bluuebunny/crossref_metadata_2025_split huggingface dataset:
The added value of an internet-based intervention for treatment of aggression in forensic psychiatric outpatients—study protocol for a multicentre, mixed-methods randomized controlled trial
Authors: Kip Hanneke , Haneveld Lisa Klein , Kelders Saskia M 
Published: December 2024

Background Even though internet-based interventions have been used in treatment of forensic psychiatric outpatients for over 10 years, no robust effectiveness studies have been conducted in this complex branch of mental healthcare. Objectives To present the protocol of a study that investigates whether the addition of the internet-based intervention “Dealing with Aggression” to treatment as usual (TAU) leads to better treatment outcomes than TAU that is delivered solely in-person. Methods This study uses a multicentre mixed-methods randomized controlled trial (RCT) design, with four Dutch forensic outpatient organizations. Patients are included if they receive outpatient treatment for aggression. They will be randomized into an experimental condition, in which the intervention is added to TAU (n = 64), or a control condition, with only TAU (n = 64). Participants are assessed four times: at baseline (T0), halfway during the 10-week intervention (T1), after completing the intervention (T2), and after 3 months (T3). Primary outcome measure is self-reported aggression, other outcome measures are regulatory emotional self-efficacy and treatment readiness, the number of treatment sessions, and dynamic risk factors. Adherence to and engagement with the internet-based intervention will be investigated as predictors for effectiveness. Perceived effect and points of improvement are identified via semistructured interviews with patients and therapists. Discussion This will be the first study to investigate the effectiveness of an internet-based intervention in a forensic psychiatric outpatient sample. By means of the mixed-methods design and use of adherence and engagement as predictors, this study will answers questions about if, but also why and for whom this intervention works.
Safety Leadership Training Effectiveness Evaluation on Behavior Change Among Large-Herd U.S. Dairy Farm Supervisors
Authors: Douphrate David I. , Rodriguez Anabel , Kines Pete , Hossein Javid Amir 
Published: December 2024

Background Prior research suggests leader-based interventions are considered to have a much stronger influence on worker safety behavior and climate than worker-based interventions. However, no prior research has evaluated training effectiveness of safety-specific leadership skill development for front-line supervisors on dairy farms. A tailored safety leadership training program targeting dairy farm supervisors was developed, delivered, and evaluated for its training effect on the supervisor’s safety leadership behavior. Methods A 12-module safety leadership training program was developed and delivered in an asynchronous format using e-learning methods to 73 dairy farm supervisors, representing 30 farms across five western U.S. states. We employed the Kirkpatrick Model to evaluate different levels of training effectiveness. Findings Evaluation of knowledge gained among participants revealed significant differences between pre- and post-test scores with medium to very large learning effect sizes across all training modules, particularly with training modules addressing safety culture, workplace conflict, and safety meetings. Safety leadership behavior change evaluation revealed significant pre-post training effects across most training modules, particularly regarding safety dialogue, hazard assessment, safety modeling, and conducting safety meetings. Conclusions Our findings suggest that safety leadership training can result in essential leadership behavior change among front-line dairy farm supervisors. Application to Practice This study provides many insights into the successful implementation of a safety leadership training program in a challenging industrial sector (rural/remote workplaces, immigrant workforce), as well as training effectiveness evaluation using novel data collection methodology. Additional research is needed on the effectiveness and sustainability of safety leadership training in high-risk industrial sectors such as agriculture.
Formative evaluation of the implementation of digital therapeutics for opioids and other substance use disorders in primary care (DIGITS trial)
Authors: Palazzo Lorella , Dorsey Caitlin N. , Mogk Jess , Beatty Tara , King Deborah , Stefanik-Guizlo Kelsey , Key Dustin , Matson Tessa E. , Shea Mary , Caldeiro Ryan M. , McWethy Angela Garza , Wong Edwin S. , Idu Abisola E. , Glass Joseph E. 
Published: December 2024

Background Substance use disorders (SUDs) result in individual and societal burden. However, most individuals with SUD receive no treatment. Implementing SUD interventions in primary care could address this population's treatment needs. In the USA, reSET® and reSET-O® were the first prescription digital therapeutics (PDTs) for SUDs and opioid use disorder (OUD), respectively. The Digital Treatments for Substance Use Disorder (DIGITS) study tested the effectiveness of practice facilitation and health coaching strategies to support reSET and reSET-O implementation into primary care. A formative evaluation was conducted to monitor implementation, inform adaptations, and learn what promotes PDT sustainment. Method The Dynamic Sustainability Framework and the Framework for Reporting Adaptations and Modifications to Evidence-based Implementation Strategies guided the evaluation. Using rapid qualitative methods, we collected and analyzed observational fieldnotes, key informant interviews, and document sources (e.g., meeting minutes) for synthesis and dissemination to clinical partners and the study team via formative reports. We analyzed the reports to generate evaluation results. Results Twenty-four primary care clinics participated. Evaluation data included 98 observational fieldnotes, 16 interviews, and 253 document sources. We produced nine formative reports. The study encountered barriers and facilitators in each DSF domain (ecological system, practice setting, and intervention). In the ecological system, the PDT vendor enabled the study, but the COVID-19 pandemic, laws, regulations, and contracting delayed implementation. In the practice setting, staff shortages and low clinic capacity were implementation challenges, while electronic health record capabilities were both barriers and facilitators. At the intervention level, non-routine workflows, clinician burden, and low patient engagement were barriers despite clinicians’ efforts. Conclusions Digital therapeutics are promising SUD and OUD treatments, but integration into primary care requires conducive laws and regulations, organizational capacity, and patient and clinician engagement. Formative evaluation identified important lessons for future PDT implementation.
Physiological significance of antithrombin D-helix interaction with vascular GAGs
Authors: Biswas Indranil , Panicker Sumith R. , Lupu Florea , Rezaie Alireza R. 
Published: December 2024

Abstract
Antithrombin (AT) is an anticoagulant serpin involved in the regulation of proteolytic activities of coagulation proteases. AT also possesses a direct anti-inflammatory function. The anticoagulant function of AT is mediated through its reactive center loop–dependent inhibition of coagulation proteases, but anti-inflammatory function of AT is mediated via its D-helix–dependent interaction with vascular glycosaminoglycans (GAGs). In vitro assays have established that therapeutic heparins promote the anticoagulant function of AT by binding D-helix and activating the serpin, however, the contribution of vascular GAGs to D-helix–dependent anticoagulant function of AT has remained poorly understood in vivo. Here, we explored this question by using 2 AT mutants, (AT-4Mut), which exhibits neither affinity for heparin nor D-helix–dependent anti-inflammatory signaling but possesses normal protease-inhibitory function and an inactive signaling-selective AT mutant in which its P1-Arg425 is deleted (AT-R425del). In vivo properties of mutants were compared with wild-type AT (AT-WT) in a small interfering RNA (siRNA)-mediated AT-deficient mouse model. The siRNA knockdown efficiently reduced expression of AT and induced robust procoagulant and proinflammatory phenotypes in mice. Infusion of both AT-WT and AT-4Mut rescued the procoagulant phenotype of AT-deficient mice as evidenced by restoration of the plasma clotting time and inhibition of fibrin deposition. AT-WT also attenuated inflammation as evidenced by reduced VCAM-1 expression and leukocyte infiltration in the liver and lungs; however, AT-4Mut failed to attenuate inflammation. Interestingly, AT-R425del also effectively attenuated inflammation in AT-depleted mice. These results suggest that interaction of AT D-helix with vascular GAGs may primarily be responsible for anti-inflammatory signaling rather than protease-inhibitory function of the serpin.
Tuberculosis in adult migrants in Europe: a TBnet consensus statement
Authors: Kunst Heinke , Lange Berit , Hovardovska Olga , Bockey Annabelle , Zenner Dominik , Andersen Aase B , Hargreaves Sally , Pareek Manish , Friedland Jon S , Wejse Chrsitain , Bothamley Graham , Guglielmetti Lorenzo , Chesov Dima , Tiberi Simon , Matteelli Alberto , Mandalakas Anna M , Heyckendorf Jan , Eimer Johannes , Malhotra Akanksha , Zamora Javier , Vasiliu Anca , Lange Christoph ,   for the TBnet
Published: December 2024

IntroductionGlobal migration has increased in recent decades due to war, conflict, persecutions, and natural disasters, but also secondary to increased opportunities related to work or study. Migrants’ risk of tuberculosis (TB) differs by reasons for migration, socioeconomic status, mode of travel and TB risk in transit, TB incidence and healthcare provision in country of origin. Despite advances in TB care for migrants and new treatment strategies, decisions for the management of migrants at risk of TB often rely on expert opinions, rather than clinical evidence.MethodsA systematic literature search was conducted, studies were mapped to different recommendation groups and included studies were synthesized by meta-analysis where appropriate. Current evidence on diagnosis of active TB in migrants entering the European Union /European Economic Area (EU/EEA) &UK including the clinical presentation and diagnostic delay, treatment outcomes of drug susceptible TB, prevalence and treatment outcomes of multidrug/rifampicin-resistant (MDR/RR)-TB and TB/HIV co-infection was summarised. A consensus process was used based on the evidence.ResultsWe document a higher vulnerability of migrants for TB, including an increased risk of extrapulmonary TB, MDR/RR-TB, TB/HIV co-infection and worse TB treatment outcomes compared to host populations. Consensus recommendations include screening of migrants for TB/ latent TB infection (LTBI) according to country data; a minimal package for TB care in drug susceptible and MDR/RR-TB; implementation of migrant-sensitive strategies; free healthcare and preventive treatment for migrants with HIV co-infection.ConclusionDedicated care for TB prevention and treatment in migrant populations within the EU/EEA &UK is essential.
Disorientation as a delirium feature in non-intubated patients: development and evaluation of diagnostic accuracy of the ‘Confusion Assessment Method for Intermediate Care Unit’ (CAM-IMC) - a prospective cohort study
Authors: Beyer L. P. , Gathen L. von zur , Rayah B. El , Dewald O. , Zieschang T. , Diers A. , Ely E. Wesley , Guenther U. 
Published: December 2024

Abstract
Background
Disorientation is an early indicator of developing postoperative delirium (POD), which is associated with increased mortality and cognitive decline. The well-established “Confusion-Assessment-Method-for-Intensive-Care-Unit” (CAM-ICU) for diagnosing POD in intubated patients cannot make use of the feature ‘disorientation’, as this requires verbal communication. Other tools such as the 4AT test for disorientation but are not established in ICU settings. We therefore combined test-variables of the CAM-ICU (level of consciousness, fluctuating mental status and inattention) with verbal testing for disorientation to develop and enhance diagnostic accuracy of the “Confusion Assessment Method for Intermediate Care Unit” (CAM-IMC). In the present study we describe the development and the evaluation of the diagnostic accuracy of the CAM-IMC.

Methods
We conducted a prospective cohort-study to develop and evaluate the diagnostic accuracy of the CAM-IMC and disorientation for diagnosing POD in non-intubated patients undergoing elective cardiac surgery. All patients were eligible during data collection period. Exclusion criteria were preexisting brain-organic disease, age < 50 years, preoperative intubation, and insufficient language skills. Patients were assessed for POD using the CAM-IMC as the index-test by two independent examiners over three postoperative days. Reference-testing was conducted by experienced reference-raters. The primary outcome was the diagnostic test-performance.

Results
Among 178 eligible patients, 624 paired observations were completed with 155 patients. Of these, 9% experienced POD. Sensitivity and specificity were 0.96 (CI-95%: 0.87-1.00) and 0.94 (CI-95%: 0.92–0.96), respectively. Area-Under-the-Receiver-Operating-Characteristic-Curve (AUROC; equivalent to c-statistic) for CAM-IMC with a cut-off at three points was 0.95 (CI-95%: 0.93–0.98). The interrater reliability was 0.80 (CI-95%: 0.69–0.91).

Conclusion
The CAM-IMC demonstrates excellent test performance for diagnosing POD in non-intubated patients by combining features of the CAM-ICU with ‘disorientation’. Given an aging community with an increasing delirium risk, the CAM-IMC provides a highly structured assessment tool for POD. It enables early and accurate detection of delirium, which is critical for timely intervention and improved patient outcomes. The CAM-IMC appears to be a useful tool to be implemented in units for not-intubated patients and seems to be the perfect match where the CAM-ICU is already in use for monitoring POD.

Trial registration
DRKS00026980 (German registry of clinical studies).
Mental health symptoms and burdens after a SARS-CoV-2 infection
Authors: Hettich-Damm Nora , Petersen Julia , Baumkoetter Rieke , Prochaska Jürgen H. , Koenig Jochem , Schuster Alexander K. , Muenzel Thomas , Lackner Karl J. , Wild Philipp S. , Beutel Manfred 
Published: December 2024

Abstract
Background
Previous studies have found adverse effects on mental health following infection with SARS-CoV-2. This study investigates whether mental health is also impaired in unknowingly infected individuals. In addition, the relevance of the severity of the infection and the time since the onset of infection were analyzed.

Methods
Data from the population-representative Gutenberg COVID-19 Study (GCS) were used (N = 2,267). SARS-CoV-2 infection was determined multimodally by self-report, throat swabs (acute infections) and antibody measurements (previous infections). Participants completed self-report questionnaires on mental health.

Results
Neither unknowing nor knowing SARS-CoV-2 infection had an impact on mental health. However, symptom severity and previous depression or anxiety predicted higher levels of depressiveness, anxiety and somatic complaints. Our results confirm findings suggesting that the severity of the initial infection and previous mental illness, but not knowledge of the infection, are the most important predictors of negative mental health outcomes following SARS-CoV-2 infection.

Conclusion
The results suggest that mental health care should focus on individuals who suffer from a severe acute COVID-19 infection or have a history of mental illness.
Tyro3 and Gas6 are associated with white matter and myelin integrity in multiple sclerosis
Authors: Rosenstein Igal , Novakova Lenka , Kvartsberg Hlin , Nordin Anna , Rasch Sofia , Rembeza Elzbieta , Sandgren Sofia , Malmeström Clas , Fruhwürth Stefanie , Axelsson Markus , Blennow Kaj , Zetterberg Henrik , Lycke Jan 
Published: December 2024

Abstract
Background
The Gas6/TAM (Tyro3, Axl, and Mer) receptor system has been implicated in demyelination and delayed remyelination in experimental animal models, but data in humans are scarce. We aimed to investigate the role of Gas6/TAM in neurodegenerative processes in multiple sclerosis (MS).

Methods
From a prospective 5-year follow-up study, soluble Gas6/TAM biomarkers were analyzed in cerebrospinal fluid (CSF) by enzyme-linked immunosorbent assay (ELISA) at baseline in patients with relapsing–remitting MS (RRMS) (n = 40), progressive MS (PMS) (n = 20), and healthy controls (HC) (n = 25). Brain volumes, including myelin content (MyC) and white matter (WM) were measured by synthetic magnetic resonance imaging at baseline, 12 months, and 60-month follow-up. Associations with brain volume changes were investigated in multivariable linear regression models. Gas6/TAM concentrations were also determined at 12 months follow-up in RRMS to assess treatment response.

Results
Baseline concentrations of Tyro3, Axl, and Gas6 were significantly higher in PMS vs. RRMS and HC. Mer was higher in PMS vs. HC. Tyro3 and Gas6 were associated with reduced WM (β = 25.5, 95% confidence interval [CI] [6.11–44.96, p = 0.012; β = 11.4, 95% CI [0.42–22.4], p = 0.042, respectively) and MyC (β = 7.95, 95%CI [1.84–14.07], p = 0.012; β = 4.4, 95%CI [1.04–7.75], p = 0.012 respectively) at 60 months. Patients with evidence of remyelination at last follow-up had lower baseline soluble Tyro3 (p = 0.033) and Gas6 (p = 0.014). Except Mer, Gas6/TAM concentrations did not change with treatment in RRMS.

Discussion
Our data indicate a potential role for the Gas6/TAM receptor system in neurodegenerative processes influencing demyelination and ineffective remyelination.
Immunological effects of CD19.CAR-T cell therapy in systemic sclerosis: an extended case study
Authors: Claus Maren , Freitag Merle , Ewald Meike , Rodon Lea , Deicher Franca , Watzl Carsten , Kolb Philipp , Lorenz Hanns-Martin , Schmitt Michael , Merkt Wolfgang 
Published: December 2024

Abstract
Objective
The high potential of CD19.CAR-T cells to treat autoimmune diseases such as Systemic Sclerosis (SSc) supposedly relies on the disappearance of autoantibodies. Here we investigated effects of CAR-T cells on the innate immune system which is an important contributor to pathology in SSc.

Methods
Longitudinal analysis of peripheral blood mononuclear cells from an Scl70 + SSc patient treated with CAR-T cells sampled over 18 months by 29-color spectral flow cytometry, in vitro experiments using sera from patient cohorts.

Results
In the patient treated with CAR-T cells, the substantial clinical improvement was paralleled by dynamic changes in innate lymphoid cells, namely Fcγ-receptor IIIA-expressing natural killer (NK) cells. NK cells adopted a more juvenile, less activated, and less differentiated phenotype. In parallel, the potency of serum to form Scl70-containing immune complexes that activate Fcγ-receptor IIIA decreased over time. These observations suggested a mechanistic link between reversal of adaptive autoimmunity and recovering Fcγ-receptor IIIA-expressing innate immune cells after CAR-T cell therapy via regressing immune complex activity. Experiments with sera from the non-CAR-T-treated SSc cohort confirmed that Scl70-containing immune complexes activate Fcγ-receptor IIIA-expressing NK cells in a dose-dependent manner, substantiating the relevance of this link between adaptive and innate immunity in SSc.

Conclusion
This report describes for the first time the phenotypic recovery of innate Fcγ-receptor-expressing cells in an SSc patient treated with CAR-T cells. Decreasing autoantibody levels associated with a reduced ability to form functional immune complexes, the latter appearing to contribute to pathology in SSc via activation of Fcγ receptor IIIA + cells such as NK cells.

Graphical Abstract

Proposed mechanism of involvement of NK cells and soluble Immune Complexes (sICs) in disease progression during active autoimmunity in SSc (left) and resolution of fibrosis after deep B cell depletion by CD19.CAR-T cells and disappearance of autoantibodies (right).
Nanomaterial-based detection of circulating tumor cells and circulating cancer stem cells for cancer immunotherapy
Authors: Yun Yeochan , Kim Seewoo , Lee Sang-Nam , Cho Hyeon-Yeol , Choi Jeong-Woo 
Published: December 2024

AbstractNanomaterials have emerged as transformative tools for detecting circulating tumor cells (CTCs) and circulating cancer stem cells (CCSCs), significantly enhancing cancer diagnostics and immunotherapy. Nanomaterials, including those composed of gold, magnetic materials, and silica, have enhanced the sensitivity, specificity, and efficiency of isolating these rare cells from blood. These developments are of paramount importance for the early detection of cancer and for providing real-time insights into metastasis and treatment resistance, which are essential for the development of personalized immunotherapies. The combination of nanomaterial-based platforms with phenotyping techniques, such as Raman spectroscopy and microfluidics, enables researchers to enhance immunotherapy protocols targeting specific CTC and CCSC markers. Nanomaterials also facilitate the targeted delivery of immunotherapeutic agents, including immune checkpoint inhibitors and therapeutic antibodies, directly to tumor cells. This synergistic approach has the potential to enhance therapeutic efficacy and mitigate the risk of metastasis and relapse. In conclusion, this review critically examines the use of nanomaterial-driven detection systems for detecting CTCs and CCSCs, their application in immunotherapy, and suggests future directions, highlighting their potential to transform the integration of diagnostics and treatment, thereby paving the way for more precise and personalized cancer therapies.
Graphical Abstract
Role of water in dynamics of slabs and surrounding mantle
Authors: Ohtani Eiji , Ishii Takayuki 
Published: December 2024

AbstractWater bound to various hydrous minerals can be transported deep into the mantle by slab subduction. Serpentine is one of most important hydrous minerals in the crust and shallow upper mantle. A partially serpentinized slab mantle limits the amount of water that can enter deep into the mantle. The partitioning of water between hydrous minerals and nominally anhydrous minerals (NAMs) is a crucial factor in controlling the physical properties and dynamics of slabs. Recent experiments on water partitioning have revealed that water strongly partitions to coexisting hydrous minerals. NAMs, such as olivine and its high-pressure polymorphs, have limited water content in water-undersaturated wet slabs. Metastable olivine wedges are not a feature of dry slabs, but can be of wet slabs that are not saturated with water. The transformation kinetics of the dry state, which generates deep-focus earthquakes and produces significant deformation in the slab, can work under wet slabs. Water bound to hydrous minerals is transported by the slab to the mantle transition zone and lower mantle. Hydrous minerals in stagnant slabs over 660 km depth release water as the slab warms, producing locally hydrated mantle transition zones and dense water-bearing magmas at the base of the upper mantle, and generating intraplate volcanism, which are referred to as the big mantle wedge model. Seismic scatterers are observed in the lower mantle at depths from 700 to 1900 km. These scatterers may be caused by water release at the top of the lower mantle by dehydration of hydrous minerals such as dense hydrous magnesium silicates. The shear instability due to the second order phase transformation from stishovite to CaCl2-type phase in hydrous aluminous SiO2 also causes the depth variation of seismic scatterers in the lower mantle. The high-pressure polymorphs of aluminous SiO2 contain a large amount of water more than 1 wt%, which can be important water carriers under lower mantle conditions.