Psychiatry Research/Trial Protocols

The depression response trajectory after a course of repetitive transcranial magnetic stimulation(rTMS) remains understudied. We searched for blinded randomized controlled trials(RCTs) that examined conventional rTMS over left dorsolateral prefrontal cortex(DLPFC) for major depressive episodes(MDE). The effect size was calculated as the difference in depression improvement, between active and sham rTMS. We conducted a random-effects dose-response meta-analysis to model the response trajectory from the beginning of rTMS to the post-treatment follow-up phase. The area under curve (AUC) of the first 8-week response trajectory was calculated to compare antidepressant efficacy between different rTMS protocols. We included 40 RCTs(n = 2012). The best-fitting trajectory model exhibited a logarithmic curve(X=17.7, P < 0.001), showing a gradual ascent with tapering off around the 3-4th week mark and maintaining until week 16. The maximum effect size was 6.1(95 %CI: 1.25-10.96) at week 16. The subgroup analyses showed distinct trajectories across different rTMS protocols. Besides, the comparisons of AUC showed that conventional rTMS protocols with more pulse/session group or more total pulses were associated with greater efficacy than those with fewer pulse/session or fewer total pulses, respectively. A course of conventional left DLPFC rTMS could lead to both acute antidepressant effects and sustained after-effects, which were modeled by different rTMS protocols in MDE.

Many patients with schizophrenia have symptoms that do not respond to antipsychotics. This condition is called treatment-resistant schizophrenia and has not received specific attention as opposed to general schizophrenia. Psychological and psychosocial interventions as an add-on treatment to pharmacotherapy could be useful, but their role and comparative efficacy to each other and to standard care in this population are not known. We investigated the efficacy, acceptability, and tolerability of psychological and psychosocial interventions for patients with treatment-resistant schizophrenia.

Long-term potentiation (LTP)-like activity can be induced by stimulation protocols such as paired associative stimulation (PAS). We aimed to determine whether PAS-induced LTP-like activity (PAS-LTP) of the dorsolateral prefrontal cortex (DLPFC) is associated with cortical thickness and other structural measures impaired in Alzheimer's dementia (AD). We also explored longitudinal relationships between these brain structures and PAS-LTP response after a repetitive PAS (rPAS) intervention. Mediation and regression analyses were conducted using data from randomized controlled trials with AD and healthy control participants. PAS-electroencephalography assessed DLPFC PAS-LTP. DLPFC thickness and surface area were acquired from T1-weighted magnetic resonance imaging. Fractional anisotropy and mean diffusivity (MD) of the superior longitudinal fasciculus (SLF)-a tract important to induce PAS-LTP-were measured with diffusion-weighted imaging. AD participants exhibited reduced DLPFC thickness and increased SLF MD. There was also some evidence that reduction in DLPFC thickness mediates DLPFC PAS-LTP impairment. Longitudinal analyses showed preliminary evidence that SLF MD, and to a lesser extent DLPFC thickness, is associated with DLPFC PAS-LTP response to active rPAS. This study expands our understanding of the relationships between brain structural changes and neuroplasticity. It provides promising evidence for a structural predictor to improving neuroplasticity in AD with neurostimulation. This article is part of a discussion meeting issue 'Long-term potentiation: 50 years on'.

Transcranial Magnetic Stimulation (TMS) studies examining exercise-induced neuroplasticity in pain populations have produced contradictory findings. We conducted a systematic review to explore how exercise impacts cortical excitability in pain populations using TMS metrics. This review aims to summarize the effect sizes and to understand their sources of heterogeneity.

Traditional methadone treatment (MT) for opioid use disorder (OUD) fails to systematically address the physical pain, emotion dysregulation, and reward processing deficits that co-occur with OUD, and novel interventions that address these issues are needed to improve MT outcomes. Mindfulness-Oriented Recovery Enhancement (MORE) remediates the hedonic dysregulation in brain reward systems that is associated with OUD. Our pilot and phase 2 randomized controlled trials of MORE were the first to demonstrate MORE's feasibility, acceptability, and efficacy as delivered in MT clinics; MORE significantly reduced drug use (eg, benzodiazepines, barbiturates, cocaine, marijuana, opioids, and other drugs), craving, depression, anxiety, and pain among people with OUD. However, uptake of novel, efficacious interventions like MORE may be slow in MT because time and resources are often limited. Therefore, to best address potential implementation issues and to optimize future MORE implementation and dissemination, in this study, we will utilize a Type 2, Hybrid Implementation-Effectiveness study design. We will not only evaluate MORE's effectiveness but also assess barriers and facilitators to integrating MORE into MT. MT clinicians will receive training in (1) a higher intensity MORE implementation strategy consisting of training in the full MORE treatment manual or (2) a minimal intensity implementation strategy consisting of a simple, scripted mindfulness practice (SMP) extracted from the MORE treatment manual with minimal training. We aim to: (1) using a Reach, Effectiveness, Adoption, Implementation, and Maintenance (RE-AIM) framework, examine barriers and facilitators to implementation of MORE and SMP in MT, and evaluate strategies for optimizing training, fidelity, and engagement, (2) optimize existing MORE and SMP training and implementation toolkits, including adaptable resources that can accelerate the translation of evidence into practice, and (3) compared to usual MT, evaluate the relative effectiveness of MORE plus MT or SMP plus MT (N = 450).

Chronic pain is a significant factor for patients with opioid use disorder (OUD) contributing to suboptimal retention in buprenorphine treatment, which is a crucial predictor of long-term health outcomes. This study aims to address the critical need for effective interventions targeting chronic pain management within office-based opioid treatment (OBOT) programs. We are conducting a multisite, hybrid type 1, 2 × 2 factorial randomized clinical trial to determine the effectiveness of 2 novel interventions, pain self-management (PSM) and patient-oriented buprenorphine dosing (POD), to decrease pain interference and improve retention in buprenorphine treatment. PSM, a manualized and customizable approach delivered through individual and peer-led group sessions, aims to decrease pain-related symptoms and quality of life. POD involves split dosing of buprenorphine to extend the duration of analgesia to better match its duration of efficacy at managing OUD symptoms, leading to improved retention in buprenorphine treatment. Eligible participants will be randomized into 1 of 4 groups: (1) PSM + POD, (2) PSM + Standard Buprenorphine Dosing, (3) Usual Care + POD, or (4) Usual Care + Standard Buprenorphine Dosing. Usual Care refers to usual care for chronic pain and Standard Buprenorphine Dosing refers to the participant's current dosing regimen. Secondary objectives encompass overall pain reduction, decreased opioid use, improved pain symptom management, and exploration of implementation strategies. The supplemental approved protocol provides comprehensive insights into the procedures and variables being investigated. As part of the HEAL Initiative-funded Integrative Management of Chronic Pain and OUD for Whole Recovery (IMPOWR) network, this study aims to fill gaps in behavioral and medication treatments for individuals with co-occurring chronic pain and OUDs, improving pain management and retention in care. Successful outcomes from this trial may inform future larger trials, offering essential evidence for implementation considerations and reimbursement decisions.

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs), currently marketed for type 2 diabetes and obesity, may offer novel mechanisms to delay or prevent neurotoxicity associated with Alzheimer's disease (AD). The impact of semaglutide in amyloid positivity (ISAP) trial is investigating whether the GLP-1 RA semaglutide reduces accumulation in the brain of cortical tau protein and neuroinflammation in individuals with preclinical/prodromal AD.

Patient expectations, including both positive (placebo) and negative (nocebo) effects, influence treatment outcomes, yet their impact on acute repetitive transcranial magnetic stimulation (rTMS) for treatment-resistant depression (TRD) is unclear.

There are no approved pharmacotherapies for methamphetamine use disorder. Two preliminary phase 2 randomised controlled trials have found mirtazapine, a tetracyclic antidepressant, to be effective in reducing methamphetamine use. The proposed Tina Trial is the first phase 3 placebo-controlled randomised trial to examine the effectiveness and safety of mirtazapine as an outpatient pharmacotherapy for methamphetamine use disorder.

The three types of evidence-based treatment options for adults with overweight and obesity - behavioral weight management, anti-obesity medications (AOM), and bariatric surgery - are underutilized in the Veterans Health Administration (VHA) system. Our objective in this manuscript is to describe the study protocol for an adequately powered randomized controlled trial (RCT) of a behavioral intervention: TOTAL (Teaching Obesity Treatment Options to Adult Learners) to increase patient uptake of obesity treatment.

There is a growing literature exploring the placebo response within specific mental disorders, but no overarching quantitative synthesis of this research has analyzed evidence across mental disorders. We carried out an umbrella review of meta-analyses of randomized controlled trials (RCTs) of biological treatments (pharmacotherapy or neurostimulation) for mental disorders. We explored whether placebo effect size differs across distinct disorders, and the correlates of increased placebo effects. Based on a pre-registered protocol, we searched Medline, PsycInfo, EMBASE, and Web of Knowledge up to 23.10.2022 for systematic reviews and/or meta-analyses reporting placebo effect sizes in psychopharmacological or neurostimulation RCTs. Twenty meta-analyses, summarising 1,691 RCTs involving 261,730 patients, were included. Placebo effect size varied, and was large in alcohol use disorder (g = 0.90, 95% CI [0.70, 1.09]), depression (g = 1.10, 95% CI [1.06, 1.15]), restless legs syndrome (g = 1.41, 95% CI [1.25, 1.56]), and generalized anxiety disorder (d = 1.85, 95% CI [1.61, 2.09]). Placebo effect size was small-to-medium in obsessive-compulsive disorder (d = 0.32, 95% CI [0.22, 0.41]), primary insomnia (g = 0.35, 95% CI [0.28, 0.42]), and schizophrenia spectrum disorders (standardized mean change = 0.33, 95% CI [0.22, 0.44]). Correlates of larger placebo response in multiple mental disorders included later publication year (opposite finding for ADHD), younger age, more trial sites, larger sample size, increased baseline severity, and larger active treatment effect size. Most (18 of 20) meta-analyses were judged 'low' quality as per AMSTAR-2. Placebo effect sizes varied substantially across mental disorders. Future research should explore the sources of this variation. We identified important gaps in the literature, with no eligible systematic reviews/meta-analyses of placebo response in stress-related disorders, eating disorders, behavioural addictions, or bipolar mania.

The use of antidepressants has been on the rise among adolescents and young adults, populations also increasingly at risk for type 2 diabetes. However, the relationship between antidepressant uses and diabetes incidence in these age groups remains poorly understood.

Recent years have seen a growing interest in the use of digital tools for delivering person-centred mental health care. Experience Sampling Methodology (ESM), a structured diary technique for capturing moment-to-moment variation in experience and behaviour in service users' daily life, reflects a particularly promising avenue for implementing a person-centred approach. While there is evidence on the effectiveness of ESM-based monitoring, uptake in routine mental health care remains limited. The overarching aim of this hybrid effectiveness-implementation study is to investigate, in detail, reach, effectiveness, adoption, implementation, and maintenance as well as contextual factors, processes, and costs of implementing ESM-based monitoring, reporting, and feedback into routine mental health care in four European countries (i.e., Belgium, Germany, Scotland, Slovakia).

The ELEKT-D: Electroconvulsive Therapy (ECT) vs Ketamine in Patients With Treatment Resistant Depression (TRD) (ELEKT-D) trial demonstrated noninferiority of intravenous ketamine vs ECT for nonpsychotic TRD. Clinical features that can guide selection of ketamine vs ECT may inform shared decision-making for patients with TRD.

Near Real-Time Feedback (NRTF) on the patient's experience with care, coupled with data relay to providers, can inform quality-of-care improvements, including at the point of care. The objective is to systematically review contemporary literature on the impact of the use of NRTF and data relay to providers on standardized patient experience measures. Six scientific databases and five specialty journals were searched supplemented by snowballing search strategies, according to the registered study protocol. Eligibility included studies in English (2015-2023) assessing the impact of NRTF and data relay on standardized patient-reported experience measures as a primary outcome. Eligibility and quality appraisals were performed by two independent reviewers. An expert former patient (Patient and Family Advisory Council and communication sciences background) helped interpret the results. Eight papers met review eligibility criteria, including three randomized controlled trials (RCTs) and one non-randomized study. Three of these studies involved in-person NRTF prior to data relay (patient-level data for immediate corrective action or aggregated and peer-compared) and led to significantly better results in all or some of the experience measures. In turn, a kiosk-based NRTF achieved no better experience results. The remaining studies were pre-post designs with mixed or neutral results and greater risks of bias. In-person NRTF on the patient experience followed by rapid data relay to their providers, either patient-level or provider-level as peer-compared, can improve the patient experience of care. Reviewed kiosk-based or self-reported approaches combined with data relay were not effective. Further research should determine which approach (e.g. who conducts the in-person NRTF) will provide better, more efficient improvements and under which circumstances.

Systemic sclerosis (SSc) is a rare, complex autoimmune rheumatic disease with multiple factors that contribute to pain. People with SSc emphasize the effect pain has on their quality of life, but no studies have systematically examined the frequency and relative importance of different SSc pain sources, patterns of pain from different sources, and pain management experiences. Our objectives are to (1) develop a tool, jointly with researchers, health care providers, and patients, to map sources of pain in SSc, determine patterns of pain from different sources, and understand pain management experiences; and (2) administer the final tool version to participants in the large multinational Scleroderma Patient-centered Intervention Network (SPIN) Cohort.

The rise of mental health problems in youth highlights the need for accessible and cost-effective psychological interventions. Blended interventions, which combine face-to-face and online sessions, can be an adequate response to the increase in demands for youth mental health services. Although this can be a promising approach, effective dissemination depends on the professionals´ acceptance.

Standard assessment and management protocols exist for first episode psychosis (FEP) in high income countries. Due to cultural and resource differences, these need to be modified for application in low-and middle-income countries.

Fibromyalgia is associated with chronic widespread pain and disturbed sleep. Multidisciplinary, multimodal management often includes pharmacotherapy; however, current drugs used to treat fibromyalgia provide meaningful benefit to only 30-60% of treated individuals. Combining two or more different drugs is common in clinical practice with the expectation of better efficacy, tolerability or both; however, further research is needed to identify which combinations actually provide added benefit. Thus, we are planning a clinical trial to evaluate melatonin (MLT)-pregabalin (PGB) combination in participants with fibromyalgia.

Children and young people with epilepsy are more likely to experience multiple mental health problems than those without chronic physical health conditions, yet they often do not receive evidence-based (or indeed any) psychological interventions. Integrated healthcare is recommended as a solution to address these inequalities, but remains limited in the United Kingdom. This is partly due to the lack of training and availability of ongoing supervision for clinicians to ensure the safe and effective delivery of treatments. This study aimed to train and provide supervision for health professionals to deliver a modular cognitive-behavioural intervention for common mental health problems, optimised for use in paediatric epilepsy. Specifically, this study aimed to measure therapist competence and evaluate the acceptability of training and supervision.

Globally, transgender ('trans') women experience extreme social and economic marginalisation due to intersectional stigma, defined as the confluence of stigma that results from the intersection of social identities and positions among those who are oppressed multiple times. Among trans women, gender-based stigma intersects with social positions such as engagement in sex work and substance use, as well as race-based stigma to generate a social context of vulnerability and increased risk of HIV acquisition. In Brazil, trans women are the 'most at-risk' group for HIV, with 55 times higher estimated odds of HIV infection than the general population; further, uptake of HIV testing and pre-exposure prophylaxis (PrEP) among trans women is significantly lower than other at-risk groups. Through extensive formative work, we developed Manas por Manas, a multilevel intervention using HIV prevention strategies with demonstrated feasibility and acceptability by trans women in Brazil, to address intersectional stigma and increase engagement in the HIV prevention continuum.

The ventral pallidum (VP) receives its primary inputs from the nucleus accumbens (NAC) and the basolateral amygdala (BLA). We demonstrated recently that in the VP, the D2 DA receptor (DR) agonist quinpirole dose-dependently facilitates memory consolidation in inhibitory avoidance and spatial learning. In the VP, DR can be found both on NAC and BLA terminals. According to our hypothesis, quinpirole microinjected into the VP can facilitate memory consolidation via modulation of synaptic plasticity on NAC and/or BLA terminals. The effect of intra-VP quinpirole on BLA-VP and NAC shell-VP synapses was investigated via a high frequency stimulation (HFS) protocol. Quinpirole was administered in three doses into the VP of male Sprague-Dawley rats after HFS; controls received vehicle. To examine whether an interaction between the NAC shell and the BLA at the level of the VP was involved, tetrodotoxin (TTX) was microinjected into one of the nuclei while stimulating the other nucleus. Our results showed that quinpirole dose-dependently modulates BLA-VP and NAC shell-VP synapses, similar to those observed in inhibitory avoidance and spatial learning, respectively. The lower dose inhibits BLA inputs, while the larger doses facilitates NAC shell inputs. The experiments with TTX demonstrates that the two nuclei do not influence each others' evoked responses in the VP. Power spectral density analysis demonstrated that independent from the synaptic facilitation, intra-VP quinpirole increases the amplitude of gamma frequency band after NAC HFS, and BLA tonically suppresses the NAC's HFS-induced gamma facilitation. In contrast, HFS of the BLA results in a delayed, transient increase in the amplitude of the gamma frequency band correlating with the LTP of the P1 component of the VP response to BLA stimulation. Furthermore, our results demonstrate that the BLA plays a prominent role in the generation of the delta oscillations: HFS of the BLA leads to a gradually increasing delta frequency band facilitation over time, while BLA inhibition blocks the NAC's HFS induced strong delta facilitation. These findings demonstrate that there is a complex interaction between the NAC shell region and the VP, as well as the BLA and the VP, and support the important role of VP DRs in the regulation of limbic information flow.

Black individuals in the United States (US) have a higher incidence of and mortality from colorectal cancer (CRC) compared to other racial groups, and CRC is the second leading cause of death among Hispanic/Latino populations in the US. Patient navigation is an evidence-based approach to narrow inequities in cancer screening among Black and Hispanic/Latino patients. Despite this, limited healthcare systems have implemented patient navigation for screening at scale.

To test esmethadone (REL-1017) as adjunctive treatment in patients with major depressive disorder (MDD) and inadequate response to standard antidepressants. In this phase 3, double-blind, placebo-controlled trial, outpatients with MDD () were randomized to daily oral esmethadone (75 mg on day 1, followed by 25 mg daily on days 2 through 28) or placebo between December 2020 and December 2022. The primary efficacy measure was change from baseline (CFB) to day 28 in the Montgomery-Asberg Depression Rating Scale (MADRS) score. The intent-to-treat (ITT) population included all randomized participants. The per-protocol (PP) population included completers without major protocol deviations impacting assessment. Post hoc analyses included participants with severe depression (baseline MADRS score ≥35). For the ITT analysis (n = 227), mean CFB was 15.1 (SD 11.3) for esmethadone (n = 113) and 12.9 (SD 10.4) for placebo (n = 114), with a mean difference (MD) of 2.3, which was not statistically significant ( = .154; Cohen effect size [ES] = 0.21). Remission rates were 22.1% and 13.2% ( = .076), and response rates were 39.8% and 27.2% ( = .044) with esmethadone and placebo, respectively. For the PP analysis (n = 198), mean CFB was 15.6 (SD 11.2) for esmethadone (n = 101) and 12.5 (SD 9.9) for placebo (n = 97), with an MD of 3.1 ( = .051; ES =0.29). In post hoc analyses of patients with baseline MADRS ≥35 in the ITT population (n = 112), MD was 6.9; = .0059; ES = 0.57, and for the PP population (n = 98), MD was 7.9; = .0015; ES = 0.69. Adverse events (AEs) were predominantly mild or moderate and transient, with no significant differences between groups. The primary end point was not met. Esmethadone showed stronger efficacy in PP than in ITT analyses, with the discrepancy not attributable to AEs impacting treatment adherence. Significant efficacy occurred in post hoc analyses of patients with severe depression. Esmethadone was well tolerated, consistent with prior studies. ClinicalTrials.gov identifier: NCT04688164.

Prolonged exposure (PE) therapy is widely recognized as an effective treatment for post-traumatic stress disorder (PTSD) and is often considered one of the primary options for addressing this condition. Nevertheless, a significant proportion of patients (30-51%) fail to demonstrate clinically significant symptom changes. One of the reasons is that a high proportion of patients drop out from treatment, which often lasts for a minimum of 3-4 months. Hence, there is an urgent need for PTSD treatments that can be delivered to decrease dropout rates. A more intensive PE treatment approach has been suggested to decrease dropout rates and in addition achieve faster recovery rates and has shown promising effects on reducing PTSD symptoms but needs to be tested against firsthand treatment.

There have only been two efficacy trials reporting a head-to-head comparison of medications and psychotherapy for posttraumatic stress disorder (PTSD), and neither was conducted in primary care. Therefore, in this pragmatic trial we compare outcomes of primary care patients randomized to initially receive a brief trauma-focused psychotherapy or a choice of three antidepressants. In addition, because there are few trials examining the effectiveness of subsequent treatments for patients not responding to the initial treatment, we also compare the outcomes of those switching or augmenting treatments.

Germany is reforming its legal approach to cannabis, allowing the possession and cultivation of cannabis for recreational purposes. The objective of this study is to investigate the impact of the policy reform on (1) The prevalence of cannabis use in the general population and (2) Driving under the influence of cannabis (DUIC) among regular users.

Mental health disorders are linked to prolonged concussion symptoms. However, the association of premorbid anxiety/depression symptoms with postconcussion return-to-play timelines and total symptom burden is unclear.

Persons receiving prescription buprenorphine for opioid use disorder experience high rates of comorbid conditions such as chronic pain and depression, which present barriers to buprenorphine care retention. This paper describes the protocol of the TOPPS (Treating Opioid Patients' Pain and Sadness) study, which compares a values-based, behavioral activation intervention with a health education contact-control condition, with the aim of decreasing chronic pain and depression, and increasing buprenorphine care retention for persons with opioid use disorder.

During pregnancy and childbirth, alongside positive feelings, women undergo feelings such as fear of childbirth (FoC) and worry about its consequences, which could leave negative effects on the mother and her child during pregnancy, delivery, and postpartum. The study was carried out to determine the effectiveness of prenatal non-pharmacological interventions on reducing the FoC.

The autonomic nervous system plays a vital role in regulating physiological functions. Transcutaneous auricular vagus nerve stimulation (taVNS) is a method that provides insights into autonomic nerve modulation. This paper presents a research protocol investigating proof of mechanism for the impact of taVNS on autonomic functions and aims to both deepen theoretical understanding and pave the way for clinically relevant applications.

Due to a change in diagnostic prerequisites and the inclusion of novel diagnostic entities, the implementation of the 11th revision of the International Classification of Diseases (ICD-11) will presumably change prevalence rates of specific mental, behavioural or neurodevelopmental disorders and result in an altered prevalence rate for this grouping overall. This scoping review aims to summarise the characteristics of primary studies examining the prevalence of mental, behavioural or neurodevelopmental disorders based on ICD-11 criteria. The knowledge attained through this review will primarily characterise the methodological approaches of this research field and additionally assist in deciding which psychiatric diagnoses are-given the current literature-most relevant for subsequent systematic reviews and meta-analyses intended to approximate the magnitude of prevalence rates while providing a first glimpse of the range of expected (differences in) prevalence rates in these conditions.

: Substance use disorders present a tremendous challenge within contemporary healthcare systems. Specifically, in the domain of opioid use disorders (OUDs), several foundational elements are crucial for the efficacious management of afflicted individuals. Regrettably, the premature discontinuation of inpatient opioid withdrawal treatment is a prevalent phenomenon. This study aims to elucidate the prevalence of the premature termination of inpatient opioid withdrawal treatment among patients with comorbid ADHD. : We conducted a comprehensive assessment of all participants currently undergoing inpatient opioid withdrawal treatment. Our assessment protocol included the administration of the ADHD Self-Report Scale (ADHD-SR) and the Wender Utah Rating Scale (WURS-k). Additionally, participants who met the thresholds on one or both questionnaires underwent further evaluation using the Diagnostic Interview for ADHD in Adults (DIVA-2.0). : The prevalence of individuals diagnosed with ADHD within the studied cohort was determined to be 29.3%. Among the subset of participants identified as ADHD-positive, a notable 54.5% prematurely ceased therapy. In contrast, among those identified as ADHD-negative, the premature discontinuation rate was substantially lower at 28.3%. : In summary, the impact of ADHD as a comorbid condition on the efficacy of inpatient opioid withdrawal treatment has been underscored. By identifying comorbid ADHD early in the treatment process, tailored therapeutic approaches may help to maximize the effectiveness of interventions and may improve patient outcomes. This underscores the importance of proactive screening for ADHD as a psychiatric comorbidity in optimizing the management of individuals undergoing inpatient opioid withdrawal treatment.

: HIV is a severe and incurable disease that has a devastating impact worldwide. It affects the immune system and negatively affects the nervous system, leading to various cognitive and behavioral problems. Scientists are actively exploring different therapeutic approaches to combat these issues. One promising method is transcranial direct current stimulation (tDCS), a non-invasive technique that stimulates the brain. : This review aims to examine how tDCS can help HIV patients. Searches were conducted in the Pubmed/Medline, Research Gate, and Cochrane databases. : The literature search resulted in six articles focusing on the effects of tDCS on cognitive and behavioral measures in people with HIV. In some cases, tDCS showed positive improvements in the measures assessed, improving executive functions, depression, attention, reaction time, psychomotor speed, speed of processing, verbal learning and memory, and cognitive functioning. Furthermore, the stimulation was safe with no severe side effects. However, the included studies were of low quality, had small sample sizes, and did not use any relevant biomarkers that would help to understand the mechanisms of action of tDCS in HIV. : tDCS may help patients with HIV; however, due to the limited number of studies and the diversity of protocols used, caution should be exercised when recommending this treatment option in clinical settings. More high-quality research, preferably involving neurophysiological and neuroimaging measurements, is necessary to better understand how tDCS works in individuals with HIV.

Osteoporotic vertebral fractures (OVFs) significantly impair quality of life. This study evaluates the impact of STIR sequence MR imaging on clinical decision-making for treating OVFs, mainly focusing on how MRI findings influence treatment modifications compared to those based solely on CT scans. This retrospective analysis reviewed cases from the Manninger Jenő National Traumatology Institute over ten years, where patients with suspected OVFs underwent CT and STIR sequence MR imaging. The study examined changes in treatment plans initiated by MRI findings. The diagnostic effectiveness of MRI was compared against CT in terms of sensitivity, specificity, and the ability to influence clinical treatment paths. MRI detected 1.65 times more fractures than CT scans. MRI influenced treatment adjustments in 67% of cases, leading to significant changes from conservative-conservative, conservative-surgery, and surgery-surgery based on fracture characterizations provided by MRI. This study demonstrates that integrating STIR sequence MR imaging into the diagnostic pathway for OVFs significantly enhances the accuracy of fracture detection and profoundly impacts treatment decisions. The ability of MRI to reveal specific fracture features that are not detectable by CT scans supports its importance in the clinical evaluation of OVFs, suggesting that MRI should be incorporated more into diagnostic protocols to improve patient management and outcomes. The findings advocate for further research to establish STIR MRI as a standard osteoporosis management tool and explore its long-term benefits in preventing secondary fractures.

Despite the growing incidence of burn injuries globally and the advancements in physical recovery, the psychological aspect of burn trauma recovery remains inadequately addressed. This review aims to consolidate existing literature posttraumatic stress disorder (PTSD) and depression in adult burn survivors, recognizing the need for a holistic approach to burn recovery that encompasses both physical and mental health. The comprehensive analysis of 156 studies revealed significant variations in methodological approaches, leading to challenges in creating standardized protocols for mental health assessment in burn care. Key findings include the identification of a wide range of psychological assessment tools and a substantial research gap in low and middle-income countries, where the majority of burn injuries occur. Only 7.0% of the studies assessed interventions for PTSD or depression, indicating a lack of focus on treatment modalities. The studies identified demographic factors, patient history, psychosocial factors, burn injury characteristics, and treatment course as risk factors for PTSD and depression post-burn injury. The review highlights the need for early screening, intervention, and attention to subjective experiences related to burn injury, as these are strong predictors of long-term psychological distress. It also emphasizes the complexity of addressing psychological distress in burn survivors and the need for more standardized practices in assessing PTSD and depression specific to this population.

It is unclear whether antibiotics impact delirium outcomes in older adults with pyuria or bacteriuria in the absence of systemic signs of infection or genitourinary symptoms.

There is uncertainty about the optimum dose of omega-3 fatty acids for anxiety symptoms. We aimed to find the dose-dependent effect of omega-3 supplementation on anxiety symptoms.

There is an urgent need to derive quantitative measures based on coherent neurobiological dysfunctions or 'biotypes' to enable stratification of patients with depression and anxiety. We used task-free and task-evoked data from a standardized functional magnetic resonance imaging protocol conducted across multiple studies in patients with depression and anxiety when treatment free (n = 801) and after randomization to pharmacotherapy or behavioral therapy (n = 250). From these patients, we derived personalized and interpretable scores of brain circuit dysfunction grounded in a theoretical taxonomy. Participants were subdivided into six biotypes defined by distinct profiles of intrinsic task-free functional connectivity within the default mode, salience and frontoparietal attention circuits, and of activation and connectivity within frontal and subcortical regions elicited by emotional and cognitive tasks. The six biotypes showed consistency with our theoretical taxonomy and were distinguished by symptoms, behavioral performance on general and emotional cognitive computerized tests, and response to pharmacotherapy as well as behavioral therapy. Our results provide a new, theory-driven, clinically validated and interpretable quantitative method to parse the biological heterogeneity of depression and anxiety. Thus, they represent a promising approach to advance precision clinical care in psychiatry.

Observational studies are fraught with several biases including reverse causation and residual confounding. Overview of reviews of observational studies (ie, umbrella reviews) synthesise systematic reviews with or without meta-analyses of cross-sectional, case-control and cohort studies, and may also aid in the grading of the credibility of reported associations. The number of published umbrella reviews has been increasing. Recently, a reporting guideline for overviews of reviews of healthcare interventions (Preferred Reporting Items for Overviews of Reviews (PRIOR)) was published, but the field lacks reporting guidelines for umbrella reviews of observational studies. Our aim is to develop a reporting guideline for umbrella reviews on cross-sectional, case-control and cohort studies assessing epidemiological associations.

Autism is a common neurodevelopmental condition with a complex genetic aetiology that includes contributions from monogenic and polygenic factors. Many autistic people have unmet healthcare needs that could be served by genomics-informed research and clinical trials. The primary aim of the European Autism GEnomics Registry (EAGER) is to establish a registry of participants with a diagnosis of autism or an associated rare genetic condition who have undergone whole-genome sequencing. The registry can facilitate recruitment for future clinical trials and research studies, based on genetic, clinical and phenotypic profiles, as well as participant preferences. The secondary aim of EAGER is to investigate the association between mental and physical health characteristics and participants' genetic profiles.

The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, Text Revision (DSM-5-TR), recently identified internet gaming disorder (IGD) as a condition warranting more research, and few empirically validated treatments exist. Mindfulness meditation (MM) has multiple health benefits; however, its efficacy in treating IGD and potential neural mechanisms underlying MM treatment of the disorder remain largely unknown.

The purpose of this study was to examine the effects of a brief family psychoeducation (BFP) programme provided by psychiatric visiting nurses on caregiver burden of family caregivers of people with schizophrenia through a cluster randomised controlled trial (cRCT).

Few studies have examined the associations between pregnancy and birth complications and long-term (>12 months) maternal mental health outcomes.

Early childhood development forms the foundations for functioning later in life. Thus, accurate monitoring of developmental trajectories is critical. However, such monitoring often relies on time-intensive assessments which necessitate administration by skilled professionals. This difficulty is exacerbated in low-resource settings where such professionals are predominantly concentrated in urban and often private clinics, making them inaccessible to many. This geographic and economic inaccessibility contributes to a significant 'detection gap' where many children who might benefit from support remain undetected. The Scalable Transdiagnostic Early Assessment of Mental Health (STREAM) project aims to bridge this gap by developing an open-source, scalable, tablet-based platform administered by non-specialist workers to assess motor, social and cognitive developmental status. The goal is to deploy STREAM through public health initiatives, maximising opportunities for effective early interventions.

Diabetes and depression are among the 10 biggest health burdens globally. They often coexist and exhibit a strong bidirectional relationship. Depression leads to decreased adherence to self-care activities. This impacts glycaemic control and worsens type 2 diabetes mellitus (T2D). Both conditions have a synergistic effect and lead to greater complications, hospitalisations, healthcare expenditure and a worse quality of life. There is no consensus on managing people with comorbid T2D and depression. Bupropion is an efficacious antidepressant with many properties suitable for T2D with depression, including a favourable metabolic profile, persistent weight loss and improvement in sexual dysfunction. We will assess the efficacy and safety of add-on bupropion compared with standard care in people with T2D and mild depression. This study can give valuable insights into managing the multimorbidity of T2D and depression. This can help mitigate the health, social and economic burden of both these diseases.

People are able to voluntarily suppress unwanted thoughts or memories, a phenomenon known as suppression-induced forgetting or memory suppression. Despite harmful alcohol use, such as binge drinking, has been linked to impaired inhibitory control (IC) and augmented alcohol-cue reactivity, no study to date has assessed memory inhibition abilities towards alcohol-related cues in binge drinkers (BDs). Thus, the present preregistered study aimed to evaluate the behavioral and neurofunctional mechanisms associated with memory inhibition, specifically those related to the suppression of alcohol-related memories, in young BDs. For this purpose, electroencephalographic activity was recorded in eighty-two college students aged between 18 and 24 years old from the University of Minho (50% females; 40 non/low-drinkers [N/LDS] and 42 BDs) while they performed the Think/No-Think Alcohol task. Brain functional connectivity (FC) was calculated using the phase locking value and, subsequently, a dynamic seed-based analysis was conducted to explore the FC patterns between IC and memory networks. Comparatively to N/LDs, BDs exhibited decreased alpha-band FC between the anterior cingulate cortex and the left fusiform gyrus during attempts to suppress non-alcohol memories, accompanied by unsuccessful forgetting of those memories. Conversely, BDs displayed augmented gamma-band FC between the IC network and memory regions -i.e., hippocampus, parahippocampus and fusiform gyrus- during suppression of alcohol-related memories. Inhibitory abnormalities in BDs may lead to hypoconnectivity between IC and memory networks and deficient suppression of non-alcohol-related memories. However, while suppressing highly salient and reward-predicting stimuli, such as alcohol-related memories, BDs display a hyperconnectivity pattern between IC and memory networks, likely due to their augmented attention towards intrusive alcoholic memories and the attempts to compensate for potential underlying IC deficits. These findings hold important implications for alcohol research and treatment, as they open up new avenues for reducing alcohol use by shifting the focus to empowering suppression/control over alcohol-related memories. CLINICAL TRIAL REGISTRATION: [http://www.ClinicalTrials.gov], identifier [NCT05237414].

In absence of drug therapy options, standard treatment for spinocerebellar ataxia consists of symptomatic physiotherapy and speech therapy. New therapeutic options are urgently needed. Transcranial magnetic stimulation is a promising therapeutic option, but applicability is limited by lengthy duration of stimulation protocols.

Several psychotherapy protocols have been evaluated as adjuncts to pharmacotherapy for patients with bipolar disorder (BD). Little is known about their comparative effectiveness.

Bouts of military load carriage are rarely completed in isolation; however, limited research has investigated the physiological responses to repeated load carriage tasks. Twelve civilian men (age, 28 ± 8 years; stature, 185.6 ± 5.8 cm; body mass 84.3 ± 11.1 kg and maximal oxygen uptake, 51.5 ± 6.4 mL·kg min) attended the laboratory on two occasions to undertake a familiarisation and an experimental session. Following their familiarisation session, participants completed three bouts of a fast load carriage protocol (FLCP; ∼65 min), carrying 25 kg, interspersed with a 65-min recovery period. Physiological strain (oxygen uptake [V̇O] and heart rate [HR]) was assessed during the FLCP bouts, and physical performance assessments (weighted counter-movement jump [wCMJ], maximal isometric voluntary contraction of the quadriceps [MIVC] and seated medicine ball throw [SMBT]) was measured pre and post each FLCP bout. A main effect for bout and measurement time was evident for V̇O and HR (both p < 0.001 and Ѡ = 0.103-0.816). There was no likely change in SMBT distance (p = 0.201 and Ѡ = 0.004), but MIVC peak force reduced by approximately 25% across measurement points (p < 0.001 and Ѡ = 0.133). A mean percentage change of approximately -12% from initial values was also evident for peak wCMJ height (p = 0.001 and Ѡ = 0.028). Collectively, these data demonstrate that repeated FLCP bouts result in an elevated physiological strain for each successive bout, along with a substantial reduction in lower body power (wCMJ and MIVC). Therefore, future research should investigate possible mitigation strategies to maintain role-related capability.

Transcranial magnetic stimulation (TMS) is entering increasingly widespread use in treating depression. The most common stimulation target, in the dorsolateral prefrontal cortex (DLPFC), emerged from early neuroimaging studies in depression. Recently, more rigorous casual methods have revealed whole-brain target networks and anti-networks based on the effects of focal brain lesions and focal brain stimulation on depression symptoms. Symptom improvement during therapeutic DLPFC-TMS appears to involve directional changes in signaling between the DLPFC, subgenual and dorsal anterior cingulate cortex, and salience-network regions. However, different networks may be involved in the therapeutic mechanisms for other TMS targets in depression, such as dorsomedial prefrontal cortex or orbitofrontal cortex. The durability of therapeutic effects for TMS involves synaptic neuroplasticity, and specifically may depend upon dopamine acting at the D1 receptor family, as well as NMDA-receptor-dependent synaptic plasticity mechanisms. Although TMS protocols are classically considered 'excitatory' or 'inhibitory', the actual effects in individuals appear quite variable, and might be better understood at the level of populations of synapses rather than individual synapses. Synaptic meta-plasticity may provide a built-in protective mechanism to avoid runaway facilitation or inhibition during treatment, and may account for the relatively small number of patients who worsen rather than improve with TMS. From an ethological perspective, the antidepressant effects of TMS may involve promoting a whole-brain attractor state associated with foraging/hunting behaviors, centered on the rostrolateral periaqueductal gray and salience network, and suppressing an attractor state associated with passive threat defense, centered on the ventrolateral periaqueductal gray and default-mode network.

A better understanding of the earliest stages of Alzheimer's disease (AD) could expedite the development or administration of treatments. Large population biobanks hold the promise to identify individuals at an elevated risk of AD and related dementias based on health registry information. Here, we establish the protocol for an observational clinical recall and biomarker study called TWINGEN with the aim to identify individuals at high risk of AD by assessing cognition, health and AD-related biomarkers. Suitable candidates were identified and invited to participate in the new study among THL Biobank donors according to TWINGEN study criteria.

In clinical practice, theta burst stimulation (TBS) presents as a more efficient and potentially more effective therapeutic modality than conventional repetitive transcranial magnetic stimulation (rTMS), as it allows for the delivery of more stimuli in less time and at similar intensities. To date, accelerated treatment plans according to various continuous (cTBS) and intermittent TBS (iTBS) protocols for depression have been proposed. To investigate which of the TBS protocols provided a favorable risk-benefit balance for individuals with depression, this systematic review and random-effects model network meta-analysis was conducted. The study outcomes included response rate (primary), depression symptom improvement, remission rate, all-cause discontinuation rate, incidence of switch to mania, and incidence of headache/discomfort at treatment site. In this meta-analysis, a total of 23 randomized controlled trials (n = 960, mean age = 41.88 years, with 60.78% females) were included. Approximately 69.57% of the trials included individuals with an exclusive diagnosis of major depressive disorder. The following six TBS protocols (target) were evaluated: cTBS (right-dorsolateral prefrontal cortex [R-DLPFC]), cTBS (R-DLPFC) + iTBS (left-DLPFC [L-DLPFC]), iTBS (L-DLPFC), iTBS (L-DLPFC) + iTBS (R-DLPFC), iTBS (left-dorsomedial prefrontal cortex) + iTBS (right-dorsomedial prefrontal cortex), and iTBS (occipital lobe). Compared to sham, cTBS (R-DLPFC) + iTBS (L-DLPFC), iTBS (L-DLPFC), and iTBS (occipital lobe) had a higher response rate (k = 23); cTBS (R-DLPFC) + iTBS (L-DLPFC) and iTBS (L-DLPFC) dominated in the depression symptom improvement (k = 23); and iTBS (L-DLPFC) had a higher remission rate (k = 15). No significant differences were found for all-cause discontinuation rate (k = 17), incidence of switch to mania (k = 7), and incidence of headache/discomfort at treatment site (k = 10) between any TBS protocols and sham. Thus, cTBS (R-DLPFC) + iTBS (L-DLPFC) and iTBS (L-DLPFC) demonstrate favorable risk-benefit balance for the treatment of depression.

Food addiction (FA) shows phenotypic and diagnostic overlap with eating disorders characterised by binge eating, though it is unknown how momentary processes driving binge-eating symptoms differ by FA. The present study examined the possible moderating influence of FA severity on momentary mechanisms underlying binge-eating symptomatology using ecological momentary assessment (EMA).

To present the protocol and methods for the prospective longitudinal assessments-including clinical and digital phenotyping approaches-of the Identifying Depression Early in Adolescence Risk Stratified Cohort (IDEA-RiSCo) study, which comprises Brazilian adolescents stratified at baseline by risk of developing depression or presence of depression.

The frequently reported high theta/beta ratio (TBR) in the electroencephalograms (EEGs) of children with attention-deficit/hyperactivity disorder (ADHD) has been suggested to include at least two distinct neurophysiological subgroups, a subgroup with high TBR and one with slow alpha peak frequency, overlapping the theta range. We combined three large ADHD cohorts recorded under standardized procedures and used a meta-analytical approach to leverage the large sample size (N = 417; age range: 6-18 years), classify these EEG subtypes and investigate their behavioral correlates to clarify their brain-behavior relationships. To control for the fact that slow alpha might contribute to theta power, three distinct EEG subgroups (non-slow-alpha TBR (NSAT) subgroup, slow alpha peak frequency (SAF) subgroup, not applicable (NA) subgroup) were determined, based on a halfway cut-off in age- and sex-normalized theta and alpha, informed by previous literature. For the meta-analysis, Cohen's d was calculated to assess the differences between EEG subgroups for baseline effects, using means and standard deviations of baseline inattention and hyperactivity-impulsivity scores. Non-significant, small Grand Mean effect sizes (-0.212 < d < 0.218) were obtained when comparing baseline behavioral scores between the EEG subgroups. This study could not confirm any association of EEG subtype with behavioral traits. This confirms previous findings suggesting that TBR has no diagnostic value for ADHD. TBR could, however, serve as an aid to stratify patients between neurofeedback protocols based on baseline TBR. A free online tool was made available for clinicians to calculate age- and sex-corrected TBR decile scores (Brainmarker-IV) for stratification of neurofeedback protocols.

Insomnia is a highly prevalent disorder associated with numerous adverse health outcomes. Cognitive behavioural therapy for insomnia (CBT-I) is recommended as first-line treatment by clinical guidelines but is accessible to only a minority of patients suffering from insomnia. Internet-delivered CBT-I (iCBT-I) could contribute to the widespread dissemination of this first-line treatment. As there is insufficient evidence regarding non-inferiority, this study directly aims to compare therapist-guided internet-delivered versus face-to-face CBT-I in terms of insomnia severity post-treatment. Furthermore, a health-economic evaluation will be conducted, and potential benefits and disadvantages of therapist-guided iCBT-I will be examined.

Objective and quantifiable markers are crucial for developing novel therapeutics for mental disorders by 1) stratifying clinically similar patients with different underlying neurobiological deficits and 2) objectively tracking disease trajectory and treatment response. Schizophrenia is often confounded with other psychiatric disorders, especially bipolar disorder, if based on cross-sectional symptoms. Awake and sleep EEG have shown promise in identifying neurophysiological differences as biomarkers for schizophrenia. However, most previous studies, while useful, were conducted in European and American populations, had small sample sizes, and utilized varying analytic methods, limiting comprehensive analyses or generalizability to diverse human populations. Furthermore, the extent to which wake and sleep neurophysiology metrics correlate with each other and with symptom severity or cognitive impairment remains unresolved. Moreover, how these neurophysiological markers compare across psychiatric conditions is not well characterized. The utility of biomarkers in clinical trials and practice would be significantly advanced by well-powered transdiagnostic studies. The Global Research Initiative on the Neurophysiology of Schizophrenia (GRINS) project aims to address these questions through a large, multi-center cohort study involving East Asian populations. To promote transparency and reproducibility, we describe the protocol for the GRINS project.

Very low-field MR has emerged as a promising complementary device to high-field MRI scanners, offering several advantages. One of the key benefits is that very low-field scanners are generally more portable and affordable to purchase and maintain, making them an attractive option for medical facilities looking to reduce costs. Very low-field MRI systems also have lower RF power deposition, making them safer and less likely to cause tissue heating or other safety concerns. They are also simpler to maintain, as they do not require cooling agents such as liquid helium. However, these portable MR scanners are impacted by temperature, lower magnetic field strength, and inhomogeneity, resulting in images with lower signal-to-noise ratio (SNR) and higher geometric distortions. It is essential to investigate and tabulate the variations in these parameters to establish bounds so that subsequent in vivo studies and deployment of these portable systems can be well informed.

Specific phobia is a common anxiety disorder, but the literature on associated brain structure alterations exhibits substantial gaps. The ENIGMA Anxiety Working Group examined brain structure differences between individuals with specific phobias and healthy control subjects as well as between the animal and blood-injection-injury (BII) subtypes of specific phobia. Additionally, the authors investigated associations of brain structure with symptom severity and age (youths vs. adults).

Treatment of locally advanced rectal cancer (LARC) involves neoadjuvant chemoradiotherapy plus total mesorectal excision and adjuvant chemotherapy. However, total neoadjuvant therapy (TNT) protocols (ie, preoperative chemotherapy in addition to radiotherapy) may allow better adherence and early treatment of distant micrometastases and may increase pathological complete response (pCR) rates.

Borderline personality disorder (BPD) is considered a disorder of emotion regulation resulting from the expression of a biologically determined emotional vulnerability (that is, heightened sensitivity to emotion, increased emotional intensity/reactivity, and a slow return to emotional baseline) combined with exposure to invalidating environments. Vagal tone has been associated with activity in cortical regions involved in emotion regulation and a lower resting state of vagal tone has been observed in BPD patients relative to healthy controls. Non-invasive transcutaneous auricular vagus nerve stimulation (taVNS) has been shown to reduce temper outbursts in adults with Prader-Willi Syndrome, to enhance recognition of emotions in healthy students, and to improve depressive and anxiety symptoms. Furthermore, a single session of taVNS has been shown to acutely alter the recognition of facial expressions of negative valence in adolescents with MDD and increase emotion recognition in controls. However, the effect of taVNS on emotional vulnerability and regulation in individuals diagnosed with BPD has not been investigated. Our aims are to determine if taVNS is effective in acutely reducing emotional vulnerability and improve emotional regulation in BPD patients.

While research into adolescent mental health has developed a considerable understanding of environmental and psychosocial risk factors, equivalent biological evidence is lacking and is not representative of economic, social and ethnic diversity in the adolescent population. It is important to understand the possible barriers and facilitators to conduct this research. This will then allow us to improve our understanding of how biology interacts with environmental and psychosocial risk factors during adolescence. The objective of this scoping review is to identify and understand the needs, barriers and facilitators related to the collection of biological data in adolescent mental health research.

This study aims to validate the Seizure-Related Impact Assessment Scale (SERIAS). This novel patient-reported outcome measure (PROM) compares the 'trade-off' between seizures and treatment-related adverse effects, and measures epilepsy disability qualitatively and quantitively. It fills an important gap in PROMs for epilepsy clinical trials and practice.

In the last century, the paradigm of fear conditioning has greatly evolved in a variety of scientific fields. The techniques, protocols, and analysis methods now most used have undergone a progressive development, theoretical and technological, improving the quality of scientific productions. Fear-induced bradycardia is among these techniques and represents the temporary deceleration of heart beats in response to negative outcomes. However, it has often been used as a secondary measure to assess defensive responding to threat, along other more popular techniques. In this review, we aim at paving the road for its employment as an additional tool in fear conditioning experiments in humans. After an overview of the studies carried out throughout the last century, we describe more recent evidence up to the most contemporary research insights. Lastly, we provide some guidelines concerning the best practices to adopt in human fear conditioning studies which aim to investigate fear-induced bradycardia.

Synucleinopathies such as Parkinson's disease (PD) are defined by the accumulation and aggregation of the α-synuclein protein in neurons, glia and other tissues. We have previously shown that destabilization of α-synuclein tetramers is associated with familial PD due to SNCA mutations and demonstrated brain-region specific alterations of α-synuclein multimers in sporadic PD patients following the classical Braak spreading theory. In this study, we assessed relative levels of disordered and higher-ordered multimeric forms of cytosolic α-synuclein in blood from familial PD with G51D mutations and sporadic PD patients. We used an adapted in vitro-cross-linking protocol for human EDTA-whole blood. The relative levels of higher-ordered α-synuclein tetramers were diminished in blood from familial PD and sporadic PD patients compared to controls. Interestingly, the relative amount of α-synuclein tetramers was already decreased in asymptomatic G51D carriers, supporting the hypothesis that α-synuclein multimer destabilization precedes the development of clinical PD. Our data, therefore suggest that measuring α-synuclein tetramers in blood may have potential as a facile biomarker assay for early detection and quantitative tracking of PD progression.

Virtual reality (VR) has emerged as a promising technology for enhancing the health care of older individuals, particularly in the domains of cognition, physical activity, and social engagement. However, existing VR products and services have limited availability and affordability; hence, there is a need for a scientifically validated and personalized VR service to be used by older adults in their homes, which can improve their overall physical, cognitive, and social well-being.

Patient participation in treatment decision making is a pillar of recovery-oriented care and is associated with improvements in empowerment and well-being. Although demand for increased involvement in treatment decision-making is high among veterans with serious mental illness, rates of involvement are low. Collaborative decision skills training (CDST) is a recovery-oriented, skills-based intervention designed to support meaningful patient participation in treatment decision making. An open trial among veterans with psychosis supported CDST's feasibility and demonstrated preliminary indications of effectiveness. A randomized control trial (RCT) is needed to test CDST's effectiveness in comparison with an active control and further evaluate implementation feasibility.

Specific selective serotonin reuptake inhibitors (SSRIs) metabolism is strongly influenced by two pharmacogenes, CYP2D6 and CYP2C19. However, the effectiveness of prospectively using pharmacogenetic variants to select or dose SSRIs for depression is uncertain in routine clinical practice. The objective of this prospective, multicenter, pragmatic randomized controlled trial is to determine the effectiveness of genotype-guided selection and dosing of antidepressants on control of depression in participants who are 8 years or older with ≥3 months of depressive symptoms who require new or revised therapy. Those randomized to the intervention arm undergo pharmacogenetic testing at baseline and receive a pharmacy consult and/or automated clinical decision support intervention based on an actionable phenotype, while those randomized to the control arm have pharmacogenetic testing at the end of 6-months. In both groups, depression and drug tolerability outcomes are assessed at baseline, 1 month, 3 months (primary), and 6 months. The primary end point is defined by change in Patient-Reported Outcomes Measurement Information System (PROMIS) Depression score assessed at 3 months versus baseline. Secondary end points include change inpatient health questionnaire (PHQ-8) measure of depression severity, remission rates defined by PROMIS score < 16, medication adherence, and medication side effects. The primary analysis will compare the PROMIS score difference between trial arms among those with an actionable CYP2D6 or CYP2C19 genetic result or a CYP2D6 drug-drug interaction. The trial has completed accrual of 1461 participants, of which 562 were found to have an actionable phenotype to date, and follow-up will be complete in April of 2024.

Emergency departments (EDs) are facing an epidemic of overcrowding and ED boarding, particularly of older adults who often present with, or develop, delirium in the ED. Delirium is associated with increased complications, longer hospital length of stay, mortality, and costs to the healthcare system. However, we only have limited knowledge of how to successfully prevent and treat delirium in the ED in a pragmatic, sustainable, and cost-effective way. We present a narrative review of recent literature of delirium prevention and treatment programs in the ED. We aim to describe the components of successful delirium management strategies to be used by EDs in building delirium management programs.

This research aimed to devise and assess a mobile game therapy software for children with Attention-Deficit/Hyperactivity Disorder (ADHD), as well as evaluating its suitability and effectiveness in improving the cognitive ability of typically developing children. The study encompassed 55 children diagnosed with ADHD and 55 neurotypical children. Initial assessments involved ADHD-related scales, computerized tests for information processing, and physiological-psychological evaluations. After a 4-week home-based game intervention, participants underwent re-evaluation using baseline measures and provided feedback on treatment satisfaction. Considering the small proportion of study participants who dropped out, data was analyzed using both the Intention-to-Treat (ITT) analysis and the Per-protocol (PP) analysis. The trial was registered at ClinicalTrials.gov (NCT06181747). In ITT analysis, post-intervention analysis using linear mixed models indicated that the ADHD group improved significantly more than the neurotypical group particularly in Continuous Performance Test (CPT) accuracy (B = -23.92, p < 0.001) and reaction time (B = 86.08, p < 0.01), along with enhancements in anti-saccade (B = -10.65, p < 0.05) and delayed-saccade tasks (B = 0.34, p < 0.05). A reduction in parent-rated SNAP-IV scores was also observed (B = 0.43, p < 0.01). In PP analysis, paired-sample t-tests suggested that the ADHD group had significant changes pre- and post-intervention, in terms of CPT Accuracy (t = -7.62, p < 0.01), Anti-saccade task Correct Rate (t = -3.90, p < 0.01) and SNAP-IV scores (t = -4,64, p < 0.01). However, no significant changes post-intervention were observed in the neurotypical group. Survey feedback highlighted a strong interest in the games across both groups, though ADHD participants found the game more challenging. Parents of ADHD children reported perceived benefits and a willingness to continue the game therapy, unlike the neurotypical group's parents. The findings advocated for the integration of serious video games as a complementary tool in ADHD treatment strategies, demonstrating the potential to augment attentional abilities and alleviate clinical symptoms. However, a randomized controlled trial (RCT) is needed to further verify its efficacy.

Human spaceflight has historically been managed by government agencies, such as the NASA Twins Study, but new commercial spaceflight opportunities have opened spaceflight to a broader population. In 2021, the SpaceX Inspiration4 mission launched the first-ever all civilian crew to low Earth orbit, which included the youngest American astronaut (age 29), novel in-flight experimental technologies (handheld ultrasound imaging, smartwatch wearables, and immune profiling), ocular alignment measurements, and new protocols for in-depth, multi-omic molecular and cellular profiling. Here we report the primary findings from the 3-day spaceflight mission, which induced a broad range of physiological and stress responses, neurovestibular changes indexed by ocular misalignment, and altered neurocognitive functioning, some of which match long-term spaceflight, but almost all of which did not differ from baseline (pre-flight) after return to Earth. Overall, these preliminary civilian spaceflight data suggest that short-duration missions do not pose a significant health risk, and moreover present a rich opportunity to measure the earliest phases of adaptation to spaceflight in the human body at anatomical, cellular, physiologic, and cognitive levels. Finally, these methods and results lay the foundation for an open, rapidly expanding biomedical database for astronauts, which can inform countermeasure development for both private and government-sponsored space missions.

Loneliness has been identified as an important public health issue, peaking during adolescence. Previous research has suggested that social interaction is a key factor in loneliness, and positive social interaction can act as a protective factor against loneliness. However, it is unclear whether there are differing impacts of in-person and online social interaction on adolescents' loneliness and mental health. Ecological Momentary Assessment (EMA) designs are ideally suited for better understanding these associations.

There is a lack of distinct and measurable outcomes in psychiatric and/or mental health nursing which negatively impacts guiding clinical practice, assessing evidence-based nursing interventions, ensuring future-proof nursing education and establishing visibility as a profession and discipline. Psychiatric and/or mental health nursing struggle to demonstrate patient-reported outcomes to assess the effectiveness of their practice. A systematic review that summarising patient-reported outcomes, associated factors, measured nursing care/interventions and used measurement scales of psychiatric and/or mental health nursing in the adult population in acute, intensive and forensic psychiatric wards in hospitals will capture important information on how care can be improved by better understanding what matters and what is important to patients themselves. This review can contribute to the design, planning, delivery and assessment of the quality of current and future nursing care METHODS AND ANALYSIS: This protocol follows the Cochrane methodological guidance on systematic reviews of interventions and The Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocol. The search strategy will be identified by consultations with clinical and methodological experts and by exploring the literature. The databases Ovid MEDLINE, CINAHL, EMBASE, APA PsychARTICLES, Web of Science and Scopus will be searched for all published studies. Studies will be screened and selected with criteria described in the population, intervention, control and outcomes format after a pilot test by two researchers. Studies will be screened in two stages: (1) title and abstract screening and (2) full-text screening. Data extraction and the quality assessment based on the Johanna Briggs Institute guidelines will be conducted by two researchers. Data will be presented in a narrative synthesis.

African Americans (AAs) face cardiovascular health (CVH) disparities linked to systemic racism. The 2020 police killing of Mr. George Floyd in Minneapolis, Minnesota, alongside the COVID-19 pandemic, exacerbated adverse psychosocial factors affecting CVH outcomes among AAs. This manuscript describes the study protocol and participant characteristics in an ancillary study exploring the relationship between biopsychosocial factors and CVH among AAs.

4-repeat (4R) tauopathies are neurodegenerative diseases characterized by cerebral accumulation of 4R tau pathology. The most prominent 4R-tauopathies are progressive-supranuclear-palsy (PSP) and corticobasal-degeneration (CBD) characterized by subcortical tau accumulation and cortical neuronal dysfunction, as shown by PET-assessed hypoperfusion and glucose hypometabolism. Yet, there is a spatial mismatch between subcortical tau deposition patterns and cortical neuronal dysfunction, and it is unclear how these two pathological brain changes are interrelated. Here, we hypothesized that subcortical tau pathology induces remote neuronal dysfunction in functionally connected cortical regions to test a pathophysiological model that mechanistically links subcortical tau accumulation to cortical neuronal dysfunction in 4R tauopathies. We included 51 Aβ-negative patients with clinically diagnosed PSP variants (n=26) or Corticobasal Syndrome (CBS; n=25) who underwent structural MRI and 18F-PI-2620 tau-PET. 18F-PI-2620 tau-PET was recorded using a dynamic one-stop-shop acquisition protocol, to determine an early 0.5-2.5 min post-tracer-injection perfusion window for assessing cortical neuronal dysfunction, as well as a 20-40 min post-tracer-injection window to determine 4R-tau load. Perfusion-PET (i.e. early-window) was assessed in 200 cortical regions, and tau-PET was assessed in 32 subcortical regions of established functional brain atlasses. We determined tau epicenters as subcortical regions with highest 18F-PI-2620 tau-PET signal and assessed the connectivity of tau epicenters to cortical ROIs using a resting-state fMRI-based functional connectivity template derived from 69 healthy elderly controls from the ADNI cohort. Using linear regression, we assessed whether i) higher subcortical tau-PET was associated with reduced cortical perfusion and ii) whether cortical perfusion reductions were observed preferentially in regions closely connected to subcortical tau epicenters. As hypothesized, higher subcortical tau-PET was associated with overall lower cortical perfusion, which remained consistent when controlling for cortical tau-PET. Using group-average and subject-level PET data, we found that the seed-based connectivity pattern of subcortical tau epicenters aligned with cortical perfusion patterns, where cortical regions that were more closely connected to the tau epicenter showed lower perfusion. Together, subcortical tau-accumulation is associated with remote perfusion reductions indicative of neuronal dysfunction in functionally connected cortical regions in 4R-tauopathies. This suggests that subcortical tau pathology may induce cortical dysfunction, which may contribute to clinical disease manifestation and clinical heterogeneity.

Transcranial magnetic stimulation (TMS) to the dorsolateral prefrontal cortex (dlPFC) is an effective treatment for depression, but the neural effects after TMS remains unclear. TMS paired with electroencephalography (TMS-EEG) can causally probe these neural effects. Nonetheless, variability in single pulse TMS-evoked potentials (TEPs) across dlPFC subregions, and potential artifact induced by muscle activation, necessitate detailed mapping for accurate treatment monitoring.

Psilocybin-assisted psychotherapy (PAP) is a promising treatment option for depression, with randomized controlled trials (RCTs) providing preliminary support for its safety and efficacy. However, there is a lack of consistency across existing treatment protocols and psychotherapeutic approaches. The objective of this review is to summarize and compare current psychotherapy methods of PAP in treating depression and distress in life-threatening illnesses. We sought to comprehensively summarize published psychotherapy protocols from clinical trials to provide insights for future practices.

Sleep-wake disturbances frequently present in Veterans with mild traumatic brain injury (mTBI). These TBI-related sleep impairments confer significant burden and commonly exacerbate other functional impairments. Therapies to improve sleep following mTBI are limited and studies in Veterans are even more scarce. In our previous pilot work, morning bright light therapy (MBLT) was found to be a feasible behavioral sleep intervention in Veterans with a history of mTBI; however, this was single-arm, open-label, and non-randomized, and therefore was not intended to establish efficacy. The present study, LION (light vs ion therapy) extends this preliminary work as a fully powered, sham-controlled, participant-masked randomized controlled trial (NCT03968874), implemented as fully remote within the VA (target n=120 complete). Randomization at 2:1 allocation ratio to: 1) active: MBLT (n=80), and 2) sham: deactivated negative ion generator (n=40); each with identical engagement parameters (60-min duration; within 2-hrs of waking; daily over 28-day duration). Participant masking via deception balanced expectancy assumptions across arms. Outcome measures were assessed following a 14-day baseline (pre-intervention), following 28-days of device engagement (post-intervention), and 28-days after the post-intervention assessment (follow-up). Primary outcomes were sleep measures, including continuous wrist-based actigraphy, self-report, and daily sleep dairy entries. Secondary/exploratory outcomes included cognition, mood, quality of life, circadian rhythm via dim light melatonin onset, and biofluid-based biomarkers. Participant drop out occurred in <10% of those enrolled, incomplete/missing data was present in <15% of key outcome variables, and overall fidelity adherence to the intervention was >85%, collectively establishing feasibility and acceptability for MBLT in Veterans with mTBI.

Determine the association of inflammatory biomarkers with clinical measures and recovery in participants with concussion.

Older adults comprise a large portion of back pain (BP) sufferers but are under-represented in the literature. Patients over age 65 present with different clinical characteristics and psychosocial needs than younger patients. Therefore, recommended patient-centered outcomes for BP may not be relevant to older patients.

Unexplained physical signs and symptoms represent a significant portion of patient presentations in acute care settings. Even in cases where a patient presents with a known medical condition, functional or somatic symptoms may complicate the diagnostic and treatment processes and prognostic outcome. One umbrella category for neurologically related somatic symptoms, functional neurological disorder (FND), presents as involuntary neurological symptoms incompatible with another medical condition. Symptoms may include weakness and/or paralysis, movement disorders, non-epileptic seizures, speech or visual impairment, swallowing difficulty, sensory disturbances, or cognitive symptoms (1). While FND presents as neuropsychiatric, providers commonly report feeling hesitant to diagnose these disorders. Inexperience or lack of appropriate education on relevant research regarding evidence-based practices or standard of practice (SOP) may result in over- or underperforming diagnostic workups and consultations, utilizing inappropriate medications, and failing to offer evidence-based psychological interventions. Being mindful of these challenges when treating patients presenting with functional symptoms in acute care settings can help to support and protect the patients and care team and appropriately control healthcare costs.

Frailty is a clinical state that increases susceptibility to minor stressor events. The risk of frailty is higher in chronic conditions, such as Chronic Obstructive Pulmonary Disease (COPD). Recent studies on COPD have shown that patients living with frailty have an increased risk of mortality. The presence of cardiovascular diseases or conditions are common in COPD and may increase the risk of death.

Children with cleft palate, with or without cleft lip (CP±L), exhibit language delays on average compared to children without clefts. Interventions to address these disparities are scarce. In this multi-center study, Book Sharing for Toddlers with Clefts (BOOST), we will test a remote, parent-focused intervention to promote language development in children with CP±L.

This study aimed to investigate the effects of opioid-free anesthesia (OFA) in laparoscopic gastrectomy and identify the psychological factors that could influence the efficacy of OFA.

Negative symptoms and cognitive impairments are highly frequent in schizophrenia spectrum disorders (SSD), associated with adverse functional outcomes and quality of life. Repetitive transcranial magnetic stimulation (rTMS) has been considered a promising therapeutic option in SSD. However, placebo effects of rTMS on these symptoms remained unclear.

In 2020, New Mexico had the highest alcohol related death and the 11th highest drug overdose rate in the U.S. Towards the long-term goal of addressing this public health problem, we are implementing and evaluating an multi-level intervention designed to identify adults at risk of substance use disorder (SUD) and encourage linkage to and retention in treatment. The first level includes equipping the ED and medical inpatient units of a safety-net hospital with a method to screen individuals at risk of a SUD. The second level includes Seeking Safety (SS), a trauma-specific treatment for PTSD and SUD; and pharmacotherapy for SUD. Motivational Interviewing (MI) is used throughout both levels. Using the SPIRIT guidelines and checklist, this study protocol describes the multi-level intervention and the methodology we are using to assess feasibility and effectiveness.

Informal caregivers of persons with dementia (PWD) often suffer adverse impacts on their mental health and require interventions for effective support. As they are often occupied with providing care, web-based interventions could be more convenient and efficient for them. However, there is currently a dearth of evidence-based mobile interventions to enhance the mental well-being of dementia caregivers locally, especially ones that are user-centered and culturally relevant. Hence, having designed an app based on feedback from local dementia caregivers, this study will evaluate the effectiveness of this mobile app in promoting the mental health of informal caregivers of PWD in Singapore.

With ultramarathon attracting burgeoning interest, evidence has emerged about doping behaviors. However, currently, research into the anti-doping policy landscape and the adoption of testing and athlete surveillance is limited, including the applicability of rubric from the World Anti-Doping Agency (WADA) and National Anti-Doping Organizations (NADOs). Consequently, it remains unclear if anti-doping provisions have been developed and enforced in ultramarathon, which is a timely consideration given growth in the sport.

Depression is a common and disabling condition. Digital apps may augment or facilitate care, particularly in under-served populations. We tested the efficacy of juli, a digital self-management app for depression in a fully remote randomised controlled trial.

Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) is a rare genetic condition with a broad phenotypic presentation. This study aims to establish the first Australian cohort of individuals affected by CADASIL (AusCADASIL) and examine its clinical features and longitudinal course, and to investigate neuroimaging and blood biomarkers to assist in early diagnosis and identify disease progression.

Carpal Tunnel Syndrome (CTS) has traditionally been viewed as a specialized medical condition. However, its escalating prevalence among professionals across a multitude of industries has sparked substantial interest in recent years. This review aims to delve into CTS as an occupational disease, focusing on its epidemiological patterns, risk factors, symptoms, and management options, particularly emphasizing its relevance in professional environments. The complex interaction of anatomical, biomechanical, and pathophysiological factors that contribute to the development of CTS in different work settings underlines the critical role of ergonomic measures, prompt clinical identification, and tailored treatment plans in reducing its effects. Nevertheless, the challenges presented by existing research, including diverse methodologies and definitions, highlight the need for more unified protocols to thoroughly understand and tackle this issue. There's a pressing demand for more in-depth research into the epidemiology of CTS, its injury mechanisms, and the potential role of targeted medicine. Moreover, recognizing CTS's wider ramifications beyond personal health is essential. The economic burden associated with CTS-related healthcare costs, productivity losses, and compensation claims can significantly impact both businesses and the broader society. Therefore, initiatives aimed at preventing CTS through workplace interventions, education, and early intervention programs not only benefit the affected individuals but also contribute to the overall well-being of the workforce and economic productivity. By fostering a collaborative approach among healthcare professionals, employers, policymakers, and other stakeholders, we can strive towards creating safer and healthier work environments while effectively managing the challenges posed by CTS in occupational settings.

Advances have been made in understanding the aetiology of functional neurological disorder (FND); however, its pathophysiological mechanisms have not been definitively demonstrated. Evidence suggests interacting roles for altered emotional processing and interoception, elevated autonomic arousal, and dissociation, but there is limited evidence demonstrating their causal influence on specific FND symptoms. Our superordinate aim is to elucidate potentially shared and distinct aetiological factors and mechanisms in two common FND subtypes, functional seizures (FS) and functional motor symptoms (FMS).

Psychological distress affects the treatment and rehabilitation of patients with stroke, affects their long-term functional exercise and quality of life, and increases the risk of stroke recurrence and even death. This is a multi-dimensional and multi-level mental health problem and a dynamic process variable that shows a dynamic development trend with time. However, previous studies have been insufficient to deeply study the change mechanism of psychological distress, and there remains a lack of forward-looking longitudinal studies to analyze its change trajectory. This study aimed to investigate potential categories and how psychological distress changes over time and to examine conversion probability in these transformation processes.

PREVENT is a multi-centre prospective cohort study in the UK and Ireland that aims to examine midlife risk factors for dementia and identify and describe the earliest indices of disease development. The PREVENT dementia programme is one of the original epidemiological initiatives targeting midlife as a critical window for intervention in neurodegenerative conditions. This paper provides an overview of the study protocol and presents the first summary results from the initial baseline data to describe the cohort. Participants in the PREVENT cohort provide demographic data, biological samples (blood, saliva, urine and optional cerebrospinal fluid), lifestyle and psychological questionnaires, undergo a comprehensive cognitive test battery and are imaged using multi-modal 3-T MRI scanning, with both structural and functional sequences. The PREVENT cohort governance structure is described, which includes a steering committee, a scientific advisory board and core patient and public involvement groups. A number of sub-studies that supplement the main PREVENT cohort are also described. The PREVENT cohort baseline data include 700 participants recruited between 2014 and 2020 across five sites in the UK and Ireland (Cambridge, Dublin, Edinburgh, London and Oxford). At baseline, participants had a mean age of 51.2 years (range 40-59, SD ± 5.47), with the majority female ( = 433, 61.9%). There was a near equal distribution of participants with and without a parental history of dementia (51.4% versus 48.6%) and a relatively high prevalence of APOEɛ4 carriers ( = 264, 38.0%). Participants were highly educated (16.7 ± 3.44 years of education), were mainly of European Ancestry ( = 672, 95.9%) and were cognitively healthy as measured by the Addenbrookes Cognitive Examination-III (total score 95.6 ± 4.06). Mean white matter hyperintensity volume at recruitment was 2.26 ± 2.77 ml (median = 1.39 ml), with hippocampal volume being 8.15 ± 0.79 ml. There was good representation of known dementia risk factors in the cohort. The PREVENT cohort offers a novel data set to explore midlife risk factors and early signs of neurodegenerative disease. Data are available open access at no cost via the Alzheimer's Disease Data Initiative platform and Dementia Platforms UK platform pending approval of the data access request from the PREVENT steering group committee.

This qualitative study explored the perceptions of adult clients participating in a new psychological treatment for attention-deficit/hyperactivity disorder inattentive presentation (ADHD-I, also called "attention deficit disorder", ADD). The study aimed to explore (i) what aspects of treatment the participants found to be helpful, and (ii) if there were areas that ought to be developed to make the protocol more useful to clients with ADHD-I.

This protocol presents a multilevel cluster randomized study in 24 communities in Cape Town, South Africa. The study comprises four specific aims. Aim 1, conducted during the formative phase, was to modify the original Couples Health CoOp (CHC) intervention to include antiretroviral therapy/pre-exposure prophylaxis (ART/PrEP), called the Couples Health CoOp Plus (CHC+), with review from our Community Collaborative Board and a Peer Advisory Board. Aim 1 has been completed for staging the trial. Aim 2 is to evaluate the impact of a stigma awareness and education workshop on community members' attitudes and behaviors toward young women and men who use AODs and people in their community seeking HIV services (testing/ART/PrEP) and other health services in their local clinics. Aim 3 is to test the efficacy of the CHC+ to increase both partners' PrEP/ART initiation and adherence (at 3 and 6 months) and to reduce alcohol and other drug use, sexual risk and gender-based violence, and to enhance positive gender norms and communication relative to HIV testing services (n = 480 couples). Aim 4 seeks to examine through mixed methods the interaction of the stigma awareness workshop and the CHC+ on increased PrEP and ART initiation, retention, and adherence among young women and their primary partners. Ongoing collaborations with community peer leaders and local outreach staff from these communities are essential for reaching the project's aims. Additionally, a manualized field protocol with regular training, fidelity checks, and quality assurance are critical components of this multilevel community trial for successful ongoing data collection. Trial registration. Clinicaltrials.gov Registration Number: NCT05310773. Pan African Trials: pactr.samrc.ac.za/ Registration Number: PACTR202205640398485.

Childhood sexual abuse persists as a painful societal reality, necessitating responses from institutions and healthcare professionals to prevent and address its severe long-term consequences in victims. This study implements an intervention comprising two psychotherapeutic approaches recommended by the WHO and international clinical guidelines for addressing short-, medium-, and long-term posttraumatic symptomatology: Trauma-Focused Cognitive Behavioral Therapy (TF-CBT) and Eye Movement Desensitization and Reprocessing (EMDR). Both approaches are adapted from group formats for implementation in small online groups via Zoom.

Depression is a very common psychiatric disorder in worldwide. Globally, Human Immunodeficiency Virus (HIV) is highly prevalent among women, and are disproportionately affected by depression. Antiretroviral Therapy (ART) adherence which could highly be affected by depression is yet to be explored effectively. Depression affects overall poor HIV clinical outcomes, socioeconomic and social interactions. However, it is not well understood specifically how depression affects ART adherence in women living with HIV (WLWHIV). Investigating the effects of depression on ART adherence is critical in order to develop nuanced new evidence to address non-adherence in WLWHIV.