BACKGROUND: Knee osteoarthritis (KOA) presents a prevalent orthopedic condition causing substantial impairment in the quality of life and imposing a significant societal and economic burden. Mesenchymal stromal/stem cells (MSCs), known for their regenerative properties and immunomodulatory effects, have emerged as a promising therapeutic avenue in regenerative medicine. Despite MSCs\' therapeutic potential, their precise mechanisms of action in KOA remain underexplored.
METHODS: Conducted as a randomized, open-label clinical trial, 20 patients will be enrolled, with 10 in the intervention group and 10 in the control group. The primary focus will be to explore the molecular mechanisms associated with MSC therapy. Biomarkers and gene expressions related to cartilage metabolism, inflammation, immune modulation, and pain in the synovial fluid, blood, and tissue samples will be analyzed. Patients will undergo pre- and post-treatment evaluations using patient-reported outcome measures (PROMs) and comprehensive clinical assessments.
CONCLUSIONS: This is an exploratory study with the goal to provide comprehensive insights into the therapeutic effects of MSCs on a molecular level, potentially paving the way for optimized and more effective MSC-based therapies in the management of KOA, as well as furthering the development of novel treatment strategies.
BACKGROUND: ClinicalTrials.gov, NCT06078059. Registered on 5 October 2023.

Diabetic cardiomyopathy (DCM) represents a distinct myocardial disorder elicited by diabetes mellitus, characterized by aberrations in myocardial function and structural integrity. This pathological condition predominantly manifests in individuals with diabetes who do not have concurrent coronary artery disease or hypertension. An escalating body of scientific evidence substantiates the pivotal role of programmed cell death (PCD)-encompassing apoptosis, autophagy, pyroptosis, ferroptosis, and necroptosis-in the pathogenic progression of DCM, thereby emerging as a prospective therapeutic target. Additionally, numerous non-coding RNAs (ncRNAs) have been empirically verified to modulate the biological processes underlying programmed cell death, consequently influencing the evolution of DCM. This review systematically encapsulates prevalent types of PCD manifest in DCM as well as nascent discoveries regarding the regulatory influence of ncRNAs on programmed cell death in the pathogenesis of DCM, with the aim of furnishing novel insights for the furtherance of research in PCD-associated disorders relevant to DCM.

As investigations into the efficacy of psychedelic-assisted psychotherapy to treat depression continue, there is a need to study the possible mechanisms of action that may contribute to the treatment\'s antidepressant effects. Through a two-round Delphi design, the current study investigated experts\' opinions on the psychological mechanisms of action associated with the antidepressant effects of psychedelic-assisted psychotherapy and the ways such mechanisms may be promoted through the preparation, dosing, and integration components of treatment. Fourteen and fifteen experts, including both clinical psychedelic researchers and therapists, participated in Round 1 and Round 2 of the study, respectively. Thematic analysis identified nine important or promising \'mechanistic themes\' from Round 1 responses: psychological flexibility, self-compassion, mystical experiences, self-transcendence, meaning enhancement, cognitive reframing, awe, memory reconsolidation and ego dissolution. These mechanisms were presented back to experts in Round 2, where they rated \'psychological flexibility\' and \'self-compassion\' to be the most important psychological mechanisms in psychedelic-assisted psychotherapy for depression. Strategies or interventions recommended to promote identified mechanisms during the preparation, dosing, and integration components of treatment were nonspecific to the endorsed mechanism. The findings from this study provide direction for future confirmatory mechanistic research as well as provisional ideas for how to support these possible therapeutic mechanisms.

Trauma-Focused Cognitive-Behavioral Therapy (TF-CBT) is a well-established treatment for pediatric posttraumatic stress disorder (PTSD). Animal-assisted therapy (AAT) has been proposed as an adjunct to TF-CBT that may improve treatment effects through enhanced targeting of affect regulation, as indexed by specific changes in the respiratory sinus arrhythmia (RSA). The current study reports results from a randomized controlled feasibility trial (N = 33; Mage = 11.79 [SD = 3.08]; 64% White; 67% female) that measured RSA during Sessions 1, 4, 8, and 12 of a twelve-session TF-CBT protocol and tested whether: 1) TF-CBT + AAT achieved higher average RSA amplitudes relative to TF-CBT alone, and 2) RSA regulation, defined as less variability around person-specific RSA slopes during treatment, explained variation in post-treatment PTSD symptoms. Multilevel modeling failed to support an effect for TF-CBT + AAT on RSA amplitudes (δ001 = 0.08, p = 0.844). However, regardless of treatment condition, greater RSA withdrawal was observed within Sessions 4 (γ11 = -.01, p < .001) and 12 (γ13 = -.01, p = .015) relative to the Session 1 baseline. The average level of RSA amplitude in Session 8 was also significantly lower compared to Session 1 (γ02 = -0.70, p = .046). Intraindividual regression models demonstrated that greater RSA regulation predicted improved PTSD symptoms at post-treatment after adjusting for pre-treatment levels (b3 = 20.00, p = .012). These preliminary results offer support for future confirmatory trials testing whether affect regulation, as indexed by changes in RSA, is a mechanism of action for TF-CBT in the treatment of pediatric PTSD.

The aims of the present study were: (a) to determine the mechanism of action of taurolidine against bacterial species associated with periodontal disease, and (b) to evaluate the potential development of resistance against taurolidine as compared with minocycline. After visualizing the mode of action of taurolidine by transmission electron micrographs, the interaction with most important virulence factors (lipopolysaccharide (LPS), Porphyromonas gingivalis gingipains, Aggregatibacter actinomycetemcomitans leukotoxin), was analyzed. Then, 14 clinical isolates from subgingival biofilm samples were transferred on agar plates containing subinhibitory concentrations of taurolidine or minocycline up to 50 passages. Before and after each 10 passages, minimal inhibitory concentrations (MICs) were determined. Increasing MICs were screened for efflux mechanism. Taurolidine inhibited in a concentration-dependent manner the activities of LPS and of the arginine-specific gingipains; however, an effect on A. actinomycetemcomitans leukotoxin was not detected. One P. gingivalis strain developed a resistance against taurolidine, which was probably linked with efflux mechanisms. An increase of MIC values of minocycline occurred in five of the 14 included strains after exposure to subinhibitory concentrations of the antibiotic. The present results indicate that: a) taurolidine interacts with LPS and gingipains, and b) development of resistance seems to be a rare event when using taurolidine.

Drugs targeting N-methyl-d-aspartate (NMDA) receptors and the ability to learn new associations have been proposed as adjunct treatments to boost the success of exposure therapy for anxiety disorders. However, the effects of the NMDA partial agonist d-cycloserine on psychological treatment have been mixed. We investigated potential neurocognitive mechanisms underlying the clinical effects of d-cycloserine-augmented exposure, to inform the optimal combination of this and similar agents with psychological treatment. Panic disorder patients were randomised to single-dose d-cycloserine (250 mg; N = 17) or matching placebo (N = 16) 2hrs before one session of exposure therapy. Neurocognitive markers were assessed one day after treatment, including reaction-time based threat bias for fearful faces (primary outcome) and amygdala response to threat (secondary outcome). Clinical symptom severity was measured the day before and after treatment, and at 1- and 6-months follow-up (secondary outcome). d-cycloserine was associated with greater clinical recovery at 1-month follow-up than placebo (d-cyloserine 71% vs placebo 25%), with the placebo group matching the clinical gains of the d-cycloserine group during 6-months follow-up (d-cycloserine 71% vs placebo 44%). One day after treatment, threat bias for fearful faces and amygdala threat response was lower in the drug compared to placebo group. Lower amygdala magnitude predicted greater clinical improvement during follow-up across groups. While this experimental study is of a preliminary nature due to the limited sample size, these findings highlight a neurocognitive potential mechanism by which d-cycloserine may exert its augmentative effects on psychological treatment and bring forward a marker that may help understand and facilitate development of combination treatments for anxiety. (d-cycloserine Augmented CBT for Panic Disorder; clinicaltrials.gov; NCT01680107).

BACKGROUND: Apart from the clinical efficacy of high frequency spinal cord stimulation at 10 kHz, the underlying mechanism of action remains unclear. In parallel with spinal or segmental theories, supraspinal hypotheses have been recently proposed. In order to unveil hidden altered brain connectome patterns, a resting state functional magnetic resonance imaging (rsfMRI) protocol was performed in subjects routinely treated for back and/or leg pain with high-frequency spinal cord stimulation (HF-SCS) HF-SCS at 10 kHz.
METHODS: RsfMRI imaging was obtained from ten patients with failed back surgery syndrome who were eligible for HF-SCS at 10 kHz. Specifically-chosen regions of interest with different connectivity networks have been investigated over time. Baseline measurements were compared with measurements after 1 month and 3 months of HF-SCS at 10 kHz. Additionally, clinical parameters on pain intensity, central sensitization, pain catastrophizing, and sleep quality were correlated with the functional connectivity strengths.
RESULTS: The study results demonstrate an increased connectivity over time between the anterior insula (affective salience network) and regions of the frontoparietal network and the central executive network. After 3 months of HF-SCS, the increased strength in functional connectivity between the left dorsolateral prefrontal cortex and the right anterior insula was significantly correlated with the minimum clinically important difference (MCID) value of the Pittsburgh sleep quality index.
CONCLUSIONS: These findings support the hypothesis that HF-SCS at 10 kHz might influence the salience network and therefore also the emotional awareness of pain.

An increasing number of multidrug-resistant Acinetobacter baumannii (MDR-AB) infections have been reported worldwide, posing a threat to public health. The establishment of methods to elucidate the mechanism of action (MOA) of A. baumannii-specific antibiotics is needed to develop novel antimicrobial therapeutics with activity against MDR-AB We previously developed bacterial cytological profiling (BCP) to understand the MOA of compounds in Escherichia coli and Bacillus subtilis Given how distantly related A. baumannii is to these species, it was unclear to what extent it could be applied. Here, we implemented BCP as an antibiotic MOA discovery platform for A. baumannii We found that the BCP platform can distinguish among six major antibiotic classes and can also subclassify antibiotics that inhibit the same cellular pathway but have different molecular targets. We used BCP to show that the compound NSC145612 inhibits the growth of A. baumannii via targeting RNA transcription. We confirmed this result by isolating and characterizing resistant mutants with mutations in the rpoB gene. Altogether, we conclude that BCP provides a useful tool for MOA studies of antibacterial compounds that are active against A. baumannii.

Despite best evidence demonstrating the effectiveness of increased intensity of exercise after stroke, current levels of therapy continue to be below those required to optimise motor recovery. We developed and tested an implementation intervention that aims to increase arm exercise in stroke rehabilitation. The aim of this study was to illustrate the use of a behaviour change framework, the Behaviour Change Wheel, to identify the mechanisms of action that explain how the intervention produced change.
We implemented the intervention at three stroke rehabilitation units in the United Kingdom. A purposive sample of therapy team members were recruited to participate in semi-structured interviews to explore their perceptions of how the intervention produced change at their work place. Audio recordings were transcribed and imported into NVivo 10 for content analysis. Two coders separately analysed the transcripts and coded emergent mechanisms. Mechanisms were categorised using the Theoretical Domains Framework (TDF) (an extension of the Capability, Opportunity, Motivation and Behaviour model (COM-B) at the hub of the Behaviour Change Wheel).
We identified five main mechanisms of action: \'social/professional role and identity\', \'intentions\', \'reinforcement\', \'behavioural regulation\' and \'beliefs about consequences\'. At the outset, participants viewed the research team as an external influence for whom they endeavoured to complete the study activities. The study design, with a focus on implementation in real world settings, influenced participants\' intentions to implement the intervention components. Monthly meetings between the research and therapy teams were central to the intervention and acted as prompt or reminder to sustain implementation. The phased approach to introducing and implementing intervention components influenced participants\' beliefs about the feasibility of implementation.
The Behaviour Change Wheel, and in particular the Theoretical Domains Framework, were used to investigate mechanisms of action of an implementation intervention. This approach allowed for consideration of a range of possible mechanisms, and allowed us to categorise these mechanisms using an established behaviour change framework. Identification of the mechanisms of action, following testing of the intervention in a number of settings, has resulted in a refined and more robust intervention programme theory for future testing.

Treatment offered at present to the vast majority of patients with myelodysplastic syndromes (MDS), mostly refractory anemia (RA) and refractory anemia with ringed sideroblasts, is retricted to supportive care only. This report delineates an unusual experience with Hydroxyurea (HU) given to a patient with RA subtype of MDS with myeloproliferative feature (thrombocytosis) and abnormal chromosome. A significant improvement of anemia along with a decrease in the platelet count and a parallel decrease in the number of the cells with abnormal karyotype followed invariably after a short-term HU therapy. Cytotoxic effects to abnormal hematopoietic cell clone, suppressive effect to c-myc which enhances apoptosis, decrement of the cells susceptible to pathogenetic cytokine effects, and erythroid differentiation activity were considered pertinent mechanisms of action of HU.