The role of early cerebral edema and hematoma assessment in aneurysmal subarachnoid hemorrhage (a-SAH) in predicting structural brain abnormalities in cognitive impairments-- case controlled study.

BACKGROUND: Early assessment and management of cerebral edema and hematoma following aneurysmal subarachnoid hemorrhage (a-SAH) can significantly impact clinical cognitive outcomes. However, current clinical practices lack predictive models to identify early structural brain abnormalities affecting cognition. To address this gap, we propose the development of a predictive model termed the a-SAH Early Brain Edema/Hematoma Compression Neural (Structural Brain) Networks Score System (SEBE-HCNNSS). METHODS: In this study, 202 consecutive patients with spontaneous a-SAH underwent initial computed tomography (CT) or magnetic resonance imaging (MRI) scans within 24 hours of ictus with follow-up 2 months after discharge. Using logistic regression analysis (univariate and multivariate), we evaluated the association of clinically relevant factors and various traditional scale ratings with cognitive impairment (CI). Risk factors with the highest area under the curve (AUC) values were included in the multivariate analysis and least absolute shrinkage and selection operator (LASSO) analysis or Cox regression analysis. RESULTS: A total of 177 patients were enrolled in the study, and 43 patients were classified with a high SEBE-HCNNSS grade (3 to 5). After a mean follow-up of 2 months, 121 individuals (68.36%) with a-SAH and 3 control subjects developed incident CI. The CT inter-observer reliability of the SEBE-HCNNSS scale was high, with a Kappa value of 1. Furthermore, ROC analysis identified the SEBE-HCNNSS scale (OR 3.322, 95% CI 2.312-7.237, P=0.00025) as an independent predictor of edema, CI, and unfavorable prognosis. These results were also replicated in a validation cohort. CONCLUSION: Overall, the SEBE-HCNNSS scale represents a simple assessment tool with promising predictive value for CI and clinical outcomes post-a-SAH. Our findings indicate its practical utility as a prognostic instrument for risk evaluation after a-SAH, potentially facilitating early intervention and treatment.

Role of regulatory non-coding RNAs in traumatic brain injury.

Traumatic brain injury (TBI) is a potentially fatal health event that cannot be predicted in advance. After TBI occurs, it can have enduring consequences within both familial and social spheres. Yet, despite extensive efforts to improve medical interventions and tailor healthcare services, TBI still remains a major contributor to global disability and mortality rates. The prompt and accurate diagnosis of TBI in clinical contexts, coupled with the implementation of effective therapeutic strategies, remains an arduous challenge. However, a deeper understanding of changes in gene expression and the underlying molecular regulatory processes may alleviate this pressing issue. In recent years, the study of regulatory non-coding RNAs (ncRNAs), a diverse class of RNA molecules with regulatory functions, has been a potential game changer in TBI research. Notably, the identification of microRNAs (miRNAs), long non-coding RNAs (lncRNAs), circular RNAs (circRNAs), and other ncRNAs has revealed their potential as novel diagnostic biomarkers and therapeutic targets for TBI, owing to their ability to regulate the expression of numerous genes. In this review, we seek to provide a comprehensive overview of the functions of regulatory ncRNAs in TBI. We also summarize regulatory ncRNAs used for treatment in animal models, as well as miRNAs, lncRNAs, and circRNAs that served as biomarkers for TBI diagnosis and prognosis. Finally, we discuss future challenges and prospects in diagnosing and treating TBI patients in the clinical settings.

Amphiregulin couples IL1RL1+ regulatory T cells and cancer-associated fibroblasts to impede antitumor immunity.

Regulatory T (Treg) cells and cancer-associated fibroblasts (CAFs) jointly promote tumor immune tolerance and tumorigenesis. The molecular apparatus that drives Treg cell and CAF coordination in the tumor microenvironment (TME) remains elusive. Interleukin 33 (IL-33) has been shown to enhance fibrosis and IL1RL1+ Treg cell accumulation during tumorigenesis and tissue repair. We demonstrated that IL1RL1 signaling in Treg cells greatly dampened the antitumor activity of both IL-33 and PD-1 blockade. Whole tumor single-cell RNA sequencing (scRNA-seq) analysis and blockade experiments revealed that the amphiregulin (AREG)-epidermal growth factor receptor (EGFR) axis mediated cross-talk between IL1RL1+ Treg cells and CAFs. We further demonstrated that the AREG/EGFR axis enables Treg cells to promote a profibrotic and immunosuppressive functional state of CAFs. Moreover, AREG mAbs and IL-33 concertedly inhibited tumor growth. Our study reveals a previously unidentified AREG/EGFR-mediated Treg/CAF coupling that controls the bifurcation of fibroblast functional states and is a critical barrier for cancer immunotherapy.

Synergism Between IL21 and Anti-PD-1 Combination Therapy is Underpinned by the Coordinated Reprogramming of the Immune Cellular Network in the Tumor Microenvironment.

T cell-stimulating cytokines and immune checkpoint inhibitors (ICI) are an ideal combination for increasing response rates of cancer immunotherapy. However, the results of clinical trials have not been satisfying. It is important to understand the mechanism of synergy between these two therapeutic modalities. Here, through integrated analysis of multiple single-cell RNA sequencing (scRNA-seq) datasets of human tumor-infiltrating immune cells, we demonstrate that IL21 is produced by tumor-associated T follicular helper cells and hyperactivated/exhausted CXCL13+CD4+ T cells in the human tumor microenvironment (TME). In the mouse model, the hyperactivated/exhausted CD4+ T cell-derived IL21 enhances the helper function of CD4+ T cells that boost CD8+ T cell-mediated immune responses during PD-1 blockade immunotherapy. In addition, we demonstrated that IL21's antitumor activity did not require T-cell trafficking. Using scRNA-seq analysis of the whole tumor-infiltrating immune cells, we demonstrated that IL21 treatment in combination with anti-PD-1 blockade synergistically drives tumor antigen-specific CD8+ T cells to undergo clonal expansion and differentiate toward the hyperactive/exhausted functional state in the TME. In addition, IL21 treatment and anti-PD-1 blockade synergistically promote dendritic cell (DC) activation and maturation to mature DC as well as monocyte to type 1 macrophage (M1) differentiation in the TME. Furthermore, the combined treatment reprograms the immune cellular network by reshaping cell-cell communication in the TME. Our study establishes unique mechanisms of synergy between IL21 and PD-1-based ICI in the TME through the coordinated promotion of type 1 immune responses. Significance: This study reveals how cytokine and checkpoint inhibitor therapy can be combined to increase the efficacy of cancer immunotherapy.

Inflammation-related proteomics demonstrate landscape of fracture blister fluid in patients with acute compartment syndrome.

Background: Blisters are tense vesicles or bullae that arise on swollen skin and are found in a wide range of injuries. As a complication of fracture, fracture blisters are considered soft tissue injuries, which often lead to adverse effects such as prolonged preoperative waiting time and increased risk of surgical site infection. However, our previous study found that in patients with acute compartment syndrome, fracture blisters may be a form of compartment pressure release, but the specific mechanism has not been revealed. Here, we mapped out the proteomic landscape of fracture blister fluid for the first time and compared its expression profile to cupping and burn blisters. Methods: First, fluid samples were collected from 15 patients with fracture blisters, 7 patients with cupping blisters, and 9 patients with burn blisters. Then, the expression levels of 92 inflammatory proteins were measured using the Olink Target 96 Inflammation panel. Protein profiles were compared across the three groups using Differential Protein Expression Analysis and Principal Component Analysis (PCA). Results: Fracture blisters had significantly higher levels of 50 proteins in comparison to cupping and 26 proteins in comparison to burn blisters. Notably, PCA showed fracture blisters closely resembled the protein expression profile of burn blisters but were distinct from the protein expression profile of cupping blisters. Conclusion: Our study provides the first characterization of fracture blister fluid using proteomics, which provides a valuable reference for further analysis of the difference between blisters caused by fractures and those caused by other pathogenic factors. This compendium of proteomic data provides valuable insights and a rich resource to better understand fracture blisters.

Ketamine exposure demographics and outcomes over 16 years as reported to US poison centers.

BACKGROUND: This study sought to examine ketamine exposures reported to US poison centers over the past 16 years and identify trends in exposures and outcomes. METHODS: A retrospective review was performed of all cases involving ketamine exposures reported to US poison centers and entered into the National Poison Data System from 2000 to 2015. Cases were divided into those involving ketamine alone and those involving ketamine and other agents. Data collected included: age, sex, form of ketamine used, reason for exposure, and outcome. RESULTS: A total of 3109 cases were evaluated. 1595 (51%) reported ketamine to be the only substance exposure, while 1514 (49%) involved multiple substances with ketamine. For single agent exposures, more involved males (67%) between the ages of 16-25 years (49%). Single agent ketamine exposures peaked between 2000 and 2002, fell consistently until 2008; then rebounded to previous peak levels through 2015. Intentional exposures (65% of all cases) were the most common reason for single agent ketamine exposures. 53% of ketamine-only cases resulted in minor effects, with two deaths. In contrast, ketamine exposures with multiple agents resulted in outcomes judged as moderate or worse in 62% of cases, including 20 deaths. CONCLUSION: Single-agent ketamine exposures reported to US poison centers have rebounded to historical peaks in recent years. More deaths and serious outcomes were reported in ketamine exposures involving multiple substances.

Bridging cell surface receptor with nuclear receptors in control of bile acid homeostasis.

Bile acids (BAs) are traditionally considered as "physiological detergents" for emulsifying hydrophobic lipids and vitamins due to their amphipathic nature. But accumulating clinical and experimental evidence shows an association between disrupted BA homeostasis and various liver disease conditions including hepatitis infection, diabetes and cancer. Consequently, BA homeostasis regulation has become a field of heavy interest and investigation. After identification of the Farnesoid X Receptor (FXR) as an endogenous receptor for BAs, several nuclear receptors (SHP, HNF4α, and LRH-1) were also found to be important in regulation of BA homeostasis. Some post-translational modifications of these nuclear receptors have been demonstrated, but their physiological significance is still elusive. Gut secrets FGF15/19 that can activate hepatic FGFR4 and its downstream signaling cascade, leading to repressed hepatic BA biosynthesis. However, the link between the activated kinases and these nuclear receptors is not fully elucidated. Here, we review the recent literature on signal crosstalk in BA homeostasis.

Incorporating CanMEDS and subspecialty training into paediatric residency programs: Why are we still deficient?

BACKGROUND: The Royal College of Physician and Surgeons of Canada mandates that paediatric training programs in Canada incorporate subspecialty training and the teaching and evaluation of the seven CanMEDS roles into their curriculum. The literature suggests that newly practicing paediatricians feel inadequately prepared in many subspecialties and CanMEDS roles. HYPOTHESIS: That either current training programs underestimate the importance of these areas for future practice, or that residents themselves feel that these areas are less important. METHOD: An online survey of Canadian paediatric residents and paediatric residency program directors was conducted to determine their views on various subspecialty areas and CanMEDS roles. RESULTS: Fourteen of 16 Canadian paediatric programs participated, and 127 of 486 (26%) paediatric residents completed the survey. Overall, trainees were satisfied with their current training (86%), and 90% believed they would be adequately prepared for independent practice. Forty-six residents (40%) believed training programs place less importance on 10 of the subspecialties that newly practicing paediatricians felt less comfortable with (from a previous study conducted in 2006). However, at least 25% of residents themselves placed less importance on nine of these 10 areas. Residents also place less importance on two CanMEDS competencies which practicing paediatricians felt less comfortable with, including the medical aspects of palliative care (medical expert) and managing an efficient office practice (manager). CONCLUSIONS: Residents and programs place less importance on specific areas of paediatric training, thus creating potential deficiencies in graduating paediatricians. Promotion of these topics during training may better prepare residents for future practice.

Does the presence of polycystic ovary syndrome increase the risk of obstetrical complications in women with gestational diabetes?

OBJECTIVE: To determine whether women with both polycystic ovary syndrome (PCOS) and gestational diabetes mellitus (GDM) have an increased risk of obstetric complications compared with women with GDM alone. METHODS: A retrospective cohort study of maternal/fetal outcomes in women with GDM and PCOS was compared with women with GDM alone. Outcomes were compared using Fisher's exact test for categorical variables and t-test for continuous variables. Logistic regression models allowed for the calculation of odds ratios and 95% confidence intervals (CIs) for each outcome, adjusted for confounding. RESULTS: One hundred seventy one women were included in the study. Significantly more women with both GDM and PCOS had pregnancy-induced hypertension/preeclampsia (15.9% vs. 3.9%, p = 0.019, OR = 4.62, 95% CI = 1.38-15.41). Multiple logistic regression revealed that this increase persisted after controlling for body mass index (p = 0.028, OR = 4.43, 95% CI = 1.17-16.72) and parity (p = 0.050, OR = 3.45, 95% CI = 1.00-11.92). Women with GDM and PCOS tended to have more preterm deliveries (25.0% vs. 11.8%, p = 0.063). More infants of women with GDM and PCOS required phototherapy treatment for hyperbilirubinemia (25.0% vs. 7.9%, p = 0.0066, OR = 3.90, 95% CI = 1.52-9.98). Logistic regression revealed that this association persisted after controlling for preterm delivery (OR = 3.18, 95% CI = 1.14-8.82, p = 0.026). CONCLUSIONS: Mothers with both disorders should be monitored more carefully and counseled regarding their increased risk of both maternal and fetal complications.