Clinical trajectories preceding incident dementia up to 15 years before diagnosis: a large prospective cohort study.

BACKGROUND: Dementia has a long prodromal stage with various pathophysiological manifestations; however, the progression of pre-diagnostic changes remains unclear. We aimed to determine the evolutional trajectories of multiple-domain clinical assessments and health conditions up to 15 years before the diagnosis of dementia. METHODS: Data was extracted from the UK-Biobank, a longitudinal cohort that recruited over 500,000 participants from March 2006 to October 2010. Each demented subject was matched with 10 healthy controls. We performed logistic regressions on 400 predictors covering a comprehensive range of clinical assessments or health conditions. Their evolutional trajectories were quantified using adjusted odds ratios (ORs) and FDR-corrected p-values under consecutive timeframes preceding the diagnosis of dementia. FINDINGS: During a median follow-up of 13.7 [Interquartile range, IQR 12.9-14.2] years until July 2022, 7620 subjects were diagnosed with dementia. In general, upon approaching the diagnosis, demented subjects witnessed worse functional assessments and a higher prevalence of health conditions. Associations up to 15 years preceding the diagnosis comprised declined physical strength (hand grip strength, OR 0.65 [0.63-0.67]), lung dysfunction (peak expiratory flow, OR 0.78 [0.76-0.81]) and kidney dysfunction (cystatin C, OR 1.13 [1.11-1.16]), comorbidities of coronary heart disease (OR 1.78 [1.67-1.91]), stroke (OR 2.34 [2.1-1.37]), diabetes (OR 2.03 [1.89-2.18]) and a series of mental disorders. Cognitive functions in multiple tests also demonstrate decline over a decade before the diagnosis. Inadequate activity (3-5 year, overall time of activity, OR 0.82 [0.73-0.92]), drowsiness (3-5 year, sleep duration, OR 1.13 [1.04-1.24]) and weight loss (0-5 year, weight, OR 0.9 [0.83-0.98]) only exhibited associations within five years before the diagnosis. In addition, serum biomarkers of enriched endocrine, dysregulations of ketones, deficiency of brand-chain amino acids and polyunsaturated fatty acids were found in a similar prodromal time window and can be witnessed as the last pre-symptomatic conditions before the diagnosis. INTERPRETATION: Our findings present a comprehensive temporal-diagnostic landscape preceding incident dementia, which could improve selection for preventive and early disease-modifying treatment trials.

Exploration of the Clinical Effect of Different Autotransfusion Methods on Patients With Femoral Shaft Fracture Surgery.

OBJECTIVE: To explore the clinical effect of predeposit, salvage, and hemodilution autotransfusion on patients with femoral shaft fracture (FSF) surgery. METHODS: Selected patients with FSF were randomly divided into three groups: intraoperative blood salvage autotransfusion, preoperative hemodilution autohemotransfusion, and predeposit autotransfusion. Five days after the operation, the body temperature, heart rate, blood platelet (PLT), and hemoglobin (Hb) of patients were determined. The concentrations of EPO and GM-CSF in the three groups were calculated by ELISA. The content of CD14+ monocytes was calculated by FCM assay. The growth time and condition of the patient's callus were determined at the 30th, 45th, and 60th day after operation. Cox regression analysis was used to analyze the correlation between EPO, GM-CSF, CD14+ mononuclear content, callus growth, and autotransfusion methods. RESULTS: There were no statistically significant differences in body temperature and heart rate between the three groups (p > 0.05). PLT and Hb in the Predeposit group were markedly increased compared with that in the Salvage and Hemodilution groups. The concentrations of EPO and GM-CSF in the Predeposit group were markedly increased compared with that in the Salvage and Hemodilution groups. The content of CD14+ monocytes in the Predeposit group was significantly higher than that in the Salvage and Hemodilution groups. Predeposit autotransfusion promotes callus growth more quickly. CONCLUSION: Predeposit autotransfusion promoted the recovery of patients with FSF after the operation more quickly than salvage autotransfusion and hemodilution autotransfusion.

Plasma metabolomics identifies S-adenosylmethionine as a biomarker and potential therapeutic target for vascular aging in older adult males.

Brachial-ankle pulse wave velocity (baPWV) is a noninvasive index of vascular aging. However, the metabolic profile underlying vascular aging has not yet been fully elucidated. The current study aimed to identify circulating markers of vascular aging as assessed by baPWV and to elucidate its mechanism from a metabolomic perspective in older adults. A total of 60 and 61 Chinese male participants aged ≥80 years were recruited to the metabolome and validation cohorts, respectively. The baPWV of participants was measured using an automatic waveform analyzer. Plasma metabolic profile was investigated using ultra-performance liquid chromatography coupled with triple quadrupole linear ion trap tandem mass spectrometry. Orthogonal partial least squares (OPLS) regression modeling established the association between metabolic profile and baPWV to determine important metabolites predictive of vascular aging. Additionally, an enzyme-linked immunosorbent assay was employed to validate the metabolites in plasma and culture media of vascular smooth muscle cells in vitro. OPLS modeling identified 14 and 22 metabolites inversely and positively associated with baPWV, respectively. These 36 biomarkers were significantly enriched in seven metabolite sets, especially in cysteine and methionine metabolism (p <0.05). Notably, among metabolites involved in cysteine and methionine metabolism, S-adenosylmethionine (SAM) level was inversely related to baPWV, with a significant correlation coefficient in the OPLS model (p <0.05). Furthermore, the relationship between SAM and vascular aging was reconfirmed in an independent cohort and at the cellular level in vitro. SAM was independently associated with baPWV after adjustments for clinical covariates (ß = -0.448, p <0.001) in the validation cohort. In summary, plasma metabolomics identified an inverse correlation between SAM and baPWV in older males. SAM has the potential to be a novel biomarker and therapeutic target for vascular aging.

A biomimetic orthogonal flow sensor based on an asymmetric optical fiber sensory structure for marine sensing.

With increasing attention on the world's oceans, a significant amount of research has been focused on the sensing of marine-related parameters in recent years. In this paper, a bioinspired flow sensor with corrosion resistance, anti-interference capability, a portable design structure, easy integration, and directional sensing ability is presented to realize flow speed sensing in open water. The sensor is realized by a flexible artificial cupula that seals one side of an optical fiber acting as an artificial kinocilium. Below the artificial kinocilium, an encapsulated s-tapered optical fiber mimics the fish neuromast sensory mechanism and is supported by a 3D-printed structure that acts as the artificial supporting cell. To characterize the sensor, the optical transmission spectra of the sensory fiber under a set of water flow velocities and four orthogonal directions were monitored. The sensor's peak intensity responses were found to demonstrate flow sensing ability for velocity and direction, proving that this biomimetic portable sensing structure is a promising candidate for flow sensing in marine environments.

Autologous transplantation of P63+ lung progenitor cells for chronic obstructive pulmonary disease therapy.

Adult lung resident stem/progenitor cells, including P63+ progenitor cells, have demonstrated the capacity for regeneration of lung epithelium in preclinical models. Here, we report a clinical trial of intrapulmonary P63+ progenitor cell transplantation in 28 participants with stage II to IV chronic obstructive pulmonary disease (COPD). Autologous P63+ progenitor cells were isolated from the airway basal layer of participants in the intervention group via bronchoscopic brushing, cultured for 3 to 5 weeks, and then transplanted back into the lungs via bronchoscopy at 0.7 × 106 to 5.2 × 106 cells per kilogram of body weight. Twenty patients were evaluable at the end of the study (intervention group, n = 17; control group, n = 3). No grade 3 to 5 adverse events (AEs) or serious AEs occurred. Although bronchoscopy-associated AEs were recorded in participants in the intervention group, other AEs were not substantial different between groups. Twenty-four weeks after transplantation, participants in the intervention group displayed improvement in gas transfer capacity [diffusing capacity of the lung for carbon monoxide (DLCO) change from baseline: +18.2%], whereas the control group experienced a decrease (DLCO change from baseline: -17.4%; P = 0.008). Furthermore, participants in the intervention group showed >30-meter increase in walking distance within 6 minutes. Transcriptomic analysis of progenitor cells isolated from responding and nonresponding individuals in the intervention group showed that higher expression of P63 was associated with treatment efficacy. In conclusion, transplantation of cultured P63+ lung progenitor cells was safe and might represent a potential therapeutic strategy for COPD.

Pharmacological inhibition of MYC to mitigate chemoresistance in preclinical models of squamous cell carcinoma.

Rationale: Cisplatin-based chemotherapy is the first-line treatment for late-stage head and neck squamous cell carcinoma (HNSCC). However, resistance to cisplatin has become a major obstacle for effective therapy. Cancer stem cells (CSCs) are critical for tumor initiation, growth, metastasis, and chemoresistance. How to effectively eliminate CSCs and overcome chemoresistance remains a key challenge. Herein, we confirmed that MYC plays critical roles in chemoresistance, and explored targeting MYC to overcome cisplatin resistance in preclinical models. Methods: The roles of MYC in HNSCC cisplatin resistance and cancer stemness were tested in vitro and in vivo. The combined therapeutic efficiency of MYC targeting using the small molecule MYC inhibitor MYCi975 and cisplatin was assessed in a 4­nitroquinoline 1-oxide-induced model and in a patient-derived xenograft model. Results: MYC was highly-expressed in cisplatin-resistant HNSCC. Targeting MYC using MYCi975 eliminated CSCs, prevented metastasis, and overcame cisplatin resistance. MYCi975 also induced tumor cell-intrinsic immune responses, and promoted CD8+ T cell infiltration. Mechanistically, MYCi975 induced the DNA damage response and activated the cGAS-STING-IRF3 signaling pathway to increase CD8+ T cell-recruiting chemokines. Conclusions: Our findings suggested that targeting MYC might eliminate CSCs, prevent metastasis, and activate antitumor immunity to overcome cisplatin resistance in HNSCC.

Relationship between bullous pemphigoid and malignancy: A Mendelian randomization study.

Bullous pemphigoid (BP) is the most common autoimmune blistering disease, which primarily affects the elderly. However, the relationship between BP and malignancy remains controversial in traditional observational studies. The aim of this study, which included only European populations, was to assess the potential causative link between BP and 13 types of malignant tumors in a two-sample Mendelian randomization (MR) study. BP was not associated with an increased risk of developing 13 types of malignant tumors. This study did not find a causal relationship between BP and malignant tumors. However, further research is warranted to examine the generalizability of this conclusion in non-European populations.

Replacing cholesterol with asiatic acid to prolong circulation and enhance anti-metastatic effects of non-PEGylated liposomes.

Cholesterol is an indispensable component of most liposomes, heavily influencing their physical and surface properties. In this study, cholesterol in non-PEGylated liposomes was replaced by its analog, asiatic acid (AA), to generate liposomes with an alternative composition. These AA liposomes are generally smaller and more rigid than conventional liposomes, circulate longer in the body, and accumulate more in primary tumors and lung metastases in vivo. On the other hand, as an active ingredient, AA can decrease TGF-ß secretion to inhibit the epithelial-mesenchymal transition (EMT) process, increase the sensitivity of tumor cells to doxorubicin (DOX), and synergize with DOX to enhance the immune response, thus improving their antitumor and anti-metastasis efficiency. Based on this rationale, DOX-loaded AA liposomes were fabricated and tested against triple-negative breast cancer (TNBC). Results showed that compared with conventional liposomes, the DOX-AALip provided approximately 28.4% higher tumor volume reduction with almost no metastatic nodules in the mouse model. Our data demonstrate that AA liposomes are safe, simple, and efficient, and thus in many situations may be used instead of conventional liposomes, having good potential for further clinical translational development.

Targeted drug delivery systems for matrix metalloproteinase-responsive anoparticles in tumor cells: A review.

Nanodrug delivery systems based on tumor microenvironment responses have shown excellent performance in tumor-targeted therapy, given their unique targeting and drug-release characteristics. Matrix metalloproteinases (MMPs) have been widely explored owing to their high specificity and expression in various tumor microenvironments. The design of an enzyme-sensitive nanodelivery system using MMPs as targeted receptors could markedly improve the performance of drug targeting. The current review focuses on the development and application of MMP-responsive drug carriers, and summarizes the classification of single- and multi-target nanocarriers based on their MMP responsiveness. The potential applications and challenges of this nanodrug delivery system are discussed to provide a reference for designing high-performance nanodrug delivery systems.

Synergistic effects of multidrug/material combination deliver system for anti-mutidrug-resistant tumor.

Multidrug resistance (MDR) is a public health issue of particular concern, for which nanotechnology-based multidrug delivery systems are considered among the most effective suppressive strategies for such resistance in tumors. However, for such strategies to be viable, the notable shortcomings of reduced loading efficiency and uncontrollable drug release ratio need to be addressed. To this end, we developed a novel "multidrug/material" co-delivery system, using d-α-tocopheryl polyethylene glycol 1000 succinate (TPGS, P-gp efflux pump inhibitor) and poly(amidoamine) (PAMAM) to fabricate a precursor material with the properties of reversing MDR and having a long-cycle. Further, to facilitate multidrug co-delivery, we loaded doxorubicin(Dox) and curcumin(Cur, cardiotoxicity modifier and P-gp inhibitor) into PAMAM-TPGS nano-micelles respectively, and mixed in appropriate proportions. The multidrug/material co-delivery system thus obtained was characterized by high drug loading and a controllable drug release ratio in the physiological environment. More importantly, in vitro and in vivo pharmacodynamic studies indicated that the multidrug/material co-delivery system facilitated the reversal of MDR. Moreover, the system has increased anti-tumor activity and is biologically safe. We accordingly propose that the "multidrug/material" co-delivery system developed in this study could serve as a potential platform for reversing MDR and achieving safe and effective clinical treatment.

A Novel LncRNA MASCC1 Regulates the Progression and Metastasis of Head and Neck Squamous Cell Carcinoma by Sponging miR-195.

The altered expression of long noncoding RNAs (lncRNAs) is associated with human carcinogenesis. We performed a high-throughput analysis of lncRNA expression in strictly selected pairs of metastatic head and neck squamous cell carcinoma (HNSCC) and non-metastatic HNSCC samples. We identified a novel lncRNA, which was highly expressed in metastatic HNSCC, named Metastasis Associated Squamous Cell Carcinoma 1 (MASCC1), for further study. Using qRT-PCR, we further compared MASCC1 expression in 60 HNSCC samples. The results show that high expression of MASCC1 in patients with HNSCC was related to poor prognosis. In vitro, MASCC1 knockdown (KD) inhibited HNSCC proliferation, migration, invasion, and tumor sphere formation, while promoting apoptosis. In vivo, MASCC1 KD inhibited HNSCC growth and lymph node metastasis. Mechanistically, MASCC1 acted as a competing endogenous RNA (ceRNA) by binding to miR-195, subsequently regulating the expression of Cyclin D1, BCL-2, and YAP1. Moreover, miR-195 overexpression rescued the effects of MASCC1 on the biological behaviors of HNSCC. Taken together, our results suggest that MASCC1 is a novel oncogene that can predict the prognosis of patients with HNSCC and is a potential therapeutic target for HNSCC intervention.

A meta-analysis of the risk factors for surgical site infection in patients with colorectal cancer.

The purpose of the meta-analysis was to evaluate and compare the surgical site infection (SSI) risk factors in patients with colorectal cancer (CC). The results of this meta-analysis were analysed, and the odds ratio (OR) and mean difference (MD) with 95% confidence intervals (CIs) were calculated using dichotomous or contentious random or fixed-effect models. For the current meta-analysis, 23 examinations spanning from 2001 to 2023 were included, encompassing 89 859 cases of CC. Clean-contaminated surgical site wounds had significantly lower infections (OR, 0.36; 95% CI, 0.20-0.64, p < 0.001) compared to contaminated surgical site wounds in patients with CCs. Males had significantly higher SSIs (OR, 1.18; 95% CI, 1.12-1.24, p < 0.001) compared to females in patients with CC. American Society of Anesthesiology score ≥3 h had a significantly higher SSI (OR, 1.42; 95% CI, 1.18-1.71, p < 0.001) compared to <3 score in patients with CCs. Body mass index ≥25 had significantly higher SSIs (OR, 1.54; 95% CI, 1.11-2.14, p = 0.01) compared to <25 in patients with CCs. The presence of stoma creation had a significantly higher SSI rate (OR, 2.28; 95% CI, 1.37-3.79, p = 0.001) compared to its absence in patients with CC. Laparoscopic surgery had significantly lower SSIs (OR, 0.68; 95% CI, 0.59-0.78, p < 0.001) compared to open surgery in patients with CC. The presence of diabetes mellitus had a significantly higher SSI rate (OR, 1.24; 95% CI, 1.15-1.33, p < 0.001) compared to its absence in patients with CCs. No significant difference was found in SSI rate in patients with CCs between <3 and ≥3 h of operative time (OR, 1.07; 95% CI, 0.75-1.51, p = 0.72), between the presence and absence of blood transfusion (OR, 1.60; 95% CI, 0.69-3.66, p = 0.27) and between the presence and absence of previous laparotomies (OR, 1.47; 95% CI, 0.93-2.32, p = 0.10). The examined data revealed that contaminated wounds, male sex, an American Society of Anesthesiology score ≥3 h, a body mass index ≥25, stoma creation, open surgery and diabetes mellitus are all risk factors for SSIs in patients with CC. However, operative time, blood transfusion and previous laparotomies were not found to be risk factors for SSIs in patients with CC. However, given that several comparisons had a small number of chosen research, consideration should be given to their values.

Prediction of radiation pneumonia after radiotherapy for esophageal cancer using a unified fractional dosiomics combined model.

OBJECTIVE: This study aimed to construct an optimal model to predict radiation pneumonia (RP) after radiotherapy for esophageal cancer using unified fractional dosiomics and to investigate the improvements in the prediction efficiency of each model for RP. METHODS: The clinical data, DVH, pre-treatment CT, and dose distribution of 182 patients were retrospectively analyzed.The independent risk factors were screened using univariate and multivariate logistic regression. The mutual information (MI),least absolute shrinkage and selection operator (LASSO), and recursive feature elimination (RFE) methods were used to screen the omics features. The AUC values of ROC, calibration curves, and clinical decision curves were calculated to evaluate the efficacy and trends of each model. RESULTS: The AUC of dosiomics model were 0.783 and 0.760 in the training and test cohorts, higher than 0.585 and 0.579 in the training and test cohorts of the DVH model. The AUC value of the R + D combination was the highest, reaching 0.833. The combined R + D model had a better calibration degree than the other models (mean absolute error = 0.018) and better net benefit in clinical decision-making. CONCLUSIONS: The radiomics combined dosiomics model was the best combined model to predict RP after radiotherapy for esophageal cancer. The dosiomics model could cover the efficiency of the DVH model and significantly improve the efficiency of the combined model.In the future, we will include other centers for further verification. ADVANCES IN KNOWLEDGE: For the first time, this study used CT images combined dose distribution to predict the occurrence of radiation pneumonitis after radiotherapy for esophageal cancer.

Impaired thymic iNKT cell differentiation at early precursor stage in murine haploidentical bone marrow transplantation with GvHD.

Introduction: Early recovery of donor-derived invariant natural killer T (iNKT) cells are associated with reduced risk of graft-versus-host disease (GvHD) and overall survival. Patients with severe GvHD, however, had much slower iNKT cell reconstitution relative to conventional T cells. Methods: To characterize the delay of iNKT cell reconstitution and explore its possible causes, we used a haploidentical bone marrow transplantation (haplo-BMT) mouse model with GvHD. We found the delayed recovery of thymic and peripheral iNKT cell numbers with markedly decreased thymic NKT1 subset in GvHD mice. The defective generation of thymic iNKT precursors with egress capability contributed to the reduced peripheral iNKT cells in GvHD mice. We further identified intermediate NK1.1- NKT1 precursor subpopulations under steady-state conditions and found that the differentiation of these subpopulations was impaired in the thymi of GvHD mice. Detailed characterization of iNKT precursors and thymic microenvironment showed a close association of elevated TCR/co-stimulatory signaling provided by double positive thymocytes and macrophages with defective down-regulation of proliferation, metabolism, and NKT2 signature in iNKT precursor cells. Correspondingly, NKT2 but not NKT1 differentiation was favored in GvHD mice. Discussion: These data underline the important roles of TCR and co-stimulatory signaling in the differentiation of thymic iNKT subsets under transplantation conditions.

[Effect of catgut implantation on macrophage CD68, tumor necrosis factor-α and interleukin-1ß in "Zusanli" (ST 36) region of rats].

OBJECTIVE: To observe the expression of local macrophages and related cytokines tumor necrosis factor-α (TNF-α) and interleukin-1ß (IL-1ß) after catgut implantation in "Zusanli"(ST 36) in rats, so as to explore its underlying mechanisms in inducing therapeutic effect. METHODS: A total of 110 male SD rats were randomly divided into blank control group (n=10), catgut embedding (CE) group (n=50), and sham CE group (n=50). The CE and sham CE groups were randomly divided into 8 h, 3 d, 7 d, 14 d and 21 d subgroups after the intervention (n=10 in each time point group). Rats of the CE group were uniformly subjected into catgut embedding at ST36 once, and those of the sham CE group received embedding needle puncture at ST36 without catgut retention, and the blank control group was only grasped and fixed without other treatments. Tissues from the ST36 area in each group were collected at the corresponding time points, and the expression of CD68 in macrophages in the acupoint area was detected by immunofluorescence, the contents of TNF-α and IL-1ß in the acupoint area were detected by ELISA. RESULTS: Following catgut embedment at ST36, the contents of TNF-α and IL-1ß, and macrophage CD68 expression level began to increase at 8 h, peaked at 3 d, and then gradually decreased at 7, 14, and 21 d, being still higher in the CE group than in the blank control group at 21 d (P<0.05). Compared with the blank control group, the contents of TNF-α and IL-1ß, and macrophage CD68 expression were significantly increased at 8 h, and 3, 7, 14 and 21 d in the CE group (P<0.05). Following sham CE at ST36, the content of TNF-α at 8 h and 3 d, IL-1ß at 8 h and 3, 7 and 14 d, and expression of CD68 at 8 h were significantly increased in comparison with the blank control group (P<0.05). Comparison between the CE and sham CE groups showed that the contents of IL-1ß at 3, 7, 14 and 21 d, and contents of TNF-α，CD68 expression at 8 h, and 3, 7, 14 and 21 d were significantly higher in the CE group than in the sham CE group (P<0.05). CONCLUSION: Catgut embedding at ST36 can induce an increase levels of inflammatory cytokines TNF-α, IL-1ß and macrophage CD68 in the local microenvironment in rats, which may contribute to its functions in initiating therapeutic effect.

The activation of CaN/NFAT signaling pathway in macrophages aggravated Lactobacillus casei cell wall extract-induced Kawasaki disease vasculitis.

OBJECTIVES: By using GWAS(genome-wide association studies) and linkage disequilibrium analysis to investigate the susceptibility genes of KD(Kawasaki disease), previous studies have identified that the CaN(calcineurin)-NFAT(the nuclear factor of activated T cell) signal pathway were significantly associated with susceptibility to KD. However, little is known about the molecular basis of the CaN/NFAT pathway involved in KD. Therefore, in our study we investigate the role of Ca2+/CaN/NFAT signaling pathway in macrophages in vitro and in vivo on coronary artery lesions induced by LCWE (Lactobacillus casei cell wall extract). METHODS AND RESULTS: We observed that LCWE could increase the expression of NFAT1 and NFAT2 in macrophages in vitro, and also enhance the transcriptional activity of NFAT by promoting the nucleus translocation. Similarly, in LCWE-induced mice model, the expression of NFAT1 and NFAT2 and associated proinflammatory factors were increased significantly. In addition, by knocking down or overexpressing NFAT1 or NFAT2 in macrophages, the results indicated that NFAT signaling pathway mediated LCWE-induced immune responses in macrophages and regulated the synthesis of IL(interleukin)-6, IL-1ß and TNF(tumor necrosis factor)-α in LCWE-induced macrophage activation. As well, we found that this process could be suppressed by CaN inhibitor CsA(cyclosporinA). CONCLUSIONS: Therefore, the CaN/NFAT signaling pathway mediated LCWE-induced immune responses in macrophages, and also participated in the LCWE-induced CALs(coronary artery lesions). And also the inhibitory effect of CsA in LCWE-induced cell model towards a strategy to modulate the CaN/NFAT pathway during the acute course of KD might be helpful in alleviate KD-induced CALs.

Actionability classification of variants of unknown significance correlates with functional effect.

Genomically-informed therapy requires consideration of the functional impact of genomic alterations on protein expression and/or function. However, a substantial number of variants are of unknown significance (VUS). The MD Anderson Precision Oncology Decision Support (PODS) team developed an actionability classification scheme that categorizes VUS as either "Unknown" or "Potentially" actionable based on their location within functional domains and/or proximity to known oncogenic variants. We then compared PODS VUS actionability classification with results from a functional genomics platform consisting of mutant generation and cell viability assays. 106 (24%) of 438 VUS in 20 actionable genes were classified as oncogenic in functional assays. Variants categorized by PODS as Potentially actionable (N = 204) were more likely to be oncogenic than those categorized as Unknown (N = 230) (37% vs 13%, p = 4.08e-09). Our results demonstrate that rule-based actionability classification of VUS can identify patients more likely to have actionable variants for consideration with genomically-matched therapy.

Identification of patients with acute coronary syndrome and representation of their degree of inflammation: application of pericoronary adipose tissue within different radial distances of the proximal coronary arteries.

Background: Pericoronary adipose tissue (PCAT) around the proximal right coronary artery (RCA) is considered a marker of coronary inflammation. We aimed to explore the segments of PCAT that represent coronary inflammation in patients with acute coronary syndrome (ACS) and to identify patients with ACS and stable coronary artery disease (CAD) prior to intervention. Methods: We retrospectively enrolled consecutive patients with ACS and stable CAD who underwent invasive coronary angiography (ICA) after coronary computed tomography angiography (CCTA) from November 2020 to October 2021 at the Fourth Affiliated Hospital of Harbin Medical University. The fat attenuation index (FAI) was obtained using PCAT quantitative measurement software, and the coronary Gensini score was also calculated to indicate the severity of CAD. The differences and correlations between FAI within different radial distances of proximal coronary arteries were evaluated, and the recognition ability of FAI for patients with ACS and stable CAD was evaluated by establishing receiver operator characteristic (ROC) curves. Results: A total of 267 patients were included in the cross-sectional study, including 173 patients with ACS. With the increase of radial distance from the outer wall of proximal coronary vessels, the FAI decreased (P<0.001). The FAI around the proximal left anterior descending artery (LAD) within the reference diameter from the outer wall of the vessel (LADref) had the highest correlation with the FAI around culprit lesions [r=0.587; 95% confidence interval (CI): 0.489-0.671; P<0.001]. The model based on clinical features, Gensini score, and LADref had the highest recognition performance for patients with ACS and stable CAD [area under the curve (AUC): 0.663; 95% CI: 0.540-0.785]. Conclusions: LADref is most correlated with FAI around culprit lesions in patients with ACS and has higher value in the preintervention differentiation of patients with ACS and stable CAD compared to the use of clinical features alone.

Extraction of impacted mandibular third molars in close proximity to the inferior alveolar canal with coronectomy-miniscrew traction to avoid nerve injury.

OBJECTIVES: Extraction of impacted mandibular third molars (IMTMs) is the most common surgery performed in the Department of Oral and Maxillofacial Surgery. Inferior alveolar nerve (IAN) injury is a rare but severe complication, and the risk is significantly higher in cases of IMTM near the inferior alveolar canal (IAC). The existing surgical method to extract such IMTMs is either not safe enough or is time-consuming. A better surgical design is needed. MATERIALS AND METHODS: From August 2019 to June 2022, 23 patients underwent IMTM extraction by Dr. Zhao at Nanjing Stomatological Hospital, Affiliated Hospital of Medical School, Nanjing University, and were found to have IMTMs in close proximity to the IAC. Due to high IAN injury risk, these patients underwent coronectomy-miniscrew traction to extract their IMTMs. RESULTS: The time between coronectomy-miniscrew insertion and complete removal of the IMTM was 32.65 ± 2.110 days, which was significantly shorter than that of traditional orthodontic traction. Two-point discrimination testing revealed no IAN injury, and no injury was reported by patients during follow-up. Other complications, such as severe swelling, severe bleeding, dry socket, and limited mouth opening, were not observed. Postoperative pain levels were not significantly higher in the coronectomy-miniscrew traction group than in the traditional IMTM extraction group. CLINICAL RELEVANCE: For IMTMs that are in close proximity to the IAC and must be extracted, coronectomy-miniscrew traction is a novel approach to minimize the risk of IAN injury in a less time-consuming way with a lower possibility of complications.