Mfn2 regulates mitochondria and mitochondria-associated endoplasmic reticulum membrane function in neurodegeneration induced by repeated sevoflurane exposure.

Repeated sevoflurane exposure in neonatal mice can leads to neuronal apoptosis and mitochondrial dysfunction. The mitochondria are responsible for energy production to maintain homeostasis in the central nervous system. The mitochondria-associated endoplasmic reticulum membrane (MAM) is located between the mitochondria and endoplasmic reticulum (ER), and it is critical for mitochondrial function and cell survival. MAM malfunction contributes to neurodegeneration, however, whether it is involved in sevoflurane-induced neurotoxicity remains unknown. Our study demonstrated that repeated sevoflurane exposure induced mitochondrial dysfunction and dampened the MAM structure. The upregulated ER-mitochondria tethering enhanced Ca2+ transition from the cytosol to the mitochondria. Overload of mitochondrial Ca2+ contributed to opening of the mitochondrial permeability transition pore (mPTP), which caused neuronal apoptosis. Mitofusin 2(Mfn2), a key regulator of ER-mitochondria contacts, was found to be suppressed after repeated sevoflurane exposure, while restoration of Mfn2 expression alleviated cognitive dysfunction due to repeated sevoflurane exposure in the adult mice. These evidences suggest that sevoflurane-induced MAM malfunction is vulnerable to Mfn2 suppression, and the enhanced ER-mitochondria contacts promotes mitochondrial Ca2+ overload, contributing to mPTP opening and neuronal apoptosis. This paper sheds light on a novel mechanism of sevoflurane-induced neurotoxicity. Furthermore, targeting Mfn2-mediated regulation of the MAM structure and mitochondrial function may provide a therapeutic advantage in sevoflurane-induced neurodegeneration.

Risk of Pediatric Bipolar Disorder After General Anesthesia in Infants and Toddlers: A Propensity Score-Matched Population-Based Cohort Study.

BACKGROUND AND HYPOTHESIS: The potential role of anesthesia as an independent risk factor for childhood bipolar disorder (BD) remains unclear. To address this, we conducted a population-based cohort study employing propensity score matching to compare BD incidence between pediatric patients undergoing surgery with and without general anesthesia. STUDY DESIGN: Our study included patients aged 0-3 years who received at least 1 episode of general anesthesia and were hospitalized for over 1 day in Taiwan between January 2004 and December 2014. They were matched 1:1 with a population not receiving general anesthesia to assess pediatric BD incidence. STUDY RESULTS: The study cohort comprised 15 070 patients, equally distributed between the general anesthesia and nongeneral anesthesia groups (7535 each). Multivariate Cox regression analysis revealed adjusted hazard ratios (aHRs; 95% CIs) for pediatric BD in the general anesthesia group as 1.26 (1.04-1.54; P = .021) compared to the nongeneral anesthesia group. Moreover, the incidence rate ratio (95% CI) for the general anesthesia group was 1.26 (1.03-1.53) compared to the nongeneral anesthesia group. CONCLUSIONS: Early childhood exposure to general anesthesia is significantly associated with an increased risk of pediatric BD. This expands understanding of pediatric BD's complex development, informing preventive strategies, and enhancing mental health outcomes for vulnerable young patients and global pediatric healthcare.

Dose-Dependent Effect of Aspirin Use in Reducing Diabetes-Associated Dementia Risk Among Elderly Patients With Type 2 Diabetes Mellitus.

OBJECTIVE: This study investigated the association between aspirin use and diabetes-associated dementia in older patients with type 2 diabetes mellitus (T2DM), assessing aspirin's potential protective effects, intensity of use, and dose-dependency against dementia. DESIGN: A cohort study evaluating the dose-dependent protective impact of aspirin against dementia in a population-based sample. SETTING AND PARTICIPANTS: Older patients with T2DM (≥60 years), comparing aspirin users with nonusers. METHODS: Used a time-varying Cox hazards model to assess dementia incidence. RESULTS: Older aspirin users exhibited a significant reduction in dementia risk (adjusted hazard ratio [aHR], 0.44; 95% CI, 0.41-0.46). The lowest aHRs for dementia were observed at a daily intensity of 0.91 defined daily doses (DDDs), and higher daily dosages (>0.91 DDD) showed gradually increasing aHRs (although still <1). Analysis of cumulative DDD revealed a dose-response relationship, with progressively lower aHRs across quartiles (0.16, 0.42, 0.57, and 0.63 for quartiles 4, 3, 2, and 1, respectively) compared with never aspirin users (P for trend < .0001). CONCLUSIONS AND IMPLICATIONS: Aspirin use in older patients with T2DM significantly reduces dementia risk. The optimal daily intensity of aspirin use (0.91 DDD) is associated with the lowest aHR for dementia. These findings suggest a dose-dependent relationship, supporting the potential benefits of higher cumulative dosages of aspirin in reducing dementia risk in this population.

SFXN1-mediated immune cell infiltration and tumorigenesis in lung adenocarcinoma: A potential therapeutic target.

BACKGROUND: Sideroflexin 1 (SFXN1), a mitochondrial serine transporter implicated in one-carbon metabolism, is a prognostic biomarker in lung adenocarcinoma (LUAD). However, its role in LUAD progression remains elusive. This study aimed to investigate the functional significance of SFXN1 in LUAD and evaluate its potential as a therapeutic target. METHODS: We analyzed SFXN1 expression and its diagnostic and prognostic value in LUAD using the Pan-cancer TCGA dataset. In vitro assays (CCK-8, cell cycle, EDU, wound-healing, and transwell) were employed to assess the role of SFXN1, complemented by in vivo experiments. RNA sequencing elucidated SFXN1-mediated cellular functions and potential mechanisms. Bulk RNA-seq and scRNA-seq data from TCGA and GEO were used to investigate the correlation between SFXN1 and the tumor immune microenvironment. RT-qPCR, Western blot, and IHC assays validated SFXN1 expression and its impact on the immune microenvironment in LUAD. RESULTS: SFXN1 was upregulated in LUAD tissues and associated with poor prognosis. RNA-seq and scRNA-seq analyses revealed increased SFXN1 expression in tumor cells, accompanied by decreased infiltration of NK and cytotoxic T cells. SFXN1 knockdown significantly reduced cell proliferation and migration, and the inhibition of ERK phosphorylation and CCL20 expression may be the molecular mechanism involved. In vivo, targeting SFXN1 decreased Tregs infiltration and inhibited tumor growth. CONCLUSIONS: Our findings suggest that SFXN1 may be a potential therapeutic target for LUAD treatment.

Adapted diabetes complications severity index predicts dementia risk in ageing type 2 diabetes mellitus patients.

This study investigated the link between the adapted diabetes complication severity index at the time of type 2 diabetes mellitus diagnosis and diabetes-induced dementia risk in elderly patients. Elderly type 2 diabetes mellitus patients (age ≥ 60) were matched using propensity score matching. Cox regression was used to determine dementia hazard ratios; Kaplan-Meier method to assess cumulative incidence. The cohort included 256 214 elderly type 2 diabetes mellitus patients. Adapted diabetes complication severity index ≥ 1 showed higher dementia risk (adjusted hazard ratio: 1.30; 95% confidence interval: 1.27-1.34), increasing by 1.17-fold per adapted diabetes complication severity index point. Dementia risk rose progressively across adapted diabetes complication severity index scores (P < 0.0001). Higher adapted diabetes complication severity index scores at the time of type 2 diabetes mellitus diagnosis elevated dementia risk in elderly patients. Adapted diabetes complication severity index ≥ 1 is linked to increased dementia risk. Adapted diabetes complication severity index evaluation at the time of type 2 diabetes mellitus diagnosis could predict risk, aiding early interventions. Effective diabetes management is crucial for reducing dementia risk in this population.

The impact of postoperative agitated delirium on dementia in surgical patients.

This study investigates the association between postoperative agitated delirium and the risk of dementia in patients who were cognitively intact before undergoing major inpatient surgery. The study included inpatients aged 20 years or older who underwent major surgery requiring general, epidural, or spinal anaesthesia and hospitalization for over one day in Taiwan between 2008 and 2018. Patients were categorized into two groups based on the presence or absence of postoperative agitated delirium. Propensity score matching was conducted to balance various covariates known to influence dementia risk. The final analysis included 10 932 patients (5466 in each group). Multivariate Cox regression analysis was performed to assess the risk of dementia, and incidence rates and incidence rate ratios were calculated. After Propensity score matching, the study cohort comprised 5467 patients without postoperative agitated delirium and 5467 patients with postoperative agitated delirium. In the multivariate Cox regression analysis, the adjusted hazard ratio for dementia were 1.26 (95% confidence intervals, 1.08-1.46; P = 0.003) in the postoperative agitated delirium group compared to the no postoperative agitated delirium group. The incidence rates of dementia was significantly higher in patients with postoperative agitated delirium (97.65 versus 70.85 per 10 000 person-years), with an incidence rate ratio of 1.21 (95% CI: 1.04-1.40). Our study demonstrates a substantial rise in dementia incidence linked to postoperative agitated delirium. These findings stress the need for effective prevention and management strategies. Addressing this issue emerges as a vital clinical approach to reduce subsequent dementia risk, with broad implications for enhancing overall perioperative patient outcomes.

Persistence of analgesic usage and opioid consumption in sarcopenic patients undergoing neuraxial anesthesia: a nationwide retrospective cohort study.

Introduction: This study investigates the association between chronic postsurgical pain (CPSP) and long-term postsurgical analgesic usage in patients undergoing neuraxial anesthesia, with a specific focus on the presence or absence of sarcopenia. Objectives: To assess the rate of analgesic prescription, including opioids, at 3 and 6 months postsurgery for patients with and without preoperative sarcopenia, and to determine the impact of sarcopenia on analgesic use after neuraxial anesthesia surgery. Methods: Patients undergoing surgery under neuraxial anesthesia were categorized into sarcopenic and nonsarcopenic groups based on preoperative diagnosis using the ICD-10-CM code M62.84. Propensity score matching in a 1:4 ratio was applied for group matching. Analgesic prescription rates were evaluated at 3 and 6 months postsurgery, and multivariable logistic regression was used to analyze analgesic use, comparing patients with and without preoperative sarcopenia. Results: Among 3805 surgical patients, 761 had sarcopenia, while 3044 did not. At 3 months postsurgery, 62.3% of sarcopenic patients received analgesics, with 2.9% receiving opioids, compared to 57.1% of nonsarcopenic patients receiving analgesics and 0.8% receiving opioids. At 6 months postsurgery, 30.8% of sarcopenic patients received analgesics (1.7% opioids), while 26.3% of non-sarcopenic patients received analgesics (0.3% opioids). Multivariable logistic regression analysis revealed that preoperative sarcopenia was significantly associated with higher analgesic prescription rates at both 3 months (adjusted odds ratio [aOR], 1.27; 95% confidence interval [CI], 1.05-1.53) and 6 months (aOR, 1.17; 95% CI, 1.07-1.42) postsurgery. Furthermore, sarcopenic patients exhibited significantly higher opioid prescription rates at 3 months (aOR, 1.11; 95% CI, 1.05-2.45) and 6 months (aOR, 1.89; 95% CI, 1.12-4.96) postsurgery. Conclusion: Sarcopenia emerges as an independent risk factor for prolonged analgesic use after neuraxial anesthesia surgery and significantly elevates the risk of developing CPSP.

Effect of dexmedetomidine on postoperative nausea and vomiting in female patients undergoing radical thoracoscopic lung cancer resection.

Introduction: Postoperative nausea and vomiting (PONV) is a prevalent postsurgical complication. The objective of our study was to compare the effect of different doses of dexmedetomidine on PONV in female patients undergoing radical thoracoscopic lung cancer resection. Methods: A total of 164 female patients undergoing elective thoracoscopic radical lung cancer surgery were enrolled and assigned to one of four groups. Patients received 0.2 µg/kg/h, 0.4 µg/kg/h, 0.8 µg/kg/h dexmedetomidine and normal saline in the Dex1, Dex2, Dex3 and Control groups, respectively. The primary outcome was the incidence of PONV during 48 h postoperatively. The second outcomes included the incidence of PONV and postoperative vomiting (POV) at four time points postoperatively (T1: PACU retention period; T2: PACU discharge to postoperative 12 h; T3: postoperative 12 h-postoperative 24 h; T4: postoperative 24 h-postoperative 48 h), the area under the curve of PONV grade (PONVAUC), PONV grade, POV grade and other postoperative recovery indicators. Results: The incidence of PONV differed among the four groups. The Dex2 group (29.27%) was lower than that in the Dex1 group (61.90%) and Control group (72.50%). The incidence of PONV at T2 in the Dex1 group (11.90%) and Dex2 group (9.76%) was lower than that in the Control group (42.50%). The incidence of PONV at T3 in the Dex2 group (29.27%) was lower than that in the Dex1 group (61.90%) and Control group (62.50%). The PONVAUC was lower in the Dex2 group than in the Control group. The incidence of POV at T3 in the Dex2 and Dex3 groups was lower than that in the Control group. The consumption of remifentanil, norepinephrine, PACU dwell time, VAS scores, postoperative PCA press frequency, and the time for the first postoperative oral intake were different among the four groups. The regression model shows that the Dex2 group is a protective factor for PONV. Conclusion: Dexmedetomidine can reduce the incidence of PONV and accelerate postoperative recovery in female patients undergoing radical thoracoscopic lung cancer resection. Compared with the other two dosages, 0.4 µg/kg/h dexmedetomidine is preferable. Clinical Trial Registration: chictr.org.cn, identifier ChiCTR2300071831.

Dysregulation of iron homeostasis and ferroptosis in sevoflurane and isoflurane associated perioperative neurocognitive disorders.

In recent years, sevoflurane and isoflurane are the most popular anesthetics in general anesthesia for their safe, rapid onset, and well tolerant. Nevertheless, many studies reported their neurotoxicity among pediatric and aged populations. This effect is usually manifested as cognitive impairment such as perioperative neurocognitive disorders. The wide application of sevoflurane and isoflurane during general anesthesia makes their safety a major health concern. Evidence indicates that iron dyshomeostasis and ferroptosis may establish a role in neurotoxicity of sevoflurane and isoflurane. However, the mechanisms of sevoflurane- and isoflurane-induced neuronal injury were not fully understood, which poses a barrier to the treatment of its neurotoxicity. We, therefore, reviewed the current knowledge on mechanisms of iron dyshomeostasis and ferroptosis and aimed to promote a better understanding of their roles in sevoflurane- and isoflurane-induced neurotoxicity.

Nerve block reduces the incidence of 3-year postoperative mortality: a retrospective cohort study.

Purpose: A retrospective cohort study was performed to determine the effect of nerve block on the incidence of postoperative mortality in patients with hip replacement. Methods: According to the inclusion and exclusion criteria, patients who were undergoing hip replacement for the first time under general or intraspinal anesthesia, classified as ASA class I-IV, and aged ≥65 years were selected. We collected the general data, past medical history, preoperative laboratory test results, perioperative fluid intake and outflow data, perioperative anesthesia and related drug data, postoperative laboratory results, and correlation time index. Patients with preoperative combined nerve block were included in the N group, and those without combined nerve block were included in the NN group. The patients were followed up via telephone call to assess survival outcomes at 3 years after surgery. Propensity score matching and uni- and multivariate analyses were performed to determine the influence of nerve block and other related factors on postoperative mortality. Results: A total of 743 patients were included in this study, including 262 in the N group and 481 in the NN group. Two hundred five patients in both groups remained after propensity score matching. Main result: Preoperative nerve block was associated with reduced mortality three years after surgery. Conclusion: Nerve block reduces the incidence of 3-year postoperative mortality, and composite nerve block with general anesthesia and neuraxial anesthesia is worthy of promotion.

Sarcopenia and diabetes-induced dementia risk.

This study aimed to investigate whether sarcopenia independently increases the risk of diabetes-induced dementia in elderly individuals diagnosed with type 2 diabetes mellitus. The study cohort consisted of a large sample of elderly individuals aged 60 years and above, who were diagnosed with type 2 diabetes mellitus between 2008 and 2018. To minimize potential bias and achieve covariate balance between the sarcopenia and non-sarcopenia groups, we employed propensity score matching. Various statistical analyses, including Cox regression models to assess dementia risk and associations, competing risk analysis to account for mortality and Poisson regression analysis for incidence rates, were used. Before propensity score matching, the study included 406 573 elderly type 2 diabetes mellitus patients, with 20 674 in the sarcopenia group. Following propensity score matching, the analysis included a total of 41 294 individuals, with 20 647 in the sarcopenia group and 20 647 in the non-sarcopenia group. Prior to propensity score matching, elderly type 2 diabetes mellitus patients with sarcopenia exhibited a significantly higher risk of dementia (adjusted hazard ratio: 1.12, 95% confidence interval: 1.07-1.17). After propensity score matching, the risk remained significant (adjusted hazard ratio: 1.14, 95% confidence interval: 1.07-1.21). Incidence rates of dementia were notably higher in the sarcopenia group both before and after propensity score matching, underscoring the importance of sarcopenia as an independent risk factor. Our study highlights sarcopenia as an independent risk factor for diabetes-induced dementia in elderly type 2 diabetes mellitus patients. Advanced age, female gender, lower income levels, rural residency, higher adapted diabetes complication severity index and Charlson Comorbidity Index scores and various comorbidities were associated with increased dementia risk. Notably, the use of statins was linked to a reduced risk of dementia. This research underscores the need to identify and address modifiable risk factors for dementia in elderly type 2 diabetes mellitus patients, offering valuable insights for targeted interventions and healthcare policies.

Improved postoperative outcomes in pediatric major surgery: evidence from hospital volume analysis.

This study aimed to examine the association between hospital volume and postoperative outcomes in pediatric major surgery using a nationwide database. The study included pediatric patients who underwent first major elective inpatient surgery and hospitalization for more than 1 day. The results showed no significant difference in the risk of 30-day postoperative mortality based on hospital volume. However, patients in the middle- and high-volume groups had significantly lower rates of 30-day major complications, particularly deep wound infection. In terms of 90-day postoperative outcomes, patients in the high-volume group had a significantly lower risk of mortality and lower rates of major complications, particularly deep wound infection, pneumonia, and septicemia.  Conclusions: The study suggests that pediatric patients undergoing major surgery in high and middle-volume groups have better outcomes in terms of major complications compared to the low-volume group. What is Known: • Limited evidence exists on the connection between hospital volume and pediatric surgery outcomes. What is New: • A Taiwan-based study, using national data, found that high and middle hospital-volume groups experienced significantly lower rates of major complications within 30 and 90 days after surgery. • High-volume hospitals demonstrated a substantial decrease in the risk of 90-day postoperative mortality. • The study underscores the importance of specialized pediatric surgical centers and advocates for clear guidelines for hospital selection, potentially improving outcomes and informing future health policies.

Early childhood general anesthesia and risk of Attention Deficit Hyperactivity Disorder.

BACKGROUND: The relationship between early childhood exposure to general anesthesia (GA) and the risk of developing Attention Deficit Hyperactivity Disorder (ADHD) is still uncertain and previous studies have presented conflicting results. This population-based cohort study aimed to investigate the potential relationship between GA exposure and ADHD risk using propensity score matching (PSM) in a large sample size. METHODS: The study included 15,072 children aged 0-3 years who received GA and were hospitalized for more than 1 day in Taiwan from 2004 to 2014. The nonexposed group was randomly selected through 1:1 PSM from the Taiwan Maternal and Child Health Database (TMCHD). The primary objectives of this study were to determine the incidence rates (IR) and incidence rate ratios (IRR) of ADHD in the two cohorts, employing Poisson regression models. RESULTS: The GA group and non-GA group each comprised 7,536 patients. The IR of ADHD was higher in the GA group (122.45 per 10,000 person-years) than in the non-GA group (64.15 per 10,000 person-years), and the IRR of ADHD in the GA group was 1.39 (95% CI: 1.26, 1.55). The study found that the number of times of exposure to GA, duration of exposure, male gender, and central nervous system surgery were significant risk factors for ADHD in the future. CONCLUSIONS: This study's findings suggest that there is a significant correlation between early childhood exposure to GA and the risk of developing ADHD, and GA may be an important risk factor for ADHD in children undergoing surgery. The study also identified several risk factors for ADHD, including the number of times of exposure to GA, duration of exposure, male gender, and central nervous system surgery.

A prognostic model based on Scissor+ cancer associated fibroblasts identified from bulk and single cell RNA sequencing data in head and neck squamous cell carcinoma.

Head and neck squamous cell carcinoma (HNSCC) is one of the most lethal diseases in the world, which often recur after multimodality treatment approaches, leading to a poor prognosis. Fibroblasts, a heterogeneous component of the tumor microenvironment, can modulate numerous aspects of tumor biology and have been increasingly acknowledged in dictating the clinical outcome of patients with HNSCC. However, the subpopulation of fibroblasts that are related to the prognosis of HNSCC has not yet been fully explored. To do so, we combined a single-cell RNA sequencing (scRNA-seq) dataset and bulk RNA-sequencing dataset with clinical information, identifying the fibroblast population that are related to poor prognosis of HNSCC. We found these specific population of fibroblasts are less differentiated. In addition, to identify the prognostic signatures of HNSCC, bioinformatics analysis included least absolute shrinkage and selection operator (LASSO) analyses and univariate cox and were performed. We selected 12 prognosis-related genes for constructing a risk model using The Cancer Genome Atlas (TCGA). The AUC values and calibration plots of this model indicated good prognostic prediction efficacy. This model also was validated in two Gene Expression Omnibus (GEO) datasets. In conclusion, we constructed an optimal model that was derived from single cell RNA-seq and bulk RNA-seq to predict the survival probability of HNSCC patients. Among this model, AKR1C3 higher expression in cancer associated fibroblasts (CAFs) of HNSCC has been confirmed by preliminary experiments.

Metformin in elderly type 2 diabetes mellitus: dose-dependent dementia risk reduction.

This study aimed to investigate the controversial association between metformin use and diabetes-associated dementia in elderly patients with type 2 diabetes mellitus (T2DM) and evaluate the potential protective effects of metformin, as well as its intensity of use and dose-dependency, against dementia in this population. The study used a time-dependent Cox hazards model to evaluate the effect of metformin use on the incidence of dementia. The case group included elderly patients with T2DM (≥60 years old) who received metformin, while the control group consisted of elderly patients with T2DM who did not receive metformin during the follow-up period. Our analysis revealed a significant reduction in the risk of dementia among elderly individuals using metformin, with an adjusted hazard ratio of 0.34 (95% confidence interval: 0.33 to 0.36). Notably, metformin users with a daily intensity of 1 defined daily dose (DDD) or higher had a lower risk of dementia, with an adjusted hazard ratio (95% confidence interval) of 0.46 (0.22 to 0.6), compared to those with a daily intensity of <1 DDD. Additionally, the analysis of cumulative DDDs of metformin showed a dose-response relationship, with progressively lower adjusted hazard ratio across quartiles (0.15, 0.21, 0.28, and 0.53 for quartiles 4, 3, 2 and 1, respectively), compared to never metformin users (P for trend < 0.0001). Metformin use in elderly patients with T2DM is significantly associated with a substantial reduction in the risk of dementia. Notably, the protective effect of metformin demonstrates a dose-dependent relationship, with higher daily and cumulative dosages of metformin showing a greater risk reduction.

The influence of advanced age on long-term postsurgical analgesic use in patients receiving neuraxial anaesthesia for elective surgery.

OBJECTIVE: To determine the relationship between age and long-term postsurgical analgesic use in patients who underwent elective surgery with neuraxial anaesthesia. DESIGN: Retrospective observational study using data from the National Health Insurance Research Database of Taiwan from 2015 to 2019. SETTING: National Health Insurance Research Database of Taiwan. PATIENTS: A total of 12,810 patients (6405 younger and 6405 older) matched using propensity score matching. INTERVENTIONS: Older (≥65 years). MEASUREMENTS: The use of long-term (3 or 6 months) postoperative analgesics, including opioids, as a surrogate marker of chronic postsurgical pain (CPSP) was analysed using logistic regression. MAIN RESULTS: After 3 months of surgery, older adults had higher use of all analgesics (odds ratio [OR] = 1.15; 95% CI = 1.03-1.28) and opioids (OR = 1.18; 95% CI = 1.09-1.28) compared to younger patients. Similar results were observed after 6 months of surgery (all analgesic use: OR = 1.11; 95% CI = 1.03-1.20; opioid use: OR = 1.33; 95% CI = 1.07-1.81). CONCLUSION: The findings from this study suggest that older adults are more likely to experience CPSP and have increased use of long-term analgesics, including opioids, after undergoing elective surgery with neuraxial anaesthesia. The study highlights the need for improved pain management strategies for older adults after surgery. SIGNIFICANCE: Older age is an independent risk factor for long-term analgesic use after surgery under neuraxial anaesthesiaanesthesia, indicating an increased risk for chronic postsurgical pain.

Protective Effects Against Dementia Undergo Different Statin Type, Intensity, and Cumulative Dose in Older Adult Type 2 Diabetes Mellitus Patients.

OBJECTIVES: This study investigated the relationship between statin use and dementia risk in older adults with type 2 diabetes (T2DM). It also assessed the impact of various statin types, dosage intensity, and cumulative doses on dementia risk. DESIGN: Employing the inverse probability of treatment weighting (IPTW) Cox hazards model, this research explored the influence of statin utilization on dementia incidence. SETTING AND PARTICIPANTS: The study included older adult T2DM patients aged 60 years or older who received statins (case group) and those who did not (control group) during the follow-up period. METHODS: The IPTW Cox hazards model quantified the association between statin use and dementia incidence. Subgroup analyses investigated different statin types, usage intensity, and cumulative dose-dependent relationships with dementia risk, measured by adjusted hazard ratios (aHRs) with corresponding 95% CIs. RESULTS: Statin users experienced a significant reduction in dementia risk (aHR: 0.47, 95% CI: 0.46-0.48). Subgroup analysis using IPTW Cox regression revealed varying dementia incidence reductions among users of different statin types, with aHRs (95% CIs) ranging from 0.09 to 0.69. Multivariate analyses unveiled a dose-dependent relationship, showing reduced dementia incidence based on cumulative defined daily doses (cDDDs) per year. The corresponding aHRs (95% CIs) were 0.20 to 0.72 across quartiles 4 to 1 of cDDD-years, with a significant trend (P < .001). The optimal daily statin use was 0.88 defined daily doses (DDDs), associated with the lowest dementia risk. CONCLUSIONS AND IMPLICATIONS: Statins significantly reduced dementia risk in older adult T2DM patients. Higher cumulative defined daily doses (cDDD-years) were linked to more substantial risk reductions. This research underscores the clinical benefits of statin use in preventing dementia in this population and calls for further investigation into the underlying mechanisms. It also raises the possibility of influencing policy decisions to manage dementia risk in this vulnerable group.

TP53 missense mutation reveals gain-of-function properties in small-sized KRAS transformed pancreatic ductal adenocarcinoma.

BACKGROUND: Although the molecular features of pancreatic ductal adenocarcinoma (PDAC) have been well described, the impact of detailed gene mutation subtypes on disease progression remained unclear. This study aimed to evaluate the impact of different TP53 mutation subtypes on clinical characteristics and outcomes of patients with PDAC. METHODS: We included 639 patients treated with PDAC in Ruijin Hospital affiliated to Shanghai Jiaotong University School of Medicine between Jan 2019 and Jun 2021. The genomic alterations of PDAC were analyzed, and the association of TP53 mutation subtypes and other core gene pathway alterations with patients' clinical characteristics were evaluated by Chi-squared test, Kaplan-Meier method and Cox regression model. RESULTS: TP53 missense mutation was significantly associated with poor differentiation in KRASmut PDAC (50.7% vs. 36.1%, P = 0.001). In small-sized (≤ 2 cm) KRASmut tumors, significantly higher LNs involvement (54.8% vs. 23.5%, P = 0.010) and distal metastic rate (20.5% vs. 2.9%, P = 0.030) were observed in those with TP53 missense mutation instead of truncating mutation. Compared with TP53 truncating mutation, missense mutation was significantly associated with reduced DFS (6.6 [5.6-7.6] vs. 9.2 [5.2-13.3] months, HR 0.368 [0.200-0.677], P = 0.005) and OS (9.6 [8.0-11.1] vs. 18.3 [6.7-30.0] months, HR 0.457 [0.248-0.842], P = 0.012) in patients who failed to receive chemotherapy, while higher OS (24.2 [20.8-27.7] vs. 23.8 [19.0-28.5] months, HR 1.461 [1.005-2.124], P = 0.047) was observed in TP53missense cases after chemotherapy. CONCLUSIONS: TP53 missense mutation was associated with poor tumor differentiation, and revealed gain-of-function properties in small-sized KRAS transformed PDAC. Nonetheless, it was not associated with insensitivity to chemotherapy, highlighting the neoadjuvant therapy before surgery as the potential optimized strategy for the treatment of a subset of patients.

Application of Butorphanol versus Sufentanil in Multimode Analgesia via Patient Controlled Intravenous Analgesia After Hepatobiliary Surgery: A Retrospective Cohort Study.

Purpose: We investigate the efficacy and safety of butorphanol in multimodal analgesia combined with dexmedetomidine and ketorolac via patient-controlled intravenous analgesia (PCIA) after hepatobiliary surgery, as compared with sufentanil. Patients and Methods: Postoperative follow-up data of hepatobiliary surgery patients in Henan Provincial People's Hospital from March 2018 to June 2021 were collected retrospectively and divided into butorphanol group (group B) or sufentanil group (group S) according to the postoperative intravenous controlled analgesia scheme. The baseline characteristics and surgical information of the two groups were matched through propensity score matching (PSM). Results: A total of 3437 patients were screened, and PSM yielded 1816 patients after matching, including 908 in the butorphanol group and 908 in the sufentanil group. Compared with group S, the incidence of moderate-to-severe pain on the first postoperative day and the second postoperative day was lower in group B during rest (3.2% vs 10.9%, P<0.001; 1.2% vs 4.6%, P<0.001), and during movement (7.0% vs 18.9%, P<0.001; 2.6% vs 8.7%, P<0.001). Patients receiving butorphanol had a lower morphine consumption (50mg vs 120mg, P<0.001). The bolus attempts of an analgesic pump in group B were significantly lower than in group S (1 vs 2, P<0.001). Postoperative hospital length of stay was shortened in group B (11d vs 12d, P=0.017). The occurrence of postoperative vomiting was lower in group B (1.4% vs 3.0%, P=0.025) than in group S. However, more patients in group B experienced dizziness (0.9% vs 0.1%, P=0.019). Conclusion: Compared with sufentanil, the application of butorphanol in multimodal analgesia combined with dexmedetomidine and ketorolac via PCIA ameliorated postoperative pain after hepatobiliary surgery, with reduced opioid consumption and shorter postoperative hospital length of stay.