Comparative Effectiveness of Anticoagulants in Patients With Cancer-Associated Thrombosis.

Importance: Patterns of clinical utilization and comparative effectiveness of anticoagulants for cancer-associated thrombosis (CAT) remain largely unexplored. Objectives: To assess patterns of and factors associated with anticoagulant use and to evaluate the comparative effectiveness of contemporary anticoagulants in patients with active cancer in a clinical setting. Design, Setting, and Participants: This retrospective cohort study obtained deidentified OptumLabs electronic health record claims data from January 1, 2012, to September 30, 2019. Adult patients (≥18 years of age) with a primary cancer diagnosis (except skin cancer) during at least 1 inpatient or 2 outpatient visits within 6 months before the venous thromboembolism (VTE) date were included. Data were analyzed from April 2020 to September 2021. Exposures: The patients were grouped according to the anticoagulant prescribed: (1) direct oral anticoagulants (DOACs), (2) low-molecular-weight heparin (LMWH), and (3) warfarin. Main Outcomes and Measures: Odds ratios (ORs) were used to present the association between factors of interest and utilization of anticoagulants. Main efficacy outcomes included risk of VTE recurrence and all-cause mortality. Main safety outcomes included the risk of hospitalization due to major bleeding. Relative treatment effect estimates were expressed as hazard ratios (HRs) with 95% CIs. Results: This study included 5100 patients (mean [SD] age, 66.3 [12.3] years; 2670 [52.4%] women; 799 [15.7%] Black, 389 [7.6%] Hispanic, and 3559 [69.8%] White individuals). Overall, 2512 (49.3%), 1488 (29.2%), and 1460 (28.6%) filled prescriptions for DOACs, LMWH, and warfarin, respectively. The median (IQR) treatment duration was 3.2 (1.0-6.5) months for DOACs, 3.1 (1.0-6.8) months for warfarin, and 1.8 (0.9-3.8) months for LWMH. Patients with lung (OR, 2.07; 95% CI, 1.12-3.65), urological (OR, 1.94; 95% CI,1.08-3.49), gynecological (OR, 4.25; 95% CI, 2.31-7.82), and colorectal (OR, 2.26; 95% CI, 1.20-4.32) cancer were associated with increased prescriptions for LMWH compared with DOACs. LMWH (HR, 1.47; 95% CI, 1.14-1.90) and warfarin (HR, 1.46; 95% CI, 1.13-1.87) were associated with an increased risk of VTE recurrences compared with DOACs. LMWH was associated with an increased risk of major bleeding (HR, 2.27; 95% CI, 1.62-3.20) and higher all-cause mortality (HR, 1.61; 95% CI, 1.15-2.25) compared with DOACs. Conclusions and Relevance: In this comparative effectiveness study of claims-based data, patients with CAT received anticoagulation for a remarkably short duration in clinical settings. DOACs was associated with a lower risk of VTE recurrence, major bleeding, and mortality. Warfarin may still be considered for patients with contraindications to DOACs and those with poor persistence on LMWH.

The investigation of construction and clinical application of image recognition technology assisted bronchoscopy diagnostic model of lung cancer.

Background: The incidence and mortality of lung cancer ranks first in China. Bronchoscopy is one of the most common diagnostic methods for lung cancer. In recent years, image recognition technology(IRT) has been more and more widely studied and applied in the medical field. We developed a diagnostic model of lung cancer under bronchoscopy based on deep learning method and tried to classify pathological types. Methods: A total of 2238 lesion images were collected retrospectively from 666 cases of lung cancer diagnosed by pathology in the bronchoscopy center of the Third Xiangya Hospital from Oct.01 2017 to Dec.31 2020 and 152 benign cases from Jun.01 2015 to Dec.31 2020. The benign and malignant images were divided into training, verification and test set according to 7:1:2 respectively. The model was trained and tested based on deep learning method. We also tried to classify different pathological types of lung cancer using the model. Furthermore, 9 clinicians with different experience were invited to diagnose the same test images and the results were compared with the model. Results: The diagnostic model took a total of 30s to diagnose 467 test images. The overall accuracy, sensitivity, specificity and area under curve (AUC) of the model to differentiate benign and malignant lesions were 0.951, 0.978, 0.833 and 0.940, which were equivalent to the judgment results of 2 doctors in the senior group and higher than those of other doctors. In the classification of squamous cell carcinoma (SCC) and adenocarcinoma (AC), the overall accuracy was 0.745, including 0.790 for SCC, 0.667 for AC and AUC was 0.728. Conclusion: The performance of our diagnostic model to distinguish benign and malignant lesions in bronchoscopy is roughly the same as that of experienced clinicians and the efficiency is much higher than manually. Our study verifies the possibility of applying IRT in diagnosis of lung cancer during white light bronchoscopy.

Artificial intelligence-guided screening for atrial fibrillation using electrocardiogram during sinus rhythm: a prospective non-randomised interventional trial.

BACKGROUND: Previous atrial fibrillation screening trials have highlighted the need for more targeted approaches. We did a pragmatic study to evaluate the effectiveness of an artificial intelligence (AI) algorithm-guided targeted screening approach for identifying previously unrecognised atrial fibrillation. METHODS: For this non-randomised interventional trial, we prospectively recruited patients with stroke risk factors but with no known atrial fibrillation who had an electrocardiogram (ECG) done in routine practice. Participants wore a continuous ambulatory heart rhythm monitor for up to 30 days, with the data transmitted in near real time through a cellular connection. The AI algorithm was applied to the ECGs to divide patients into high-risk or low-risk groups. The primary outcome was newly diagnosed atrial fibrillation. In a secondary analysis, trial participants were propensity-score matched (1:1) to individuals from the eligible but unenrolled population who served as real-world controls. This study is registered with ClinicalTrials.gov, NCT04208971. FINDINGS: 1003 patients with a mean age of 74 years (SD 8·8) from 40 US states completed the study. Over a mean 22·3 days of continuous monitoring, atrial fibrillation was detected in six (1·6%) of 370 patients with low risk and 48 (7·6%) of 633 with high risk (odds ratio 4·98, 95% CI 2·11-11·75, p=0·0002). Compared with usual care, AI-guided screening was associated with increased detection of atrial fibrillation (high-risk group: 3·6% [95% CI 2·3-5·4] with usual care vs 10·6% [8·3-13·2] with AI-guided screening, p<0·0001; low-risk group: 0·9% vs 2·4%, p=0·12) over a median follow-up of 9·9 months (IQR 7·1-11·0). INTERPRETATION: An AI-guided targeted screening approach that leverages existing clinical data increased the yield for atrial fibrillation detection and could improve the effectiveness of atrial fibrillation screening. FUNDING: Mayo Clinic Robert D and Patricia E Kern Center for the Science of Health Care Delivery.

Rates of, and factors associated with, switching among generic levothyroxine preparations in commercially insured American adults.

IMPORTANCE: Some practice guidelines warn against generic L-thyroxine preparation switching. OBJECTIVE: To examine the rates of generic L-thyroxine preparation switching within one year of initiating L-thyroxine, and to examine factors associated with switching. DESIGN AND SETTING: Retrospective study using national data from a large administrative claims database from January 2008 through November 2018. PATIENTS: Medicare or commercially insured adults (≥18 years) who filled a generic L-thyroxine preparation. MAIN OUTCOME MEASURES: At least one switch from one generic L-thyroxine preparation to another within 1 year of L-thyroxine initiation defined by prescription fills. RESULTS: From January 2008 to November 2018, we included 483,390 patients who initiated generic L-thyroxine: mean (SD) age was 61.4 years (15.2), 75.2% were female, 72.6% were white. Within 1 year of initiating therapy, 98,013 (20%) switched to another L-thyroxine generic preparation at least once. In a multivariate logistic regression analysis, factors associated with switching included the number of pharmacies visited to fill L-thyroxine (>2 vs 1 adjusted OR [aOR] 7.15, 95% confidence interval [CI] 6.97-7.34), age ≥75 vs. <45 years (aOR 1.29, 95% CI 1.26-1.33), history of thyroid surgery (aOR 1.22, 95% CI 1.13-1.31), and first L-thyroxine fill date in 2018 vs. 2008 (aOR 3.32, 95% CI 3.14-3.51). CONCLUSIONS AND RELEVANCE: One in five patients switched among generic L-thyroxine manufacturers within one year of treatment initiation. Generic L-thyroxine switching occurred more often when more pharmacies were used to fill L-thyroxine. Given existing guideline recommendations, additional studies should clarify the impact of generic L-thyroxine switching on thyroid hormone values.

Real-world Cardiovascular Outcomes Associated With Degarelix vs Leuprolide for Prostate Cancer Treatment.

Importance: With a growing interest in the use of real-world evidence for regulatory decision-making, it is important to understand whether real-world data can be used to emulate the results of randomized clinical trials. Objective: To use electronic health record and administrative claims data to emulate the ongoing PRONOUNCE trial (A Trial Comparing Cardiovascular Safety of Degarelix Versus Leuprolide in Patients With Advanced Prostate Cancer and Cardiovascular Disease). Design, Setting, and Participants: This retrospective, propensity-matched cohort study included adult men with a diagnosis of prostate cancer and cardiovascular disease who initiated either degarelix or leuprolide between December 24, 2008, and June 30, 2019. Participants were commercially insured individuals and Medicare Advantage beneficiaries included in a large US administrative claims database. Exposures: Degarelix or leuprolide. Main Outcomes and Measures: The primary end point was time to first occurrence of a major adverse cardiovascular event (MACE), defined as death due to any cause, myocardial infarction, or stroke, analogous to the PRONOUNCE trial. Secondary end points were time to death due to any cause, myocardial infarction, stroke, and angina. Cox proportional hazards regression was used to evaluate primary and secondary end points. Results: A total of 32 172 men initiated degarelix or leuprolide for prostate cancer; of them, 9490 (29.5%) had cardiovascular disease, and 7800 (24.2%) met the PRONOUNCE trial eligibility criteria and were included in this study. Overall, 165 participants (2.1%) were Asian, 1390 (17.8%) were Black, 663 (8.5%) were Hispanic, and 5258 (67.4%) were White. The mean (SD) age was 74.4 (7.4) years. Among 2226 propensity score-matched patients, no significant difference was observed in the risk of MACE for patients taking degarelix vs those taking leuprolide (10.18 vs 8.60 events per 100 person-years; hazard ratio [HR], 1.18; 95% CI, 0.86-1.61). Degarelix was associated with a higher risk of death from any cause (HR, 1.48; 95% CI, 1.01-2.18) but not of myocardial infarction (HR, 1.16; 95% CI, 0.60-2.25), stroke (HR, 0.92; 95% CI, 0.45-1.85), or angina (HR, 1.36; 95% CI, 0.43-4.27). Conclusions and Relevance: In this emulation of a clinical trial of men with cardiovascular disease undergoing treatment for prostate cancer, degarelix was not associated with a lower risk of cardiovascular events than leuprolide. Comparison of these data with PRONOUNCE trial results, when published, will help enhance our understanding of the appropriate role of using real-world data to emulate clinical trials.

Cardiovascular outcomes and rates of fractures and falls among patients with brand-name versus generic L-thyroxine use.

PURPOSE: To compare cardiovascular outcomes and rates of fractures and falls among patients with persistent brand-name versus generic L-thyroxine use. METHODS: Retrospective, 1:1 propensity-matched longitudinal study using a national administrative claims database to examine adults (≥18 years) who initiated either brand or generic L-thyroxine between 2008 and 2018, censored at switch or discontinuation of L-thyroxine formulation or disenrollment from the health plan. Main outcome measures included rates of hospitalization for atrial fibrillation, myocardial infarction, congestive heart failure, stroke, spine and hip fractures, and rate of falls in the outpatient or inpatient setting. Hospitalizations for pneumonia were used as a negative control. RESULTS: 195,046 adults initiated treatment with L-thyroxine between 2008 and 2017: 87% generic and 13% brand formulations. They were mostly women (76%), young (94.6% under age 65), white (66%), and 47% had baseline thyroid stimulating hormone levels between 4.5 and 9.9 mIU/L. Among 35,667 propensity-matched patients, there were no significant differences between patients treated with brand versus generic L-thyroxine in atrial fibrillation (HR 0.96, 0.58-1.60), myocardial infarction (HR 0.66, 0.39-1.14), congestive heart failure (HR 1.30, 0.78-2.16), stroke (0.72, 0.49-1.06), spine (HR 0.87, 0.38-1.99) and hip fractures (HR 0.86, 0.26-2.82), or fall outcomes (HR 1.02, 0.14-7.32). Hospitalization rates for pneumonia (used as negative control) did not differ between groups (HR 0.85, 0.61-1.19). There were no interactions between brand versus generic L-thyroxine, these outcomes, and thyroid cancer, age, or L-thyroxine dose subgroups. CONCLUSIONS: We found no significant differences in cardiovascular outcomes and rates of falls and fractures for patients who filled brand versus generic L-thyroxine.

Proprotein convertase subtilisin/kexin type 9 inhibitor utilization and low-density lipoprotein-cholesterol control in familial hypercholesterolemia.

BACKGROUND: Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors were approved in August 2015 as an adjunct to maximally tolerated statin treatment in those with familial hypercholesterolemia (FH). OBJECTIVE: To assess PCSK9 inhibitor utilization patterns and cholesterol control in the high-risk FH population. METHODS: This study was a retrospective analysis of a large administrative database that includes privately insured and Medicare Advantage patients. Individuals with diagnosis codes for FH from October 2016-September 2019 were identified. Differences in PCSK9 inhibitor utilization between various groups were evaluated using multivariable logistic regression. RESULTS: During the study period, 1:371 people enrolled in medical/pharmacy plans had a diagnosis of FH. While 62.5% (n = 33,649) had medication fills for statins (without PCSK9 inhibitors), only 2.0% (n = 1062) had medication fills for PCSK9 inhibitors (with or without other medications). Compared to men, women were more likely to be untreated (OR 1.23, 95% confidence interval (CI):1.18-1.28, p < 0.01) but more likely to be treated with PCSK9 inhibitors (OR 2.18, 95%CI:1.90-2.49, p < 0.01). Compared to those younger than 55 years of age, older individuals were more likely to be treated (OR 1.64, 95%CI:1.56-1.72, p < 0.01) but less likely to be treated with PCSK9 inhibitors (OR 0.40, 95%CI:0.34-0.47, p < 0.01). Lastly, those with household incomes ≥$40,000 were more likely to be treated with PCSK9 inhibitors than those with lower household incomes (OR 1.69, 95%CI:1.41-2.02, p < 0.01). CONCLUSION: PCSK9 inhibitor utilization in FH remains low. Significant differences exist based on demographic factors. Female sex, higher household incomes, and younger age were associated with increased PCSK9 inhibitor utilization.

Apoptosis of Acanthamoeba castellanii Trophozoites Induced by Oleic Acid.

Acanthamoeba spp. can be parasitic in certain situations and are responsible for serious human infections, including Acanthamoeba keratitis, granulomatous amoebic encephalitis, and cutaneous acanthamoebiasis. We analyzed the fatty acid composition of Acanthamoeba castellanii trophozoites and tested the inhibitory activity of the main fatty acids, oleic acid and arachidonic acid, in vitro. Oleic acid markedly inhibited the growth of A. castellanii, with trophozoite viability of 57.4% at a concentration of 200 µM. Caspase-3 staining and annexin V assays showed that apoptotic death occurred in A. castellanii trophozoites. Quantitative PCR and dot blot analysis showed increased levels of metacaspase and interleukin-1ß converting enzyme, which is also an indication of apoptosis. In contrast, arachidonic acid showed negligible inhibition of growth of A. castellanii trophozoites. Stimulated expression of Atg3, Atg8 and LC3A/B genes and monodansylcadaverine labeling suggested that oleic acid induces apoptosis by triggering autophagy of trophozoites.

Exendin-4 Loaded Nanoparticles with a Lipid Shell and Aqueous Core Containing Micelles for Enhanced Intestinal Absorption.

The purpose of this study was to formulate nanoparticles with an elaborate structure for oral delivery of exendin-4 using a simple preparation process. The nanoparticles possessed a mixed lipid shell and an aqueous core which contained drug-loaded micelles. Formulation was optimized by a central composite design and the structure of the nanoparticles was validated. The efficacy for delivery of exendin-4 was evaluated both in vitro and in vivo. The drug encapsulation efficiency of the nanoparticles reached 97.7%. The nanoparticles greatly enhanced the cellular uptake and transport of encapsulated exendin-4 in vitro. The in situ study showed that exendin-4 could be transported across the epithelium into intestinal capillaries, while the lipid materials largely remained in the epithelium. Pharmacodynamic studies in diabetic KKAy mice demonstrated that the exendin-4-loaded nanoparticles exhibited a marked hypoglycemia effect with a pharmacological availability of 12.7% after intestinal administration.

Artemether Exhibits Amoebicidal Activity against Acanthamoeba castellanii through Inhibition of the Serine Biosynthesis Pathway.

Acanthamoeba sp. parasites are the causative agents of Acanthamoeba keratitis, fatal granulomatous amoebic encephalitis, and cutaneous infections. However, there are currently no effective drugs for these organisms. Here, we evaluated the activity of the antimalarial agent artemether against Acanthamoeba castellanii trophozoites and identified potential targets of this agent through a proteomic approach. Artemether exhibited in vitro amoebicidal activity in a time- and dose-dependent manner and induced ultrastructural modification and cell apoptosis. The iTRAQ quantitative proteomic analysis identified 707 proteins that were differentially expressed after artemether treatment. We focused on phosphoglycerate dehydrogenase and phosphoserine aminotransferase in the serine biosynthesis pathway because of their importance to the growth and proliferation of protozoan and cancer cells. The expression of these proteins in Acanthamoeba was validated using quantitative real-time PCR and Western blotting after artemether treatment. The changes in the expression levels of phosphoserine aminotransferase were consistent with those of phosphoglycerate dehydrogenase. Therefore, the downregulation of phosphoserine aminotransferase may be due to the downregulation of phosphoglycerate dehydrogenase. Furthermore, exogenous serine might antagonize the activity of artemether against Acanthamoeba trophozoites. These results indicate that the serine biosynthesis pathway is important to amoeba survival and that targeting these enzymes would improve the treatment of Acanthamoeba infections. Artemether may be used as a phosphoglycerate dehydrogenase inhibitor to control or block Acanthamoeba infections.

[(1)H-MRS study of auditory cortex in patients with presbycusis].

OBJECTIVE: To study the metabolic changes of auditory cortex in patients with presbycusis by using proton magnetic resonance spectroscopy ((1)H-MRS). METHODS: Ten normal hearing volunteers (youth group), 10 normal hearing of elderly (aged group) and 8 patients with presbycusis (presbycusis group) were checked with proton magnetic resonance spectroscopy. N-acetylaspartic acid (NAA), creatine (Cr), choline (Cho), γ-aminobutyric acid (GABA), glutamic acid (Glu) compound were measured. The differences between the groups were semi-quantitatively analyzed. RESULTS: When compared with youth group, reduced NAA/Cr, increased Cho/Cr were found in the aged group and presbycusis group (P < 0.05). GABA/Cr ratio and Glu/Cr ratio were significant difference between presbycusis group and youth group (P < 0.05). There were no significant difference in the GABA/Cr and Glu/Cr ratios in the bilateral auditory cortex between the youth group and the aged group (P > 0.05). When compared with aged group, the metabolic changes of auditory cortex in patients with presbycusis were remarkable (P < 0.05). CONCLUSIONS: (1)H-MRS is a noninvasive technique that can provide useful information concerning the metabolic changes of auditory cortex in human. In comparison to the aged group and the youth group, the changes of NAA, GABA, Cho and Glu is found in auditory cortex in patients with presbycusis.