SPHK1 promotes bladder cancer metastasis via PD-L2/c-Src/FAK signaling cascade.

SPHK1 (sphingosine kinase type 1) is characterized as a rate-limiting enzyme in sphingolipid metabolism to phosphorylate sphingosine into sphingosine-1-phosphate (S1P) that can bind to S1P receptors (S1PRs) to initiate several signal transductions leading to cell proliferation and survival of normal cell. Many studies have indicated that SPHK1 is involved in several types of cancer development, however, a little is known in bladder cancer. The TCGA database analysis was utilized for analyzing the clinical relevance of SPHK1 in bladder cancer. Through CRISPR/Cas9 knockout (KO) and constitutive activation (CA) strategies on SPHK1 in the bladder cancer cells, we demonstrated the potential downstream target could be programmed cell death 1 ligand 2 (PD-L2). On the other hand, we demonstrated that FDA-approved SPHK1 inhibitor Gilenya® (FTY720) can successfully suppress bladder cancer metastasis by in vitro and in vivo approaches. This finding indicated that SPHK1 as a potent therapeutic target for metastatic bladder cancer by dissecting the mechanism of action, SPHK1/S1P-elicited Akt/ß-catenin activation promoted the induction of PD-L2 that is a downstream effector in facilitating bladder cancer invasion and migration. Notably, PD-L2 interacted with c-Src that further activates FAK. Here, we unveil the clinical relevance of SPHK1 in bladder cancer progression and the driver role in bladder cancer metastasis. Moreover, we demonstrated the inhibitory effect of FDA-approved SPHK1 inhibitor FTY720 on bladder cancer metastasis from both in vitro and in vivo models.

Identifying heterogeneous subgroups of systemic autoimmune diseases by applying a joint dimension reduction and clustering approach to immunomarkers.

BACKGROUND: The high complexity of systemic autoimmune diseases (SADs) has hindered precise management. This study aims to investigate heterogeneity in SADs. METHODS: We applied a joint cluster analysis, which jointed multiple correspondence analysis and k-means, to immunomarkers and measured the heterogeneity of clusters by examining differences in immunomarkers and clinical manifestations. The electronic health records of patients who received an antinuclear antibody test and were diagnosed with SADs, namely systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and Sjögren's syndrome (SS), were retrieved between 2001 and 2016 from hospitals in Taiwan. RESULTS: With distinctive patterns of immunomarkers, a total of 11,923 patients with the three SADs were grouped into six clusters. None of the clusters was composed only of a single SAD, and these clusters demonstrated considerable differences in clinical manifestation. Both patients with SLE and SS had a more dispersed distribution in the six clusters. Among patients with SLE, the occurrence of renal compromise was higher in Clusters 3 and 6 (52% and 51%) than in the other clusters (p < 0.001). Cluster 3 also had a high proportion of patients with discoid lupus (60%) than did Cluster 6 (39%; p < 0.001). Patients with SS in Cluster 3 were the most distinctive because of the high occurrence of immunity disorders (63%) and other and unspecified benign neoplasm (58%) with statistical significance compared with the other clusters (all p < 0.05). CONCLUSIONS: The immunomarker-driven clustering method could recognise more clinically relevant subgroups of the SADs and would provide a more precise diagnosis basis.

Self-adjusted Nitrous Oxide During Urodynamic Studies Reduces Patient Pain Without Compromising Study Quality: A Randomized Controlled Trial.

Background and objective: A urodynamic study (UDS) is a routine clinic procedure that can cause significant discomfort for certain patients, with no satisfactory analgesic alternatives currently available. Our aim was to evaluate the effectiveness of low-dose self-adjusted nitrous oxide (SANO), titrated to the patient's desired effect, on standard metrics for bladder function and on patient-reported pain and anxiety. Methods: We conducted a single-institution, double-blind, randomized crossover trial in adults undergoing UDS. Each patient underwent two consecutive UDS runs, randomized to receive oxygen during the first run followed by SANO during the second run, or vice versa. UDS outcomes (capacity, detrusor strength, residual volume) and patient subjective outcomes (Visual Analog Scale for pain and anxiety, operator assessment of verbal feedback) were compared between the two runs. Secondary analyses were performed to compare outcomes during the first UDS run and adjust for treatment order. A paired Wilcoxon signed rank-sum test and McNemar's χ2 test were used to compare continuous and categorical variables, respectively. Adverse events were recorded. Key findings and limitations: Nineteen patients were randomized (10 to oxygen for the first run, 9 to SANO for the first run). UDS outcomes did not differ between the two arms. Patients reported significantly less pain during the SANO run than during the oxygen run (p = 0.046). Verbal feedback was significantly better with SANO (p = 0.001). Most patients (15/19, 79%) stated that they would prefer to receive SANO during future UDS. There were no significant complications. Conclusions and clinical implications: SANO oxide is a safe and effective means of preserving standard adult UDS metrics while significantly reducing patient-reported pain. Patient summary: Urodynamic tests (UDS) for evaluation of lower urinary tract symptoms can cause discomfort and pain. Our study shows that nitrous oxide gas self-adjusted by patients had no effect on UDS test outcomes or on verbal feedback during the procedure, and reduced discomfort and pain in comparison to oxygen. Nitrous oxide may an attractive option for patients who are reluctant to undergo UDS.

Delta Immature Platelet Fraction Is Associated With Mortality in Bacteremia Patients.

OBJECTIVES: Immature platelet fraction (IPF) for differentiating bacteremia has been explored, whereas its prognostic correlation remains uncertain. This study aims to confirm the predictive capability of IPF for bacteremia and investigate its association with prognosis. METHODS: Patients with complete blood count (CBC) on the blood culture day (D1) and the preceding day (D0) were retrospectively recruited and categorized into bacteremia and nonbacteremia groups. Immature platelet (IP) analysis, alongside CBC, was conducted. Delta IPF, defined by the absolute values of D1 minus D0 results was calculated. The ability to distinguish bacteremia from nonbacteremia patients, and the correlation with mortality were analyzed. RESULTS: From February to December 2020, a total of 150 patients were enrolled, with 75 having bacteremia. The specificity for delta IPF ≥3.4% to predict bacteremia was 97.3% (95% confidence interval [CI]: 90.7-99.7). When delta IPF ≥3.4% combined with procalcitonin ≥0.5 (ng/mL), the sensitivity was 90.5% (95% CI: 69.6%-98.8%). Within the bacteremia group, delta IPF and the proportion of patients with delta IPF ≥1.5% were significantly higher in nonsurvival, while delta platelet levels did not. Furthermore, delta IPF ≥1.5% was independently associated with 30-day mortality (adjusted odds ratio: 3.88, 95% CI: 1.2%-11.4%; p = 0.020). The 30-day survival curve demonstrated a significant difference between patients with delta IPF ≥1.5% and those without (p < 0.001). CONCLUSIONS: Delta IPF correlates with mortality in bacteremia patients. Our findings suggest IPF not only helps detect bacteremia but also predicts prognosis in the early stage.

A cis-acting ligase ribozyme generates circular RNA in vitro for ectopic protein functioning.

Delivering synthetic protein-coding RNA bypassing the DNA stage for ectopic protein functioning is a novel therapeutic strategy. Joining the linear RNA head-to-tail covalently could be a state-of-the-art strategy for functioning longer. Here we enroll a cis-acting ligase ribozyme (RzL) to generate circular RNA (circRNA) in vitro for ectopic protein expression. The RNA circularization is confirmed by masking the 5' phosphate group, resisting exonuclease RNase R digestion, failing for further tailing, and sequencing the RT-PCR products of the joined region. Interestingly, one internal ribosome entry site (IRES) renders circRNA translation competent, but two IRES in cis, not trans, hamper the translation. The circRNA with highly potent in translation is conferred for antiviral functioning. Accompanying specific guided RNA, a circRNA expressing ribonuclease Cas13 shows excellent potential against the corresponding RNA virus, further extending circRNA functioning in its growing list of applications.

PPARγ activation ameliorates PM2.5-induced renal tubular injury by inhibiting ferroptosis and epithelial-mesenchymal transition.

Exposure to fine particulate matter (PM2.5) has been associated with the development and progression of renal disease. Peroxisome proliferator-activated receptor gamma (PPARγ), a key transcription factor involved in inflammation as well as lipid and glucose metabolism, helps maintain the integrity of tubular epithelial cells. However, the precise role of PPARγ in PM2.5-induced tubular injury remains unclear. In this study, we investigated the regulatory effects of PPARγ on PM2.5-induced ferroptotic stress and epithelial-mesenchymal transition (EMT) in tubular (HK-2) cells. We found that downregulation of PPARγ expression was correlated with EMT in PM2.5-exposed cells. Pretreatment with the PPARγ agonist 15d-PGJ2 protected the cells from EMT by reducing ferroptotic stress, whereas that with the PPARγ antagonist GW9662 promoted EMT. Furthermore, pretreatment with ferrostatin-1 (Fer-1) significantly prevented PM2.5-induced EMT and downregulation of PPARγ expression. Notably, overexpression of PPARγ blocked PM2.5-induced downregulation of E-cadherin and GPX4 expression and upregulation of α-SMA expression. This study highlights the complex associations of PPARγ with ferroptosis and EMT in PM2.5-exposed tubular cells. Our findings suggest that PPARγ activation confers protection against PM2.5-induced renal injury.

Development and evaluation of a deep neural network model for orthokeratology lens fitting.

PURPOSE: To optimise the precision and efficacy of orthokeratology, this investigation evaluated a deep neural network (DNN) model for lens fitting. The objective was to refine the standardisation of fitting procedures and curtail subjective evaluations, thereby augmenting patient safety in the context of increasing global myopia. METHODS: A retrospective study of successful orthokeratology treatment was conducted on 266 patients, with 449 eyes being analysed. A DNN model with an 80%-20% training-validation split predicted lens parameters (curvature, power and diameter) using corneal topography and refractive indices. The model featured two hidden layers for precision. RESULTS: The DNN model achieved mean absolute errors of 0.21 D for alignment curvature (AC), 0.19 D for target power (TP) and 0.02 mm for lens diameter (LD), with R2 values of 0.97, 0.95 and 0.91, respectively. Accuracy decreased for myopia of less than 1.00 D, astigmatism exceeding 2.00 D and corneal curvatures >45.00 D. Approximately, 2% of cases with unique physiological characteristics showed notable prediction variances. CONCLUSION: While exhibiting high accuracy, the DNN model's limitations in specifying myopia, cylinder power and corneal curvature cases highlight the need for algorithmic refinement and clinical validation in orthokeratology practice.

Attentional Bias for Opioids in Taiwanese Heavy Smokers with Chronic Noncancer Pain.

Background and Objectives: Attentional bias (AB) for addictive substances is a feature of attention found in individuals with substance misuse or diagnosed with substance use disorders. When AB exists, the attention of the addicted individual may be quickly oriented to cues related to the addictive substance or be maintained on these cues for a longer time. AB toward opioids was found in Western samples of smokers with chronic noncancer pain. The level of AB was dose-responsive. However, similar studies in the Taiwanese population are lacking. This study compared the patterns of AB for opioid analgesics in Taiwanese participants with chronic noncancer pain to that of individuals without pain. This study aimed to investigate if AB toward opioids is presented in Taiwanese heavy smokers who are on long-term opioid therapy for pain control. Materials and Methods: Participants were grouped into chronic noncancer pain smokers, chronic pain nonsmokers, and smokers without pain, according to smoking habits and whether or not on long-term opioid therapy for pain control. Each participant completed demographic questionnaires, mood scales, and the opioid-related visual probe task. Differences in AB among the groups were compared using a three-way analysis of covariance controlling for daily cigarette consumption. Results: Chronic noncancer pain smokers (n = 17) and chronic pain nonsmokers (n = 16) displayed more severe levels of depression, anxiety, and pain, compared to smokers without pain (n = 28). Only did chronic pain nonsmokers show significant AB for opioid cues that were displayed for a short time. Analysis on reaction time found that smokers without pain consistently responded faster to the tasks. No difference in reaction time was found between the pain groups. Conclusions: The current study did not fully replicate findings from studies that were based in Western countries. Formulary availability and regulatory limitations might have affected patient's perception of prescription opioids in Taiwan. However, chronic pain nonsmokers exhibited initial orientation toward opioid-related cues when daily cigarette consumption was accounted for. According to previous research, this AB for shortly displayed opioid cues can be associated with the expectation of pain relief. The current finding also indicated general psychomotor retardation in individuals who were on long-term use of opioids.

Glutathione determines chronic myeloid leukemia vulnerability to an inhibitor of CMPK and TMPK.

Bcr-Abl transformation leads to chronic myeloid leukemia (CML). The acquirement of T315I mutation causes tyrosine kinase inhibitors (TKI) resistance. This study develops a compound, JMF4073, inhibiting thymidylate (TMP) and cytidylate (CMP) kinases, aiming for a new therapy against TKI-resistant CML. In vitro and in vivo treatment of JMF4073 eliminates WT-Bcr-Abl-32D CML cells. However, T315I-Bcr-Abl-32D cells are less vulnerable to JMF4073. Evidence is presented that ATF4-mediated upregulation of GSH causes T315I-Bcr-Abl-32D cells to be less sensitive to JMF4073. Reducing GSH biosynthesis generates replication stress in T315I-Bcr-Abl-32D cells that require dTTP/dCTP synthesis for survival, thus enabling JMF4073 susceptibility. It further shows that the levels of ATF4 and GSH in several human CML blast-crisis cell lines are inversely correlated with JMF4073 sensitivity, and the combinatory treatment of JMF4073 with GSH reducing agent leads to synthetic lethality in these CML blast-crisis lines. Altogether, the investigation indicates an alternative option in CML therapy.

The Effect of Oncology Nurse Navigation on Mental Health in Patients with Cancer in Taiwan: A Randomized Controlled Clinical Trial.

In this study, we investigated the prevalence of mental health problems among patients with cancer and whether oncology nurse navigation improved their mental health outcomes and medical experience. In this randomized controlled clinical trial, we recruited 128 outpatients with cancer via purposive sampling from a teaching hospital in northern Taiwan. Participants were randomly assigned to the navigation group (N = 61) or the usual care group (N = 67). Data were collected from January 2019 to July 2020 using questionnaires, including the self-reported Distress Thermometer, Hospital Anxiety and Depression Scale, Demoralization Scale, and Patient Assessment of Chronic Illness Care. Data were collected at baseline and after three and six months of the intervention. Descriptive and analytical statistical analyses were performed. The prevalence rates of anxiety, depression, distress, and demoralization were 17.9%, 15.7%, 29.7%, and 29.7%, respectively. After three months, the participants in the navigation group exhibited significantly reduced levels of anxiety, demoralization, and emotional distress (reduced by 92%, 75%, and 58%, respectively) and reported a better medical experience (odds ratio = 1.40) than those in the usual care group.

Plasmonics nanorod biosensor for in situ intracellular detection of gene expression biomarkers in intact plant systems.

The intracellular developmental processes in plants, particularly concerning lignin polymer formation and biomass production are regulated by microRNAs (miRNAs). MiRNAs including miR397b are important for developing efficient and cost-effective biofuels. However, traditional methods of monitoring miRNA expression, like PCR, are time-consuming, require sample extraction, and lack spatial and temporal resolution, especially in real-world conditions. We present a novel approach using plasmonics nanosensing to monitor miRNA activity within living plant cells without sample extraction. Plasmonic biosensors using surface-enhanced Raman scattering (SERS) detection offer high sensitivity and precise molecular information. We used the Inverse Molecular Sentinel (iMS) biosensor on unique silver-coated gold nanorods (AuNR@Ag) with a high-aspect ratio to penetrate plant cell walls for detecting miR397b within intact living plant cells. MiR397b overexpression has shown promise in reducing lignin content. Thus, monitoring miR397b is essential for cost-effective biofuel generation. This study demonstrates the infiltration of nanorod iMS biosensors and detection of non-native miRNA 397b within plant cells for the first time. The investigation successfully demonstrates the localization of nanorod iMS biosensors through TEM and XRF-based elemental mapping for miRNA detection within plant cells of Nicotiana benthamiana. The study integrates shifted-excitation Raman difference spectroscopy (SERDS) to decrease background interference and enhance target signal extraction. In vivo SERDS testing confirms the dynamic detection of miR397b in Arabidopsis thaliana leaves after infiltration with iMS nanorods and miR397b target. This proof-of-concept study is an important stepping stone towards spatially resolved, intracellular miRNA mapping to monitor biomarkers and biological pathways for developing efficient renewable biofuel sources.

Glucocorticoid resistance remodels liver lipids and prompts lipogenesis, eicosanoid, and inflammatory pathways.

We have previously demonstrated that the glucocorticoid receptor ß (GRß) isoform induces hepatic steatosis in mice fed a normal chow diet. The GRß isoform inhibits the glucocorticoid-binding isoform GRα, reducing responsiveness and inducing glucocorticoid resistance. We hypothesized that GRß regulates lipids that cause metabolic dysfunction. To determine the effect of GRß on hepatic lipid classes and molecular species, we overexpressed GRß (GRß-Ad) and vector (Vec-Ad) using adenovirus delivery, as we previously described. We fed the mice a normal chow diet for 5 days and harvested the livers. We utilized liquid chromatography-mass spectrometry (LC-MS) analyses of the livers to determine the lipid species driven by GRß. The most significant changes in the lipidome were monoacylglycerides and cholesterol esters. There was also increased gene expression in the GRß-Ad mice for lipogenesis, eicosanoid synthesis, and inflammatory pathways. These indicate that GRß-induced glucocorticoid resistance may drive hepatic fat accumulation, providing new therapeutic advantages.

The sleep problems in individuals with Rett syndrome and their caregivers.

LAY ABSTRACT: Sleep problems are common and impactful among individuals with Rett syndrome (RTT) and their caregivers. We examined the sleep patterns of 29 RTT patients and their primary caregivers using various assessment tools. The study found that a majority of the patients experienced sleep disturbances, with younger patients showing more sleep difficulties. Caregivers also reported poor sleep quality. The findings emphasize the need to address sleep problems in RTT management, as improving sleep quality can positively impact the well-being of individuals with RTT and their caregivers.

Anticholinergic Burden in Patients Treated for Overactive Bladder: Second-Line Therapy with Tibial Nerve Stimulation as a Solution.

Overactive bladder (OAB) is a highly prevalent condition with significant associated comorbidities. Current management guidelines suggest the utilization of anticholinergic medication as a second line after nonpharmacological treatment. Tibial nerve stimulation (TNS), which has previously been thought to have been expensive and inaccessible, was relegated to a third-line therapy. However, given the recently discovered association between anticholinergic medication use and dementia as well as the recent FDA approval of transcutaneous tibial nerve stimulation (TTNS), there may be a need to revisit management guidelines. In this commentary, we identify the two types of TNS, percutaneous tibial nerve stimulation (PTNS) and TTNS and compare them with anticholinergics. By considering their respective efficacies, side-effects profiles, and associated costs, we make the case in this commentary for an update to guidelines that includes TNS as second-line OAB management ahead of anticholinergic medication.

The neuropathological landscape of small vessel disease and Lewy pathology in a cohort of Hispanic and non-Hispanic White decedents with Alzheimer disease.

Cerebrovascular and α-synuclein pathologies are frequently observed alongside Alzheimer disease (AD). The heterogeneity of AD necessitates comprehensive approaches to postmortem studies, including the representation of historically underrepresented ethnic groups. In this cohort study, we evaluated small vessel disease pathologies and α-synuclein deposits among Hispanic decedents (HD, n = 92) and non-Hispanic White decedents (NHWD, n = 184) from three Alzheimer's Disease Research Centers: Columbia University, University of California San Diego, and University of California Davis. The study included cases with a pathological diagnosis of Intermediate/High AD based on the National Institute on Aging- Alzheimer's Association (NIA-AA) and/or NIA-Reagan criteria. A 2:1 random comparison sample of NHWD was frequency-balanced and matched with HD by age and sex. An expert blinded to demographics and center origin evaluated arteriolosclerosis, cerebral amyloid angiopathy (CAA), and Lewy bodies/Lewy neurites (LBs/LNs) with a semi-quantitative approach using established criteria. There were many similarities and a few differences among groups. HD showed more severe Vonsattel grading of CAA in the cerebellum (p = 0.04), higher CAA density in the posterior hippocampus and cerebellum (ps = 0.01), and increased LBs/LNs density in the frontal (p = 0.01) and temporal cortices (p = 0.03), as determined by Wilcoxon's test. Ordinal logistic regression adjusting for age, sex, and center confirmed these findings except for LBs/LNs in the temporal cortex. Results indicate HD with AD exhibit greater CAA and α-synuclein burdens in select neuroanatomic regions when compared to age- and sex-matched NHWD with AD. These findings aid in the generalizability of concurrent arteriolosclerosis, CAA, and LBs/LNs topography and severity within the setting of pathologically confirmed AD, particularly in persons of Hispanic descent, showing many similarities and a few differences to those of NHW descent and providing insights into precision medicine approaches.

Factors Impacting Fall Severity in Hospitalized Patients: A Retrospective Cohort Study.

Objectives: This retrospective case-controlled study aimed to evaluate the association between the severity of fall-related injuries and fall-risk-increasing drugs (FRIDs) in hospitalized patients. Methods: Data were collected from Changhua Christian Hospital, Taiwan, of all adult inpatients who experienced falls between January 2017 and December 2021, and were divided into two groups based on whether they sustained severe fall-related injuries. Retrospective data that may affect the severity of fall-related injuries and the use of FRIDs were investigated. Results: Among 1231 documented cases of falls, 26 patients sustained severe fall-related injuries. Older patients and those with osteoporosis were more susceptible to more severe injuries from a fall. The use of mobility aids and osteoporosis medications showed protective effects against fall injuries. No significant association was observed between fall-related injuries and comorbidities or FRIDs. Multivariate analysis confirmed the inverse correlation between the use of mobility aids, osteoporosis medications, and fall severity. Patients with osteoporosis exhibited significantly higher odds of sustaining more severe injuries with a fall (odds ratio = 3.02, 95% confidence interval: 1.21-7.53). Conclusions: This study highlights the importance of addressing risk factors associated with fall severity among hospitalized patients. Providing mobility aids to persons at greater risk.

The effect of antifibrotic agents on acute respiratory failure in COVID-19 patients: a retrospective cohort study from TriNetX US collaborative networks.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic has had a significant impact on global health and economies, resulting in millions of infections and deaths. This retrospective cohort study aimed to investigate the effect of antifibrotic agents (nintedanib and pirfenidone) on 1-year mortality in COVID-19 patients with acute respiratory failure. METHODS: Data from 61 healthcare organizations in the TriNetX database were analyzed. Adult patients with COVID-19 and acute respiratory failure were included. Patients with a pre-existing diagnosis of idiopathic pulmonary fibrosis before their COVID-19 diagnosis were excluded. The study population was divided into an antifibrotic group and a control group. Propensity score matching was used to compare outcomes, and hazard ratios (HR) for 1-year mortality were calculated. RESULTS: The antifibrotic group exhibited a significantly lower 1-year mortality rate compared to the control group. The survival probability at the end of the study was 84.42% in the antifibrotic group and 69.87% in the control group. The Log-Rank test yielded a p-value of less than 0.001. The hazard ratio was 0.434 (95% CI: 0.264-0.712), indicating a significant reduction in 1-year mortality in the antifibrotic group. Subgroup analysis demonstrated significantly improved 1-year survival in patients receiving nintedanib treatment and during periods when the Wuhan strain was predominant. DISCUSSION: This study is the first to demonstrate a survival benefit of antifibrotic agents in COVID-19 patients with acute respiratory failure. Further research and clinical trials are needed to confirm the efficacy of these antifibrotic agents in the context of COVID-19 and acute respiratory failure.

Synergistic B and T lymphocyte interaction: prognostic implications in non-small cell lung cancer.

While T-cell-mediated immune responses in solid tumors have been well-established and have driven major therapeutic advances, our understanding of B-cell biology in cancer is comparatively less developed. A total of 60 lung cancer patients were included, of which 53% were diagnosed at an early stage while 47% were diagnosed at an advanced stage. Flow cytometry was used to analyze the proportion of T and B cells in all blood samples, and the levels of human serum cytokines were also assessed. Compared to the control group, cancer patients showed lower frequencies of IgD+CD27+ marginal B cells and CD32+ B cells, and higher frequencies of T cells with lower CD8+ T cells and higher central memory and naïve CD4+ T cells. Additionally, advanced-stage cancer patients exhibited higher levels of cytokines, a higher proportion of effector memory CD8+ T cells, and a lower frequency of CD27+CD28+CD4+/CD8+ T cells. Linear regression analysis revealed significant correlations between cancer stage and the frequency of B and T cell subsets, leukocyte count, and cytokine levels. Survival analysis demonstrated that patients with higher frequency of class-switched B cells had a worse prognosis, while patients with higher frequency of CD8+ effector T cells and lower frequency of CD4+57+ T cells appeared to have a better survival rate. These findings provide valuable insight into the immunological changes that occur during lung cancer progression and have the potential to inform the development of new immunotherapeutic strategies.

Metformin alters dendrite development and synaptic plasticity in rat cortical neurons.

Synaptic plasticity is crucial as it dynamically molds the strength and connectivity of neural circuits, influencing learning, memory, and the development of neurological disorders. Metformin, a widely prescribed anti-diabetic medication, has been shown to readily cross the blood-brain barrier (BBB) and the placenta. However, its prolonged impact on neuronal morphology and functions remains underexplored. In this study, we investigated the influence of metformin on dendrite development and synaptic plasticity in embryonic brains and primary rat cortical neurons. Our findings reveal a negative modulation of dendrite development by metformin, as evidenced by altered dendritic arborization, impaired dendritic spine morphology and disruptions in synaptic plasticity, suggesting a potential link between metformin exposure and aberrations in neuronal connectivity. In addition, we extend our insights to the impact of maternal metformin exposure on embryonic brains, revealing a significant inhibition of dendrite development in E18.5 rat brains. In conclusion, this study adds to the expanding knowledge base on the non-metabolic effects of metformin, emphasizing the significance of assessing its potential influence on both neuronal structure and function. There is an urgent need for further investigations into the enduring impact of prolonged metformin administration on the structural and functional aspects of neurons.

Erector spinae plane block level does not impact analgesic efficacy in enhanced recovery for lumbar spine surgery.

BACKGROUND CONTEXT: Postoperative pain control following spine surgery can be difficult. The Enhanced Recovery After Surgery (ERAS) programs use multimodal approaches to manage postoperative pain. While an erector spinae plane block (ESPB) is commonly utilized, the ideal distance for injection from the incision, referred to as the ES (ESPB to mid-surgical level) distance, remains undetermined. PURPOSE: We evaluated the impact of varying ES distances for ESPB on Numerical Rating Scale (NRS) measures of postoperative pain within the ERAS protocol. STUDY DESIGN/SETTING: Retrospective observational study. PATIENT SAMPLE: Adult patients who underwent elective lumbar spine fusion surgery. OUTCOME MEASURES: Primary outcome measures include the comparative postoperative NRS scores across groups at immediate (T1), 24 (T2), 48 (T3), and 72 (T4) hours postsurgery. For secondary outcomes, a propensity matching analysis compared these outcomes between the ERAS and non-ERAS groups, with opioid-related recovery metrics also assessed. METHODS: All included patients were assigned to one of three ERAS groups according to the ES distance: Group 1 (G1, ES > 3 segments), Group 2 (G2, ES = 2-3 segments), and Group 3 (G3, ES<2 segments). Each patient underwent a bilateral ultrasound-guided ESPB with 60 mL of diluted ropivacaine or bupivacaine. RESULTS: Patients within the ERAS cohort reported mild pain (NRS < 3), with no significant NRS variation across G1 to G3 at any time. Sixty-five patients were matched across ERAS and non-ERAS groups. The ERAS group exhibited significantly lower NRS scores from T1 to T3 than the non-ERAS group. Total morphine consumption during hospitalization was 26.7 mg for ERAS and 41.5 mg for non-ERAS patients. The ERAS group resumed water and food intake sooner and had less postoperative nausea and vomiting. CONCLUSIONS: ESPBs can be effectively administered at or near the mid-surgical level to the low thoracic region for lumbar spine surgeries. Given challenges with sonovisualization, a lumbar ESPB may be preferred to minimize the risk of inadvertent pleural injury.