Mapping the spatial dynamics of the CD4+ T cell spectrum in classical Hodgkin lymphoma.

As around 25-30% of classical Hodgkin Lymphoma (cHL) patients with advanced stages do not respond to standard therapies, the tumor microenvironment (TME) of cHL is one avenue that may be explored with the aim of improving risk stratification. CD4+ T cells are thought to be one of the main cell types in the TME. However, few immune signatures have been studied, and many of these lack related spatial data. Thus, our aim is to spatially resolve the CD4+ T cell subtypes that influence cHL outcome, depicting new immune signatures or transcriptional patterns that are in crosstalk with the tumor cells. This study was conducted using the Nanostring GeoMx DSP technology, based on the selection of distinct functional areas of patients' tissues followed by the gene-expression profiling. The goals were to assess the differences in CD4+ T cell populations between tumor-rich and immune-predominant areas defined by different CD30 and PD-L1 expression levels and to seek correlations with clinical metadata. Our results depict a complex map of CD4+ T cells with different functions and differentiation states that are enriched at distinct locations, the flux of cytokines and chemokines that could be related to these, and the specific relationships with the clinical outcome.

Feasibility, acceptability and preliminary effectiveness of a community-based group psychosocial support model for conflict survivors in Colombia: An assessment of in-person and remote intervention modalities during the COVID-19 pandemic.

Background: Community-based psychosocial support (CB-PSS) interventions utilizing task sharing and varied (in-person, remote) modalities are essential strategies to meet mental health needs, including during the COVID-19 pandemic. However, knowledge gaps remain regarding feasibility and effectiveness. Methods: This study assesses feasibility, acceptability and preliminary effectiveness of a CB-PSS intervention for conflict-affected adults in Colombia through parallel randomized controlled trials, one delivered in-person (n = 165) and the other remotely (n = 103), implemented during the COVID-19 pandemic and national protests. Interventions were facilitated by nonspecialist community members and consisted of eight problem-solving and expressive group sessions. Findings: Attendance was moderate and fidelity was high in both modalities. Participants in both modalities reported high levels of satisfaction, with in-person participants reporting increased comfort expressing emotions and more positive experiences with research protocols. Symptoms of depression, anxiety and posttraumatic stress disorder improved among in-person participants, but there were no significant changes for remote participants in comparison to waitlist controls. Implications: This CB-PSS intervention appears feasible and acceptable in both in-person and remote modalities and associated with reduction in some forms of distress when conducted in-person but not when conducted remotely. Methodological limitations and potential explanations and areas for future research are discussed, drawing from related studies.

Corrigendum: Anatomical variations of the atlas arches: prevalence assessment, systematic review and proposition for an updated classification system.

[This corrects the article DOI: 10.3389/fnins.2024.1348066.].

Tribulus terrestris and Sport Performance: A Quantitative and Qualitative Evaluation of Its Advertisement and Availability via Online Shopping in Six Different Countries.

Dietary supplements are commonly used among athletes, and the Internet may be an easy source of these products. Tribulus terrestris is an herbal supplement with multiple properties. Of interest to athletes are reports that its consumption can lead to muscle mass gain and a faster recovery process. The objective of this cross-sectional study was to determine the availability of Tribulus terrestris via the Internet in six countries (Canada, Puerto Rico, Russia, Spain, Ukraine, and the United States of America) via a specifically designed computer program. The characteristics of the websites selling this substance, the country from which it can be purchased, the route of administration, and recommendations for its use were analyzed. The results of the study show that this supplement is marketed mainly in Russia, Ukraine, and Spain on many websites that are mostly dedicated to sports products. Just over half of the webpages (59.14%) identified only distribute this supplement within the same country. The main claims for its consumption refer to sports performance benefits, but there are also claims that it may improve male hormone levels and sexual function. Athletes should be encouraged to seek professional advice prior to ingesting this supplement to ensure that it is suitable for their specific training and sports objectives.

Generation and External Validation of a Histologic Transformation Risk Model for Patients with Follicular Lymphoma.

Follicular lymphoma (FL) is the most frequent indolent lymphoma. Some patients (10%-15%) experience histologic transformation (HT) to a more aggressive lymphoma, usually diffuse large B-cell lymphoma (DLBCL). This study aimed to validate and improve a genetic risk model to predict HT at diagnosis.We collected mutational data from diagnosis biopsies of 64 FL patients. We combined them with the data from a previously published cohort (total n = 104; 62 from nontransformed and 42 from patients who did transform to DLBCL). This combined cohort was used to develop a nomogram to estimate the risk of HT. Prognostic mutated genes and clinical variables were assessed using Cox regression analysis to generate a risk model. The model was internally validated by bootstrapping and externally validated in an independent cohort. Its performance was evaluated using a concordance index and a calibration curve. The clinicogenetic nomogram included the mutational status of 3 genes (HIST1HE1, KMT2D, and TNFSR14) and high-risk Follicular Lymphoma International Prognostic Index and predicted HT with a concordance index of 0.746. Patients were classified as being at low or high risk of transformation. The probability HT function at 24 months was 0.90 in the low-risk group vs 0.51 in the high-risk group and, at 60 months, 0.71 vs 0.15, respectively. In the external validation cohort, the probability HT function in the low-risk group was 0.86 vs 0.54 in the high-risk group at 24 months, and 0.71 vs 0.32 at 60 months. The concordance index in the external cohort was 0.552. In conclusion, we propose a clinicogenetic risk model to predict FL HT to DLBLC, combining genetic alterations in HIST1H1E, KMT2D, and TNFRSF14 genes and clinical features (Follicular Lymphoma International Prognostic Index) at diagnosis. This model could improve the management of FL patients and allow treatment strategies that would prevent or delay transformation.

Evaluation of the clinical use of MGMT methylation in extracellular vesicle-based liquid biopsy as a tool for glioblastoma patient management.

Glioblastoma (GB) is a devastating tumor of the central nervous system characterized by a poor prognosis. One of the best-established predictive biomarker in IDH-wildtype GB is O6-methylguanine-DNA methyltransferase (MGMT) methylation (mMGMT), which is associated with improved treatment response and survival. However, current efforts to monitor GB patients through mMGMT detection have proven unsuccessful. Small extracellular vesicles (sEVs) hold potential as a key element that could revolutionize clinical practice by offering new possibilities for liquid biopsy. This study aimed to determine the utility of sEV-based liquid biopsy as a predictive biomarker and disease monitoring tool in patients with IDH-wildtype GB. Our findings show consistent results with tissue-based analysis, achieving a remarkable sensitivity of 85.7% for detecting mMGMT in liquid biopsy, the highest reported to date. Moreover, we suggested that liquid biopsy assessment of sEV-DNA could be a powerful tool for monitoring disease progression in IDH-wildtype GB patients. This study highlights the critical significance of overcoming molecular underdetection, which can lead to missed treatment opportunities and misdiagnoses, possibly resulting in ineffective therapies. The outcomes of our research significantly contribute to the field of sEV-DNA-based liquid biopsy, providing valuable insights into tumor tissue heterogeneity and establishing it as a promising tool for detecting GB biomarkers. These results have substantial implications for advancing predictive and therapeutic approaches in the context of GB and warrant further exploration and validation in clinical settings.

Anatomical variations of the atlas arches: prevalence assessment, systematic review and proposition for an updated classification system.

Objective and background: This study focuses on the atlas, a pivotal component of the craniovertebral junction, bridging the cranium and spinal column. Notably, variations in its arches are documented globally, necessitating a thorough assessment and categorization due to their significant implications in clinical, diagnostic, functional, and therapeutic contexts. The primary objective is to ascertain the frequency of these anatomical deviations in the atlas arches among a Colombian cohort using cone-beam computed tomography (CBCT). Methodology: Employing a descriptive, cross-sectional approach, this research scrutinizes the structural intricacies of the atlas arches in CBCT scans. Analytical parameters included sex distribution and the nature of anatomical deviations as per Currarino's classification. Statistical analyses were conducted to identify significant differences, including descriptive statistics and Chi-square tests. A systematic review of the literature was conducted in order to enhance the current Currarino's classification. Results: The study examined 839 CBCT images, with a nearly equal sex distribution (49.7% female, 50.3% male). Anatomical variations were identified in 26 instances (3%), displaying a higher incidence in females (X2 [(1, N = 839) = 4.0933, p = 0.0430]). The most prevalent variation was Type A (2.5%), followed by Type B (0.4%), and Type G (0.2%) without documenting any other variation. The systematic review yielded 7 studies. A novel classification system for these variations is proposed, considering global prevalence data in the cervical region. Conclusion: The study highlights a statistically significant predominance of Type A variations in the female subset. Given the critical nature of the craniovertebral junction and supporting evidence, it recommends an amendment to Currarino's classification to better reflect these clinical observations. A thorough study of anatomical variations of the upper cervical spine is relevant as they can impact important functional aspects such as mobility as well as stability. Considering the intricate anatomy of this area and the pivotal function of the atlas, accurately categorizing the variations of its arches is crucial for clinical practice. This classification aids in diagnosis, surgical planning, preventing iatrogenic incidents, and designing rehabilitation strategies.

High risk of coronary artery obstruction during TAVR, how to avoid it?

BACKGROUND: Coronary artery obstruction after percutaneous aortic replacement is a complication with high short-term mortality secondary to the lack of timely treatment. There are various predictors of coronary obstruction prior to valve placement such as the distance from the ostia, the degree of calcification, the distance from the sinuses; In such a situation some measures must be taken to prevent and treat coronary obstruction. CASE PRESENTATION: An 84-year-old male, with severe aortic stenosis and high surgical risk, who was treated with TAVR. However, during the deployment of the valve he presented hemodynamic instability secondary to LMCA obstruction. The intravascular image showed obstruction of the ostium secondary to the displacement of calcium that he was successfully treated with a chimney stent technique. CONCLUSIONS: The high degree of calcification and the left ostium near the annulus are conditions for obstruction of the ostium at the time of valve release; In this context, provisional stenting prior to TAVR in patients at high risk of obstruction should be considered as a safe prevention strategy to achieve the success of the procedure.

Transcatheter aortic valve replacement planning with cardiac computed tomography in quadricuspid aortic valve stenosis: a case series.

Background: The presence of severe aortic stenosis in quadricuspid aortic valve (QAV) is an extremely rare combination, and it is unknown whether transcatheter aortic valve replacement (TAVR) is a safe option due to the low incidence. Case summary: We present two patients diagnosed with severe aortic stenosis with QAV morphology type 1 (Nakamura classification). All patients presented to our hospital for evaluation because of worsening functional class, dyspnoea, or syncope. During tomographic planning, the aortic annulus was measured at the level of the deepest sinus for the selection of the number of devices. Due to the presence of four cusps, the smallest cusp was excluded, and three sinuses were virtualized for placement of the pigtail catheter during the procedure. Without complications, a 23 mm Edwards SAPIEN 3 was deployed through the femoral artery in both patients. Control aortography showed no valve leakage or regurgitation. Discussion: In patients with QAV and aortic stenosis undergoing TAVR, similar to the tricuspid valve, tomographic planning can be used to ensure the success of the procedure. However, unlike the tricuspid valve, where the selection of the device number is based on the measurements of the aortic annulus at the level of the non-coronary sinus, in these QAV cases, we perform the measurements at the level of the deepest aortic sinus (right coronary sinus).

Circulating tumor DNA for monitoring classic Hodgkin lymphoma patients: Correlation with FDG-PET/CT.

The value of circulating tumor DNA (ctDNA) as a biomarker of disease activity in classic Hodgkin lymphoma (cHL) patients has not yet been well established. By profiling primary tumors and ctDNA, we identified common variants between primary tumors and longitudinal plasma samples in most of the cases, confirming high spatial and temporal heterogeneity. Although ctDNA analyses mirrored HRS cell genetics overall, the prevalence of variants shows that none of them can be used as a single biomarker. Conversely, the estimation of hGE/mL, based on measures of total ctDNA, reflects disease activity and is almost perfectly correlated with standard parameters such as PET/CT that are associated with refractoriness.

Immune and stromal transcriptional patterns that influence the outcome of classic Hodgkin lymphoma.

Classic Hodgkin lymphoma (cHL) is characterized by a rich immune microenvironment as the main tumor component. It involves a broad range of cell populations, which are largely unexplored, even though they are known to be essential for growth and survival of Hodgkin and Reed-Sternberg cells. We profiled the gene expression of 25 FFPE cHL samples using NanoString technology and resolved their microenvironment compositions using cell-deconvolution tools, thereby generating patient-specific signatures. The results confirm individual immune fingerprints and recognize multiple clusters enriched in refractory patients, highlighting the relevance of: (1) the composition of immune cells and their functional status, including myeloid cell populations (M1-like, M2-like, plasmacytoid dendritic cells, myeloid-derived suppressor cells, etc.), CD4-positive T cells (exhausted, regulatory, Th17, etc.), cytotoxic CD8 T and natural killer cells; (2) the balance between inflammatory signatures (such as IL6, TNF, IFN-γ/TGF-ß) and MHC-I/MHC-II molecules; and (3) several cells, pathways and genes related to the stroma and extracellular matrix remodeling. A validation model combining relevant immune and stromal signatures identifies patients with unfavorable outcomes, producing the same results in an independent cHL series. Our results reveal the heterogeneity of immune responses among patients, confirm previous findings, and identify new functional phenotypes of prognostic and predictive utility.

Online information and availability of three doping substances (anabolic agents) in sports: role of pharmacies.

Background: The Internet has become an important source for easy access to doping substances, where people and athletes may acquire, outside pharmacies and without a (medical) prescription. These online websites do not always offer quality-assured products, and are outside the regular distribution channels of medicines. The aim of this study was to estimate the availability and accessible information on the Internet about the sale of three doping substances (oxandrolone, DHEA, androstenedione). Methods: Cross-sectional exploratory study, being an observation at a point in time of the online availability of these three doping substances (WADA S1 category: anabolic agents), purchased from Spain, Puerto Rico, Canada, United States, Ukraine and Russia. The characteristics of the websites, the countries the webs sold to, the pharmaceutical forms offered and the recommendations for its use were analyzed by using a computer tool designed ad hoc. Results: There were significant differences between countries in the number of webpages that sold the products (Chi-square test, p < 0.05). Oxandrolone was available for purchase mainly when buying from Spain (27.12%) and Ukraine (26.58%), in websites dedicated to sports (77.26%). For DHEA, most of the pages offered it if the search was done from Canada (23.34%) and Russia (21.44%). Products containing androstenedione or DHEA are claimed to enhance sports performance or for sports use without providing details. Compared to the total number of websites checked, the proportion of pharmacies offering these products was low, ranging from 4.86% for DHEA to 15.79% for androstenedione. Conclusion: The three substances selected are easily available without control through the Internet. Only a small number of websites offering them were online pharmacies, and requested a prescription. Most of the doping substances are purchased from the country where they are requested. Product information described benefits for sports performance, but did not do the same with their side effects. It would be advisable for these products to be sold through pharmacies, to guarantee their quality and provide evidence-based information on their safe use, benefits and risks, and only with a prescription. Athletes should be encouraged to consult health professionals about those supplements suitable for their type of training and sports objectives.

Valve-in-valve as a rescue treatment in retrograde migration of the transcatheter aortic valve to the left ventricle: a case report.

Background: The treatment of choice for patients with severe symptomatic pure native aortic valve regurgitation (PNAVR) is surgical aortic valve replacement (SAVR). However, not all patients are candidates for surgery because of comorbidities or are deemed high risk for surgery. In such cases, transcatheter aortic valve replacement (TAVR) has proved to be better than medical treatment. Case summary: A 78-year-old male with a history of ankylosing spondylitis was admitted with New York Heart Association III heart failure. The echocardiogram showed severe aortic regurgitation and a left ventricular ejection fraction of 52%. Because of high surgical risk and being refractory to medical RX, he was accepted for TAVR. The tomography of anatomical characteristics reported the absence of calcium and dilation of the aortic ring and aortic root. During the TAVR procedure, the patient experienced valve migration, but it was autonomously repositioned in the aortic annulus. As a rescue measure, a second valve was placed. Here, we present a case of valve migration to the left ventricle treated with a valve-in-valve procedure without the need for surgical treatment. Discussion: The absence of annulus calcification in PNAVR increases the risk of post-TAVR paravalvular leak and device embolization. Valve migration generally requires valve recovery and conversion to SAVR.

ß-Alanine Supplementation in Combat Sports: Evaluation of Sports Performance, Perception, and Anthropometric Parameters and Biochemical Markers-A Systematic Review of Clinical Trials.

ß-alanine does not have an ergogenic effect by itself, but it does as a precursor for the synthesis of carnosine in human skeletal muscle. ß-alanine and carnosine together help improve the muscles' functionality, especially in high-intensity exercises such as combat sports. Therefore, ß-alanine could be considered a nutritional ergogenic aid to improve sports performance in combat athletes. We aimed to critically review clinical trial evidence on the impact of ß-alanine supplementation on sports performance, perception, and anthropometric parameters, as well as circulating biochemical markers in combat athletes. This systematic review was conducted following the specific methodological guidelines of the Preferred Report Items for Systematic Reviews and Meta-Analyses guidelines (PRISMA), the PICOS question model, the Critical Review Form of McMaster, and the PEDro scale. Furthermore, the Cochrane risk-of-bias assessment tool was used. The search was carried out in the SCOPUS, Web of Science (WOS), and Medline (PubMed) databases for studies published from the beginning of the database until July 31, 2023. Of the 41 registers identified, only 7 met the established criteria and were included in this systematic review. Overall, performance parameters related to strength, power, total exercise work capacity, and combat-specific parameters were significantly improved (p < 0.05). Perception parameters increased non-significantly (p > 0.05). Regarding biochemical parameters, carnosine increased significantly (p < 0.05), pH decreased non-significantly (p > 0.05), and the results for blood bicarbonate and blood lactate were heterogeneous. Finally, there was a non-significant (p > 0.05) improvement in the anthropometric parameters of lean mass and fat mass. ß-alanine supplementation appears to be safe and could be a suitable nutritional ergogenic aid for combat athletes.

Supramaximal versus gross total resection in Glioblastoma, IDH wild-type and Astrocytoma, IDH-mutant, grade 4, effect on overall and progression free survival: systematic review and meta-analysis.

PURPOSE: To synthesize the evidence on the impact on progression-free survival (PFS) and overall survival (OS) of supramaximal resection (SMR) over gross total resection (GTR) in Glioblastoma, IDH wild-type and Astrocytoma, IDH-mutant, grade 4 (Glioblastoma). METHODS: The PubMed, Scopus, Web of Science, Ovid and Cochrane databases were systematically searched (up to November 30, 2022). Studies reporting OS and PFS on adult humans with a suspected Glioblastoma, treated either with a SMR or GTR were included. Hazard ratios were estimated for each study and treatment effects were calculated through DerSimonian and Laird random effects models. RESULTS: The literature search yielded 14 studies published between 2013 and 2022, enrolling a total of 6779 patients. Analysis of the included studies reveals significantly better clinical outcomes favoring SMR over GTR in terms of PFS (HR 0.67; p = 0.0007), and OS (HR 0.7; p = 0.0001). CONCLUSION: Glioblastoma, IDH wild-type and Astrocytoma, IDH-mutant, grade 4, are aggressive tumors with a very short long-term OS. SMR is an effective therapeutic approach contributing to increased PFS and OS in patients with this catastrophic disease.

BET inhibitors induce NF-κB and E2F downregulation in Hodgkin and Reed-Sternberg cells.

The prognosis of patients with relapsed and/or refractory classic Hodgkin lymphoma (cHL) continues to be poor. Therefore, there is a continuing need to develop novel therapies and to rationalize the use of target combinations. In recent years there has been growing interest in epigenetic targets for hematological malignancies under the rationale of the presence of common alterations in epigenetic transcriptional regulation. Since Hodgkin and Reed-Sternberg (HRS) cells have frequent inactivating mutations of the CREBBP and EP300 acetyltransferases, bromodomain and extra-terminal (BET) inhibitors can be a rational therapy for cHL. Here we aimed to confirm the efficacy of BET inhibitors (iBETs) using representative cell models and functional experiments, and to further explore biological mechanisms under iBET treatment using whole-transcriptome analyses. Our results reveal cytostatic rather than cytotoxic activity through the induction of G1/S and G2/M cell-cycle arrest, in addition to variable MYC downregulation. Additionally, massive changes in the transcriptome induced by the treatment include downregulation of relevant pathways in cHL disease: NF-kB and E2F, among others. Our findings support the therapeutic use of iBETs in selected cHL patients and reveal previously unknown biological mechanisms and consequences of pan-BET inhibition.