CodonBert large language model for mRNA vaccines.

mRNA-based vaccines and therapeutics are gaining popularity and usage across a wide range of conditions. One of the critical issues when designing such mRNAs is sequence optimization. Even small proteins or peptides can be encoded by an enormously large number of mRNAs. The actual mRNA sequence can have a large impact on several properties including expression, stability, immunogenicity, and more. To enable the selection of an optimal sequence, we developed CodonBERT, a large language model (LLM) for mRNAs. Unlike prior models, CodonBERT uses codons as inputs which enables it to learn better representations. CodonBERT was trained using more than 10 million mRNA sequences from a diverse set of organisms. The resulting model captures important biological concepts. CodonBERT can also be extended to perform prediction tasks for various mRNA properties. CodonBERT outperforms previous mRNA prediction methods including on a new flu vaccine dataset.

Residual plastic film decreases crop yield and water use efficiency through direct negative effects on soil physicochemical properties and root growth.

Film mulching has been extensively used to improve agricultural production in arid regions of China. However, without sufficient mulch film recovery, large amounts of residual film accumulated in the farmland, which would affect crop yield and water use efficiency (WUE). In order to comprehensively analyze the effects of residual film on crop yield and WUE, and clarify its influencing mechanism, present study adopted a meta-analysis to systematically evaluate the impacts of residual film on soil physicochemical properties, crop root growth, yield, and WUE. The results showed that residual film significantly increased soil bulk density and the soil moisture content in 0-20 cm soil layer, but decreased soil porosity, soil organic matter, soil total nitrogen content, and soil moisture content in >20 cm soil layer, especially when residual film amount was >400 kg ha-1. Residual film significantly reduced crop root dry weight, root length, root diameter, root volume and root surface area. Generally, crop yield and WUE decreased with the increase of residual film amount; and crop yield was reduced by about 14.00 % when the residual film amount increased by 1000 kg ha-1. In average, crop yield and WUE under film residual condition were significantly decreased by 13.46 % and 9.21 %, respectively. The negative effects of residual film on root growth, yield and WUE were greater for cash crops (cotton, tomato and potato) than for cereal crops (wheat, maize). The structural equation model indicated that residual film generated indirect negative effects on crop yield and WUE by directly affecting soil physicochemical properties and crop root growth, with the standard path coefficients of -0.302 and - 0.217, respectively. The results would provide a theoretical basis for reducing residual film pollution on farmland and promoting the green and sustainable development of agriculture.

Association between clinical symptoms during the COVID-19 infection and SARS-CoV-2 immunoglobulin G titers in COVID-19 convalescent whole-blood donors in China.

BACKGROUND: Limited studies have explored the association between clinical symptoms and titers of SARS-CoV-2 antibodies. STUDY DESIGN AND METHODS: In this cross-sectional study, whole-blood donors who had experienced a confirmed or suspected COVID-19 infection completed questionnaires at the time of blood donation. Plasma SARS-CoV-2 immunoglobulin G (IgG) titers were measured using an enzyme-linked immunosorbent assay. Logistic regression models were used to calculate odds ratios (ORs) for high-titer COVID-19 convalescent plasma (CCP) for each variable. RESULTS: Among the total 386 donors, 120 (31%) donors with IgG titers ≥1:160 were classified as high-titer donors. The multivariable ORs (95% confidence intervals [CIs]) for high titers were 2.33 (1.45-3.75), 2.11 (1.29-3.43), 1.10 (1.01-1.21), 1.19 (1.00-1.43), and 1.97 (1.05-3.71) for sore throat, cough, symptom count, fever duration, and low fever (compared with non-fever), respectively. No significant association was observed between other symptoms and medical visits and the odds of high-titer CCP. The association between high-titer CCP and fever duration was restricted to confirmed COVID-19-infected donors, while associations with sore throat and cough remained significant in suspected infected donors. In addition, medical visit was positively associated with high-titer CCP in suspected donors, but not in confirmed donors. In bootstrapped logistic regression models, the associations remained significant and reproducible for medical visit in suspected donors and for sore throat and cough in both suspected donors and total donors. DISCUSSION: Experiencing a sore throat and cough were associated with high-titer CCP in overall donors. We also identified sore throat, cough, and medical visits as potential predictors of high-titer CCP for suspected donors during the pandemic.

Clinical manifestations and outcomes of otitis media with effusion in adult patients following Omicron infection in China.

This study investigates the clinical features and therapeutic outcomes of otitis media with effusion (OME) in adults following infection with the Omicron variant of coronavirus disease 2019 (COVID-19), in the context of China ending its "Zero-COVID-19" policy. Conducted as a multicenter, retrospective analysis at two medical institutions in Eastern China from December 2022 to February 2023, the study included patients with confirmed Omicron infection who were diagnosed with OME within two months, adhering to guidelines from the American Academy of Otolaryngology-Head and Neck Surgery Foundation (AAO-HNSF). Data on demographics, time from infection to OME manifestation, associated symptoms, and treatment outcomes were collected. Among 68 patients (73 affected ears) with OME post-Omicron infection, common symptoms included cough and nasal obstruction (69.1%). All reported ear fullness, with 86.8% experiencing hearing loss. Tympanic bullae were observed in 72.6% during otoscopy, and most tympanometry results showed a B-type tympanogram (80.0%). An integrated treatment strategy led to an 83.6% cure rate, although 8.2% experienced relapse within 2-3 months. Our findings highlight OME as a prevalent ear complication associated with COVID-19 during the Omicron pandemic, underscoring the necessity for further investigation into its complexities. While the integrated treatment approach proved effective, the 8.2% post-treatment recurrence rate underscores the importance of ongoing monitoring and signals an urgent need for more comprehensive research.

Factors associated with the SARS-CoV-2 immunoglobulin-G titer levels in convalescent whole-blood donors: a Chinese cross-sectional study.

Blood transfusions from convalescent Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infected patients could be used to treat patients with severe infections or immunocompromised patients. However, it is necessary to select the optimal donors to maximize the utilization of resources. In this study, we investigated the associations among body mass index (BMI), tobacco smoking, exercise frequency and duration, and alcohol consumption with the SARS-CoV-2 immunoglobulin-G (IgG) antibody titer levels with in the Chinese convalescent blood donor population. Here we show that BMI, smoking habits, and exercise frequency appear to be predictive factors for IgG levels in convalescent male blood donors. However, these variables were not observed as predictive of IgG levels in female convalescent blood donors. The findings could be used to optimize the screening for potential blood donors to treat immunocompromised or severely ill COVID-19 patients.

Corrigendum: Predictors of high SARS-CoV-2 immunoglobulin G titers in COVID-19 convalescent whole-blood donors: a cross-sectional study in China.

[This corrects the article DOI: 10.3389/fimmu.2023.1191479.].

A Combination of BRAF and EZH1/SPOP/ZNF148 Three-Gene Mutational Classifier Improves Benign Call Rate in Indeterminate Thyroid Nodules.

Reliable preoperative diagnosis of thyroid nodules remained challenging because of the inconclusiveness of fine-needle aspiration (FNA) cytology. In the present study, 583 formalin-fixed paraffin embedded (FFPE) thyroid nodule tissues and 161 FNA specimens were enrolled retrospectively. Then BRAF V600E, EZH1 Q571R, SPOP P94R, and ZNF148 mutations among these samples were identified using Sanger sequencing. Based on this four-gene genomic classifier, we proposed a two-step modality to diagnose thyroid nodules to differentiate benign and malignant thyroid nodules. In the FFPE group, thyroid cancers were effectively diagnosed in 37.7% (220/583) of neoplasms by the primary BRAF V600E testing, and 15.7% (57/363) of thyroid nodules could be further determined as benign by subsequent EZH1 Q571R, SPOP P94R, and ZNF148 (we called them "ESZ") mutation testing. In the FNA group, 161 BRAF wild-type specimens were classified according to The Bethesda System for Reporting Thyroid Cytopathology (TBSRTC). A total of 7 mutated samples fell within Bethesda categories III-IV, and the mutation rate of "ESZ" in Bethesda III-IV categories was 8.4%. The two-step genomic classifier could further improve thyroid nodule diagnosis, which may inform more optimal patient management.

Predictors of high SARS-CoV-2 immunoglobulin G titers in COVID-19 convalescent whole-blood donors: a cross-sectional study in China.

Background: Demographic information has been shown to help predict high antibody titers of COVID-19 convalescent plasma (CCP) in CCP donors. However, there is no research on the Chinese population and little evidence on whole-blood donors. Therefore, we aimed to investigate these associations among Chinese blood donors after SARS-CoV-2 infection. Methods: In this cross-sectional study, 5,064 qualified blood donors with confirmed or suspected SARS-CoV-2 infection completed a self-reported questionnaire and underwent tests of SARS-CoV-2 Immunoglobulin G (IgG) antibody and ABO blood type. Logistic regression models were used to calculate odds ratios (ORs) for high SARS-CoV-2 IgG titers according to each factor. Results: Totally, 1,799 participants (with SARS-CoV-2 IgG titers≥1:160) had high-titer CCPs. Multivariable analysis showed that a 10-year increment in age and earlier donation were associated with higher odds of high-titer CCP, while medical personnel was associated with lower odds. The ORs (95% CIs) of high-titer CCP were 1.17 (1.10-1.23, p< 0.001) and 1.41 (1.25-1.58, p< 0.001) for each 10-year increment in age and earlier donation, respectively. The OR of high-titer CCP was 0.75 (0.60-0.95, p = 0.02) for medical personnel. Female early donors were associated with increased odds of high-titer CCP, but this association was insignificant for later donors. Donating after 8 weeks from the onset was associated with decreased odds of having high-titer CCP compared to donating within 8 weeks from the onset, and the HR was 0.38 (95% CI: 0.22-0.64, p <0.001). There was no significant association between ABO blood type or race and the odds of high-titer CCP. Discussion: Older age, earlier donation, female early donors, and non-medical-related occupations are promising predictors of high-titer CCP in Chinese blood donors. Our findings highlight the importance of CCP screening at the early stage of the pandemic.

GC-MS Untargeted Analysis of Volatile Compounds in Four Red Grape Varieties (Vitis vinifera L. cv) at Different Maturity Stages near Harvest.

Grape volatile compounds directly determine the aroma quality of wines. Although the aroma profile of grapes evolved greatly at different maturity stages, there were less considerations for aroma status when determining grape harvest time. In the present study, several maturation indicators, namely, sugars/acids ratio, free volatile compounds, bound volatile compounds and IBMP (3-isobutyl-2-methoxypyrazine) content were monitored in four red wine grape varieties (Vitis vinifera L. cv Cabernet Sauvignon, Cabernet Gernischet, Cabernet Franc and Merlot) near harvest time (42 days) in Ningxia, China. The results showed that the highest sugars/acids ratio was reached on day 21 and day 28 for Merlot and the other three varieties, respectively. For both free and bound volatile compounds, the content of carbonyl compounds decreased continuously in the process of ripening. The contents of free alcohols, esters and terpenes increased in the ripening stage and decreased in the stage of over-ripening. The accumulation of favorable bound aroma compounds peaked at day 35. The content of IBMP presenting a green smell in all four varieties descended continuously and kept steady from day 28. Therefore, the present findings revealed that the best aroma maturity time of four studied grape varieties was later than the sugars/acids ratio in Ningxia region. Aroma maturity should be taken into account during harvest time determination.

Identification and Characterization of Malolactic Bacteria Isolated from the Eastern Foothills of Helan Mountain in China.

Malolactic fermentation (MLF) converts malic acid into lactic acid by lactic acid bacteria (LAB). MLF may affect potential wine quality impact as global warming intensifies, and the alcohol in the wine increases, which threatens MLF. Lactiplantibacillus plantarum is considered a new generation of MLF starter because of the ability of high ethanol tolerance and good enological characteristics. In this research, 132 LAB strains were isolated from the eastern foothills of Helan Mountain in Ningxia, China. Twenty-one higher ethanol tolerance isolates were obtained by 15% (v/v) ethanol preliminary screening. They were identified by 16S rRNA sequencing and differentiated by randomly amplified polymorphic DNA (RAPD). Stress factors include ethanol, pH, and SO2, and the combination of stresses was used to screen stress-tolerance strains. ß-D-glucosidase activity, MLF performance, and biogenic amine content were tested to evaluate the enological characteristics. GC-MS detected the volatile components of the wine after MLF. The results showed that twenty strains were identified as L. plantarum, and one strain was Lentilactobacillus hilgardii. Especially, the strains of A7, A18, A23, A50, and B28 showed strong resistance to high ethanol, low pH, and high SO2. A7, A50, and B28 showed better ß-D-glucosidase activity and thus were inoculated into cabernet sauvignon wines whose ethanol content was 14.75% (v/v) to proceed MLF. A7 finished MLF in 36 d, while the control strains Oenococcus oeni 31-DH and L. plantarum BV-S2 finished MLF in 24 d and 28 d, respectively. Nevertheless, A50 and B28 did not finish MLF in 36 d. The data showed that A7 brought a more volatile aroma than control. Notably, the esters and terpenes in the wine increased. These results demonstrated the potential applicability of L. plantarum A7 as a new MLF starter culture, especially for high-ethanol wines.

Application of Smartphone Otoscope in Telemedicine in Rural Medical Consortium in Eastern China in the COVID-19 Era.

Purpose: This study aimed to evaluate the effectiveness of smartphone otoscope telemedicine in the rural medical consortium in East China in the COVID-19 era. Methods: This prospective study was conducted within a rural medical consortium that provides health care services by integrating medical resources in the same area. When a patient visited primary health care (PHC) for ear diseases, the PHC provider used a smartphone otoscope to examine the patient's external ear canal and eardrum, and then sent photos or videos of the patient's ear to the otolaryngologist at the lead hospital via WeChat group. The otolaryngologist provided remote diagnosis and management recommendations to the PHC provider. The following data were recorded: age and gender, outpatient diagnosis, disease duration, sides, duration of treatment, telemedicine visits, treatment outcomes, patient satisfaction, and PHC providers' self-evaluation score. Results: A total of 83 patients were included in the study, including 43 males and 40 females, with a mean age of 44.6 ± 19.7 years (range 3-83 years). The duration of treatment for these patients was 14.0 (7,14) days. PHC visits were 2.2 ± 1.1 times (range: 1-7 times). Telemedicine visits ranged from 1 to 5, with a mean of 1.8 ± 0.9. Among of patients, 62 (74.7%) were cured, 21 (25.3%) improved, and 0 (0%) were ineffective. Sixty-five patients (78.3%) were very satisfied, 16 (19.3%) patients were somewhat satisfied, and two patients (2.4%) were dissatisfied. Based on the self-reported helpfulness, the primary health care providers assessed telemedicine as very helpful (n = 63, 75.9%), helpful (n = 20, 24.1%), and unhelpful (n = 0, 0%). Conclusions: Smartphone otoscope telemedicine in the medical consortium can effectively improve the ability of rural PHC providers to diagnose and treat ear diseases, save time and costs for patients, and improve patient satisfaction.

Adsorption of soil organic matter by gel-like ferrihydrite and dense ferrihydrite.

Soil is the largest terrestrial carbon pool, and adsorption of soil organic matter (SOM) by ferrihydrite is an essential geochemical process for preservation of organic carbon in soil. Freshly formed gel-like ferrihydrite and seasonally dried dense ferrihydrite are two typical morphologies of ferrihydrite in soil. However, the differences in SOM adsorption by gel-like ferrihydrite and dense ferrihydrite and the underlying mechanisms are unknown. In this study, adsorption of eight SOM or SOM-like compounds by gel-like ferrihydrite and dense ferrihydrite were compared. It was observed that the adsorption capacity of SOM by gel-like ferrihydrite (e.g., 304 mg C/g) was two orders of magnitude higher than that by dense ferrihydrite (e.g., 3.44 mg C/g). SOM adsorbed by the nanosized gel-like ferrihydrite could be mainly attributed to the heteroaggregation, confirmed by not only the TEM images but also the positive linear correlation between adsorption capacity and molecular weight of SOM. However, SOM adsorbed by the microsized dense ferrihydrite should be attributed to the pore-filling adsorption with molecular sieve effects, confirmed by the negative linear correlation between adsorption capacity and molecular weight of SOM. The obtained results could provide a new insight to understand the preservation of organic carbon by ferrihydrite in soil.

Anti-ageing and Anti-lung Carcinoma Effects of Vulpinic Acid and Usnic Acid Compounds and Biological Investigations with Molecular Modeling Study.

Disorganization and breakdown of extracellular matrix proteins like fibronectin, collagen, and elastin are key characteristics of skin aging due to the increased activation of important proteolytic enzymes like elastases and collagenase enzymes. Also, inhibition of their enzymatic activities by natural molecules might be a promising factor to prevent extrinsic skin aging. All chemicals were obtained from Sigma-Aldrich unless otherwise stated. The assay employed was based on spectrophotometric methods reported in the literature. The collagenase and elastase inhibition assays of some phenolic compounds were performed according to the previous studies. These compounds showed excellent to good inhibitory activities of vulpinic acid against studied these enzymes with IC50 values of 195.36 µM for collagenase and 25.24 µM for elastase. The molecular docking calculations were conducted to investigate the chemical and biological activity of vulpinic acid and usnic acid against collagenase and elastase. The results indicated that these two compounds can interact with the essential residues of the enzymes and affect their activities. The calculations of binding free energies were also performed to obtain more details about the characteristics and free energies of the ligand-enzyme complexes. Additionally, both compounds exhibited the most potent inhibition in the three lung cancer cells, with an IC50 value of 21-68 µM, indicating that vulpinic acid is more potent than Doxorubicin, which exhibited an IC50 value of 21-29 µM.

Pan-SARS neutralizing responses after third boost vaccination in non-human primate immunogenicity model.

The emergence of SARS-CoV-2 variants, especially Beta and Delta, has raised concerns about the reduced protection from previous infection or vaccination based on the original Wuhan-Hu-1 (D614) virus. To identify promising regimens for inducing neutralizing titers towards new variants, we evaluated monovalent and bivalent mRNA vaccines either as primary vaccination or as a booster in nonhuman primates (NHPs). Two mRNA vaccines, D614-based MRT5500 and Beta-based MRT5500ß, tested in sequential regimens or as a bivalent combination in naïve NHPs produced modest neutralizing titers to heterologous variants. However, when mRNA vaccines were administered as a booster to pre-immune NHPs, we observed a robust increase in neutralizing titers with expanded breadth towards all tested variants, and notably SARS-CoV-1. The breadth of the neutralizing response was independent of vaccine sequence or modality, as we further showed either MRT5500 or recombinant subunit Spike protein (with adjuvant) can serve as boosters to induce broadly neutralizing antibodies in the NHPs primed with MRT5500. The data support the notion that a third vaccination is key to boosting existing titers and improving the breadth of antibodies to address variants of concern, including those with an E484K mutation in the Receptor Binding Domain (RBD) (Beta, Gamma).

Intelligent grading method for walnut kernels based on deep learning and physiological indicators.

Walnut grading is an important step before the product enters the market. However, traditional walnut grading primarily relies on manual assessment of physiological features, which is difficult to implement efficiently. Furthermore, walnut kernel grading is, at present, relatively unsophisticated. Therefore, this study proposes a novel deep-learning model based on a spatial attention mechanism and SE-network structure to grade walnut kernels using machine vision to ensure accuracy and improve assessment efficiency. In this experiment, we found through the literature that both the lightness (L* value) and malondialdehyde (MDA) contens of walnut kernels were correlated with the oxidation phenomenon in walnuts. Subsequently, we clustered four partitionings using the L* values. We then used the MDA values to verify the rationality of these partitionings. Finally, four network models were used for comparison and training: VGG19, EfficientNetB7, ResNet152V2, and spatial attention and spatial enhancement network combined with ResNet152V2 (ResNet152V2-SA-SE). We found that the ResNet152V2-SA-SE model exhibited the best performance, with a maximum test set accuracy of 92.2%. The test set accuracy was improved by 6.2, 63.2, and 74.1% compared with that of ResNet152V2, EfficientNetB7, and VGG19, respectively. Our testing demonstrated that combining spatial attention and spatial enhancement methods improved the recognition of target locations and intrinsic information, while decreasing the attention given to non-target regions. Experiments have demonstrated that combining spatial attention mechanisms with SE networks increases focus on recognizing target locations and intrinsic information, while decreasing focus on non-target regions. Finally, by comparing different learning rates, regularization methods, and batch sizes of the model, we found that the training performance of the model was optimal with a learning rate of 0.001, a batch size of 128, and no regularization methods. In conclusion, this study demonstrated that the ResNet152V2-SA-SE network model was effective in the detection and evaluation of the walnut kernels.

A clinical appraisal of the different types of enteral nutrition support and humanized nursing among cerebral apoplexy ICU patients on mechanical ventilation.

OBJECTIVE: To study the clinical effectiveness of different types of enteral nutrition support combined with humanized nursing in intensive care unit (ICU) stroke patients on mechanical ventilation. METHODS: One hundred patients with stroke admitted to our hospital's ICU from April 2019 to July 2020 were established as the study cohort and divided into a control group and an experimental group, with 50 cases in each group. The control group was administered one-time injections of enteral nutrition combined with general nursing, and the experimental group was administered enteral nutrition pump infusions combined with humanized nursing. The nursing efficiency, the nursing satisfaction, the Barthel index (BI) scores, the National Institutes of Health Stroke Scale (NIHSS) scores, the adverse reactions, the serum albumin, serum total protein, and serum prealbumin levels, the ICU stay durations, the hospital stay durations, and the mini-nutritional assessment (MNA) scores at 1, 2, and 3 weeks were compared between the two groups. RESULTS: Compared with the control group, the nursing efficiency and satisfaction levels, the BI index scores, the serum albumin, serum total protein, serum pre-albumin levels and the MNA nutritional evaluation scores at weeks 1, 2, and 3 in the experimental group were significantly higher (P < 0.05), while the NIHSS scores, the adverse reactions, the time costs in the ICU and the hospital stay durations were significantly lower, with statistical significance (P < 0.05). CONCLUSION: Humanized nursing combined with enteral nutrition pumping can remarkably improve the quality of life and the malnutrition in ICU stroke patients on mechanical ventilation.

Immunogenicity and efficacy of mRNA COVID-19 vaccine MRT5500 in preclinical animal models.

Emergency use authorization of COVID vaccines has brought hope to mitigate pandemic of coronavirus disease 2019 (COVID-19). However, there remains a need for additional effective vaccines to meet the global demand and address the potential new viral variants. mRNA technologies offer an expeditious path alternative to traditional vaccine approaches. Here we describe the efforts to utilize an mRNA platform for rational design and evaluations of mRNA vaccine candidates based on the spike (S) glycoprotein of SARS-CoV-2. Several mRNA constructs of S-protein, including wild type, a pre-fusion stabilized mutant (2P), a furin cleavage-site mutant (GSAS) and a double mutant form (2P/GSAS), as well as others, were tested in animal models for their capacity to elicit neutralizing antibodies (nAbs). The lead 2P/GSAS candidate was further assessed in dose-ranging studies in mice and Cynomolgus macaques, and for efficacy in a Syrian golden hamster model. The selected 2P/GSAS vaccine formulation, designated MRT5500, elicited potent nAbs as measured in neutralization assays in all three preclinical models and more importantly, protected against SARS-CoV-2-induced weight loss and lung pathology in hamsters. In addition, MRT5500 elicited TH1-biased responses in both mouse and non-human primate (NHP), thus alleviating a hypothetical concern of potential vaccine-associated enhanced respiratory diseases known associated with TH2-biased responses. These data position MRT5500 as a viable vaccine candidate for entering clinical development.

Flavor Chemical Profiles of Cabernet Sauvignon Wines: Six Vintages from 2013 to 2018 from the Eastern Foothills of the Ningxia Helan Mountains in China.

The eastern foothills of the Helan Mountains in the Ningxia region (Ningxia), is a Chinese wine-producing region, where Cabernet Sauvignon is the main grape cultivar; however, little compositional or flavor information has been reported on Ningxia wines. Oenological parameters, volatile profiles, and phenolic profiles were determined for 98 Ningxia Cabernet Sauvignon wines from the 2013-2018 vintages, as well as 16 from Bordeaux and California, for comparison. Ningxia wines were characterized by high ethanol, low acidity, and high anthocyanin contents. Multivariate analysis revealed that citronellol and 12 characteristic phenolic compounds distinguish Ningxia wines from Bordeaux and California wines. The concentrations of most phenolic compounds were highest in the 2018 Ningxia vintage and decreased with the age of the vintage. To our knowledge, this is the first extensive regionality study on red wines from the Ningxia region.

BRAFV600E mutation combined with American College of Radiology thyroid imaging report and data system significantly changes surgical resection rate and risk of malignancy in thyroid cytopathology practice.

BACKGROUND: Ultrasonography patterns and molecular testing may assist in stratifying the malignancy risk of indeterminate cytology diagnosis. The purpose of this study was to assess the value of fine needle aspiration (FNA) cytology in combination with American College of Radiology Thyroid Imaging Reporting and Data System (ACR TI-RADS) and BRAFV600E mutation in differentiating high-risk thyroid nodules. METHODS: From February 2010 to February 2014, 2,643 consecutive thyroid nodules from 2,399 patients (688 men and 1,711 women; mean age, 44.3±12.5 years) who underwent preoperative FNA biopsies were enrolled. The Jiangsu Institute of Nuclear Medicine has adopted TI-RADS stratification and BRAFV600E mutation analysis as a routine procedure to assist in evaluating FNA cytopathology since January 2016. From February 2017 to July 2018, 1,905 thyroid nodules of 1,837 patients (501 men and 1,336 women, 49.5±12.8 years) who underwent preoperative ultrasound-guided FNA biopsies with BRAFV600E mutation analysis and ACR TI-RADS grading data available were enrolled for comparison in this study. RESULTS: The cancer risk in nodules with BRAFV600E mutation was 99.7% (905/908) according to the histological findings. The risk of malignancy (ROM) was found to increase with advancing ACR TI-RADS category. High-risk ultrasound features (TI-RADS 5) did show a good performance in predicting malignancy (98.1%). The combination of TI-RADS 5 and BRAFV600E mutation reached the best diagnostic efficiency [sensitivity 97.7%, specificity 94.8%, positive predictive value (PPV) 99.6%]. It is apparent that after the implementation of ACR TI-RADS and the BRAFV600E mutation analysis, the resection rates (RRs) of The Bethesda System for Reporting Thyroid Cytopathology (TBSRTC) I and III categories showed significant decreases (39.1% vs. 21.6% and 36.1% vs. 16.7%, respectively). In contrast, the risks of malignancy of TBSRTC I and III categories indicated substantial increases (41.5% vs. 80.0% and 34.6% vs. 50.0%, respectively). The ROM of thyroid nodules with nondiagnostic (ND, I) category showed the most significant increase of 41.5% to 80.0%. CONCLUSIONS: ACR TI-RADS, together with BRAFV600E mutation and cytological diagnoses, can assist in improving the prediction of malignancy of thyroid nodules, especially in the TBSRTC I and III categories.

American College of Radiology thyroid imaging report and data system combined with K-RAS mutation improves the management of cytologically indeterminate thyroid nodules.

We investigated whether use of American College of Radiology thyroid imaging report and data system (ACR TIRADS) in combination with K-RAS mutation status may facilitate risk stratification of patients with cytological Bethesda Category III and IV thyroid nodules. Ultrasonographic, cytological, and histopathological diagnoses were retrospectively correlated with K-RAS mutation status in a series of 43 cytologically indeterminate thyroid nodules (CITNs) that were referred for surgical excision. K-RAS mutations were detected in 8/43 (18.6%) fine-needle aspiration (FNA) samples as against 11/43 (25.6%) surgical specimens. ACR TIRADS level (TR) TR3 lesions had a malignancy risk of 40%; the K-RAS mutation rate in FNA samples and surgical specimens of category TR3 lesions was 40% and 60%, respectively. K-RAS mutation-positive malignancy was significantly more frequently detected in follicular neoplasm/suspicious for follicular neoplasm (FN/SFN) lesions than that in atypia or follicular lesion of undetermined significance (AUS/FLUS) (P<0.01). Combined use of ACR TIRADS (TR5 as the diagnostic threshold) and K-RAS mutation status helped identify 83.3% (10/12) malignant nodules (58.6% specificity, 45.5% positive predictive value, 89.5% negative predictive value, and 65.9% accuracy). CITNs with ACR TIRADS category TR3 showed an unexpectedly high risk of malignancy. K-RAS mutation-positive FN/SFN nodules have a 50% risk of malignancy and surgery should be recommended. Combined use of ACR TIRADS and K-RAS mutation may facilitate risk-stratification of patients with CITNs. The high negative predictive value (NPV) for malignancy seems sufficient to allow conservative management of patients with active surveillance.