Biomimetic MDSCs membrane coated black phosphorus nanosheets system for photothermal therapy/photodynamic therapy synergized chemotherapy of cancer.

Photothermal therapy is favored by cancer researchers due to its advantages such as controllable initiation, direct killing and immune promotion. However, the low enrichment efficiency of photosensitizer in tumor site and the limited effect of single use limits the further development of photothermal therapy. Herein, a photo-responsive multifunctional nanosystem was designed for cancer therapy, in which myeloid-derived suppressor cell (MDSC) membrane vesicle encapsulated decitabine-loaded black phosphorous (BP) nanosheets (BP@ Decitabine @MDSCs, named BDM). The BDM demonstrated excellent biosafety and biochemical characteristics, providing a suitable microenvironment for cancer cell killing. First, the BDM achieves the ability to be highly enriched at tumor sites by inheriting the ability of MDSCs to actively target tumor microenvironment. And then, BP nanosheets achieves hyperthermia and induces mitochondrial damage by its photothermal and photodynamic properties, which enhancing anti-tumor immunity mediated by immunogenic cell death (ICD). Meanwhile, intra-tumoral release of decitabine induced G2/M cell cycle arrest, further promoting tumor cell apoptosis. In vivo, the BMD showed significant inhibition of tumor growth with down-regulation of PCNA expression and increased expression of high mobility group B1 (HMGB1), calreticulin (CRT) and caspase 3. Flow cytometry revealed significantly decreased infiltration of MDSCs and M2-macrophages along with an increased proportion of CD4+, CD8+ T cells as well as CD103+ DCs, suggesting a potentiated anti-tumor immune response. In summary, BDM realizes photothermal therapy/photodynamic therapy synergized chemotherapy for cancer.

Lymph node targeting strategy using a hydrogel sustained-release system to load effector memory T cells improves the anti-tumor efficacy of anti-PD-1.

Communication between tumors and lymph nodes carries substantial significance for antitumor immunotherapy. Remodeling the immune microenvironment of tumor-draining lymph nodes (TdLN) plays a key role in enhancing the anti-tumor ability of immunotherapy. In this study, we constructed a biomimetic artificial lymph node structure composed of F127 hydrogel loading effector memory T (TEM) cells and PD-1 inhibitors (aPD-1). The biomimetic lymph nodes facilitate the delivery of TEM cells and aPD-1 to the TdLN and the tumor immune microenvironment, thus realizing effective and sustained anti-tumor immunotherapy. Exploiting their unique gel-forming and degradation properties, the cold tumors were speedily transformed into hot tumors via TEM cell supplementation. Meanwhile, the efficacy of aPD-1 was markedly elevated compared with conventional drug delivery methods. Our finding suggested that the development of F127@TEM@aPD-1 holds promising potential as a future novel clinical drug delivery technique. STATEMENT OF SIGNIFICANCE: Bionic artificial lymph nodes(F127@TEM@aPD-1) show unique advantages in cancer treatment. When injected subcutaneously, the artificial lymph node can continuously supplement TEM cells and aPD-1 to tumor draining lymph nodes (TdLN) and the tumor microenvironment, not only improving the efficacy of ICB therapy through slow release, but also exhibiting dual regulatory effects on the tumor and TdLN.

Transcatheter arterial tendinopathy embolization as a treatment for painful and refractory tendinopathy: a systematic review and meta-analysis.

OBJECTIVE: Transcatheter arterial embolization (TAE) is a novel minimally invasive therapy for painful tendinopathy in patients with pain refractory to conservative management. The purpose of this study was to evaluate evidence on the efficacy of TAE for tendinopathy related pain. MATERIALS AND METHODS: Using Embase, PubMed, and Web of Science, a systematic review and meta-analysis was performed to identify studies evaluating TAE for painful tendinopathy. The primary outcome measure was change in pain scale score at 6 months. A Ratio of Means (ROM) was used to compare the effect size post treatment as compared to baseline. The Visual Analog Scale (VAS) was used as the metric for comparison. RESULTS: After screening titles, abstracts, and the full text, 5 studies met inclusion criteria. A total of 97 tendinopathy embolization procedures performed in 74 patients were included. Patients who underwent TAE demonstrated declines in VAS ROM at 1 day 0.53 [95% CI 0.31,0.88], 1 week (0.51 [95% CI 0.32,0.79]), 1 month (0.45 [95% CI 0.29, 0.71]), 3-4 months (0.33 [95% CI 0.22,0.48]), and 6 months following embolization (0.18[95% CI 0.13,0.26]), respectively. DISCUSSION: TAE provides substantial short-term reductions in pain scores for patients suffering with refractory tendinopathy related pain of the rotator cuff, elbow extensor and flexor, Achilles, and patellar tendons.

Performance of VI-RADS in predicting muscle-invasive bladder cancer after transurethral resection: a single center retrospective analysis.

PURPOSE: To assess VIRADS performance and inter-reader agreement for detecting muscle-invasive bladder cancer (MIBC) following transurethral resection of bladder tumor (TURBT). METHODS: An IRB-approved, HIPAA-compliant, retrospective study from 2016 to 2020 included patients with bladder urothelial carcinoma who underwent MRI after TURBT, and cystectomy within 3 months without post-MRI treatments. Three radiologists blinded to pathology results independently reviewed MR images and assigned a VI-RADS score. Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and accuracy of VI-RADS were assessed for diagnosing MIBC using VI-RADS scores ≥ 3 and ≥ 4. Inter-reader agreement was assessed using Gwet's agreement coefficient (AC) and percent agreement. RESULTS: The cohort consisted of 70 patients (mean age, 68 years ± 11 [SD]; range 39-85; 58 men) and included 32/70 (46%) with MIBC at cystectomy. ROC analysis revealed an AUC ranging from 0.67 to 0.77 and no pairwise statistical difference between readers (p-values, 0.06, 0.08, 0.97). Percent sensitivity, specificity, PPV, NPV and accuracy for diagnosing MIBC for the three readers ranged from 81.3-93.8, 36.8-55.3, 55.6-60.5, 77.3-87.5, and 62.9-67.1 respectively for VI-RADS score ≥ 3, and 78.1-81.3, 47.4-68.4, 55.6-67.6, 72.0-78.8 and 61.4-72.9 respectively for VI-RADS score ≥ 4. Gwet's AC was 0.63 [95% confidence interval (CI): 0.49,0.78] for VI-RADS score ≥ 3 with 79% agreement [95% CI 72,87] and 0.54 [95%CI 0.38,0.70] for VI-RADS score ≥ 4 with 76% agreement [95% CI 69,84]. VIRADS performance was not statistically different among 31/70 (44%) patients who received treatments prior to MRI (p ≥ 0.16). CONCLUSION: VI-RADS had moderate sensitivity and accuracy but low specificity for detection of MIBC following TURBT, with moderate inter-reader agreement.

Genes that escape from X-chromosome inactivation and sexual dimorphism of systemic lupus erythematosus.

X chromosome inactivation can balance the effects of the two X chromosomes in females, and emerging evidence indicates that numerous genes on the inactivated X chromosome have the potential to evade inactivation. The mechanisms of escape include modification of DNA, RNA, histone, epitope, and various regulatory proteins, as well as the spatial structure of chromatin. The study of X chromosome inactivation escape has paved the way for investigating sex dimorphism in human diseases, particularly autoimmune diseases. It has been demonstrated that the presence of TLR7, CD40L, IRAK-1, CXCR3, and CXorf21 significantly contributes to the prevalence of SLE (systemic lupus erythematosus) in females. This article mainly reviews the molecular mechanisms underlying these genes that escape from X-chromosome inactivation and sexual dimorphism of systemic lupus erythematosus. Therefore, elucidating the molecular mechanisms underlying sexual dimorphism in SLE is not only crucial for diagnosing and treating the disease, but also holds theoretical significance in comprehensively understanding the development and regulatory mechanisms of the human immune system.

Microwave-responsive gadolinium metal-organic frameworks nanosystem for MRI-guided cancer thermotherapy and synergistic immunotherapy.

The clinical application of cancer immunotherapy is unsatisfied due to low response rates and systemic immune-related adverse events. Microwave hyperthermia can be used as a synergistic immunotherapy to amplify the antitumor effect. Herein, we designed a Gd-based metal-organic framework (Gd-MOF) nanosystem for MRI-guided thermotherapy and synergistic immunotherapy, which featured high performance in drug loading and tumor tissue penetration. The PD-1 inhibitor (aPD-1) was initially loaded in the porous Gd-MOF (Gd/M) nanosystem. Then, the phase change material (PCM) and the cancer cell membrane were further sequentially modified on the surface of Gd/MP to obtain Gd-MOF@aPD-1@CM (Gd/MPC). When entering the tumor microenvironment (TME), Gd/MPC induces immunogenic death of tumor cells through microwave thermal responsiveness, improves tumor suppressive immune microenvironment and further enhances anti-tumor ability of T cells by releasing aPD-1. Meanwhile, Gd/MPC can be used for contrast-enhanced MRI. Transcriptomics data revealed that the downregulation of MSK2 in cancer cells leads to the downregulation of c-fos and c-jun, and ultimately leads to the apoptosis of cancer cells after treatment. In general, Gd/MPC nanosystem not only solves the problem of system side effect, but also achieves the controlled drug release via PCM, providing a promising theranostic nanoplatform for development of cancer combination immunotherapy.

High Peritumoral and Intratumoral T2 Signal Intensity in HER2-Positive Breast Cancers on Preneoadjuvant Breast MRI: Assessment of Associations With Histopathologic Characteristics.

BACKGROUND. Intratumoral necrosis and peritumoral edema are features of aggressive breast cancer that may present as high T2 signal intensity (T2 SI). Implications of high T2 SI in HER2-positive cancers are unclear. OBJECTIVE. The purpose of this study was to assess associations with histopathologic characteristics of high peritumoral T2 SI and intratumoral T2 SI of HER2-positive breast cancer on MRI performed before initiation of neoadjuvant therapy. METHODS. This retrospective study included 210 patients (age, 24-82 years) with 211 HER2 breast cancers who, from January 1, 2015, to July 30, 2022, underwent breast MRI before receiving neoadjuvant therapy. Two radiologists independently assessed cancers for high peritumoral T2 SI and high intratumoral T2 SI on fat-suppressed T2-weighted imaging and classified patterns of high peritumoral T2 SI (adjacent to tumor vs prepectoral extension). A third radiologist resolved discrepancies. Multivariable logistic regression analyses were performed to identify associations of high peritumoral and intratumoral T2 SI with histopathologic characteristics (associated ductal carcinoma in situ, hormone receptor status, histologic grade, lymphovascular invasion, and axillary lymph node metastasis). RESULTS. Of 211 HER2-positive cancers, 81 (38.4%) had high peritumoral T2 SI, and 95 (45.0%) had high intratumoral T2 SI. A histologic grade of 3 was independently associated with high peritumoral T2 SI (OR = 1.90; p = .04). Otherwise, none of the five assessed histopathologic characteristics were independently associated with high intratumoral T2 SI or high peritumoral T2 SI (p > .05). Cancers with high T2 SI adjacent to the tumor (n = 29) and cancers with high T2 SI with prepectoral extension (n = 52) showed no significant difference in frequency for any of the histopathologic characteristics (p > .05). Sensitivities and specificities for predicting the histopathologic characteristics ranged from 35.6% to 43.7% and from 59.7% to 70.7%, respectively, for high peritumoral T2 SI, and from 37.3% to 49.6% and from 49.3% to 62.7%, respectively, for high intratumoral T2 SI. Interreader agreement was almost perfect for high peritumoral T2 SI (Gwet agreement coefficient [AC] = 0.93), high intratumoral T2 SI (Gwet AC = 0.89), and a pattern of high peritumoral T2 SI (Gwet AC = 0.95). CONCLUSION. The only independent association between histopathologic characteristics and high T2 SI of HER2-positive breast cancer was observed between a histologic grade of 3 and high peritumoral T2 SI. CLINICAL IMPACT. In contrast with previously reported findings in broader breast cancer subtypes, peritumoral and intratumoral T2 SI had overall limited utility as prognostic markers of HER2-positive breast cancer.

Impact of possible errors in natural language processing-derived data on downstream epidemiologic analysis.

Objective: To assess the impact of potential errors in natural language processing (NLP) on the results of epidemiologic studies. Materials and Methods: We utilized data from three outcomes research studies where the primary predictor variable was generated using NLP. For each of these studies, Monte Carlo simulations were applied to generate datasets simulating potential errors in NLP-derived variables. We subsequently fit the original regression models to these partially simulated datasets and compared the distribution of coefficient estimates to the original study results. Results: Among the four models evaluated, the mean change in the point estimate of the relationship between the predictor variable and the outcome ranged from -21.9% to 4.12%. In three of the four models, significance of this relationship was not eliminated in a single of the 500 simulations, and in one model it was eliminated in 12% of simulations. Mean changes in the estimates for confounder variables ranged from 0.27% to 2.27% and significance of the relationship was eliminated between 0% and 9.25% of the time. No variables underwent a shift in the direction of its interpretation. Discussion: Impact of simulated NLP errors on the results of epidemiologic studies was modest, with only small changes in effect estimates and no changes in the interpretation of the findings (direction and significance of association with the outcome) for either the NLP-generated variables or other variables in the models. Conclusion: NLP errors are unlikely to affect the results of studies that use NLP as the source of data.

[Spatiotemporal Distribution Characteristics of Air Pollution and Health Risks in Key Cities of China].

Based on the monitoring data of five pollutants in 168 key cities under air pollution prevention and control in China from 2015 to 2020, using the MAKESENS model and the aggregate risk index(ARI), this study quantitatively analyzed the spatial and temporal distribution characteristics of air pollution and health risks in China and the six urban agglomerations. The results showed that:① PM2.5 pollution was the most serious pollution in Chinese key cities. Only 15% of the cities' six-year average concentrations of PM2.5 reached the National Secondary Standard, followed by that of NO2; 77% of the cities' six-year average concentrations of NO2 reached the National Secondary Standard. The urban agglomerations of Beijing-Tianjin-Hebei and Fenwei plain had the most serious air pollution, and the six-year average concentrations of PM2.5, SO2, CO, and NO2 were higher than those of other urban agglomerations. ② The concentrations of PM2.5, SO2, CO, and NO2 in key cities of China showed a decreasing trend, whereas the concentration of O3 in other urban agglomerations showed an increasing trend, except in the Chengdu-Chongqing urban agglomeration. The concentration of SO2 in the urban agglomerations of Beijing-Tianjin-Hebei and Fenwei plain changed the most significantly. ③ The health risk of air pollution in the key cities of China generally showed a decreasing trend, with a sharp decline from 2017 to 2018, and the population exposed to extremely high risks dropped from 160 million to 32.54 million. The urban agglomeration in the middle reaches of the Yangtze River had the most significant decline in health risks, whereas the key cities in China faced higher health risks in spring and winter seasons. ④ The Beijing-Tianjin-Hebei and Fenwei plain urban agglomerations had the highest health risks, and the urban agglomeration in the middle reaches of the Yangtze River had the lowest; O3 gradually replaced PM2.5 as the main pollutant affecting the health risk. These results can provide a reference for evaluating the effectiveness of urban air pollution control in China during the 13th Five-Year Plan period.

The role of oral microbiota in cancer.

Cancer remains a significant global challenge, with an estimated 47% increase in cancer patients from 2020 to 2040. Increasing research has identified microorganism as a risk factor for cancer development. The oral cavity, second only to the colon, harbors more than 700 bacterial species and serves as a crucial microbial habitat. Although numerous epidemiological studies have reported associations between oral microorganisms and major systemic tumors, the relationship between oral microorganisms and cancers remains largely unclear. Current research primarily focuses on respiratory and digestive system tumors due to their anatomical proximity to the oral cavity. The relevant mechanism research mainly involves 47% dominant oral microbial population that can be cultured in vitro. However, further exploration is necessary to elucidate the mechanisms underlying the association between oral microbiota and tumors. This review systematically summarizes the reported correlations between oral microbiota and common cancers while also outlining potential mechanisms that may guide biological tumor treatment.

Porphyromonas gingivalis suppresses oral squamous cell carcinoma progression by inhibiting MUC1 expression and remodeling the tumor microenvironment.

Bacteria are the causative agents of various infectious diseases; however, the anti-tumor effect of some bacterial species has attracted the attention of many scientists. The human oral cavity is inhabited by abundant and diverse bacterial communities and some of these bacterial communities could play a role in tumor suppression. Therefore, it is crucial to find oral bacterial species that show anti-tumor activity on oral cancers. In the present study, we found that a high abundance of Porphyromonas gingivalis, an anaerobic periodontal pathogen, in the tumor microenvironment (TME) was positively associated with the longer survival of patients with oral squamous cell carcinoma (OSCC). An in vitro assay confirmed that P. gingivalis accelerated the death of OSCC cells by inducing cell cycle arrest at the G2/M phase, thus exerting its anti-tumor effect. We also found that P. gingivalis significantly decreased tumor growth in a 4-nitroquinoline-1-oxide-induced in situ OSCC mouse model. The transcriptomics data demonstrated that P. gingivalis suppressed the biosynthesis of mucin O-glycan and other O-glycans, as well as the expression of chemokines. Validation experiments further confirmed the downregulation of mucin-1 (MUC1) and C-X-C motif chemokine 17 (CXCL17) expression by P. gingivalis treatment. Flow cytometry analysis showed that P. gingivalis successfully reversed the immunosuppressive TME, thereby suppressing OSCC growth. In summary, the findings of the present study indicated that the rational use of P. gingivalis could serve as a promising therapeutic strategy for OSCC.

Comparing biweekly single-dose actinomycin D with multiday methotrexate therapy for low-risk gestational trophoblastic neoplasia (FIGO Score 0-4): study protocol for a prospective, multicentre, randomized trial.

BACKGROUND: Single-agent chemotherapy using methotrexate or actinomycin D is the first-line treatment for patients with low-risk gestational trophoblastic neoplasia. Various methotrexate-based and actinomycin D-based single-agent regimens can be used. However, there is insufficient evidence to determine the superior regimen. To guide doctors in selecting a single-agent chemotherapy regimen for patients with low-risk gestational trophoblastic neoplasia, we will compare two regimens. METHODS: We will conduct a multicentre, randomized, prospective clinical trial. Selected low-risk gestational trophoblastic neoplasia patients (FIGO score 0-4) will be randomized 1:1 to a biweekly single-dose actinomycin D group or a multiday methotrexate therapy group. The actinomycin D group will receive IV pulse actinomycin D (1.25 mg/m2) every 14 days, and the methotrexate group will receive methotrexate (50 mg) intramuscularly on days 1, 3, 5, and 7 (4 doses per cycle) and leucovorin (15 mg) intramuscularly on days 2, 4, 6, and 8. This process will be repeated every 14 days. The primary endpoints will include the complete remission rate by single-agent therapy and the overall complete remission rate. The secondary endpoints will include the duration needed to achieve complete remission after single-agent chemotherapy, number of courses needed to achieve complete remission after single-agent chemotherapy, incidence and severity of adverse effects, effects on menstrual conditions and ovarian function based on the anti-Mullerian hormone level, and patient-reported quality of life. DISCUSSION: Previous clinical trials comparing biweekly single-dose actinomycin D with multiday methotrexate therapy for treating low-risk gestational trophoblastic neoplasia patients failed to meet the expected case number. Through this multicentre study, the complete remission ratio and efficacy difference between biweekly single-dose actinomycin D and multiday methotrexate therapy will be obtained. This study will also provide the basis for formulating a preferred regimen for treating patients with low-risk gestational trophoblastic neoplasia. TRIAL REGISTRATION: ClinicalTrials.gov: NCT04562558, Registered on 13 September 2020 (Protocol version 2020-9-24, version 1.0).

Experience of a single healthcare system with screening mammography before and after COVID-19 shutdown.

PURPOSE: To evaluate COVID-19's longitudinal impact on screening mammography volume trends. METHODS: HIPAA-compliant, IRB-approved, single institution, retrospective study of screening mammogram volumes before (10/21/2016-3/16/2020) and greater than two years after (6/17/2020-11/30/2022) a state-mandated COVID-19 shutdown (3/17/2020-6/16/2020) were reviewed. A segmented quasi-poisson linear regression model adjusting for seasonality and network and regional population growth compared volume trends before and after the shutdown of each variable: age, race, language, financial source, risk factor for severe COVID-19, and examination location. RESULTS: Adjusted model demonstrated an overall increase of 65 screening mammograms per month before versus a persistent decrease of 5 mammograms per month for >2 years after the shutdown (p < 0.0001). In subgroup analysis, downward volume trends were noted in all age groups <70 years (age < 50: +9/month before vs. -7/month after shutdown; age 50-60: +17 vs. -7; and age 60-70: +21 vs. -2; all p < 0.001), those identifying as White (+55 vs. -8, p < 0.0001) and Black (+4 vs. +1, p = 0.009), all financial sources (Medicare: +22 vs. -3, p < 0.0001; Medicaid: +5 vs. +2, p = 0.006; private insurance/self-pay: +38 vs. -4, p < 0.0001), women with at least one risk factor for severe COVID-19 (+30 vs. -48, p < 0.0001), and screening mammograms performed at a hospital-based location (+48 vs. -14, p = 0.0001). CONCLUSION: The screening mammogram volume trend more than two years after the COVID-19 shutdown has continued to decline for most patient populations. Findings highlight the need to identify additional areas for education and outreach.

Major cardiovascular events after COVID-19, event rates post-vaccination, antiviral or anti-inflammatory therapy, and temporal trends: Rationale and methodology of the CORONA-VTE-Network study.

BACKGROUND: Coronavirus disease 2019 (COVID-19) is associated with excess risk of cardiovascular and thrombotic events in the early post-infection period and during convalescence. Despite the progress in our understanding of cardiovascular complications, uncertainty persists with respect to more recent event rates, temporal trends, association between vaccination status and outcomes, and findings within vulnerable subgroups such as older adults (aged 65 years or older), or those undergoing hemodialysis. Sex-informed findings, including results among pregnant and breastfeeding women, as well as adjusted comparisons between male and female adults are similarly understudied. METHODS: Adult patients, aged ≥18 years, with polymerase chain reaction-confirmed COVID-19 who received inpatient or outpatient care at the participating centers of the registry are eligible for inclusion. A total of 10,000 patients have been included in this multicenter study, with Brigham and Women's Hospital (Boston, MA) serving as the coordinating center. Other sites include Beth Israel Deaconess Medical Center, Anne Arundel Medical Center, University of Virginia Medical Center, University of Colorado Health System, and Thomas Jefferson University Health System. Data elements will be ascertained manually for accuracy. The two main outcomes are 1) a composite of venous or arterial thrombotic events, and 2) a composite of major cardiovascular events, defined as venous or arterial thrombosis, myocarditis or heart failure with inpatient treatment, new atrial fibrillation/flutter, or cardiovascular death. Clinical outcomes are adjudicated by independent physicians. Vaccination status and time of inclusion in the study will be ascertained for subgroup-specific analyses. Outcomes are pre-specified to be reported separately for hospitalized patients versus those who were initially receiving outpatient care. Outcomes will be reported at 30-day and 90-day follow-up. Data cleaning at the sites and the data coordinating center and outcomes adjudication process are in-progress. CONCLUSIONS: The CORONA-VTE-Network study will share contemporary information related to rates of cardiovascular and thrombotic events in patients with COVID-19 overall, as well as within key subgroups, including by time of inclusion, vaccination status, patients undergoing hemodialysis, the elderly, and sex-informed analyses such as comparison of women and men, or among pregnant and breastfeeding women.

A Wafer Pre-Alignment Algorithm Based on Weighted Fourier Series Fitting of Circles and Least Squares Fitting of Circles.

The wafer pre-aligner is a crucial component in the lithography process to correct the wafer center and notch orientation. To improve the precision and the efficiency of pre-alignment, a new method to calibrate the center and the orientation of a wafer based on the weighted Fourier series fitting of circles (WFC) method and the least squares fitting of circles (LSC) method, respectively, is proposed. The WFC method effectively suppressed the influence of the outliers and had high stability compared with the LSC method when fitted to the center of the circle. While the weight matrix degenerated to the identity matrix, the WFC method degenerated into the Fourier series fitting of circles (FC) method. The fitting efficiency of the FC method is 28% higher than that of the LSC method, and the fitting accuracy of the center of the FC method is the same as that of the LSC method. In addition, the WFC method and the FC method perform better than the LSC method in radius fitting. The pre-alignment simulation results showed that the absolute position accuracy of the wafer was ±2 µm, the absolute direction accuracy was 0.01°, and the total calculation time was less than 3.3 s in our platform.

Tumor and Ablation Margin Visibility during Cryoablation of Musculoskeletal Tumors: Comparing Intraprocedural PET/CT Images with CT-Only Images.

PURPOSE: To compare tumor and ice-ball margin visibility on intraprocedural positron emission tomography (PET)/computed tomography (CT) and CT-only images and report technical success, local tumor progression, and adverse event rates for PET/CT-guided cryoablation procedures for musculoskeletal tumors. MATERIALS AND METHODS: This Health Insurance Portability and Accountability Act (HIPAA)-compliant and institutional review board-approved retrospective study evaluated 20 PET/CT-guided cryoablation procedures performed with palliative and/or curative intent to treat 15 musculoskeletal tumors in 15 patients from 2012 to 2021. Cryoablation was performed using general anesthesia and PET/CT guidance. Procedural images were reviewed to determine the following: (a) whether the tumor borders could be fully assessed on PET/CT or CT-only images; and (b) whether tumor ice-ball margins could be fully assessed on PET/CT or CT-only images. The ability to visualize tumor borders and ice-ball margins on PET/CT images was compared with that on CT-only images. RESULTS: Tumor borders were fully assessable for 100% (20 of 20; 95% CI, 0.83-1) of procedures on PET/CT versus 20% (4 of 20; 95 CI, 0.057-0.44) of procedures on CT only (P < .001). The tumor ice-ball margin was fully assessable in 80% (16 of 20; 95% CI, 0.56-0.94) of procedures using PET/CT versus 5% (1 of 20; 95% CI, 0.0013-0.25) of procedures using CT only (P < .001). Primary technical success was achieved in 75% (15 of 20; 95% CI, 0.51-0.91) of procedures. There was local tumor progression in 23% (3/13; 95% CI, 0.050-0.54) of the treated tumors with at least 6 months of follow-up. There were 3 adverse events (1 Grade 3, 1 Grade 2, and 1 Grade 1). CONCLUSIONS: PET/CT-guided cryoablation of musculoskeletal tumors can provide superior intraprocedural visualization of the tumor and ice-ball margins compared with that provided by CT alone. Further studies are warranted to confirm the long-term efficacy and safety of this approach.

Polygoni Multiflori Radix Praeparata and Acori Tatarinowii Rhizoma ameliorate scopolamine-induced cognitive impairment by regulating the cholinergic and synaptic associated proteins.

ETHNOPHARMACOLOGICAL RELEVANCE: The combination of Polygoni Multiflori Radix Praeparata (PMRP) and Acori Tatarinowii Rhizoma (ATR) is often used in traditional Chinese medicine to prevent and treat Alzheimer's disease (AD). However, it is not clear whether the effects and mechanisms of the decoction prepared by traditional decocting method (PA) is different from that prepared by modern decocting method (P + A). AIM OF THE STUDY: The present study aimed to investigate the differences in the protective effects of PA and P + A on scopolamine induced cognitive impairment, and to explore its potential mechanism. MATERIALS AND METHODS: To assess the protective effect of PA and P + A on cognitive dysfunction, the mice were orally administrated with PA (1.56, 6.24 g kg-1•day-1) and P + A (1.56, 6.24 g kg-1•day-1) for 26 days before co-treatment with scopolamine (4 mg kg-1•day-1, i.p.). The learning and memory abilities of mice were examined by Morris water maze test, and the expressions of proteins related to cholinergic system and synaptic function were detected by the methods of ELISA, real-time PCR and Western blotting. Then, molecular docking technique was used to verify the effect of active compounds in plasma after PA administration on Acetylcholinesterase (AChE) protein. Finally, the Ellman method was used to evaluate the effects of different concentrations of PA, P + A (1 µg/mL-100 mg/mL) and the compounds (1-100 µM) on AChE activity in vitro. RESULTS: On one hand, in the scopolamine-induced cognitive impairment mouse model, both of PA and P + A could improve the cognitive impairment, while the effect of PA on cognitive amelioration was better than that of P + A. Moreover, PA regulated the cholinergic and synaptic functions by enhancing the concentration of acetylcholine (ACh), the mRNA levels of CHT1, Syn, GAP-43 and PSD-95, and the related proteins (CHT1, VACHT, Syn, GAP-43 and PSD-95), and significantly inhibiting the expression of AChE protein. Meanwhile, P + A only up-regulated the mRNA levels of GAP-43 and PSD-95, increased the expressions of CHT1, VACHT, Syn, GAP-43 and PSD-95 proteins, and inhibited the expression of AChE protein. On the other hand, the in vitro study showed that some compounds including emodin-8-o-ß-d-Glucopyranoside, THSG and α-Asarone inhibited AChE protein activity with the IC50 values 3.65 µM, 5.42 µM and 9.43 µM, respectively. CONCLUSIONS: These findings demonstrate that both of PA and P + A can ameliorate the cognitive deficits by enhancing cholinergic and synaptic related proteins, while PA has the stronger improvement effect on the cholinergic function, which may be attributed to the compounds including THSG, emodin, emodin-8-O-ß-D-glucopyranoside and α-asarone. The present study indicated that PA has more therapeutic potential in the treatment of neurodegenerative diseases such as AD. The results provide the experimental basis for the clinical use of PA.

Variation in hospital use of cardiac resynchronization therapy-defibrillator among eligible patients and association with clinical outcomes.

BACKGROUND: Despite strong guideline recommendations for cardiac resynchronization therapy-defibrillator (CRT-D) in select patients, this therapy is underutilized with substantial variation among hospitals, and the association of this variation with outcomes is unknown. OBJECTIVE: The purpose of this study was to assess whether facility variation in CRT-D utilization is associated with differences in hospital-level outcomes. METHODS: We linked Medicare claims data with the National Cardiovascular Data Registry's ICD Registry from 2010 to 2015. We calculated the intraclass correlation coefficient to quantify the degree of variation in patient-level CRT use that can be explained by interfacility variation on a hospital level. To quantify the degree of hospital variation in patient-level outcomes (all-cause mortality, readmissions, and cardiac readmissions) that can be attributed to variations in CRT-D use, we utilized multilevel modeling. RESULTS: The study included 30,134 patients across 1377 hospitals. The median rate of CRT-D implantation in those meeting guideline indications was 89%, but there was a wide variation across hospitals. After adjustment, most of the variation (74%) in hospital rates of CRT-D utilization was attributable to the hospital in which the patient was treated. Differences in hospital CRT-D utilization was associated with 8.76%, 5.26%, and 4.71% of differences in hospital mortality, readmissions, and cardiac readmission rates, respectively (P < .001 for all outcomes). CONCLUSION: There is a wide variation in the use of CRT-D across hospitals that was not explained by case mix. Hospital-level variation in CRT-D utilization was associated with clinically significant differences in outcomes. A measure of CRT-D utilization in eligible patients may serve as a useful metric for quality improvement efforts.

Assessment of Sex Disparities in Nonacceptance of Statin Therapy and Low-Density Lipoprotein Cholesterol Levels Among Patients at High Cardiovascular Risk.

Importance: Many patients at high cardiovascular risk-women more commonly than men-are not receiving statins. Anecdotally, it is common for patients to not accept statin therapy recommendations by their clinicians. However, population-based data on nonacceptance of statin therapy by patients are lacking. Objectives: To evaluate sex disparities in nonacceptance of statin therapy and assess their association with low-density lipoprotein (LDL) cholesterol control. Design, Setting, and Participants: A retrospective cohort study was conducted from January 1, 2019, to December 31, 2022, of statin-naive patients with atherosclerotic cardiovascular disease, diabetes, or LDL cholesterol levels of 190 mg/dL (to convert to millimoles per liter, multiply by 0.0259) or more who were treated at Mass General Brigham between January 1, 2000, and December 31, 2018. Exposure: Recommendation of statin therapy by the patient's clinician, ascertained from the combination of electronic health record prescription data and natural language processing of electronic clinician notes. Main Outcomes and Measures: Time to achieve an LDL cholesterol level of less than 100 mg/dL. Results: Of 24 212 study patients (mean [SD] age, 58.8 [13.0] years; 12 294 women [50.8%]), 5308 (21.9%) did not accept the initial recommendation of statin therapy. Nonacceptance of statin therapy was more common among women than men (24.1% [2957 of 12 294] vs 19.7% [2351 of 11 918]; P < .001) and was similarly higher in every subgroup in the analysis stratified by comorbidities. In multivariable analysis, female sex was associated with lower odds of statin therapy acceptance (0.82 [95% CI, 0.78-0.88]). Patients who did vs did not accept a statin therapy recommendation achieved an LDL cholesterol level of less than 100 mg/dL over a median of 1.5 years (IQR, 0.4-5.5 years) vs 4.4 years (IQR, 1.3-11.1 years) (P < .001). In a multivariable analysis adjusted for demographic characteristics and comorbidities, nonacceptance of statin therapy was associated with a longer time to achieve an LDL cholesterol level of less than 100 mg/dL (hazard ratio, 0.57 [95% CI, 0.55-0.60]). Conclusions and Relevance: This cohort study suggests that nonacceptance of a statin therapy recommendation was common among patients at high cardiovascular risk and was particularly common among women. It was associated with significantly higher LDL cholesterol levels, potentially increasing the risk for cardiovascular events. Further research is needed to understand the reasons for nonacceptance of statin therapy by patients and to develop methods to ensure that all patients receive optimal therapy in accordance with their preferences and priorities.

Potential anti-gout properties of Wuwei Shexiang pills based on network pharmacology and pharmacological verification.

ETHNOPHARMACOLOGICAL RELEVANCE: Wuwei Shexiang Pills (WWSX), a classic Tibetan medicine, consists of Chebulae Fructus (removed pit), Aucklandiae Radix, Moschus, Aconiti Fiavi Radix, and Acori Calami Rhizoma. It is used clinically in China to treat joint pain, swelling and other symptoms, and has the function of dispelling wind and relieving pain. However, to date, the mechanism of how it works against gout is still unclear. AIMS OF THE STUDY: Using network pharmacology, molecular docking and pharmacological verification to explore the potential anti-gout properties of WWSX. MATERIALS AND METHODS: With the use of UPLC-Q/TOF-MS, the main components of WWSX were obtained and screened for potential anti-inflammatory components by network pharmacology and molecular docking. The anti-inflammatory activity of the components screened from WWSX was also tested by in vitro assays. The anti-gout mechanism of WWSX was predicted by network pharmacology, and the pharmacological validation experiments using gouty arthritis model and mouse air pouch model were used to explore the multifaceted mechanism of WWSX to modify gout. RESULT: Thirty-eight active ingredients were obtained from the UPLC-Q/TOF-MS detection. The network pharmacology and molecular docking analysis showed that 104 co-targets were participated in the treatment of gout, and the main signaling pathways involved were NOD-like receptor pathway, NF-κB pathway and MAPK pathway. Pharmacological evaluation showed that WWSX could significantly improve gout in gouty arthritis models and mouse air pouch models by modulating the above pathways. CONCLUSION: This work has predicted and validated the anti-inflammatory material basis and predicted the anti-gout mechanism of WWSX which was verified by network pharmacology, molecular docking and in vitro cellular studies. The results reveal the mechanism of WWSX in the treatment of gout and provide a theoretical basis for its clinical application.