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Mycoplasma pneumonia (MPS), caused by Mycoplasma hyopneumoniae (Mhp), is a chronic, airborne respiratory disease that poses a significant threat to the global swine industry. The P97 and P46 proteins are major antigens of Mhp, with the R1 region of P97 possessing full adhesive capability. Studies have shown that the main antigenic regions of Mhp P42 and P65 proteins exhibit strong immunogenicity. In this study, we first linked the genes encoding P97R1 and P46 proteins to form the P97R1P65 gene and subsequently constructed three shuttle plasmids: pFBD-P97R1P46, pFBD-P97R1P46-p65, and pFBD-P65-P42. These proteins were expressed using the Bac to Bac system and formulated into subunit vaccines for mouse immunization. Mouse experiments indicated that the P97R1P46 + P65-P42 protein combination elicited higher levels of specific antibodies, IL-2, IL-4, and CD8+ T cells compared to other subunit vaccine groups, a finding further validated in subsequent mouse challenge protection experiments. Therefore, we utilized the MultiBac expression system to co-express P97R1P46, P65, and P42 proteins in the pFastMultibacDual vector for immunization experiments in piglets. The piglet immunization experiments demonstrated that the Mhp subunit vaccine prepared in this study could induce specific antibodies against Mhp, with the combination of P97R1P46, P65, and P42 proteins inducing the highest level of humoral immunity. This study provides valuable insights for the development of Mhp subunit vaccines. [ABSTRACT FROM AUTHOR]

Background: Motor imagery (MI) has emerged as a promising therapeutic approach for Parkinson's disease (PD). MI entails mentally rehearsing motor actions without executing them. This cognitive process has garnered attention due to its potential benefits in aiding motor function recovery in patients. The purpose of this review was to highlight the findings observed in motor symptoms, balance, gait, and quality of life. Methods: A literature search was carried out in Medline, Embase, Cochrane, and Physiotherapy Evidence Database (PEDro), from the first publication to February 2024. Studies with at least one keyword to PD and MI in the title were included. Results: The analysis included 53 studies out of the 262 identified. These comprised 12 randomized controlled trials (RCTs) with an average PEDro score of 6.6 out of 10, as well as 41 non-RCT studies. Notably, the majority of the RCTs focused on balance, gait, and lower limb exercises. The experimental group found an 85.2% improvement on the Timed Up and Go (TUG) with a cognitive task (p < 0.02), 5.8% improvement on the TUG (p < 0.05), and 5.1% improvement in walking speed (p < 0.05). Other variables did not show significant improvement. In descriptive and non-RCT studies, there were various tasks and outcomes for the lower and upper limbs. It has been demonstrated that there was no difference in execution time in MI between patients and healthy subjects (HS), whereas motor execution was slower in patients. Several tasks were analyzed for the upper limb, including thumb opposition, joystick movements, and writing tasks with variable results. RCTs were more focused on balance, lower limbs, and walking. There was no specific outcome regarding the upper limb or speech. Additionally, the heterogeneity of tasks and outcomes across studies is also a limitation. Conclusion: Current research on walking disorders in PD shows promise, but further investigations are crucial, particularly with an emphasis on upper limb function and speech. Studies with larger sample sizes and more precise methodologies are needed to enhance our understanding of the potential benefits of MI within the framework of comprehensive PD rehabilitation. [ABSTRACT FROM AUTHOR]

Background: Vγ9Vδ2 T-cells are antitumor immune effector cells that can detect metabolic dysregulation in cancer cells through phosphoantigen-induced conformational changes in the butyrophilin (BTN) 2A1/3A1 complex. In order to clinically exploit the anticancer properties of Vγ9Vδ2 T-cells, various approaches have been studied including phosphoantigen stimulation, agonistic BTN3A-specific antibodies, adoptive transfer of expanded Vγ9Vδ2 T-cells, and more recently bispecific antibodies. While Vγ9Vδ2 T-cells constitute a sizeable population, typically making up ~1-10% of the total T cell population, lower numbers have been observed with increasing age and in the context of disease. Methods: We evaluated whether bivalent single domain antibodies (VHHs) that link Vδ2-TCR specific VHHs with different affinities could support Vγ9Vδ2 T-cell expansion and could be incorporated in a bispecific engager format when additionally linked to a tumor antigen specific VHH. Results: Bivalent VHHs that link a high and low affinity Vδ2-TCR specific VHH can support Vγ9Vδ2 T-cell expansion. The majority of Vγ9Vδ2 T-cells that expanded following exposure to these bivalent VHHs had an effector or central memory phenotype and expressed relatively low levels of PD-1. Bispecific engagers that incorporated the bivalent Vδ2-TCR specific VHH as well as a tumor antigen specific VHH triggered antitumor effector functions and supported expansion of Vγ9Vδ2 T-cells in vitro and in an in vivo model in NOG-hIL-15 mice. Conclusion: By enhancing the number of Vγ9Vδ2 T-cells available to exert antitumor effector functions, these novel Vδ2-bivalent bispecific T cell engagers may promote the overall efficacy of bispecific Vγ9Vδ2 T-cell engagement, particularly in patients with relatively low levels of Vγ9Vδ2 T-cells. [ABSTRACT FROM AUTHOR]

Introduction: As the average global temperature increases, the effects of climate change worsen, through effects on worsening extreme events as well as exacerbating political, economic, and social turmoil (wars, conflicts, and migrations). This poses an existential risk to the survival of humans and nonhumans. These effects are visible due to the impact on people’s mental health and psychophysical well-being. This article aims to explore the growing phenomenon of psychoterratic syndromes, with focus on the effect of ecoanxiety on mental health. Furthermore, the relationship between eco-anxiety and behavior response (both individual and collective) in the climate crisis era is outlined. Methods: A research with interdisciplinary approach was carried out for recent literature and articles relating to psychoterratic syndromes and the effects of climate change on mental health. Results: The article explores the effects of climate change on mental health, including various research on the onset of new emotions in response to psychological effects to climate change, called psychoterratic syndromes (such as eco-anxiety, climate anxiety, solastalgia, eco-grief). Among these, eco-anxiety is the most popular term used for describing how people feel about climate change. However, the paradigm that described eco-anxiety only as a pathological emotion needs to be changed. Discussion: The article emphasizes the positive effect of eco-emotions and the need to stimulate people to move from a state of anxiety, which could bring apathy and resignation, toward eco-hope. Eco-hope could be an adaptive coping mechanism in people and communities, which is key to preventing, mitigating, and protecting mental and planetary health. [ABSTRACT FROM AUTHOR]

Background: Unstable gait leading to falls negatively impacts the quality of life in many people with Parkinson's disease (PD). Systematic review evidence provides moderate to strong evidence of efficacy for a wide range of physiotherapybased interventions to reduce gait impairment. However, outcomes have often focused on gait assessments conducted in controlled laboratory or clinical environments. Objective: This perspective investigates the complexities and challenges of conducting real-world gait assessments in people with PD and the factors that may influence the translation from improved lab-assessed gait to improved real-world gait. Methods: Through a thorough review of current literature, we present an in-depth analysis of current methodological approaches to real-world gait assessments and the challenges that may influence the translation of an intervention's success from lab-based outcomes to improved walking during daily life. Results: We identified six key factors that may influence the translation of intervention success into real-world environments at different stages of the process. These factors comprise the gait intervention, parameters analyzed, sensor setup, assessment protocols, characteristics of walking bouts, and medication status. We provide recommendations for each factor based on our synthesis of current literature. Conclusion: This perspective emphasizes the importance of measuring intervention success outside of the laboratory environment using real-world gait assessments. Our findings support the need for future studies to bridge the gap between proven efficacy for gait as assessed in controlled laboratory environments and real-world impact for people with PD. [ABSTRACT FROM AUTHOR]

Introduction: The clinicopathological characteristics and prognosis of placental site trophoblastic tumor (PSTT) and epithelioid trophoblastic tumor (ETT) have not been well summarized. Consequently, we conducted the largest to date series of samples of both types and employed machine learning (ML) to assess treatment effectiveness and develop accurate prognostic models for patients with GTN. Gestational choriocarcinoma (GCC) was used as the control group to show the clinical features of PTSS and ETT. Methods: The Surveillance, Epidemiology, and End Results (SEER) database provided the data used for this study's analysis. To identify the prognostic variables, we conducted Cox regression analysis and constructed prognostic models using five ML algorithms to predict the 5-year survival. A validation method incorporating the area under the curve (AUC) of the receiver operating characteristic (ROC) curve was used to validate the accuracy and reliability of the ML models. We also investigated the role of multiple therapeutic options using the Kaplan-Meier survival analysis. Results: The study population comprised 725 patients. Among them, 139 patients had ETT, 107 had PSTT, and 479 had GCC. There were no significant differences in survival between the different tumor groups. Multivariate Cox regression analysis revealed that metastasis was a significant prognostic factor for GCC, while older age and radiotherapy were significant prognostic factors for PTSS and ETT. ML models revealed that the Gradient Boosting classifier accurately predicted the outcomes, followed by the random forest classifier, K-Nearest Neighbors, Logistic Regression, and multilayer perceptron models. The most significant contributing factors were tumor size, year of diagnosis, age, and race. Discussion: Our study provides a method for treatment and prognostic assessment of patients with GTN. The ML we developed can be used as a convenient individualized tool to facilitate clinical decision making. [ABSTRACT FROM AUTHOR]

Purpose: Distinguished from cuproptosis and ferroptosis, disulfidptosis has been described as a newly discovered form of non-programmed cell death tightly associated with glucose metabolism. However, the prognostic profile of disulfidptosis-related lncRNAs (DRLRs) in ovarian cancer (OC) and their biological mechanisms need to be further elucidated. Materials and methods: First, we downloaded the profiles of RNA transcriptome, clinical information for OC patients from the TCGA database. Generated from Cox regression analysis, prognostic lncRNAs were utilized to identify the risk signature by least absolute shrinkage and selection operator analysis. Then, we explored the intimate correlations between disulfidptosis and lncRNAs. What's more, we performed a series of systemic analyses to assess the robustness of the model and unravel its relationship with the immune microenvironment comprehensively. Results: We identified two DRLR clusters, in which OC patients with low-risk scores exhibited a favorable prognosis, up-regulated immune cell infiltrations and enhanced sensitivity to immunotherapy. Furthermore, validation of the signature by clinical features and Cox analysis demonstrated remarkable consistency, suggesting the universal applicability of our model. It's worth noting that high-risk patients showed more positive responses to immune checkpoint inhibitors and potential chemotherapeutic drugs. Conclusion: Our findings provided valuable insights into DRLRs in OC for the first time, which indicated an excellent clinical value in the selection of management strategies, spreading brilliant horizons into individualized therapy. [ABSTRACT FROM AUTHOR]

Background: Parkinson's disease is characterized by symptoms such as bradykinesia and rigidity, which worsen as the disease progresses, significantly impacting patients' independence and quality of life. This study utilizes a network meta-analysis approach to quantify information gathered from randomized controlled trials (RCTs) regarding motor interventions that effectively improve the motor function of Parkinson's disease patients, aiming to provide evidence for selecting appropriate exercise intervention strategies for patients. Methods: A systematic search strategy for randomized controlled trials (RCTs) restricted to English was constructed based on multiple biomedical databases. Databases searched included PubMed, Embase, Cochrane, Web of Science, CINAHL, CBM, China National Knowledge Infrastructure (CNKI), Wan fang, VIP, etc., with searches conducted from inception to July 9, 2023. Two authors screened all studies, extracted data, and used frequency domain analysis methods. Network meta-analysis was performed using STATA software version 18.0 to compare and rank exercises that could effectively improve the motor function of Parkinson's disease patients (measured by indicators such as MDS-UPDRS-III, TUG, BBS, Mini-BES Test, 6MWT scores). Additionally, a series of analyses and evaluations were conducted, such as assessing the methodological quality of included studies using the Cochrane risk of bias tool. Results: The network meta-analysis included a total of 111 studies involving 5,358 participants, 133 intervention experiments, and 31 intervention measures. Although most exercise interventions showed effectiveness, cumulative ranking curves under the surface (SUCRA) values showed that archery exercise significantly improved patients' MDS-UPDRS-III scores (SUCRA = 95.6%), significantly superior to routine care [standardized mean difference (SMD = 16.92, 95%CI = -28.97, -4.87)]. High-intensity and agility exercise (High strength and agility) referred to as high-intensity exercise or agility training or a combination of both, collectively termed as high-intensity agility training, significantly improved patients' completion time for the time-up-and-go test (SUCRA = 99.7%), (SMD = -7.88, 95%CI = -9.47, -6.28). Dance and Tai Chi exercises significantly improved patients' balance abilities: Mini-Balance Evaluation Systems Test (SUCRA = 77.9%), (SMD = 5.25, 95%CI = -0.42, 10.92) for dance intervention and Berg Balance Scale (SUCRA = 94.7%), (SMD = 11.22, 95%CI = 3.26, 19.18) for Tai Chi intervention. Dance also significantly improved patients' walking ability in the 6-min walk test (SUCRA = 80.5%), (SMD = 71.31, 95%CI = 13.77, 128.84). Conclusion: Compared to other exercises, archery, dance, Tai Chi, and high-intensity agility exercises demonstrate superior efficacy in improving the motor function of Parkinson's disease patients. [ABSTRACT FROM AUTHOR]

Background: Primary care physicians (PCPs) are doctors in primary health care institutions, namely village clinics, township health centers and community health service centers (stations) who are themain providers of primary health care services in primary health care settings. Improving the overall health status of the population requires the support of a large number of primary care physicians; however, the job satisfaction of this group has not been sufficiently emphasized and recognized. Objective: The purpose of this study was to examine the effects of primary care physicians' work-family conflict on their job satisfaction, as well as the mediating role of burnout and the moderating role of social support. Methods: This cross-sectional study was conducted fromFebruary 2023 to March 2023. Participants were 749 primary care physicians from four cities of Xuzhou, Linyi, Huaibei, and Shangqiu in the Huaihai Economic Zone of China. SPSS statistical analysis was used to evaluate the relationship between work-family conflict, social support, burnout and job satisfaction among medical workers. Results: Work-family conflict had a significant negative effect on job satisfaction (b = -0.36, p< 0.001), after adding burnout in the model, work-family conflict also negatively predicted job satisfaction (b = -0.32, p< 0.001). Social support had a moderating effect on the direct effect of burnout on job satisfaction (b = 0.00, t = 2.66, p< 0.01, 95%CI [0.001, 0.007]), the predictive effect of burnout on job satisfaction at high level of social support (b = -0.45, p< 0.001) was higher than a low level of social support (b = -0.33, p< 0.001). Conclusions: This study demonstrated the negative impact of work-family conflict on primary care physicians' job satisfaction, as well as the mediating role of burnout and the moderating role of social support on burnout and job satisfaction, which are important for improving primary care physicians' job satisfaction and enhancing the quality of primary care in the future. [ABSTRACT FROM AUTHOR]

Therapeutic strategies targeting non-adaptive immune cells are currently in clinical development. γδT cells are a small subtype of T cells (1-10% of total T cells) that mediate their effector function without the necessity of the antigen presenting machinery, and also share functional properties with innate cells. Among the different γδT subtypes, antibodies against Vγ9Vδ2T have reported signs of clinical efficacy in early clinical studies. In this review we describe the biology of this subtype of non-conventional T cells and provide insights into the mechanism of action of novel antibodies that activate these cells. We will focus on antibodies targeting the BTN3A ligand and bi-specific γδT cell engagers. We will review in detail the advantages of these strategies including the potential for overcoming mechanisms of resistance to check point inhibitors, or the much more adequate safety profile compared with agents activating classical T cells. Limitations identified during the first studies in humans and strategies to overcome them will be revised and discussed. Finally, clinical options for future clinical development will be suggested. [ABSTRACT FROM AUTHOR]

Gamma delta (γδ) T cells represent a minor fraction of human T cell repertoire but play an important role in mediating anti-infectious and anti-tumorous effects in the context of allogeneic hematopoietic stem cell transplantation (allo-HSCT). We performed a prospective study to analyze the effect of different transplant modalities on immune reconstitution of γδ T cells and subsets. CD3, CD4 and CD8 T cells were analyzed in parallel. Secondly, we examined the impact of γδ T cell reconstitution on clinical outcomes including acute Graft-versus-Host-Disease (aGvHD) and viral infections. Our cohort includes 49 pediatric patients who received unmanipulated bone marrow grafts from matched unrelated (MUD) or matched related (MRD) donors. The cohort includes patients with malignant as well as non-malignant diseases. Cell counts were measured using flow cytometry at 15, 30, 60, 100, 180 and 240 days after transplantation. Cells were stained for CD3, CD4, CD8, CD45, TCRαβ, TCRγδ, TCRVδ1, TCRVδ2, HLA-DR and combinations. Patients with a MRD showed significantly higher Vδ2+ T cells than those with MUD at timepoints +30, +60, +100 (p<0.001, respectively) and +180 (p<0.01) in univariate analysis. These results remained significant in multivariate analysis. Patients recovering with a high relative abundance of total γδ T cells and Vδ2+ T cells had a significantly lower cumulative incidence of grade II-IV aGvHD after transplantation (p=0.03 and p=0.04, respectively). A high relative abundance of Vδ2+ T cells was also associated with a lower incidence of EBV infection (p=0.02). Patients with EBV infection on the other hand showed higher absolute Vδ1+ T cell counts at days +100 and +180 after transplantation (p=0.046 and 0.038, respectively) than those without EBV infection. This result remained significant in a multivariate time-averaged analysis (q<0.1). Our results suggest a protective role of γδ T cells and especially Vδ2+ T cell subset against the development of aGvHD and EBV infection after pediatric HSCT. Vδ1+ T cells might be involved in the immune response after EBV infection. Our results encourage further research on γδ T cells as prognostic markers after HSCT and as possible targets of adoptive T cell transfer strategies. [ABSTRACT FROM AUTHOR]

Background: Exercise has been proposed as the “Universal Prescription for Parkinson’s Disease”; however, the specificity of exercise dose in terms of frequency, intensity, duration, and type to be prescribed remains to be elucidated. The 2018 US updated guidelines and WHO Guidelines on Physical Activity and Sedentary Behavior recommend older adults (> 65+ years) to achieve weekly minimal activity levels, indicating the intensity of aerobic exercise as the metabolic equivalent of task and duration as minutes/week (150–300  min/week at a moderate intensity of 3–5.9 MET- or 75–150  min/week of a vigorous intensity of ≥6 MET). Translating these recommendations to PD patients, the study aimed to assess the dose–response effects of standardized volume of structured exercise, measured as METs-minutes/week (weekly energy expenditure) of two different rehabilitation settings to quantify the change in neurotrophic factors. The exercise-induced benefits between the two rehabilitation settings will be evaluated based on motor and non-motor symptoms, kinematic parameters of gait, cognitive function, quality of life, and cortical activity and brain connectivity. Methods: METEX-PD is a pilot, prospective, observational, cohort study. The study will enroll consecutively thirty (N  =  30) participants with mild-to-moderate Parkinson’s disease diagnosis to be assigned to a non-intensive or intensive rehabilitation group. The non-intensive rehabilitation group will achieve a range of 180–270 METs-min/week (90  min/week of low-intensity aerobic exercise, 2–3 METs), while the intensive rehabilitation group will exercise at 1350–1980 METs-min/week (225  min/week of high-intensity aerobic exercise, 6–8.8 METs). The METEX-PD trial will last 12  weeks, including 4  weeks of aerobic training program and two follow-ups. Assessments will be performed at baseline (T0), at the end of the exercise program (T1—end of the program), and 4- and 8  weeks after the end of the training program (FU-1 and FU-2). The primary outcome is the change from baseline in peripheral blood BDNF levels. Secondary outcomes are differences in peripheral biomarkers, functional-motor assessments, clinicalfunctional evaluations, and brain imaging. Conclusion: METEX-PD trial will enable us to estimate the change in BDNF levels and other peripheral biomarkers under precise exercise-induced energy expenditure. The primary results of the METEX-PD study will allow the development of a larger multicenter randomized controlled trial to investigate the molecular pathways inducing the change in selected neurotrophic factors, such as BDNF, IGF-1, or irisin, and the downstream mechanisms of neuroplasticity in PD patients. [ABSTRACT FROM AUTHOR]

Exosomes, as a class of small extracellular vesicles closely related to the biological behavior of various types of tumors, are currently attracting research attention in cancer diagnosis and treatment. Regarding cancer diagnosis, the stability of their membrane structure and their wide distribution in body fluids render exosomes promising biomarkers. It is expected that exosome-based liquid biopsy will become an important tool for tumor diagnosis in the future. For cancer treatment, exosomes, as the “golden communicators” between cells, can be designed to deliver different drugs, aiming to achieve low-toxicity and low-immunogenicity targeted delivery. Signaling pathways related to exosome contents can also be used for safer and more effective immunotherapy against tumors. Exosomes are derived from a wide range of sources, and exhibit different biological characteristics as well as clinical application advantages in different cancer therapies. In this review, we analyzed the main sources of exosomes that have great potential and broad prospects in cancer diagnosis and therapy. Moreover, we compared their therapeutic advantages, providing new ideas for the clinical application of exosomes. [ABSTRACT FROM AUTHOR]

Background: Childhood trauma is a potential threat to depression and can have a lifelong impact on the mental health of university students. Our study aimed to construct a moderated mediation model to explore the relationship between childhood trauma, psychache, ambivalence over emotional expression, physical activity, and depression in university students. Methods: A cross-sectional study was conducted in three universities in China, recruiting 476 university students using self-report questionnaires. The moderated mediation model was examined using the SPSS PROCESS model 21. Results: Ambivalence over emotional expression (F=12.843), childhood trauma (F=117.639), and psychache (F=581.594) all had a significant positive effect on depression (p<0.001), explaining 2.9%, 21.7%, and 56.8% of the variance, respectively. On the chain of influence between childhood trauma and depression, the mediating effect of psychache, the moderating effect of ambivalence over emotional expression, and the moderating effect of physical activity are all significant the overall indirect effect value of the three is 0.287, accounting for 61.59% of the total effect. Conclusion: This study investigated the relationship between childhood trauma, ambivalence over emotional expression, psychache, physical activity, and depression in university students. Future interventions should focus on developing good emotional expression among university students, increasing opportunities for physical activity, and reducing psychache to reduce depression. [ABSTRACT FROM AUTHOR]

Resistance to traditional treatment methods is still a major obstacle in modern psychiatry. As a result, several studies are currently being conducted to find effective alternatives to traditional therapies. One of these alternatives is psilocybin, a psychedelic substance that has been tested in clinical trials as an adjunct to psychotherapy. These studies focus on patients with major depressive disorder (MDD), obsessive-compulsive disorder (OCD) and substance use disorder (SUD), particularly alcohol and nicotine dependence. This article looks at the current understanding of psilocybin, including data from clinical trials conducted, psilocybin's mechanism of action, its safety and the level of risk associated with it. [ABSTRACT FROM AUTHOR]

Various countries and US States have legalized cannabis, and the use of the psychoactive1 and non-psychoactive cannabinoids is steadily increasing. In this review, we have collated evidence from published non-clinical and clinical sources to evaluate the abuse, dependence and associated safety risks of the individual cannabinoids present in cannabis. As context, we also evaluated various synthetic cannabinoids. The evidence shows that delta-9 tetrahydrocannabinol (D9-THC) and other psychoactive cannabinoids in cannabis have moderate reinforcing effects. Although they rapidly induce pharmacological tolerance, the withdrawal syndrome produced by the psychoactive cannabinoids in cannabis is of moderate severity and lasts from 2 to 6 days. The evidence overwhelmingly shows that non-psychoactive cannabinoids do not produce intoxicating, cognitive or rewarding properties in humans. There has been much speculation whether cannabidiol (CBD) influences the psychoactive and potentially harmful effects of Δ9-THC. Although most non-clinical and clinical investigations have shown that CBD does not attenuate the CNS effects of Δ9-THC or synthetic psychoactive cannabinoids, there is sufficient uncertainty to warrant further research. Based on the analysis, our assessment is cannabis has moderate levels of abuse and dependence risk. While the risks and harms are substantially lower than those posed by many illegal and legal substances of abuse, including tobacco and alcohol, they are far from negligible. In contrast, potent synthetic cannabinoid (CB1/CB2) receptor agonists are more reinforcing and highly intoxicating and pose a substantial risk for abuse and harm. "Psychoactive" is defined as a substance that when taken or administered affects mental processes, e.g., perception, consciousness, cognition or mood and emotions. [ABSTRACT FROM AUTHOR]

Poisoning by widow-spider (genus Latrodectus) bites occurs worldwide. The illness, termed latrodectism, can cause severe and persistent pain and can lead to muscle rigidity, respiratory complications, and cardiac problems. It is a global health challenge especially in developing countries. Equine serum-derived polyclonal anti-sera are commercially available as a medication for patients with latrodectism, but the use of sera imposes potential inherent risks related to its animal origin. The treatment may cause allergic reactions in humans (serum sickness), including anaphylactic shock. Furthermore, equine-derived antivenom is observed to have batch-to-batch variability and poor specificity, as it is always an undefined mix of antibodies. Because latrodectism can be extremely painful but is rarely fatal, the use of antivenom is controversial and only a small fraction of patients is treated. In this work, recombinant human antibodies were selected against alpha-latrotoxin of the European black widow (Latrodectus tredecimguttatus) by phage display from a naïve antibody gene library. AlphaLatrotoxin (α-LTX) binding scFv were recloned and produced as fully human IgG. A novel alamarBlue assay for venom neutralization was developed and used to select neutralizing IgGs. The human antibodies showed in vitro neutralization efficacy both as single antibodies and antibody combinations. This was also confirmed by electrophysiological measurements of neuronal activity in cell culture. The best neutralizing antibodies showed nanomolar affinities. Antibody MRU44–4-A1 showed outstanding neutralization efficacy and affinity to L. tredecimguttatus α-LTX. Interestingly, only two of the neutralizing antibodies showed cross-neutralization of the venom of the Southern black widow (Latrodectus mactans). This was unexpected, because in the current literature the alpha-latrotoxins are described as highly conserved. The here-engineered antibodies are candidates for future development as potential therapeutics and diagnostic tools, as they for the first time would provide unlimited supply of a chemically completely defined drug of constant quality and efficacy, which is also made without the use of animals. [ABSTRACT FROM AUTHOR]

Background: In times of war, mental health professionals are at an increased risk of developing psychological problems, including posttraumatic stress disorder (PTSD). The effects of conflicts or wars on mental health professionals in Palestine and their coping methods of dealing with these challenges remain unknown. This study aimed to assess the prevalence of PTSD symptoms and strategies for coping among mental health professionals in Palestine, in light of the ongoing Gaza war and political violence. Methods: The study utilized a cross-sectional research design. Self-reported questionnaires, including the PCL-5 and Brief COPE scales, were used to gather data. The relationship between the research variables and PTSD symptoms was investigated using frequencies, percentages, bivariate analysis, Pearson correlation, and Pearson’s chi-square test. Results: A total of 514 participants were recruited, with an estimated prevalence of PTSD of 38.7%. Furthermore, the multivariate analysis revealed that having a prior history of trauma and feeling disabled or unable to deal with your patients during the current Gaza war and Israeli–Palestinian political violence increases the likelihood of developing PTSD symptoms. In addition, using venting, self blame, and behavioral disengagement as coping strategies increases the likelihood of developing symptoms of PTSD. Moreover, using acceptance and substance use as coping strategies reduces the risk of developing PTSD symptoms. Conclusion: The findings revealed a high prevalence of PTSD symptoms among mental health professionals during wartime and political violence. As a result, mental health professionals need immediate assistance in enhancing their mental wellbeing through supervision, psychotherapy, and comprehensive and continuous training. [ABSTRACT FROM AUTHOR]

Background: Intimate partner violence (IPV) perpetration is highly prevalent among veterans. Suggested risk factors of IPV perpetration include combat exposure, post-traumatic stress disorder (PTSD), depression, alcohol use, and mild traumatic brain injury (mTBI). While the underlying brain pathophysiological characteristics associated with IPV perpetration remain largely unknown, previous studies have linked aggression and violence to alterations of the limbic system. Here, we investigate whether IPV perpetration is associated with limbic microstructural abnormalities in military veterans. Further, we test the effect of potential risk factors (i.e., PTSD, depression, substance use disorder, mTBI, and war zone-related stress) on the prevalence of IPV perpetration. Methods: Structural and diffusion-weighted magnetic resonance imaging (dMRI) data were acquired from 49 male veterans of the Iraq and Afghanistan wars (Operation Enduring Freedom/Operation Iraqi Freedom; OEF/OIF) of the Translational Research Center for TBI and Stress Disorders (TRACTS) study. IPV perpetration was assessed using the psychological aggression and physical assault sub-scales of the Revised Conflict Tactics Scales (CTS2). Odds ratios were calculated to assess the likelihood of IPV perpetration in veterans with either of the following diagnoses: PTSD, depression, substance use disorder, or mTBI. Fractional anisotropy tissue (FA) measures were calculated for limbic gray matter structures (amygdala-hippocampus complex, cingulate, parahippocampal gyrus, entorhinal cortex). Partial correlations were calculated between IPV perpetration, neuropsychiatric symptoms, and FA. Results: Veterans with a diagnosis of PTSD, depression, substance use disorder, or mTBI had higher odds of perpetrating IPV. Greater war zone-related stress, and symptom severity of PTSD, depression, and mTBI were significantly associated with IPV perpetration. CTS2 (psychological aggression), a measure of IPV perpetration, was associated with higher FA in the right amygdala-hippocampus complex (r  =  0.400, p  =  0.005). Conclusion: Veterans with psychiatric disorders and/or mTBI exhibit higher odds of engaging in IPV perpetration. Further, the more severe the symptoms of PTSD, depression, or TBI, and the greater the war zone-related stress, the greater the frequency of IPV perpetration. Moreover, we report a significant association between psychological aggression against an intimate partner and microstructural alterations in the right amygdala-hippocampus complex. These findings suggest the possibility of a structural brain correlate underlying IPV perpetration that requires further research. [ABSTRACT FROM AUTHOR]

Introduction: There is growing consensus that consideration of the Social Determinants of Mental Health should be at the centre of mental health care provision. To facilitate this, a validated means to assess mental health service users' social contextual information is arguably needed. We therefore developed a questionnaire to assess the Social Determinants of Mental Health in clinical practice. Methods: Our guideline-informed development consisted of three steps; i) construct and purpose definition, ii) initial item generation based on the literature, similar questionnaires, and a selection of the ICD-10, iii) evaluation, revision, and content validation of the questionnaire. Initially we developed 249 items that were reduced, revised, and validated in several stages to 73 items. Content validation of the questionnaire was achieved through surveys and focus groups including mental health care service users and professionals. Results: The surveys and focus groups indicated the need for a standardised assessment of adverse social factors and highlighted that the benefits of such an assessment would be a more holistic approach to identifying and addressing fundamental factors involved in the development of mental health difficulties. Importantly, this study also revealed how any assessment of the Social Determinants of Mental Health must prioritise the assessed person having a central role in the process and control over their own data. The focus groups identified contradicting recommendations regarding the most suitable context to administer the questionnaire. Discussion: The resulting questionnaire can be considered to be theoretically robust and partially validated. Future research is discussed. [ABSTRACT FROM AUTHOR]

Background: Recent advancements in Artificial Intelligence (AI) contributed significantly to suicide assessment, however, our theoretical understanding of this complex behavior is still limited. Objective: This study aimed to harness AI methodologies to uncover hidden risk factors that trigger or aggravate suicide behaviors. Methods: The primary dataset included 228,052 Facebook postings by 1,006 users who completed the gold-standard Columbia Suicide Severity Rating Scale. This dataset was analyzed using a bottom-up research pipeline without a-priory hypotheses and its findings were validated using a top-down analysis of a new dataset. This secondary dataset included responses by 1,062 participants to the same suicide scale as well as to well-validated scalesmeasuring depression and boredom. Results: An almost fully automated, AI-guided research pipeline resulted in four Facebook topics that predicted the risk of suicide, of which the strongest predictor was boredom. A comprehensive literature review using APA PsycInfo revealed that boredom is rarely perceived as a unique risk factor of suicide. A complementing top-down path analysis of the secondary dataset uncovered an indirect relationship between boredom and suicide, which was mediated by depression. An equivalent mediated relationship was observed in the primary Facebook dataset as well. However, here, a direct relationship between boredom and suicide risk was also observed. Conclusion: Integrating AI methods allowed the discovery of an under-researched risk factor of suicide. The study signals boredom as a maladaptive 'ingredient' that might trigger suicide behaviors, regardless of depression. Further studies are recommended to direct clinicians' attention to this burdening, and sometimes existential experience. [ABSTRACT FROM AUTHOR]

Atherosclerosis poses a significant threat to human health, impacting overall well-being and imposing substantial financial burdens. Current treatment strategies mainly focus on managing low-density lipids (LDL) and optimizing liver functions. However, it's crucial to recognize that Atherosclerosis involves more than just lipid accumulation; it entails a complex interplay of immune responses. Research highlights the pivotal role of lipid-laden macrophages in the formation of atherosclerotic plaques. These macrophages attract lymphocytes like CD4 and CD8 to the inflamed site, potentially intensifying the inflammatory response. γδ T lymphocytes, with their diverse functions in innate and adaptive immune responses, pathogen defense, antigen presentation, and inflammation regulation, have been implicated in the early stages of Atherosclerosis. However, our understanding of the roles of γδ T cells in Atherosclerosis remains limited. This mini-review aims to shed light on the characteristics and functions of γδ T cells in Atherosclerosis. By gaining insights into the roles of γδ T cells, we may uncover a promising strategy to mitigate plaque buildup and dampen the inflammatory response, thereby opening new avenues for effectively managing this condition. [ABSTRACT FROM AUTHOR]

Background: Parkinson's disease (PD) is a common neurodegenerative disorder that affects motor and non-motor functions, significantly reducing patients' quality of life. No effective drug-based treatments are known to solve this problem. Non-drug therapies such as Yijinjing exercise have shown potential in improving cognitive and motor functions in PD patients. However, solid evidence must still be provided to support their clinical efficacy. This study aims to evaluate the clinical efficacy of Yijinjing exercise interventions in PD patients and explore the underlying mechanisms between the cognitive and motor functions in PD. Methods: This is a single-center randomized controlled trial in which 96 eligible PD patients will be randomly assigned to receive either Yijinjing exercise group or brisk walking group or control group in a ratio of 1:1:1. Interventions (Yijinjing exercise or brisk walking training, 40 min per session) will be provided in 3 sessions per week (Monday, Wednesday, Friday) for 12 weeks, with a total of 36 sessions. After the treatment, there will be a 1-month follow-up period. The primary outcomes will be measured using the Montreal Cognitive Assessment (MoCA) and the Unified Parkinson's Disease Rating Scale motor section (UPDRSIII). Secondary outcomes include balance function, executive function, walking function, sleep quality, and quality of life. Additionally, the prefrontal cerebral and sensorimotor cortex blood oxygen signal level will be collected to explore the underlying mechanisms. All outcomes will be assessed at baseline, at the end of 12 weeks of treatment and after an additional 1-month follow-up period. Discussion: The results of the study protocol will provide high-quality evidence for the potential of intervention measures based on the Yijinjing exercise to improve the cognitive and activity levels of Parkinson's disease patients. We envision the Yijinjing exercise as a non-pharmacological family activity that can provide a new and more effective method for the treatment of Parkinson's disease patients or those at risk. [ABSTRACT FROM AUTHOR]

Comprising only 1-10% of the circulating T cell population, γδT cells play a pivotal role in cancer immunotherapy due to their unique amalgamation of innate and adaptive immune features. These cells can secrete cytokines, including interferon-γ (IFN-γ) and tumor necrosis factor-α (TNF-α), and can directly eliminate tumor cells through mechanisms like Fas/FasL and antibody-dependent cell-mediated cytotoxicity (ADCC). Unlike conventional αβT cells, γδT cells can target a wide variety of cancer cells independently of major histocompatibility complex (MHC) presentation and function as antigen-presenting cells (APCs). Their ability of recognizing antigens in a non-MHC restricted manner makes them an ideal candidate for allogeneic immunotherapy. Additionally, γδT cells exhibit specific tissue tropism, and rapid responsiveness upon reaching cellular targets, indicating a high level of cellular precision and adaptability. Despite these capabilities, the therapeutic potential of γδT cells has been hindered by some limitations, including their restricted abundance, unsatisfactory expansion, limited persistence, and complex biology and plasticity. To address these issues, gene-engineering strategies like the use of chimeric antigen receptor (CAR) T therapy, T cell receptor (TCR) gene transfer, and the combination with γδT cell engagers are being explored. This review will outline the progress in various engineering strategies, discuss their implications and challenges that lie ahead, and the future directions for engineered γδT cells in both monotherapy and combination immunotherapy. [ABSTRACT FROM AUTHOR]

Vγ9Vδ2 T cells represent a promising cancer therapy platform because the implementation of allogenic, off-the-shelf product candidates is possible. However, intravenous administration of human Vγ9Vδ2 T cells manufactured under good manufacturing practice (GMP)-compliant, serum-free conditions are not tested easily inmostmousemodels,mainly because they lack the ability to migrate from the blood to tissues or tumors. We demonstrate that these T cells do not migrate from the circulation to the mouse bone marrow (BM), the site of many malignancies. Thus, there is a need to better characterize human γδ T-cell migration in vivo and develop strategies to direct these cells to in vivo sites of therapeutic interest. To better understand the migration of these cells and possibly influence their migration, NSG mice were conditioned with agents to clear BM cellular compartments, i.e., busulfan or total body irradiation (TBI), or promote T-cell migration to inflamed BM, i.e., incomplete Freund's adjuvant (IFA), prior to administering γδ T cells. Conditioning with TBI, unlike busulfan or IFA, increases the percentage and number of γδ T cells accumulating in the mouse BM, and cells in the peripheral blood (PB) and BM display identical surface protein profiles. To better understand the mechanism by which cells migrate to the BM, mice were conditioned with TBI and administered γδ T cells or tracker-stained red blood cells. The mechanism by which γδ T cells enter the BM after radiation is passive migration from the circulation, not homing. We tested if these ex vivo-expanded cells can migrate based on chemokine expression patterns and showed that it is possible to initiate homing by utilizing highly expressed chemokine receptors on the expanded γδ T cells. γδ T cells highly express CCR2, which provides chemokine attraction to C-C motif chemokine ligand 2 (CCL2)-expressing cells. IFNγ-primed mesenchymal stromal cells (MSCs) (γMSCs) express CCL2, and we developed in vitro and in vivo models to test γδ T-cell homing to CCL2-expressing cells. Using an established neuroblastoma NSG mouse model, we show that intratumorally-injected γMSCs increase the homing of γδ T cells to this tumor. These studies provide insight into the migration of serum-free, ex vivo-expanded Vγ9Vδ2 T cells in NSG mice, which is critical to understanding the fundamental properties of these cells. [ABSTRACT FROM AUTHOR]

Background: The velocity storage mechanism of the central vestibular system is closely associated with the vestibulo-ocular reflex (VOR), but also contributes to the sense of orientation in space and the perception of self-motion. We postulate that mal de débarquement syndrome (MdDS) is a consequence of inappropriate sensory adaptation of velocity storage. The premise that a maladapted velocity storage may be corrected by spatial readaptation of the VOR has recently been translated into the development of the first effective treatment for MdDS. However, this treatment's initial impact may be reversed by subsequent re-triggering events. Presently, we hypothesized that MdDS symptoms could alternatively be reduced by attenuating the velocity storage contribution in the central vestibular pathways. Methods: Forty-three patients with MdDS (aged 47 ± 14 yo; 36 women) were randomly assigned to two treatment groups and followed for 6 months. The horizontal VOR was tested with chair rotation during laboratory visits, and the strength of velocity storage was quantified with model-based parameters--the time constant (Tc) and the gain of coupling from the vestibular primary afferent signals (g0). To attenuate velocity storage, Group 1 underwent a progressively intensifying series of low-frequency earth-vertical oscillatory rotation coupled to conflicting visual stimuli. Group 2 underwent an established protocol combining head tilts and visual stimulation, designed to correct maladapted spatial orientation but not change the velocity storage strength. The symptom severity was self-rated on an 11-point scale and reported before and up to 6 months after the treatment. Results: In Group 1, velocity storage was modified through reduction of g0 (p < 0.001) but not Tc. The symptom rating was at least halved initially in 43% of Group 1 (p = 0.04), the majority of whom retained a similar level of improvement during the 6-month follow-up period. In Group 2, no systematic change was induced in the parameters of velocity storage strength, as expected. The symptom rating was at least halved initially in 80% of Group 2 (p < 0.001), but paralleling previous findings, symptoms often returned subsequently. Conclusion: Attenuation of velocity storage shows promise as a lasting remedy for MdDS that can complement the VOR readaptation approach. [ABSTRACT FROM AUTHOR]

Chronic imbalance is a major complaint of patients suffering from bilateral vestibulopathy (BV) and is often reported by patients with chronic unilateral vestibulopathy (UV), leading to increased risk of falling. We used the Central SensoriMotor Integration (CSMI) test, which evaluates sensory integration, time delay, and motor activation contributions to standing balance control, to determine whether CSMI measures could distinguish between healthy control (HC), UV, and BV subjects and to characterize vestibular, proprioceptive, and visual contributions expressed as sensory weights. We also hypothesized that sensory weight values would be associated with the results of vestibular assessments (vestibulo ocular reflex tests and Dizziness Handicap Inventory scores). Twenty HCs, 15 UVs and 17 BVs performed three CSMI conditions evoking sway in response to pseudorandom (1) surface tilts with eyes open or, (2) surface tilts with eyes closed, and (3) visual surround tilts. Proprioceptive weights were identified in surface tilt conditions and visual weights were identified in the visual tilt condition. BVs relied significantly more on proprioception. There was no overlap in proprioceptive weights between BV and HC subjects and minimal overlap between UV and BV subjects in the eyes-closed surface-tilt condition. Additionally, visual sensory weights were greater in BVs and were similarly able to distinguish BV from HC and UV subjects. We found no significant correlations between sensory weights and the results of vestibular assessments. Sensory weights from CSMI testing could provide a useful measure for diagnosing and for objectively evaluating the effectiveness of rehabilitation efforts and future treatments designed to restore vestibular function such as hair cell regeneration and vestibular implants. [ABSTRACT FROM AUTHOR]

γδ T cells are important components of the immune system due to their ability to elicit a fast and strong response against infected and transformed cells. Because they can specifically and effectively kill target cells in an MHC independent fashion, there is great interest to utilize these cells in anti-tumor therapies where antigen presentation may be hampered. Since only a small fraction of T cells in the blood or tumor tissue are γδ T cells, they require extensive expansion to allow for fundamental, preclinical and ex vivo research. Although expansion protocols can be successful, most are based on depletion of other cell types rather than γδ T cell specific isolation, resulting in unpredictable purity of the isolated fraction. Moreover, the primary focus only lies with expansion of Vd2+ T cells, while Vd1+ T cells likewise have anti-tumor potential. Here, we investigated whether γδ T cells directly isolated from blood could be efficiently expanded while maintaining function. γδ T cell subsets were isolated using MACS separation, followed by FACS sorting, yielding >99% pure γδ T cells. Isolated Vd1+ and Vd2+ T cells could effectively expand immediately after isolation or upon freeze/thawing and reached expansion ratios between 200 to 2000-fold starting from varying numbers using cytokine supported feeder stimulations. MACS/FACS isolated and PHA stimulated γδ T cells expanded as good as immobilized antibody mediated stimulated cells in PBMCs, but delivered purer cells. After expansion, potential effector functions of γδ T cells were demonstrated by IFN-g, TNF-a and granzyme B production upon PMA/ionomycin stimulation and effective killing capacity of multiple tumor cell lines was confirmed in killing assays. In conclusion, pure γδ T cells can productively be expanded while maintaining their anti-tumor effector functions against tumor cells. Moreover, γδ T cells could be expanded from low starting numbers suggesting that this protocol may even allow for expansion of cells extracted from tumor biopsies. [ABSTRACT FROM AUTHOR]

Mathematical modeling is a powerful method to understand how biological systems work. By creating a mathematical model of a given phenomenon one can investigate which model assumptions are needed to explain the phenomenon and which assumptions can be omitted. Creating an appropriate mathematical model (or a set of models) for a given biological system is an art, and classical textbooks on mathematical modeling in biology go into great detail in discussing how mathematical models can be understood via analytical and numerical analyses. In the last few decades mathematical modeling in biology has grown in size and complexity, and along with this growth new tools for the analysis of mathematical models and/or comparing models to data have been proposed. Examples of tools include methods of sensitivity analyses, methods for comparing alternative models to data based on AIC/BIC/etc.), and mixed-effect-based fitting of models to data. I argue that the use of many of these "toolbox" approaches for the analysis of mathematical models has negatively impacted the basic philosophical principle of the modeling--to understand what the model does and why it does what it does. I provide several examples of limitations of these toolbox-based approaches and how they hamper generation of insights about the system in question. I also argue that while we should learn new ways to automate mathematical modeling-based analyses of biological phenomena, we should aim beyond a mechanical use of such methods and bring back intuitive insights into model functioning, by remembering that after all, modeling is an art and not simply engineering. [ABSTRACT FROM AUTHOR]

Background: Campus lockdown orders were issued for the purpose of preventing and controlling COVID-19, which resulted in psychological problems among college students. However, the experiences they have during the pandemic may also lead to positive personal changes, including posttraumatic growth (PTG). The current study examined the mediating role of belief in a just world and meaning in life in social support and PTG during the COVID-19 campus lockdown. Method: An online survey was conducted on 1711 college students in Hebei Province, China. Based on the survey results, a structural equation model was established. Results: Social support positively predicted PTG. Furthermore, belief in a just world and meaning in life played a mediating role between social support and PTG respectively. Besides, social support could also predict PTG through the multiple serial mediating effect of belief in a just world and meaning in life. Conclusion: These results indicated mechanisms by which social support influenced PTG, and this provided insights into how to promote post- traumatic growth among university students in the post-pandemic period. [ABSTRACT FROM AUTHOR]

Introduction: Wnt-signaling is a key regulator of stem cell homeostasis, extensively studied in the intestinal crypt and other metazoan tissues. Yet, there is hardly any data available on the presence of Wnt-signaling components in the adult enteric nervous system (ENS) in vivo. Methods: Therefore, we employed RNAscope HiPlex-assay, a novel and more sensitive in situ hybridization technology. By amplifying target specific signals, this technique enables the detection of low abundance, tightly regulated RNA content as is the case for Wnt-signaling components. Additionally, we compared our data to previously published physiological single cell RNA and RiboTag-based RNA sequencing analyses of enteric gliosis using data-mining approaches. Results: Our descriptive analysis shows that several components of the multidimensional regulatory network of the Wnt-signaling pathway are present in the murine ENS. The transport and secretion protein for Wnt-ligands Wntless as well as canonical (Wnt3a and Wnt2b) and non-canonical Wnt-ligands (Wnt5a, Wnt7a, Wnt8b and Wnt11) are detectable within submucosal and myenteric plexus. Further, corresponding Frizzled receptors (Fzd1, Fzd3, Fzd6, and Fzd7) and regulatory signaling mediators like R-Spondin/DKK ligands are present in the ENS of the small and large intestine. Further, data mining approaches revealed, that several Wnt-related molecules are expressed by enteric glial cell clusters and are dynamically regulated during the inflammatory manifestation of enteric gliosis. Discussion: Our results suggest, that canonical and non-canonical Wnt-signaling has a much broader impact on the mature ENS and its cellular homeostasis in health and inflammation, than previously anticipated. [ABSTRACT FROM AUTHOR]

Background: Behavioral dyscontrol occurs commonly in the general population and in United States service members and Veterans (SM/V). This condition merits special attention in SM/V, particularly in the aftermath of deployments. Military deployments frequently give rise to posttraumatic stress disorder (PTSD) and deployment-related mild TBI traumatic brain injury (TBI), potentially leading to manifestations of behavioral dyscontrol. Objective: Examine associations among PTSD symptom severity, deploymentrelated mild traumatic brain injury, and behavioral dyscontrol among SM/V. Design: Secondary cross-sectional data analysis from the Long-Term Impact of Military-Relevant Brain Injury Consortium -- Chronic Effects of Neurotrauma Consortium prospective longitudinal study among SM/V (N = 1,808). Methods: Univariable and multivariable linear regression models assessed the association and interaction effects between PTSD symptom severity, as assessed by the PTSD Checklist for the Diagnostic and Statistical Manual, 5th edition (PCL- 5), and deployment-related mild TBI on behavioral dyscontrol, adjusting for demographics, pain, social support, resilience, and general self-efficacy. Results: Among the 1,808 individuals in our sample, PTSD symptom severity (B = 0.23, 95% CI: 0.22, 0.25, p < 0.001) and deployment-related mild TBI (B = 3.27, 95% CI: 2.63, 3.90, p < 0.001) were significantly associated with behavioral dyscontrol in univariable analysis. Interaction effects were significant between PTSD symptom severity and deployment mild TBI (B = 0.03, 95% CI: -0.06, -0.01, p = 0.029) in multivariable analysis, indicating that the effect of mild TBI on behavioral dyscontrol is no longer significant among those with a PCL-5 score > 22.96. Conclusion: Results indicated an association between PTSD symptom severity, deployment-related mild TBI, and behavioral dyscontrol among SM/V. Notably, the effect of deployment-related mild TBI was pronounced for individuals with lower PTSD symptom severity. Higher social support scores were associated with lower dyscontrol, emphasizing the potential for social support to be a protective factor. General self-efficacy was also associated with reduced behavioral dyscontrol. [ABSTRACT FROM AUTHOR]

Background: Though intravenous (IV) ketamine and intranasal (IN) esketamine are noted to be efficacious for treatment-resistant depression (TRD), access to each of these treatments within healthcare systems is limited due to cost, availability, and/or monitoring requirements. IV ketamine has been offered at two public hospital sites in Edmonton, Canada since 2015. Since then, demand for maintenance ketamine treatments has grown. This has required creative solutions for safe, accessible, evidence-based patient care. Objectives: Aims of this paper are twofold. First, we will provide a synthesis of current knowledge with regards to the clinical use of ketamine for TRD. Consideration will be given regarding; off-label racemic ketamine uses versus FDA-approved intranasal esketamine, populations treated, inclusion/exclusion criteria, dosing, assessing clinical response, concomitant medications, and tolerability/safety. Second, this paper will describe our experience as a community case study in applying evidence-based treatment. We will describe application of the literature review to our clinical programming, and in particular focus on cost-effective maintenance treatments, long-term safety concerns, routes of ketamine administration other than via intravenous, and cautious prescribing of ketamine outside of clinically monitored settings. Methodology: We conducted a literature review of the on the use of ketamine for TRD up to June 30, 2023. Key findings are reviewed, and we describe their application to our ketamine program. Conclusion: Evidence for the use of ketamine in resistant depression has grown in recent years, with evolving data to support and direct its clinical use. There is an increasing body of evidence to guide judicious use of ketamine in various clinical circumstances, for a population of patients with a high burden of suffering and morbidity. While large-scale, randomized controlled trials, comparative studies, and longer-term treatment outcomes is lacking, this community case study illustrates that currently available evidence can be applied to real-world clinical settings with complex patients. As cost is often a significant barrier to accessing initial and/or maintenance IV or esketamine treatments, public ketamine programs may incorporate SL or IN ketamine to support a sustainable and accessible treatment model. Three of such models are described. [ABSTRACT FROM AUTHOR]

Background: Empirical studies have demonstrated that educational attainment (EA) is associated with neuropsychiatric disorders (NPDs), suggesting a shared etiological basis between them. However, little is known about the shared genetic mechanisms and causality behind such associations. Methods: This study explored the shared genetic basis and causal relationships between EA and NPDs using the high-definition likelihood (HDL) method, cross phenotype association study (CPASSOC), transcriptome-wide association study (TWAS), and bidirectional Mendelian randomization (MR) with summary-level data for EA (N = 293,723) and NPDs (N range = 9,725 to 455,258). Results: Significant genetic correlations between EA and 12 NPDs (rg range - 0.49 to 0.35; all p < 3.85 × 10-3) were observed. CPASSOC identified 37 independent loci shared between EA and NPDs, one of which was novel (rs71351952, mapped gene: ARFGEF2). Functional analyses and TWAS found shared genes were enriched in brain tissue, especially in the cerebellum and highlighted the regulatory role of neuronal signaling, purine nucleotide metabolic process, and cAMP-mediated signaling pathways. CPASSOC and TWAS supported the role of three regions of 6q16.1, 3p21.31, and 17q21.31 might account for the shared causes between EA and NPDs. MR confirmed higher genetically predicted EA lower the risk of ADHD (ORIVW: 0.50; 95% CI: 0.39 to 0.63) and genetically predicted ADHD decreased the risk of EA (Causal effect: -2.8 months; 95% CI: -3.9 to -1.8). Conclusion: These findings provided evidence of shared genetics and causation between EA and NPDs, advanced our understanding of EA, and implicated potential biological pathways that might underlie both EA and NPDs. [ABSTRACT FROM AUTHOR]

Objectives: To investigate the construct validity of the Trunk Impairment Scale (TIS), which was developed to assess trunk impairment in patients with stroke, in patients with Parkinson's disease (PD). Design: This retrospective, cross-sectional study enrolled consecutive PD inpatients. Correlation analysis was performed to clarify whether the TIS assessment was related to other balance functions, lower extremity muscle strength, or walking ability. Factor analysis was performed to see how the background factors of TIS differ from balance function, lower limb muscle strength, and walking ability. Results: Examining the data of 471 patients with PD, there were relationships between TIS and the Mini-Balance Evaluation Systems Test (r = 0.67), Barthel Index (r = 0.57), general lower limb extension torque (r = 0.51), two-minute walk test (r = 0.54), Hoehn and Yahr stage (r = 0.61), and Movement Disorder Society Unified Parkinson's Disease Rating Scale part III total points (r = 0.59). Factor analysis showed that TIS items were divided into three factors (an abdominal muscles and righting reflex component; a perception and verticality component; and a rotational component), differing from other scales that included clinical assessment items. Conclusion: The TIS can be useful for assessing the underlying trunk impairment as a basis for activities of daily living, gait function, and balance ability in patients with PD. [ABSTRACT FROM AUTHOR]

Introduction: Functional disorders are prevalent in all medical fields and pose a tremendous public health problem, with pain being one of the most common functional symptoms. Understanding the underlying, potentially unifying mechanism in functional (pain) disorders is instrumental in facilitating timely diagnosis, stigma reduction, and adequate treatment options. Neuroscientific models of perception suggest that functional symptoms arise due to dysregulated sensorimotor processing in the central nervous system, with brain-based predictions dominating the eventual percept. Experimental evidence for this transdiagnostic mechanism has been established in various functional symptoms. The goal of the current study was to investigate whether erroneous sensorimotor processing is an underlying transdiagnostic mechanism in chronic (functional) pain. Method: A total of 13 patients with chronic (functional) pain [three patients with chronic (functional) pain disorder, F45.40, ICD-10; 10 patients with chronic pain disorder with somatic and psychological factors, F45.41, ICD-10]; and 15 healthy controls performed large combined eye-head gaze shifts toward visual targets, naturally and with increased headmoment of inertia.We simultaneouslymeasured participants' eye and headmovements to assess head oscillations at the end of the gaze shift, which are an established indicator of (transdiagnostic) sensorimotor processing deficits of head control. Results: Using a Bayesian analysis protocol, we found that patients with chronic (functional) pain and control participants stabilized their heads equally well (Bayes Factor 01 = 3.7, Bayes Factor exclusion = 5.23; corresponding to substantial evidence) during all sessions of the experiment. Conclusion: Our results suggest that patients with chronic (functional) pain do not show measurable symptom-unspecific sensorimotor processing deficits. We discuss outcome parameter choice, organ system specificity, and selection of patient diagnoses as possible reasons for this result and recommend future avenues for research. [ABSTRACT FROM AUTHOR]

Introduction: While studies indicate that high self-control may serve as a safeguard against problematic internet use, there's evidence suggesting that problematic internet use can, in turn, diminish self-control. This study aimed to elucidate the longitudinal interplay between internet self-control and problematic internet use in adolescents, employing cross-lagged panel modeling. Furthermore, drawing from a positive psychology perspective, we examined the potential role of 'meaning in life' as a protective mediator within this longitudinal relationship. We then constructed a mediation model to explore protective factors against problematic internet use. Methods: Through a questionnaire, we tracked 659 adolescents (331 males and 328 females; mean age=13.61) in a longitudinal design across two time points, spaced at five-month intervals, to assess their internet self-control, problematic internet use, and meaning in life. Results: Results of the cross-lagged panel models showed that: Internet selfcontrol had a significant negative impact on problematic internet use after five months (β = -0.094, p < 0.01). Conversely, problematic internet use had a significant negative impact on internet self-control after five months (β = -0.099, p < 0.05). Results from the longitudinal mediation model showed that: Meaning in life mediated the effect of internet self-control on problematic internet use after five months (βinternet self-control(T1)-meaning in life(T2) = 0.142, p < 0.01; βmeaning in life(T1)-problematic internet use (T2) = -0.075, p < 0.05). Conclusion: Our study uncovers a reciprocal predictive relationship between internet self-control and problematic internet use, while highlighting the mediating role of meaning in life within this relationship. These findings suggest that fostering internet self-control and cultivating a sense of meaning in life among adolescents can serve as effective prevention and intervention strategies for addressing the issue of problematic internet use. [ABSTRACT FROM AUTHOR]

Background: Fragile X-associated tremor/ataxia syndrome (FXTAS), a neurodegenerative disease that affects carriers of a 55-200 CGG repeat expansion in the fragile X messenger ribonucleoprotein 1 (FMR1) gene, may be given an incorrect initial diagnosis of Parkinson’s disease (PD) or essential tremor (ET) due to overlapping motor symptoms. It is critical to characterize distinct phenotypes in FXTAS compared to PD and ET to improve diagnostic accuracy. Fast as possible (FP) speed and dual-task (DT) paradigms have the potential to distinguish differences in gait performance between the three movement disorders. Therefore, we sought to compare FXTAS, PD, and ET patients using quantitative measures of functional mobility and gait under self-selected (SS) speed, FP, and DT conditions. Methods: Participants with FXTAS (n  =  22), PD (n  =  23), ET (n  =  20), and controls (n  =  20) underwent gait testing with an inertial sensor system (APDM™). An instrumented Timed Up and Go test (i-TUG) was used to measure movement transitions, and a 2-min walk test (2MWT) was used to measure gait and turn variables under SS, FP, and DT conditions, and dual-task costs (DTC) were calculated. ANOVA and multinomial logistic regression analyses were performed. Results: PD participants had reduced stride lengths compared to FXTAS and ET participants under SS and DT conditions, longer turn duration than ET participants during the FP task, and less arm symmetry than ET participants in SS gait. They also had greater DTC for stride length and velocity compared to FXTAS participants. On the i-TUG, PD participants had reduced sit-to-stand peak velocity compared to FXTAS and ET participants. Stride length and arm symmetry index during the DT 2MWT was able to distinguish FXTAS and ET from PD, such that participants with shorter stride lengths were more likely to have a diagnosis of PD and those with greater arm asymmetry were more likely to be diagnosed with PD. No gait or i-TUG parameters distinguished FXTAS from ET participants in the regression model. Conclusion: This is the first quantitative study demonstrating distinct gait and functional mobility profiles in FXTAS, PD, and ET which may assist in more accurate and timely diagnosis. [ABSTRACT FROM AUTHOR]

Recent progressions in immunotherapy have transformed cancer treatment, providing a promising strategy that activates the immune system of the patient to find and eliminate cancerous cells. Bispecific antibodies, which engage two separate antigens or one antigen with two distinct epitopes, are of tremendous concern in immunotherapy. The bi-targeting idea enabled by bispecific antibodies (BsAbs) is especially attractive from a medical standpoint since most diseases are complex, involving several receptors, ligands, and signaling pathways. Several research look into the processes in which BsAbs identify different cancer targets such angiogenesis, reproduction, metastasis, and immune regulation. By rerouting cells or altering other pathways, the bispecific proteins perform effector activities in addition to those of natural antibodies. This opens up a wide range of clinical applications and helps patients with resistant tumors respond better to medication. Yet, further study is necessary to identify the best conditions where to use these medications for treating tumor, their appropriate combination partners, and methods to reduce toxicity. In this review, we provide insights into the BsAb format classification based on their composition and symmetry, as well as the delivery mode, focus on the action mechanism of the molecule, and discuss the challenges and future perspectives in BsAb development. [ABSTRACT FROM AUTHOR]

Single-cell RNA sequencing (scRNA-seq) is the state-of-the-art approach to study transcriptomic signatures in individual cells in respiratory health and disease. However, classical scRNA-seq approaches provide no spatial information and are performed using either bronchoalveolar lavage fluid (BAL) or lung single cell suspensions to assess transcript levels in airway and tissue immune cells, respectively. Herein we describe a simple method to simultaneously characterize transcriptomic features of airway, lung parenchymal and intravascular immune cells based on differential in vivo labeling with barcoded antibodies. In addition to gaining basic spatial information, this approach allows for direct comparison of cells within different anatomical compartments. Furthermore, this method provides a time- and cost-effective alternative to classical scRNA-seq where lung and BAL samples are processed individually, reducing animal and reagent use. We demonstrate the feasibility of this approach in a preclinical mouse model of bacterial lung infection comparing airway, parenchymal and vasculature neutrophils early after infection. [ABSTRACT FROM AUTHOR]

γδ T cells, a specialized subset of T lymphocytes, have garnered significant attention within the realm of cancer immunotherapy. Operating at the nexus between adaptive and innate immunological paradigms, these cells showcase a profound tumor discernment repertoire, hinting at novel immunotherapeutic strategies. Significantly, these cells possess the capability to directly identify and eliminate tumor cells without reliance on HLA-antigen presentation. Furthermore, γδ T cells have the faculty to present tumor antigens to αβ T cells, amplifying their anti-tumoral efficacy.Within the diverse and heterogeneous subpopulations of γδ T cells, distinct immune functionalities emerge, manifesting either anti-tumor or pro-tumor roles within the tumor microenvironment. Grasping and strategically harnessing these heterogeneous γδ T cell cohorts is pivotal to their integration in tumor-specific immunotherapeutic modalities. The aim of this review is to describe the heterogeneity of the γδ T cell lineage and the functional plasticity it generates in the treatment of malignant tumors. This review endeavors to elucidate the intricate heterogeneity inherent to the γδ T cell lineage, the consequential functional dynamics in combating malignancies, the latest advancements from clinical trials, and the evolving landscape of γδ T cell-based oncological interventions, while addressing the challenges impeding the field. [ABSTRACT FROM AUTHOR]

Cancer immunotherapies include monoclonal antibodies, cytokines, oncolytic viruses, cellular therapies, and other biological and synthetic immunomodulators. These are traditionally studied for their effect on the immune system’s role in eliminating cancer cells. However, some of these therapies have the unique ability to directly induce cytotoxicity in cancer cells by inducing immunogenic cell death (ICD). Unlike general immune stimulation, ICD triggers specific therapy-induced cell death pathways, based on the release of damage-associated molecular patterns (DAMPs) from dying tumour cells. These activate innate pattern recognition receptors (PRRs) and subsequent adaptive immune responses, offering the promise of sustained anticancer drug efficacy and durable antitumour immune memory. Exploring how onco-immunotherapies can trigger ICD, enhances our understanding of their mechanisms and potential for combination strategies. This review explores the complexities of these immunotherapeutic approaches that induce ICD, highlighting their implications for the innate immune system, addressing challenges in cancer treatment, and emphasising the pivotal role of ICD in contemporary cancer research. [ABSTRACT FROM AUTHOR]