Implications For Treatment Research Articles

Associations among posttraumatic stress disorder symptoms, suicidal ideation, suicide attempts, and reward discounting.

Posttraumatic stress disorder (PTSD) is associated with suicidal thoughts and behaviours. Decision-making processes and risk-taking are prominent for coping in both, but the implications for guaranteed and probabilistic reward discounting, important components in behavioural decision-making processes, are unclear. This study explored the relationships between PTSD and suicide risk with tendencies towards devaluing guaranteed rewards that are larger but delayed (i.e., delay discounting; DD) and devaluing larger but uncertain rewards (i.e., probability discounting; PD) for immediate but smaller rewards. The current study evaluated 498 participants (majority male [51.4%] and white [63.8%]; 33.3% screening positive for probable PTSD; 19.2% with lifetime suicide attempts; 30.8% with recent suicide ideation) on both delayed discounting and PD tasks. Provisional PTSD diagnosis, but not suicide attempts or ideation, was associated with increased PD (i.e., more devaluation of uncertain rewards). Conversely, PTSD interacted with both attempt history and ideation to predict increased delayed discounting (i.e., more devaluing of greater but delayed rewards). These results highlight how those with PTSD symptoms assign valuations to rewards, as well as how the addition of suicide risk interacts to impact these decision-making processes. While further research is needed, this suggests potential implications for treatment as they may benefit from structuring progress in smaller, more immediate goals.

Practical Considerations for Oncogenic Fusion Detection and Reporting in Solid Tumors.

Chromosomal rearrangements that result in oncogenic fusions can hold tremendous clinical significance in solid tumors, often with diagnostic or treatment implications. Traditionally, low-throughput methods such as fluorescence in situ hybridization were used to identify fusions in the clinical laboratory. With the rise of next-generation sequencing techniques and the broad adoption of comprehensive genomic profiling, the practice of screening for fusions as part of an oncologic workup has evolved. RNA sequencing methods are increasingly used, as these comprehensive high-throughput assays have many advantages over traditional techniques. Several RNA sequencing platforms are available, each with benefits and drawbacks. Regardless of the approach, systematic evaluation of the RNA sequencing results and the fusions identified by the assay should be performed. Assessment of fusion events relies upon evaluation of quality evidence, structural evidence, and functional evidence to ensure accurate fusion reporting and interpretation. Given the clinical significance of gene fusions in oncology, understanding the variety of assays available for fusion detection, their benefits and drawbacks, and how they are used in the identification and interpretation of gene fusions is important for the modern precision oncology practice.

Histone methyltransferase SUV39H2 regulates apoptosis and chemosensitivity in prostate cancer through AKT/FOXO signaling pathway.

Prostate cancer (PCa) is one of the most common malignant tumors that exhibit both chemoresistance and recurrence. SUV39H2 is highly expressed in many types of human tumors, but its role in the development and progression of PCa has never been clarified. The aim of this study is to elucidate the role of SUV39H2 in the development and progression of PCa, its association with the AKT/FOXO signaling pathway, and its potential implications for PCa diagnosis and treatment. SUV39H2 expression was analyzed in The Cancer Genome Atlas (TCGA) and genotype tissue expression pan-cancer data. The TCGA database was evaluated for SUV39H2 enrichment and its correlation to immune cell infiltration. SUV39H2 levels in PCa tissues and control tissues were determined in 30 patients using qPCR and IHC. Clinical relevance was assessed via The Cancer Genome Atlas (TCGA). In vitro assessments including colony formation assays, Western Blot analysis, CCK-8 assays, and flow cytometry were utilized to establish SUV39H2's contribution to PCa cell growth. The influence of SUV39H2 on PC3 and DU145 cell proliferation was assessed through a cell line-derived xenograft model. Sphere formation assays and qPCR were employed to delineate SUV39H2's role in PCa stemness and chemosensitivity. In vitro macrophage polarization assays provided insights into SUV39H2's association with M2 macrophages, while enrichment analysis shed light on its role in FOXO signaling. PCa tissues expressed higher levels of SUV39H2 than normal tissues. By knocking down SUV39H2, PCa cells were made more chemosensitive to docetaxel and cell proliferation and stemness were inhibited. Additionally, SUV39H2 knockdown significantly inhibited in vivo PCa cell growth and inhibited the polarization of macrophages. Furthermore, SUV39H2 was found to regulate AKT/FOXO signaling by increasing Akt and FOXO3a phosphorylation. Our findings highlight SUV39H2's role in PCa cell apoptosis and chemosensitivity mainly by regulating the AKT/FOXO signaling pathway and suggest that SUV39H2 could be a potential target for PCa diagnosis and treatment.

Problematic alcohol use: A relational illness

AbstractProblematic alcohol use (PAU) has been a marginalised subject within the systemic field. The present article brings PAU into focus and discusses the conceptualisation of PAU. Reflected in the dominance of individually orientated treatment approaches, PAU is widely seen as an individual condition with aetiology and maintenance attributed to individual pathology and behaviour. Pathologising and stigmatising dominant discourses surrounding PAU also appear to perpetuate this individual conceptualisation, the implications of which are discussed in this article. The present article maintains PAU is a relational illness, with relational aetiology and maintenance, thus with relational implications for treatment. Implications for the systemic field, including clinical practice, are highlighted.

Updated Case Definition of MIS-C and Implications for Clinical Care.

A broad, surveillance case definition was implemented when multisystem inflammatory syndrome in children (MIS-C) emerged in 2020. In 2023, a revised MIS-C case definition was constructed to improve specificity and reduce misclassification with other pediatric inflammatory conditions. This study aims to describe the impact of the updated definition on the classification of patients with MIS-C and Kawasaki Disease (KD). Patients hospitalized from March 2020 to November 2022 with clinician-diagnosed KD and MIS-C at a single center were studied retrospectively. Specificity and positive predictive value were assessed; McNemar test was used to compare specificity. Among 119 patients with MIS-C per the 2020 definition, 20 (17%) did not fulfill the 2023 definition. Six of these 20 (30%) had shock or cardiac involvement. Of 59 KD patients, 10 (17%) met the 2020 MIS-C definition. Five patients (8%) met the 2023 MIS-C definition. Specificity for the 2020 and 2023 MIS-C definitions among KD patients were 83.1% and 91.5% respectively (McNemar, P = .0736). Positive predictive value was higher for the 2023 MIS-C case definition compared with the 2020 MIS-C case definition (95.2% vs 92.2%). Approximately 1 in 5 patients diagnosed with MIS-C using the 2020 case definition did not meet the 2023 definition, including patients with cardiovascular dysfunction. Overlap persisted between patients meeting KD and 2023 MIS-C case definitions, with a false positive rate of 8%. Implications for treatment should be considered, particularly in settings where presumed MIS-C may be treated with corticosteroid monotherapy.

Psychotic symptoms with and without a primary psychotic disorder in children requiring inpatient mental health admission.

Psychotic symptoms are relatively common in children and adolescents attending mental health services. On most occasions, their presence is not associated with a primary psychotic disorder, and their clinical significance remains understudied. No studies to date have evaluated the prevalence and clinical correlates of psychotic symptoms in children requiring inpatient mental health treatment. All children aged 6 to 12years admitted to an inpatient children's unit over a 9-year period were included in this naturalistic study. Diagnosis at discharge, length of admission, functional impairment, and medication use were recorded. Children with psychotic symptoms without a childhood-onset schizophrenia spectrum disorder (COSS) were compared with children with COSS and children without psychotic symptoms using Chi-square and linear regressions. A total of 211 children were admitted during this period with 62.4% experiencing psychotic symptoms. The most common diagnosis in the sample was autism spectrum disorder (53.1%). Psychotic symptoms were not more prevalent in any diagnosis except for COSS (100%) and intellectual disability (81.8%). Psychotic symptoms were associated with longer admissions and antipsychotic medication use. The mean length of admission of children with psychotic symptoms without COSS seems to lie in between that of children without psychotic symptoms and that of children with COSS. We concluded that psychotic symptoms in children admitted to the hospital may be a marker of severity. Screening for such symptoms may have implications for treatment and could potentially contribute to identifying more effective targeted interventions and reducing overall morbidity.

Does pulmonary endarterectomy improve the clinical conditions of patients with chronic thromboembolic pulmonary disease without pulmonary hypertension?

To verify whether the new hemodynamic definition of PH has any implication in treatment of CTEPD patients without PH, we retrospectively analysed the clinical and functional changes determined by pulmonary endarterectomy (PEA) in 63 CTEPD patients without PH who underwent surgery at our center, comparing those in whom the hemodynamic diagnosis of PH met recent guideline recommendations versus those in whom the diagnosis only met previous hemodynamic thresholds.The results show that the vast majority of CTEPD patients without PH operated at our center would now be defined as CTEPH patients. PEA did not result in any improvement in exercise capacity nor in right ventricular function or lung function test in patients with mPAP ≤ 20 mmHg and PVR ≤ 2 WU; on the contrary, hemodynamic parameters, exercise capacity, right ventricular function and lung function significantly improved in patients with mPAP between 21 and 24 mmHg.

Cáncer de esófago

Esophageal cancer is the seventh most common cancer worldwide. It has a high mortality rate both due to its aggressive biological behavior and the delay in diagnosis due to its asymptomatic clinical course in initial phases. Epidermoid carcinoma and adenocarcinoma are the most common histological subtypes, with differences in both their epidemiology and natural history which have prognostic and treatment implications. There is an arsenal of additional tests for its proper diagnosis and staging. The multidisciplinary approach and incorporation of new therapeutic targets open up new perspectives for the treatment of this aggressive disease.

MicroRNAs in maxillofacial bone modeling and remodeling: implications for malocclusion development and orthodontic treatment.

Modeling and remodeling are essential processes in the development and refinement of maxillofacial bones. Dysregulated bone modeling during the developmental stage may lead to maxillofacial bone malformations and malocclusion. Bone remodeling under mechanical loading serves as the biological basis for orthodontic treatment. Although previous reviews have indicated the significance of microRNAs (miRNAs) in bone metabolism, their roles in orchestrating maxillofacial bone modeling and remodeling remain unclear. This review aims to discuss the mechanisms by which miRNAs regulate the morphogenesis and development of maxillofacial bones, as well as their implications for maxillofacial malformations and malocclusion. Moreover, miRNAs participating in maxillofacial bone remodeling and their impacts on cell mechanosensing are also summarized. Given the intricate interplay of cells and signaling pathways, exosomal miRNAs emerge as the orchestrators of the modeling and remodeling processes. The diagnostic and therapeutic potentials of miRNAs are also highlighted in this review for future clinical applications.

Clostridioides difficile Biofilm.

Clostridioides difficile infection (CDI), previously Clostridium difficile infection, is a symptomatic infection of the large intestine caused by the spore-forming anaerobic, gram-positive bacterium Clostridioides difficile. CDI is an important healthcare-associated disease worldwide, characterized by high levels of recurrence, morbidity, and mortality. CDI is observed at a higher rate in immunocompromised patients after antimicrobial therapy, with antibiotics disrupting the commensal microbiota and promoting C. difficile colonization of the gastrointestinal tract.A rise in clinical isolates resistant to multiple antibiotics and the reduced susceptibility to the most commonly used antibiotic molecules have made the treatment of CDI more complicated, allowing the persistence of C. difficile in the intestinal environment.Gut colonization and biofilm formation have been suggested to contribute to the pathogenesis and persistence of C. difficile. In fact, biofilm growth is considered as a serious threat because of the related antimicrobial tolerance that makes antibiotic therapy often ineffective. This is the reason why the involvement of C. difficile biofilm in the pathogenesis and recurrence of CDI is attracting more and more interest, and the mechanisms underlying biofilm formation of C. difficile as well as the role of biofilm in CDI are increasingly being studied by researchers in the field.Findings on C. difficile biofilm, possible implications in CDI pathogenesis and treatment, efficacy of currently available antibiotics in treating biofilm-forming C. difficile strains, and some antimicrobial alternatives under investigation will be discussed here.

Homeostatic Synaptic Plasticity may be Targeted for the Prevention of Post-Stroke Epilepsy

Stroke is the most common cause of acquired epilepsy, with up to 30 percent of stroke survivors developing epilepsy over time. However, the mechanisms leading to neuronal hyperexcitability and epilepsy in stroke survivors are not fully understood. In a recently published work, we demonstrate that ischemic stroke induces homeostatic plasticity regulation in the surviving neurons in the peri-stroke area. Furthermore, activity enhancement through optogenetic stimulation of excitatory pyramidal neurons in the peri-stroke area or systemic administration of D-cycloserine, a partial N-methyl-D-aspartate (NMDA) receptor agonist, reduces seizure susceptibility in mice. Here, we briefly review current understanding on the role of homeostatic plasticity in post-stroke epileptogenesis and discuss how homeostatic plasticity could be targeted to prevent post-stroke epilepsy. We comment on our activity enhancement findings and close by discussing implications for clinical treatment.

The Relationship Between Childhood Trauma, Exercise Addiction, Emotion Regulation Difficulties, and Basic Psychological Needs in Türkiye

Exercise addiction manifests as a behavioral compulsion where physical activity becomes excessively pursued, leading to potential harm to both physical and mental well-being, as well as interpersonal connections. This study aimed to investigate the mediating role of basic psychological needs and emotion regulation difficulties in the relationship between childhood trauma and exercise addiction. The study sample consisted of 386 regular exercisers who completed several questionnaires, including the Childhood Trauma Scale, Exercise Dependence Scale, Basic Need Satisfaction Scale, and Difficulty in Emotion Regulation Scale. The results of the analyses revealed that basic psychological needs and emotion regulation difficulties were significant predictors of exercise addiction symptoms, and they mediated the relationship between childhood trauma and exercise addiction. The findings contribute to the understanding of the factors that may lead to exercise addiction and have implications for prevention and treatment. In this context, the results and limitations are discussed in light of the relevant literature.

A Multi-Relational Graph Encoder Network for Fine-Grained Prediction of MiRNA-Disease Associations.

MicroRNAs (miRNAs) are critical in diagnosing and treating various diseases. Automatically demystifying the interdependent relationships between miRNAs and diseases has recently made remarkable progress, but their fine-grained interactive relationships still need to be explored. We propose a multi-relational graph encoder network for fine-grained prediction of miRNA-disease associations (MRFGMDA), which uses practical and current datasets to construct a multi-relational graph encoder network to predict disease-related miRNAs and their specific relationship types (upregulation, downregulation, or dysregulation). We evaluated MRFGMDA and found that it accurately predicted miRNA-disease associations, which could have far-reaching implications for clinical medical analysis, early diagnosis, prevention, and treatment. Case analyses, Kaplan-Meier survival analysis, expression difference analysis, and immune infiltration analysis further demonstrated the effectiveness and feasibility of MRFGMDA in uncovering potential disease-related miRNAs. Overall, our work represents a significant step toward improving the prediction of miRNA-disease associations using a fine-grained approach could lead to more accurate diagnosis and treatment of diseases.

Immunomodulatory effects of 2-deoxyglucose on peripheral blood mononuclear cells: Implications in COVID-19 treatment

Immunomodulatory effects of 2-deoxyglucose on peripheral blood mononuclear cells: Implications in COVID-19 treatment

The role of HLA genetic variants in COVID-19 susceptibility, severity, and mortality: A global review.

The COVID-19 pandemic has had a profound global impact, with variations in susceptibility, severity, and mortality rates across different regions. While many factors can contribute to the spread and impact of the disease, specifically human leukocyte antigen (HLA) genetic variants have emerged as potential contributors to COVID-19 outcomes. In this comprehensive narrative review, we conducted a thorough literature search to identify relevant studies investigating the association between HLA genetic variants and COVID-19 outcomes. Additionally, we analyzed allelic frequency data from diverse populations to assess differences in COVID-19 incidence and severity. Our review provides insights into the immunological mechanisms involving HLA-mediated responses to COVID-19 and highlights potential research directions and therapeutic interventions. We found evidence suggesting that certain HLA alleles, such as HLA-A02, may confer a lower risk of COVID-19, while others, like HLA-C04, may increase the risk of severe symptoms and mortality. Furthermore, our analysis of allele frequency distributions revealed significant variations among different populations. Considering host genetic variations, particularly HLA genetic variants, is crucial for understanding COVID-19 susceptibility and severity. These findings have implications for personalized treatment and interventions based on an individual's genetic profile. However, further research is needed to unravel the precise mechanisms underlying the observed associations and explore the potential for targeted therapies or preventive measures based on HLA genetic variants.

Neuromuscular choristoma and circumferential nerve territory desmoid-type fibromatosis: imaging findings supporting a nerve-driven mechanism.

Neuromuscular choristoma (NMC) is a rare developmental malformation of peripheral nerve that is frequently associated with the development of a desmoid-type fibromatosis (DTF). Both NMC and NMC-DTF typically contain pathogenic CTNNB1 mutations and NMC-DTF develop only within the NMC-affected nerve territory. The authors aimed to determine if there is a nerve-driven mechanism involved in the formation of NMC-DTF from the underlying NMC-affected nerve. Retrospective review was performed for patients evaluated in the authors' institution with a diagnosis of NMC-DTF in the sciatic nerve (or lumbosacral plexus). MRI and FDG PET/CT studies were reviewed to determine the specific relationship and configuration of NMC and DTF lesions along the sciatic nerve. Ten patients were identified with sciatic nerve NMC and NMC-DTF involving the lumbosacral plexus, sciatic nerve, or sciatic nerve branches. All primary NMC-DTF lesions were located in the sciatic nerve territory. Eight cases of NMC-DTF demonstrated circumferential encasement of the sciatic nerve, and one abutted the sciatic nerve. One patient had a primary DTF remote from the sciatic nerve, but subsequently developed multifocal DTF within the NMC nerve territory, including 2 satellite DTFs that circumferentially encased the parent nerve. Five patients had a total of 8 satellite DTFs, 4 of which abutted the parent nerve and 3 that circumferentially involved the parent nerve. Based on clinical and radiological data, a novel mechanism of NMC-DTF development from soft tissues innervated by NMC-affected nerve segments is proposed, reflecting their shared molecular genetic alteration. The authors believe the DTF develops outward from the NMC in a radial fashion or it arises in the NMC and wraps around it as it grows. In either scenario, NMC-DTF develops directly from the nerve, likely arising from (myo)fibroblasts within the stromal microenvironment of the NMC and grows outward into the surrounding soft tissues. Clinical implications for patient diagnosis and treatment are presented based on the proposed pathogenetic mechanism.

Immune cell markers associated with early life major depressive episodes

Emerging evidence indicates an association between altered immune system functioning, inflammatory response activation, and major depression (MD). This study examined the association between major depression in young people and the monocyte-to-lymphocyte (MLR) and neutrophil-to-lymphocyte ratio (NLR). Inflammation markers were estimated from DNA methylation data using an established cell-mixture deconvolution algorithm and examined in a well-characterized, antidepressant free epidemiological sample of young twins (N = 170). No statistically significant differences were observed between young persons with and without Lifetime MD for the MLR and NLR. A post-hoc analysis of time since last major depressive episode (MDE) indicated that more recent MDEs were associated with higher MLR and NLR levels compared to temporally distant MDEs. A second post-hoc analysis using the full sample determined that past year MDEs were associated with elevated MLR and NLR scores compared to persons unaffected by lifetime MD and person experiencing their last MDE over one year ago. Finally, T cell immunity was most consistently associated with recent MDEs, suggesting that levels of this adaptive immune cell were diminished. Young people experiencing a recent MDE demonstrated increased levels of inflammation with T cells exhibiting the most persistent associations with depression outcomes. Etiological and treatment implications of results are discussed.

Exploring the binding affinity of rutin, catechin, and epicatechin to ALK and caspase-3: implications for colorectal cancer treatment

This study explores the interaction of rutin, catechins, and epicatechins with anaplastic lymphoma kinase (ALK) and caspase-3, focusing on their potential role in modulating the apoptotic mechanisms in colorectal cancer cells. The experimental approach included the preparation of ALK (PDB ID: 5USQ) and caspase-3 (PDB ID: 2XZT), validation of the docking process, optimization of the test compounds, and docking analyses. The molecular docking methodology was validated with an RMSD value of ≤ 3 Å. The docking outcomes revealed that rutin, catechins, and epicatechin exhibited lower binding affinity to ALK, with binding energies of -8.58 kcal/mol, -8.41 kcal/mol, and -7.82 kcal/mol, respectively, compared to ALK's native ligand (-10.27 kcal/mol). Conversely, these compounds demonstrated higher affinity to caspase-3 than its native ligand (-2.54 kcal/mol), with binding energies of -6.03 kcal/mol for rutin, -5.28 kcal/mol for catechins, and -4.95 kcal/mol for epicatechin. These findings suggest that rutin, catechins, and epicatechins hold promise as colorectal anticancer agents by potentially modulating the activity of ALK and caspase-3 through inhibition and activation mechanisms, respectively.

Red Cabbage Juice-Mediated Gut Microbiota Modulation Improves Intestinal Epithelial Homeostasis and Ameliorates Colitis.

Gut microbiota plays a crucial role in inflammatory bowel diseases (IBD) and can potentially prevent IBD through microbial-derived metabolites, making it a promising therapeutic avenue. Recent evidence suggests that despite an unclear underlying mechanism, red cabbage juice (RCJ) alleviates Dextran Sodium Sulfate (DSS)-induced colitis in mice. Thus, the study aims to unravel the molecular mechanism by which RCJ modulates the gut microbiota to alleviate DSS-induced colitis in mice. Using C57BL/6J mice, we evaluated RCJ's protective role in DSS-induced colitis through two cycles of 3% DSS. Mice were daily gavaged with PBS or RCJ until the endpoint, and gut microbiota composition was analyzed via shotgun metagenomics. RCJ treatment significantly improved body weight (p ≤ 0.001), survival in mice (p < 0.001) and reduced disease activity index (DAI) scores. Further, RCJ improved colonic barrier integrity by enhancing the expression of protective colonic mucins (p < 0.001) and tight junction proteins (p ≤ 0.01) in RCJ + DSS-treated mice compared to the DSS group. Shotgun metagenomic analysis revealed an enrichment of short-chain fatty acids (SCFAs)-producing bacteria (p < 0.05), leading to increased Peroxisome Proliferator-Activated Receptor Gamma (PPAR-γ) activation (p ≤ 0.001). This, in turn, resulted in repression of the nuclear factor κB (NFκB) signaling pathway, causing decreased production of inflammatory cytokines and chemokines. Our study demonstrates colitis remission in a DSS-induced mouse model, showcasing RCJ as a potential modulator for gut microbiota and metabolites, with promising implications for IBD prevention and treatment.

Type-switching of short-acting nicotine replacement therapy products and its implications for treatment

IntroductionThe frequency with which people change from one medical treatment to another partly reflects satisfaction with the initial intervention. In this secondary analysis of observational data, we explore switch rates for short-acting nicotine replacement therapy (NRT) products, which differ in mode of use, rapidity of action, and adverse effect profiles. MethodsWe analyzed data from 46,882 participants in the Smoking Treatment for Ontario Patients program who received short-acting NRT (gum, lozenge, oral spray, or inhaler) at their initial visit. We used discrete-time survival analysis to model the time elapsing before a change was made to another product and included time-by-product interactions to explore differences over time and product-by-previous-quit-attempts interactions to examine the importance of potential previous exposure to NRT. We adjusted both models for a range of sociodemographic and tobacco use variables. ResultsOverall, 37.9% (95% CI = 37.5%, 38.4%) of participants switched to a different product at their first follow-up visit. Time-averaged and adjusted switch probabilities were 21.1% for gum, 23.8% for lozenge, 26.0% for inhaler, and 28.8% for oral spray. Switch rates were highest for people without past quit attempts, for women, and for people also using the nicotine patch. ConclusionsPeople frequently switch from one type of short-acting NRT to another. We did not assess reasons for switching, but they may include adverse effects, impracticality, and perceived ineffectiveness. Given the superior effectiveness of combination treatment, making multiple products available may improve outcomes by allowing some people to continue with short-acting products for longer.