects., Methods: We launched the Vallecas Project (VP), a cohort study of non-demented people aged 70-85, to characterize the social, clinical, neuropsychological, structural, and biochemical underpinnings of AD inception. Given the exploratory nature of the VP, multidimensional and machine learning techniques will be applied, in addition to the traditional multivariate statistical methods., Results: A total of 1169 subjects were recruited between October 2011 and December 2013. Mean age was 74.4 years (SD 3.9), 63.5% of the subjects were women, and 17.9% of the subjects were carriers of at least one ε4 allele of the apolipoprotein E gene. Cognitive diagnoses at inclusion were as follows: normal cognition 93.0% and mild cognitive impairment (MCI) 7.0% (3.1% amnestic MCI, 0.1% non-amnestic MCI, 3.8% mixed MCI). Blood samples were obtained and stored for future determinations in 99.9% of the subjects and 3T magnetic resonance imaging study was conducted in 89.9% of the volunteers. The cohort is being followed up annually for 4 years after the baseline., Conclusion: We have established a valuable homogeneous single-center cohort which, by identifying groups of variables associated with high risk of MCI or dementia conversion, should help to clarify the early physiopathological mechanisms of AD and should provide avenues for prompt diagnosis and AD prevention.

Objective: A cross-sectional study was conducted to describe the prevalence, locations, and risk factors for brain microbleeds (BMBs) in neurodegenerative dementia., Methods: The database of the Alzheimer Center Reina Sofía Foundation was searched, BMBs were described, and the potential associations of BMBs were investigated using univariate statistics., Results: A total of 148 patients (age 81.6 [standard deviation 6.7], 79.1% female) were studied. Prevalence of BMBs was 44.6%. A group of patients with unusually high (ie, ≥4) number of BMBs were identified, which displayed higher number of vascular risk factors and vascular diseases. Brain microbleeds were also associated with ischemic lesions in the basal ganglia (r = .39), clinical diagnosis of Alzheimer's disease (AD) and cerebrovascular disease (r = .33), cortical infarction (r = .20), and antiaggregant or anticoagulant treatment duration (r = .20)., Conclusions: Brain microbleeds are associated with vascular burden and AD diagnosis in old patients with neurodegenerative dementia. More research is warranted regarding the mechanisms and potential clinical implications of these results.

Randomized, controlled trials have demonstrated efficacy for second-generation antipsychotics in the treatment of acute mania in bipolar disorder. Despite depression being considered the hallmark of bipolar disorder, there are no published systematic reviews or meta-analyses to evaluate the efficacy of modern atypical antipsychotics in bipolar depression. We systematically reviewed published or registered randomized, double-blind, placebo-controlled trials (RCTs) of modern antipsychotics in adult bipolar I and/or II depressive patients (DSM-IV criteria). Efficacy outcomes were assessed based on changes in the Montgomery-Asberg Depression Rating Scale (MADRS) during an 8-wk period. Data were combined through meta-analysis using risk ratio as an effect size with a 95% confidence interval (95% CI) and with a level of statistical significance of 5% (p<0.05). We identified five RCTs; four involved antipsychotic monotherapy and one addressed both monotherapy and combination with an antidepressant. The two quetiapine trials analysed the safety and efficacy of two doses: 300 and 600 mg/d. The only olanzapine trial assessed olanzapine monotherapy within a range of 5-20 mg/d and olanzapine-fluoxetine combination within a range of 5-20 mg/d and 6-12 mg/d, respectively. The two aripiprazole placebo-controlled trials assessed doses of 5-30 mg/d. Quetiapine and olanzapine trials (3/5, 60%) demonstrated superiority over placebo (p<0.001). Only 2/5 (40%) (both aripiprazole trials) failed in the primary efficacy measure after the first 6 wk. Some modern antipsychotics (quetiapine and olanzapine) have demonstrated efficacy in bipolar depressive patients from week 1 onwards. Rapid onset of action seems to be a common feature of atypical antipsychotics in bipolar depression.

Atypical antipsychotics have been used to treat patients with schizophrenia for many years, but now there is increasing evidence of their utility in the treatment of mood disorders. In the past few years, several atypical agents have received regulatory approval for use in mania. The evidence shows that atypical antipsychotics are effective in the treatment of manic symptoms, either alone or in combination with traditional mood stabilizers, such as lithium and divalproex. Although emerging data indicate that atypical antipsychotics will be a promising addition to those therapies that are currently available for managing patients during the maintenance phase of bipolar illness, their potential in the long-term management of bipolar disorder remains to be fully explored. Aripiprazole is a recently released antipsychotic medication that differs from other atypical antipsychotic agents by its mode of action as a dopamine D2 partial agonist. It is administered orally and has a long half-life. Randomized studies have demonstrated the efficacy of aripiprazole compared with placebo in the treatment of acute relapse of schizophrenia and schizoaffective disorder, maintenance treatment of schizophrenia, treatment of acute mania, and prevention of manic relapse in patients who responded to the drug during a manic episode. Further studies are ongoing in bipolar and unipolar depression. Aripiprazole is generally well tolerated compared with other antipsychotic medications, although commonly reported side effects include extrapyramidal symptoms and motoric activation similar to akathisia. Further studies and postmarketing data will be helpful in providing additional information regarding the comparative safety, efficacy and tolerability of aripiprazole in the treatment of affective disorders.