Results Of Clinical Trials Research Articles

Impact of Audio-Visual Complexity on Symptomatology of Laryngeal Dystonia: A Virtual Reality Study.

Laryngeal dystonia (LD) is an isolated focal dystonia characterized by involuntary spasms in laryngeal muscles selectively impairing speech production. Anecdotal observations reported the worsening of LD symptoms in stressful or vocally demanding situations. To examine the impact of surrounding audio-visual complexity on LD symptomatology for a better understanding of disorder phenomenology. We developed well-controlled virtual reality (VR) environments of real-life interpersonal communications to investigate how different levels of audio-visual complexity may impact LD symptoms. The VR experiments were conducted over five consecutive days, during which each patient experienced 10 h of 4100 experimental trials in VR with gradually increasing audio-visual complexity. Daily reports were collected about patients' voice changes, as well as their comfort, engagement, concentration, and drowsiness from using VR technology. After a weekly VR exposure, 82% of patients reported changes in their voice symptoms related to changes in background audio-visual complexity. Significant differences in voice symptoms were found between the first two levels of the audio-visual challenge complexity independent of study sessions or VR environments. This study demonstrated that LD symptoms are impacted by audio-visual background across various virtual realistic settings. These findings should be taken into consideration when planning behavioral experiments or evaluating the outcomes of clinical trials in these patients. Moreover, these data show that VR presents a reliable and useful technology for providing real-life assessments of the impact of various experimental settings, such as during the testing of novel therapeutic interventions in these patients. Level 3 Laryngoscope, 2024.

Understanding Treatment Decisions and Management for Patients with Advanced Renal Cell Carcinoma Using Hypothetical Case Studies: A Vodcast.

In recent years, the armamentarium of therapies for the management of advanced renal cell carcinoma (aRCC) has grown. Combination therapies, including immuno-oncology (IO) agents and tyrosine kinase inhibitors [TKIs (IO-TKI)], and IO-IO combinations, are now approved for first-line treatment of aRCC. Decisions regarding the use of these combinations, IO-IO versus IO-TKI, can be challenging, as they have not been compared in a randomized trial; each of these combinations have been compared with sunitinib alone. In addition, patient-, disease-, and treatment-based factors must be evaluated in the decision-making process. More important is the consideration of patient management during treatment and optimal detection and management of toxicities to ensure continued benefit. In this vodcast, two experts in the field of kidney cancer will present case studies that represent typical patients seen in practice. The faculty will discuss treatment approaches, adverse event management, and which factors to consider during the treatment decision-making process. Viewers of the vodcast will get a better understanding of clinical trial outcomes related to an IO-TKI combination, such as axitinib plus pembrolizumab, that they can apply to their practice immediately. In addition, they will gain real-world insight into how experts approach the treatment of patients with aRCC and, more importantly, therapy management.

Maternal Mental Health Spillovers From Child Illness and Disability: A Dynamic Panel Analysis

ObjectivesThere is growing recognition of the consequences of a person’s health and illness experience for the health and wider welfare of those close to them. However, estimation of these health spillovers is challenging. This study adopts a longitudinal approach to examine maternal mental health spillovers associated with various forms of child illness and disability. MethodsDynamic panel models are used in estimating maternal mental health spillovers related to 7 subcategories of chronic child illness and disability. In particular, we use longitudinal data from the Growing Up in Ireland study and a system generalized method of moments approach. We also consider heterogeneity in these spillovers by the severity of the child’s illness/disability and by household deprivation. ResultsWe find that a child’s experience of chronic nervous system conditions and chronic mental and behavioral disorders are associated with 10.8 and 5.1 percentage point increases in the probability of maternal depression, respectively. Similar associations were not observed for other health conditions. Spillover magnitude is also found to be strongly related to illness/disability severity. Finally, subsample analyses reveal a larger association between severe child illness and maternal depression among deprived households. ConclusionsThis analysis, in observing health spillovers related to certain disease categories but not others, draws further attention to their context specificity. Our findings also further corroborate calls for inclusion of caregiver and family member outcomes in the economic evaluation of child health services and support consensus guidelines for collection of these outcomes alongside patient outcomes in clinical trials.

Joint Models Inform the Longitudinal Assessment of Patient-Reported Outcomes in Clinical Trials: A Simulation Study and Secondary Analysis of the Restrictive versus Liberal Fluid Therapy for Major Abdominal Surgery (RELIEF) Randomized Controlled Trial

Evaluate the utility of a joint model when analysing a patient-reported endpoint as part of a randomized controlled trial in which censoring occurs when patients die during follow-up. The present study comprises two parts: first we re-analyzed data from a previously published randomized controlled trial comparing two fluid regimens in the first 24 hours of major abdomino-pelvic surgery ('RELIEF' trial). In this trial, patient-reported disability was measured at multiple timepoints before and after surgery. Next, we conducted a simulation study to jointly emulate patient-reported disability and survival, similar to the RELIEF trial, under nine treatment-outcome scenarios. In both parts, we compared a joint model analysis to a linear mixed effect model combined with one of several traditional methods of handling longitudinal missingness: available data analysis, complete case analysis, last observation carried forward, and worst-case assumption. In part one, the joint model revealed no between-group differences in patient-reported disability at one, three, six, and 12 months after surgery. The worst-case approach consistently resulted in the largest deviation from the joint model estimates, although in this particular setting none of the approaches materially changed the study's conclusions. In part two, the simulations revealed that across all treatment-outcome scenarios, the joint model expectedly produced unbiased estimates of patient-reported disability. Similarly, employing an approach based on all available data (i.e., relying on the maximum likelihood estimator for handling missingness) yielded disability estimates close to the simulated values, albeit with slight bias across some scenarios. The last observation carried forward approach mirrored the joint model's estimates except when the treatment had a non-null effect on patient-reported disability. The worst case analysis resulted in high bias, which was particularly evident when the treatment had a large effect on survival. The complete case analysis resulted in high bias across all scenarios. In randomized trials that employ a patient-reported outcome as one of their endpoints, a joint model can address bias arising from informative missingness related to death. Methods for handling missingness based on all available data appear to be a reasonable alternative to joint models, with only slight bias across some simulated scenarios.

Proposed categories for reporting of service organization in rehabilitation in clinical trials: a discussion paper.

The lack of standardized reporting for crucial organizational factors in rehabilitation poses a significant barrier to understanding their impact on patient outcomes in clinical trials and meta-analyses. Based on the categories in the International Classification of Service Organization in Rehabilitation (ICSO-R 2.0), we aimed to develop reporting standards specifically for organizational factors in clinical trials. A comprehensive two-step process was conducted. In Step 1, important categories were identified. The identification was based on previous results from a Delphi survey with international stakeholder participation, two systematic literature reviews and results from focus groups with users in Germany, Indonesia and Norway. Step 2 involved the necessary reduction of categories and the proposal of reporting specifications, achieved through two voting rounds among key researchers, stakeholders and users. The suggested minimum reporting set comprises Context and Setting as well as Quality assurance and management. The Context and Setting is proposed to include whether the intervention is delivered by Hospital, Community or Other service providers. The Mode of delivery is proposed to be specified as Inpatient, Outpatient, In-home, or Tele-rehabilitation. Furthermore, the Level of specialization (Primary/Secondary) and the Phase of service delivery Acute, Subacute or Long-term rehabilitation services should be reported. The Quality assurance and management should be reported as Yes or No, with the option Yes requiring description of the quality assurance applied in the methods section. This study proposed a compulsory and standardized reporting of organizational factors in clinical trials to facilitate the generation of scientific evidence regarding effective service provision and delivery in rehabilitation medicine. Authors are encouraged to consider the proposed reporting set to testing, criticism, and modification to enhance its applicability and robustness.

AZD1152: Repurposing for Treatment of Lupus Nephritis Driven by the Results of Clinical Trials

AZD1152: Repurposing for Treatment of Lupus Nephritis Driven by the Results of Clinical Trials

Eligible Infants Included in Neonatal Clinical Trials and Reasons for Noninclusion

Results of clinical trials can only represent included participants, and many neonatal trials fail due to insufficient participation. Infants not included in research may differ from those included in meaningful ways, biasing the sample and limiting the generalizability of findings. To describe the proportion of eligible infants included in neonatal clinical trials and the reasons for noninclusion. A systematic search of Cochrane CENTRAL was performed by retrieving articles meeting the following inclusion criteria: full-length, peer-reviewed articles describing clinical trial results in at least 20 human infants from US neonatal intensive care units, published in English, and added to Cochrane CENTRAL between 2017 and 2022. Retrieved articles were screened for inclusion by 2 independent researchers. In total 120 articles met inclusion criteria and 91 of these (75.8%) reported the number of infants eligible for participation, which totaled 26 854 in aggregate. Drawing from these, an aggregate of 11 924 eligible infants (44.4%) were included in reported results. Among all eligible infants, most reasons for noninclusion in results were classified as modifiable or potentially modifiable by the research team. Parents declining to participate (8004 infants [29.8%]) or never being approached (2507 infants [9.3%]) were the 2 predominant reasons for noninclusion. Other modifiable reasons included factors related to study logistics, such as failure to appropriately collect data on enrolled infants (859 of 26 854 infants [3.2%]) and other reasons (1907 of 26 854 infants [7.1%]), such as loss to follow-up or eligible participants that were unaccounted for. Nonmodifiable reasons, including clinical change or death, accounted for a small proportion of eligible infants who were not included (858 of 26 854 infants [3.2%]). This systematic review of reporting on eligible infants included and not included in neonatal clinical trials highlights the need for improved documentation on the flow of eligible infants through neonatal clinical trials and may also inform recruitment expectations for trialists designing future protocols. Improved adherence to standardized reporting may clarify which potential participants are being missed, improving understanding of the generalizability of research findings. Furthermore, these findings suggest that future work to understand why parents decline to participate in neonatal research trials and why some are never approached about research may help increase overall participation.

Coping strategies and patient-reported outcomes (PROs) in early phase cancer clinical trial (EP-CT) participants.

245 Background: Individuals with cancer often rely on various coping strategies as they navigate their cancer course. Little is known about coping strategies among patients enrolled on EP-CTs or associations of these coping strategies with other PROs. Methods: We prospectively enrolled adults with cancer participating in EP-CTs at Massachusetts General Hospital from 4/2021-1/2023. Participants completed baseline surveys prior to EP-CT initiation that assessed coping strategies (Brief COPE), quality of life (QOL; Functional Assessment of Cancer Therapy-General), hope (Herth Hope Index), depression/anxiety symptoms (Patient Health Questionnaire-4), and financial wellbeing (COST tool). We used regression models to explore associations of coping strategies with patient characteristics and PROs (QOL, hope, depression/anxiety symptoms, financial wellbeing). Results: Among 205 participants (median age=63.3 [range: 31.8-88.6], 57% female), the most common cancer types were gastrointestinal (35%) and breast (20%). Patients in this cohort utilized the following coping strategies (range 0-6): acceptance (mean=4.81), emotional support (mean=4.63), active (mean=4.30), positive reframing (mean=3.13), religion (mean=2.77), self-blame (mean=.87), denial (mean=.59), and behavioral disengagement (mean=.36). Older age was associated with decreased use of self-blame coping (B=-0.02, p=.025). Female sex was associated with higher scores for denial (B=0.42, p=.009), emotional support (B=0.50, p=.037), positive reframing (B=0.57, p=.036), and religion (B=1.02, p=.001) coping compared with males. See table for associations of coping strategies with PROs (QOL, hope, depression/anxiety symptoms, financial wellbeing). Conclusions: In this cohort of EP-CT participants, we demonstrated that patients use multiple coping strategies and identified differences by age and sex. Notably, we found that some coping behaviors (acceptance, emotional support, positive reframing) were more favorably associated with QOL, hope, depression/anxiety symptoms, and financial wellbeing than others (denial, self-blame, behavioral disengagement). Interventions seeking to enhance PROs in this population should address patients’ use of coping strategies. Coping Strategy QOL Depression Anxiety Hope Financial Wellbeing Beta P Beta P Beta P Beta P Beta P Denial -2.81 .001 0.27 <.001 0.39 <.001 -1.26 <.001 -0.96 .100 Active 0.51 .428 -0.06 .315 0.01 .874 0.98 <.001 0.84 .065 Acceptance 3.13 <.001 -0.15 .013 -0.22 .004 1.31 <.001 1.40 .003 Self-Blame -5.30 <.001 0.44 <.001 0.56 <.001 -1.35 <.001 -2.94 <.001 Emotional Support 1.34 .023 -0.12 .014 0.004 .945 1.03 <.001 0.39 .328 Positive Reframing 1.19 .027 -0.11 .020 -0.08 .184 1.12 <.001 0.13 .715 Behavioral Disengagement -5.99 <.001 0.62 <.001 0.52 <.001 -2.66 <.001 -1.38 .112 Religion 0.57 .195 -0.04 .307 -0.01 .812 0.62 <.001 -0.31 .309

Enhancing pediatric oncology clinical trials through patient reported outcomes (PROs)

Survival rates of children with cancer have significantly increased over the last decades in high income countries. However, cancer survivors often face significant long-term adverse effects on physical, psychosocial, and neurocognitive health. The use of Patient-Reported Outcomes (PROs) in clinical trials may help to further optimize treatment regimens to minimize acute and late adverse events. Despite clear recommendations of regulatory agencies, the use of PROs in pediatric clinical trials remains limited. In this article, we discuss the rationale to assess PROs in pediatric clinical trials with a specific highlight on electronic PRO (ePRO) assessment. In addition, we underscore the importance of recent international guideline developments such as the Setting International Standards in Analyzing Patient-Reported Outcomes and Quality of Life Endpoints Data (SISAQOL-IMI) and the CONsolidated Standards of Reporting Trials – Patient-Reported Outcomes (CONSORT-PRO) to improve the robustness of PRO data assessment in pediatric oncology, thus facilitating better patient care and more accurate assessments of treatment effects. Best practice examples for the use of modern technologies in ePRO assessments are presented and potential barriers and challenges are discussed. We conclude that – despite some challenges and barriers – the routine assessment of (e)PROs in pediatric clinical trials has the potential to substantially improve the quality of the trials and facilitate the usability of outcome data. We call for a joint effort to take proactive steps to incorporate PROs into clinical trials in pediatric oncology, thus giving children a voice.

Future is Brighter: New Potential Paradigm-Shifting Medications and Regimens for Diabetes and Obesity.

Diabetes is a chronic illness that can become debilitating owing to its microvascular and macrovascular complications. Its prevalence is increasing and so is its cost. Diabetes, particularly type 2, appears to have a very close relationship with obesity. While lifestyle modifications, exercises, and current therapeutics have substantially improved clinical outcomes, the need for new therapeutics and regimens continue to exist. Several new medications and regimens for diabetes, obesity, and diabesity are showing promising results in advanced clinical trials. For type 1 diabetes mellitus (T1DM), they include teplizumab, ustekinumab, jakinibs, and cell therapies, whereas for type 2 diabetes mellitus (T2DM), they include once-weakly insulin, tirzepatide, high oral dose of semaglutide, orforglipron, retatrutide, CagriSema, and survodutide. Given their structural and mechanistic diversity as well as their substantial efficacy and safety profiles, these medications and regimens are paradigm shifting and promise a brighter future. They will likely enable better disease prevention and management. This review will provide details about each of the above strategies to keep the scientific community up to date about progress in the fields of diabetes and obesity.

Unraveling the intricate link between cell death and neuroinflammation using Drosophila as a model.

Protein aggregation is a common pathological occurrence in neurodegenerative diseases. This often leads to neuroinflammation, which exacerbates the aggregation and progression of diseases like Parkinson's and Alzheimer's. Here, we focus on immune responses and neurotoxicity in a Parkinson's disease model in Drosophila. Mutations in the SNCA gene that encodes the alpha (α)-Synuclein protein have been linked to familial Parkinson's disease, disrupting autophagy regulation in neuronal cells and promoting the formation of Lewy bodies, a hallmark of Parkinson's pathology. This results in the loss of dopaminergic neurons, manifesting as movement disorders. α-Synuclein aggregation triggers innate immune responses by activating microglial cells, leading to phagocytic activity and the expression of neuroprotective antimicrobial peptides (AMPs). However, sustained AMP expression or chronic inflammation resulting from inadequate microglial phagocytosis can induce neuronal toxicity and apoptosis, leading to severe dopaminergic neuron loss. This review underscores the mechanistic connection between immune response pathways and α-Synuclein-mediated neurodegeneration using Drosophila models. Furthermore, we extensively explore factors influencing neuroinflammation and key immune signaling pathways implicated in neurodegenerative diseases, particularly Parkinson's disease. Given the limited success of traditional treatments, recent research has focused on therapies targeting inflammatory signaling pathways. Some of these approaches have shown promising results in animal models and clinical trials. We provide an overview of current therapeutic strategies showing potential in treating neurodegenerative diseases, offering new avenues for future research and treatment development.

Brief report: Ivonescimab combined with etoposide plus carboplatin as first-line treatment for extensive-stage small-cell lung cancer: results of a phase Ib clinical trial

INTRODUCTIONIvonescimab is a humanized IgG1 bispecific anti-PD-1/VEGF antibody. This study aimed to evaluate the safety and tolerance of ivonescimab combined with etoposide and carboplatin as first-line treatment in patients with extensive-stage small cell lung cancer (ES-SCLC) and explore the primary efficacy of this regimen. METHODSEligible patients received intravenous ivonescimab 3 mg/kg, 10 mg/kg, or 20 mg/kg every 3 weeks combined with etoposide and carboplatin for up to 4 cycles, followed by ivonescimab as maintenance. The primary endpoints were safety and objective response rate (ORR). RESULTSBetween April 23, 2021 and December 2, 2021, 35 patients were enrolled. At data cutoff (October 25, 2023), the median follow-up was 13.3 months (range, 0.3-28.5). For all patients, the confirmed ORR and disease control rate were 80% and 91.4%, respectively. The ORR was 66.7%, 90.9%, and 76.2% at the dose of 3 mg/kg, 10 mg/kg, and 20 mg/kg, respectively. Grade ≥3 treatment-related adverse events (TRAEs) were observed in 21 patients (60%), and the most frequent toxicities were decreased neutrophil count (n=8, 22.9%), decreased white blood cell count (n=5, 14.3%), and anemia (n=5, 14.3%). Grade ≥3 TRAEs occurred in 66.7%, 54.5%, and 61.9% of patients in 3, 10, and 20 mg/kg groups, respectively. TRAEs leading to death were reported in 2 patients (5.7%). Adverse events with potential immunologic etiology, most of them grade 1 or 2, occurred in 14 patients (40.0%). CONCLUSIONSIvonescimab in combination with etoposide and carboplatin was well-tolerated and showed promising antitumor activity in ES-SCLC.

CAR immunotherapy in autoimmune diseases: promises and challenges.

In recent years, the use of chimeric antigen receptor (CAR)-T cells has emerged as a promising immunotherapy in multiple diseases. CAR-T cells are T cells genetically modified to express a surface receptor, known as CAR, for the targeting of cognate antigens on specific cells. The effectiveness of CAR-T cell therapy in hematologic malignancies including leukemia, myeloma, and non-Hodgkin's lymphoma has led to consider its use as a potential avenue of treatment for autoimmune diseases. However, broadening the use of CAR-T cell therapy to a large spectrum of autoimmune conditions is challenging particularly because of the possible development of side effects including cytokine release syndrome and neurotoxicity. The design of CAR therapy that include additional immune cells such as double-negative T cells, γδ T cells, T regulatory cells and natural killer cells has shown promising results in preclinical studies and clinical trials in oncology, suggesting a similar potential utility in the treatment of autoimmune diseases. This review examines the mechanisms, efficacy, and safety of CAR approaches with a focus on their use in autoimmune diseases including systemic lupus erythematosus, Sjögren's syndrome, systemic sclerosis, multiple sclerosis, myasthenia gravis, lupus nephritis and other autoimmune diseases. Advantages and disadvantages as compared to CAR-T cell therapy will also be discussed.

Survival Analysis on Lung Cancer Patients in Damaturu-Nigeria

Cancer is one of the leading causes of death by lung cancer in particular, is the leading cause of cancer death in both men and women, accounting for 23% of all cancer deaths in 2019 according to the Centers for Disease Control and Prevention. One particular problem with lung cancer is that it usually has a poor prognosis. With such a deadly disease, it is crucial to predict the survival likelihood of cancer patients. However, this is not an easy task due to the many factors affecting the disease progression. Survival time has become an essential outcome of clinical trial, which began to emerge among the latter half of the 20th century. A present study was carried out on the survival analysis for patients with lung cancer. The data was obtained from Yobe State Specialist Hospital, Damaturu where each sample was collected from the recipients of the treatment of radical prostatectomy. The Kaplan Meier method was used to obtain and estimate the survival function and median. The log-rank test was used to test the differences in the survival curves. The cox proportional hazard (PH) model provided an effective covariate on the hazard function. As a result of cox PH model, the influence of standard clinical prognostic factors is based on the hazard rate of lung cancer patients. We performed rigorous cross-examination on each feature's relationship and the model for each feature type using data analysis information and survival analysis models. For each feature type, we used one representative survival analysis model from semi-parametric methods (Cox proportional hazards model), one from non-parametric methods (Kaplan-Meier estimator), and one from machine learning approaches (random survival forests). Using the results obtained from these different methods, we identified the best feature types and model combinations to get the top performance for various follow-up periods. The best model is Cox proportional hazards model based on the AIC and log-likelihood functions respectively.

EFFECT OF PHYSIOTHERAPY ON THE IMPLANTATION POTENTIAL OF THIN ENDOMETRIUM

The article is dedicated to the urgent problem of infertility associated with thin endometrium. The mechanisms of action of various physiotherapeutic methods on the endometrium, such as magnetotherapy, laser therapy, ultrasound therapy, and electrical stimulation, are discussed. The beneficial effects of physiotherapy are described in detail, including improved blood flow, reduced inflammation, and stimulation of tissue regeneration. The results of clinical trials confirming the effectiveness of physiotherapy in increasing the thickness and improving the structure of the endometrium are presented. The article also includes indications and contraindications for the use of physiotherapy and emphasizes the importance of an individualized approach to treatment.

Neuromodulation for Neuropathic Pain Syndromes

ABSTRACT OBJECTIVE This article reviews the principles, applications, and emerging trends of neuromodulation as a therapeutic approach for managing painful neuropathic diseases. By parsing evidence for possible mechanisms of action and clinical trial outcomes for various diseases, this article focuses on five common therapy modalities: cutaneous, peripheral nerve, spinal cord, and brain stimulation, and intrathecal drug delivery. LATEST DEVELOPMENTS Recent advances in both invasive and noninvasive neuromodulation for pain have introduced personalized and closed-loop techniques, integrating real-time feedback mechanisms and combining therapies to improve physical and psychosocial function. Novel stimulation waveforms may influence distinct neural tissues to rectify pathologic pain signaling. ESSENTIAL POINTS With appropriate patient selection, peripheral nerve stimulation or epidural stimulation of the spinal cord can provide enduring relief for a variety of chronic pain syndromes. Newer technology using high frequencies, unique waveforms, or closed-loop stimulation may have selective advantages, but our current understanding of therapy mechanisms is very poor. For certain diagnoses and patients who meet clinical criteria, neuromodulation can provide profound, long-lasting relief that significantly improves quality of life. While many therapies are supported by data from large clinical trials, there is a risk of bias as most clinical studies were funded by device manufacturers or insurance companies, which increases the importance of real-world data analysis. Emerging methods like invasive or noninvasive brain stimulation may help us dissect basic mechanisms of pain processing and hold promise for personalized therapies for refractory pain syndromes. Finally, intrathecal delivery of drugs directly to segments of the spinal cord can also modify pain signaling to provide therapy for severe pain syndromes.

Using augmented intelligence to improve long term outcomes.

For augmented intelligence (AI) tools to realize their potential, critical care clinicians must ensure they are designed to improve long-term outcomes. This overview is intended to align professionals with the state-of-the art of AI. Many AI tools are undergoing preliminary assessment of their ability to support the care of survivors and their caregivers at multiple time points after intensive care unit (ICU) discharge. The domains being studied include early identification of deterioration (physiological, mental), management of impaired physical functioning, pain, sleep and sexual dysfunction, improving nutrition and communication, and screening and treatment of cognitive impairment and mental health disorders.Several technologies are already being marketed and many more are in various stages of development. These technologies mostly still require clinical trials outcome testing. However, lacking a formal regulatory approval process, some are already in use. Plans for long-term management of ICU survivors must account for the development of a holistic follow-up system that incorporates AI across multiple platforms. A tiered post-ICU screening program may be established wherein AI tools managed by ICU follow-up clinics provide appropriate assistance without human intervention in cases with less pathology and refer severe cases to expert treatment.

Aminoadipic acid aggravates atherosclerotic vascular inflammation through ROS/TXNIP/NLRP3 pathway, a harmful microbial metabolite reduced by paeonol

AimOur previous study has found a differential microbial metabolite in atherosclerosis (AS) mice, aminoadipic acid (AAA), which was considered as a potential harmful metabolite. However, whether it can promote AS vascular inflammation and its mechanisms remain unclear. Paeonol (Pae) plays an anti-AS role by regulating the metabolic profile, but whether Pae exerts its antiatherogenic effect by reducing serum AAA levels is unknown. ResultsThe clinical trial results showed that the AS patients’ serum AAA levels were higher than those healthy people’. Besides, AAA supplementation could increase aortic plaque size, serum inflammatory cytokines levels and liver malondialdehyde, superoxide dismutase levels in AS mice. Moreover, after AAA stimulation, the ROS levels and ASC, TXNIP, NLRP3 and caspase-1 proteins levels were increased in HUVECs, which could be reversed by antioxidant NAC and NLRP3 inhibitor. Pae significantly reduced the plaque size in the aorta, improved blood lipid levels and decreased serum inflammation factor levels in AS mice. Simultaneously, Pae could reduce the serum AAA levels of AS mice through the gut microbiota transmission. Finally, Pae inhibited NLRP3 inflammasome activation in aortas of AS mice. Broad-spectrum antibiotics could weaken the inhibitory effect of Pae on NLRP3 inflammasome. ConclusionOur study clarified that AAA could promote AS vascular inflammation via activating the ROS/TXNIP/NLRP3 pathway. Pae could inhibit AS development by reducing serum AAA levels in a microbiota-dependent manner. Taken together, we proposed that AAA could be served as a potential biomarker for AS clinical diagnosis and provided a new treatment strategy for AS.

A Comprehensive Review of Diffusing Alpha-Emitters Radiation Therapy (DaRT): From Dosimetry to Its Biological Effectiveness

Diffusing alpha-emitters radiation therapy (DaRT) represents a groundbreaking development in cancer therapy, offering a solution to the limitations of conventional radiation therapy. By deploying <sup>224</sup>Ra embedded seeds, DaRT achieves targeted delivery of high-dose alpha particles directly to tumor sites, showing considerable efficacy in tumor control and minimal damage to adjacent healthy tissues. This comprehensive review analyzes the published literature regarding mechanisms, seed production, dose calculation, measurement, and biological experiments related to DaRT. It includes in-depth discussions on mathematical models, Monte Carlo simulations for dose distribution, real-time <i>in vivo</i> dosimetry developments, and biological experiments both in vitro and <i>in vivo</i>. Clinical trial outcomes are also examined to evaluate the therapy’s effectiveness in various cancer types. DaRT utilizes <sup>224</sup>Ra-labeled seeds, using the decay chain of <sup>224</sup>Ra to deliver alpha particles effectively within a tumor. Several asymptotic diffusion-leakage models were developed to calculate the alpha dose distribution of DaRT. <i>In vivo</i> dosimetry techniques have been developed for real-time monitoring. Biological experiments demonstrated the cytotoxic effects of DaRT across various cancer cells, with varying radiosensitivity. Additionally, the enhanced effects of combined therapy with chemotherapy and immunotherapy were suggested by many <i>in vivo</i> studies. Clinical trials have shown high complete response rate in squamous cell carcinoma, with minimal side effects, suggesting DaRT’s feasibility and safety. DaRT emerges as a highly localized cancer treatment method with minimal side effects compared to traditional radiation therapy. It directly ablates tumors and potentially enhances immune responses, indicating a significant advance in cancer therapy. Future research and ongoing clinical trials will further elucidate its efficacy across different cancer types and in combination with other treatments.

Transcranial Magnetic Stimulation: A New Possibility in Obesity Treatment

Obesity is a major public health challenge and results from the complex interaction of many etiopathogenetic factors. However, food-related hedonic stimuli and poor inhibitory control often appear to be specific maintenance factors, and conventional treatments are sometimes ineffective. Transcranial magnetic stimulation is emerging as a promising treatment option. Targeting specific brain regions, such as the dorsolateral prefrontal cortex, was found to be effective in modulating acute food craving and improving cognitive control. This review traces the evolution and development of transcranial magnetic stimulation and presents the results of recent randomized clinical trials conducted in obese subjects. These suggest that repetitive transcranial magnetic stimulation and deep transcranial magnetic stimulation may be effective in reducing body weight, BMI and food cravings. The neural circuits involved and the underlying mechanisms of action of this neurostimulation technique are also reviewed. Finally, outstanding questions and future research directions are identified to further understand and develop this promising therapy.