Evaluating predictors of kinase activity of STK11 variants identified in primary human non-small cell lung cancers.

Critical evaluation of computational tools for predicting variant effects is important considering their increased use in disease diagnosis and driving molecular discoveries. In the sixth edition of the Critical Assessment of Genome Interpretation (CAGI) challenge, a dataset of 28 STK11 rare variants (27 missense, 1 single amino acid deletion), identified in primary non-small cell lung cancer biopsies, was experimentally assayed to characterize computational methods from four participating teams and five publicly available tools. Predictors demonstrated a high level of performance on key evaluation metrics, measuring correlation with the assay outputs and separating loss-of-function (LoF) variants from wildtype-like (WT-like) variants. The best participant model, 3Cnet, performed competitively with well-known tools. Unique to this challenge was that the functional data was generated with both biological and technical replicates, thus allowing the assessors to realistically establish maximum predictive performance based on experimental variability. Three out of the five publicly available tools and 3Cnet approached the performance of the assay replicates in separating LoF variants from WT-like variants. Surprisingly, REVEL, an often-used model, achieved a comparable correlation with the real-valued assay output as that seen for the experimental replicates. Performing variant interpretation by combining the new functional evidence with computational and population data evidence led to 16 new variants receiving a clinically actionable classification of likely pathogenic (LP) or likely benign (LB). Overall, the STK11 challenge highlights the utility of variant effect predictors in biomedical sciences and provides encouraging results for driving research in the field of computational genome interpretation.

Prediction of lifespan and assessing risk factors of large-sample implant prostheses: a multicenter study.

PURPOSE: This study aimed to analyze factors influencing the success and failure of implant prostheses and to estimate the lifespan of prostheses using standardized evaluation criteria. An online survey platform was utilized to efficiently gather large samples from multiple institutions. MATERIALS AND METHODS: During the one-year period, patients visiting 16 institutions were assessed using standardized evaluation criteria (KAP criteria). Data from these institutions were collected through an online platform, and various statistical analyses were conducted. Risk factors were assessed using both the Cox proportional hazard model and Cox regression analysis. Survival analysis was conducted using Kaplan-Meier analysis and nomogram, and lifespan prediction was performed using principal component analysis. RESULTS: The number of patients involved in this study was 485, with a total of 841 prostheses evaluated. The median survival was estimated to be 16 years with a 95% confidence interval. Factors found to be significantly associated with implant prosthesis failure, characterized by higher hazard ratios, included the 'type of clinic', 'type of antagonist', and 'plaque index'. The lifespan of implant prostheses that did not fail was estimated to exceed the projected lifespan by approximately 1.34 years. CONCLUSION: To ensure the success of implant prostheses, maintaining good oral hygiene is crucial. The estimated lifespan of implant prostheses is often underestimated by approximately 1.34 years. Furthermore, standardized form, online platform, and visualization tool, such as nomogram, can be effectively utilized in future follow-up studies.

Loop-mediated isothermal amplification polymerase chain reaction in place of a modified Knott test in screening dogs for heartworm (Dirofilaria immitis) infection combined with antigen detection test.

OBJECTIVE: To improve the current recommendations for the diagnosis of canine heartworm (Dirofilaria immitis) disease. ANIMALS: Blood samples collected from 35 shelter dogs in the Republic of Korea. METHODS: Samples were tested for the presence of microfilaria using the modified Knott (MK) test and D immitis DNA using species-specific loop-mediated isothermal amplification (LAMP) PCR. The blood samples were additionally assessed for the presence of heartworm antigens using the Antigen Rapid Canine Heartworm AG Test Kit 2.0 (Bionote Co). The performance of the MK test and LAMP PCR was assessed through statistical analysis, with a paired McNemar test utilized for comparison. RESULTS: The heartworm antigen was detected in 28.5% of the subjects. Of the 10 positive animals, the MK test detected microfilaria in 4 of 35 (11.4%) animals, and LAMP PCR detected D immitis DNA in 6 of 35 (17.1%). The results of this study indicate that the LAMP PCR showed more positive results in samples compared to the conventional MK test. CLINICAL RELEVANCE: The D immitis-specific LAMP PCR assay has the potential to function as an alternative to current detection methods. It could complement the existing antigen detection tests in diagnosing canine heartworm infections.

Early dose reduction of dasatinib does not compromise clinical outcomes in patients with chronic myeloid leukemia: A comparative analysis of two prospective trials.

Dasatinib is a potent second-generation tyrosine kinase inhibitor (TKI) used as a first-line treatment option for patients with chronic myeloid leukemia (CML). Currently, dose modification due to adverse events (AEs) is common in patients treated with dasatinib. This study compared the outcomes of two sequential prospective trials that enrolled patients with newly diagnosed chronic phase of CML (CP-CML) and initiated dasatinib at a starting dose of 100 mg daily. In the PCR-DEPTH study, CP-CML patients who started dasatinib 100 mg daily were enrolled and followed up, while in the DAS-CHANGE study, when patients achieved early molecular response with any grade of AEs were enrolled and treated with dasatinib 80 mg once daily. A total of 102 patients (PCR-DEPTH) and 90 patients (DAS-CHANGE) were compared. Although the median value of the relative dose intensity (RDI) of dasatinib was significantly higher in PCR-DEPTH than in DAS-CHANGE (99.6 % vs. 80.1 %, p <0.001), the MMR rate at 12months showed a trend toward superiority in DAS-CHANGE compared to PCR-DEPTH (77.1 % vs 65.2 %, p = 0.084). The frequencies of MR4.0 at 24 and 36 months were higher in DAS-CHANGE than in PCR-DEPTH (44.4 % vs 28.8 %, p = 0.052 and 63.6 % vs 40.3 %, p= 0.013, respectively). RDIs were not different according to the MMR, MR4.0 or MR4.5 in analyses using a pooled population. Our results suggest that early dose reduction of dasatinib does not compromise efficacy in patients achieving EMR at 3 months and could be an interventional strategy for improving long term outcomes.

The single-cell opioid responses in the context of HIV (SCORCH) consortium.

Substance use disorders (SUD) and drug addiction are major threats to public health, impacting not only the millions of individuals struggling with SUD, but also surrounding families and communities. One of the seminal challenges in treating and studying addiction in human populations is the high prevalence of co-morbid conditions, including an increased risk of contracting a human immunodeficiency virus (HIV) infection. Of the ~15 million people who inject drugs globally, 17% are persons with HIV. Conversely, HIV is a risk factor for SUD because chronic pain syndromes, often encountered in persons with HIV, can lead to an increased use of opioid pain medications that in turn can increase the risk for opioid addiction. We hypothesize that SUD and HIV exert shared effects on brain cell types, including adaptations related to neuroplasticity, neurodegeneration, and neuroinflammation. Basic research is needed to refine our understanding of these affected cell types and adaptations. Studying the effects of SUD in the context of HIV at the single-cell level represents a compelling strategy to understand the reciprocal interactions among both conditions, made feasible by the availability of large, extensively-phenotyped human brain tissue collections that have been amassed by the Neuro-HIV research community. In addition, sophisticated animal models that have been developed for both conditions provide a means to precisely evaluate specific exposures and stages of disease. We propose that single-cell genomics is a uniquely powerful technology to characterize the effects of SUD and HIV in the brain, integrating data from human cohorts and animal models. We have formed the Single-Cell Opioid Responses in the Context of HIV (SCORCH) consortium to carry out this strategy.

Dosimetric analysis of six whole-breast irradiation techniques in supine and prone positions.

In breast cancer radiation therapy, minimizing radiation-related risks and toxicity is vital for improving life expectancy. Tailoring radiotherapy techniques and treatment positions can reduce radiation doses to normal organs and mitigate treatment-related toxicity. This study entailed a dosimetric comparison of six different external beam whole-breast irradiation techniques in both supine and prone positions. We selected fourteen breast cancer patients, generating six treatment plans in both positions per patient. We assessed target coverage and organs at risk (OAR) doses to evaluate the impact of treatment techniques and positions. Excess absolute risk was calculated to estimate potential secondary cancer risk in the contralateral breast, ipsilateral lung, and contralateral lung. Additionally, we analyzed the distance between the target volume and OARs (heart and ipsilateral lung) while considering the treatment position. The results indicate that prone positioning lowers lung exposure in X-ray radiotherapy. However, particle beam therapies (PBTs) significantly reduce the dose to the heart and ipsilateral lung regardless of the patient's position. Notably, negligible differences were observed between arc-delivery and static-delivery PBTs in terms of target conformity and OAR sparing. This study provides critical dosimetric evidence to facilitate informed decision-making regarding treatment techniques and positions.

Radiomics-based hybrid model for predicting radiation pneumonitis: A systematic review and meta-analysis.

PURPOSE: This study reviewed and meta-analyzed evidence on radiomics-based hybrid models for predicting radiation pneumonitis (RP). These models are crucial for improving thoracic radiotherapy plans and mitigating RP, a common complication of thoracic radiotherapy. We examined and compared the RP prediction models developed in these studies with the radiomics features employed in RP models. METHODS: We systematically searched Google Scholar, Embase, PubMed, and MEDLINE for studies published up to April 19, 2024. Sixteen studies met the inclusion criteria. We compared the RP prediction models developed in these studies and the radiomics features employed. RESULTS: Radiomics, as a single-factor evaluation, achieved an area under the receiver operating characteristic curve (AUROC) of 0.73, accuracy of 0.69, sensitivity of 0.64, and specificity of 0.74. Dosiomics achieved an AUROC of 0.70. Clinical and dosimetric factors showed lower performance, with AUROCs of 0.59 and 0.58. Combining clinical and radiomic factors yielded an AUROC of 0.78, while combining dosiomic and radiomics factors produced an AUROC of 0.81. Triple combinations, including clinical, dosimetric, and radiomics factors, achieved an AUROC of 0.81. The study identifies key radiomics features, such as the Gray Level Co-occurrence Matrix (GLCM) and Gray Level Size Zone Matrix (GLSZM), which enhance the predictive accuracy of RP models. CONCLUSIONS: Radiomics-based hybrid models are highly effective in predicting RP. These models, combining traditional predictive factors with radiomic features, particularly GLCM and GLSZM, offer a clinically feasible approach for identifying patients at higher RP risk. This approach enhances clinical outcomes and improves patient quality of life. PROTOCOL REGISTRATION: The protocol of this study was registered on PROSPERO (CRD42023426565).

Estimated pulse wave velocity as a forefront indicator of developing metabolic syndrome in Korean adults.

BACKGROUND/AIMS: The predictive value of the estimated pulse wave velocity (ePWV) for the development of metabolic syndrome has not yet been extensively explored. This study aimed to fill this gap by evaluating ePWV as a potential predictor of metabolic syndrome development in middle-aged Korean adults. METHODS: Using prospective data obtained from the Ansan-Ansung cohort database, participants without metabolic syndrome at baseline were studied. ePWV was calculated using specific equations based on age and blood pressure. The primary outcome was the incidence of metabolic syndrome during a median follow-up period of 187 months. RESULTS: Among the 6,186 participants, 2,726 (44.1%) developed metabolic syndrome during the follow-up period. ePWV methvalues were categorized into tertiles to assess their predictive value for the development of metabolic syndrome. An ePWV cut-off of 7.407 m/s was identified as a predictor of metabolic syndrome development, with a sensitivity of 0.743 and a specificity of 0.464. Participants exceeding this cut-off, especially those in the third tertile (8.77-14.63 m/s), had a notably higher risk of developing metabolic syndrome. Specifically, the third tertile exhibited a 52.8% cumulative incidence compared with 30.8% in the first tertile. After adjustments, those in the third tertile faced a 1.530-fold increased risk of metabolic syndrome (95% confidence interval, 1.330-1.761). CONCLUSION: ePWV is a significant predictor of the development of metabolic syndrome. This finding underscores the potential of ePWV as a cardiometabolic risk assessment tool and can thus provide useful information for primary prevention strategies.

Geometry-Driven Fabrication of Mini-Tablets via 3D Printing: Correlating Release Kinetics with Polyhedral Shapes.

The aim of this study was to fabricate mini-tablets of polyhedrons containing theophylline using a fused deposition modeling (FDM) 3D printer, and to evaluate the correlation between release kinetics models and their geometric shapes. The filaments containing theophylline, hydroxypropyl cellulose (HPC), and EUDRAGIT RS PO (EU) could be obtained with a consistent thickness through pre-drying before hot melt extrusion (HME). Mini-tablets of polyhedrons ranging from tetrahedron to icosahedron were 3D-printed using the same formulation of the filament, ensuring equal volumes. The release kinetics models derived from dissolution tests of the polyhedrons, along with calculations for various physical parameters (edge, SA: surface area, SA/W: surface area/weight, SA/V: surface area/volume), revealed that the correlation between the Higuchi model and the SA/V was the highest (R2 = 0.995). It was confirmed that using 3D- printing for the development of personalized or pediatric drug products allows for the adjustment of drug dosage by modifying the size or shape of the drug while maintaining or controlling the same release profile.

Preparation and Evaluation of Inhalable Microparticles with Improved Aerodynamic Performance and Dispersibility Using L-Leucine and Hot-Melt Extrusion.

Dry-powder inhalers (DPIs) are valued for their stability but formulating them is challenging due to powder aggregation and limited flowability, which affects drug delivery and uniformity. In this study, the incorporation of L-leucine (LEU) into hot-melt extrusion (HME) was proposed to enhance dispersibility while simultaneously maintaining the high aerodynamic performance of inhalable microparticles. This study explored using LEU in HME to improve dispersibility and maintain the high aerodynamic performance of inhalable microparticles. Formulations with crystalline itraconazole (ITZ) and LEU were made via co-jet milling and HME followed by jet milling. The LEU ratio varied, comparing solubility, homogenization, and aerodynamic performance enhancements. In HME, ITZ solubility increased, and crystallinity decreased. Higher LEU ratios in HME formulations reduced the contact angle, enhancing mass median aerodynamic diameter (MMAD) size and aerodynamic performance synergistically. Achieving a maximum extra fine particle fraction of 33.68 ± 1.31% enabled stable deep lung delivery. This study shows that HME combined with LEU effectively produces inhalable particles, which is promising for improved drug dispersion and delivery.

Critical assessment of missense variant effect predictors on disease-relevant variant data.

Regular, systematic, and independent assessment of computational tools used to predict the pathogenicity of missense variants is necessary to evaluate their clinical and research utility and suggest directions for future improvement. Here, as part of the sixth edition of the Critical Assessment of Genome Interpretation (CAGI) challenge, we assess missense variant effect predictors (or variant impact predictors) on an evaluation dataset of rare missense variants from disease-relevant databases. Our assessment evaluates predictors submitted to the CAGI6 Annotate-All-Missense challenge, predictors commonly used by the clinical genetics community, and recently developed deep learning methods for variant effect prediction. To explore a variety of settings that are relevant for different clinical and research applications, we assess performance within different subsets of the evaluation data and within high-specificity and high-sensitivity regimes. We find strong performance of many predictors across multiple settings. Meta-predictors tend to outperform their constituent individual predictors; however, several individual predictors have performance similar to that of commonly used meta-predictors. The relative performance of predictors differs in high-specificity and high-sensitivity regimes, suggesting that different methods may be best suited to different use cases. We also characterize two potential sources of bias. Predictors that incorporate allele frequency as a predictive feature tend to have reduced performance when distinguishing pathogenic variants from very rare benign variants, and predictors supervised on pathogenicity labels from curated variant databases often learn label imbalances within genes. Overall, we find notable advances over the oldest and most cited missense variant effect predictors and continued improvements among the most recently developed tools, and the CAGI Annotate-All-Missense challenge (also termed the Missense Marathon) will continue to assess state-of-the-art methods as the field progresses. Together, our results help illuminate the current clinical and research utility of missense variant effect predictors and identify potential areas for future development.

Standardized multi-institutional data analysis of fixed and removable prosthesis: estimation of life expectancy with regards to variable risk factors.

PURPOSE: This study aims to assess and predict lifespan of dental prostheses using newly developed Korean Association of Prosthodontics (KAP) criteria through a large-scale, multi-institutional survey. MATERIALS AND METHODS: Survey was conducted including 16 institutions. Cox proportional hazards model and principal component analysis (PCA) were used to find out relevant factors and predict life expectancy. RESULTS: 1,703 fixed and 815 removable prostheses data were collected and evaluated. Statistically significant factors in fixed prosthesis failure were plaque index and material type, with a median survival of 10 to 18 years and 14 to 20 years each. In removable prosthesis, factors were national health insurance coverage, antagonist type, and prosthesis type (complete or partial denture), with median survival of 10 to 13 years, 11 to 14 years, and 10 to 15 years each. For still-usable prostheses, PCA analysis predicted an additional 3 years in fixed and 4.8 years in removable prosthesis. CONCLUSION: Life expectancy of a prosthesis differed significantly by factors mostly controllable either by dentist or a patient. Overall life expectancy was shown to be longer than previous research.

Asciminib monotherapy in patients with chronic-phase chronic myeloid leukemia with the T315I mutation after ≥1 prior tyrosine kinase inhibitor: 2-year follow-up results.

Asciminib targets the BCR::ABL1 myristoyl pocket, maintaining activity against BCR::ABL1T315I, which is resistant to most approved adenosine triphosphate-competitive tyrosine kinase inhibitors. We report updated phase I results (NCT02081378) assessing safety/tolerability and antileukemic activity of asciminib monotherapy 200 mg twice daily in 48 heavily pretreated patients with T315I-mutated chronic-phase chronic myeloid leukemia (CML-CP; data cutoff: January 6, 2021). With 2 years' median exposure, 56.3% of patients continued receiving asciminib. Overall, 62.2% of evaluable patients achieved BCR::ABL1 ≤1% on the International Scale (IS); 47.6% and 81.3% of ponatinib-pretreated and -naive patients, respectively, achieved BCR::ABL1IS ≤1%. Of 45 evaluable patients, 48.9% achieved a major molecular response (MMR, BCR::ABL1IS ≤0.1%), including 34.6% and 68.4% of ponatinib-pretreated and -naive patients, respectively. MMR was maintained until data cutoff in 19 of 22 patients who achieved it. The most common grade ≥3 adverse events (AEs) included increased lipase level (18.8%) and thrombocytopenia (14.6%). Five (10.4%) patients experienced AEs leading to discontinuation, including 2 who discontinued asciminib and died due to COVID-19; these were the only deaths reported. These results show asciminib's effectiveness, including in almost 50% of ponatinib pretreated patients, and confirm its risk-benefit profile, supporting its use as a treatment option for T315I-mutated CML-CP.

Treatment of chronic-phase chronic myeloid leukemia in patients randomized to dasatinib or imatinib after suboptimal responses to three months of imatinib therapy: final 5-year results from DASCERN.

Early molecular response (EMR) at 3 months is predictive of improved overall survival (OS) and progression-free survival (PFS) in patients with chronic myeloid leukemia in the chronic phase (CML-CP). Although about one-third of patients treated with first-line imatinib do not achieve EMR, long-term OS and PFS are still observed in most patients. DASCERN (NCT01593254) is a prospective, phase IIb, randomized trial evaluating a switch to dasatinib in patients who have not achieved EMR after 3 months of treatment with first-line imatinib. Early analysis demonstrated an improved major molecular response (MMR) rate at 12 months with dasatinib versus imatinib (29% vs. 13%, P=0.005). Here, we report results from the final 5-year follow-up. In total, 174 patients were randomized to dasatinib and 86 to remain on imatinib. Forty-six (53%) patients who remained on imatinib but subsequently experienced failure were allowed to cross over to dasatinib per protocol. At a minimum follow-up of 60 months, the cumulative MMR rate was significantly higher in patients randomized to dasatinib versus imatinib (77% vs. 44%, P.

Dose-toxicity surface histogram-based prediction of radiation dermatitis severity and shape.

Objective.This study aimed to develop a new approach to predict radiation dermatitis (RD) by using the skin dose distribution in the actual area of RD occurrence to determine the predictive dose by grade.Approach.Twenty-three patients with head and neck cancer treated with volumetric modulated arc therapy were prospectively and retrospectively enrolled. A framework was developed to segment the RD occurrence area in skin photography by matching the skin surface image obtained using a 3D camera with the skin dose distribution. RD predictive doses were generated using the dose-toxicity surface histogram (DTH) calculated from the skin dose distribution within the segmented RD regions classified by severity. We then evaluated whether the developed DTH-based framework could visually predict RD grades and their occurrence areas and shapes according to severity.Main results.The developed framework successfully generated the DTH for three different RD severities: faint erythema (grade 1), dry desquamation (grade 2), and moist desquamation (grade 3); 48 DTHs were obtained from 23 patients: 23, 22, and 3 DTHs for grades 1, 2, and 3, respectively. The RD predictive doses determined using DTHs were 28.9 Gy, 38.1 Gy, and 54.3 Gy for grades 1, 2, and 3, respectively. The estimated RD occurrence area visualized by the DTH-based RD predictive dose showed acceptable agreement for all grades compared with the actual RD region in the patient. The predicted RD grade was accurate, except in two patients.Significance. The developed DTH-based framework can classify and determine RD predictive doses according to severity and visually predict the occurrence area and shape of different RD severities. The proposed approach can be used to predict the severity and shape of potential RD in patients and thus aid physicians in decision making.

Development of shielding evaluation and management program for O-ring type linear accelerators.

The shielding parameters can vary depending on the geometrical structure of the linear accelerators (LINAC), treatment techniques, and beam energies. Recently, the introduction of O-ring type linear accelerators is increasing. The objective of this study is to evaluate the shielding parameters of new type of linac using a dedicated program developed by us named ORSE (O-ring type Radiation therapy equipment Shielding Evaluation). The shielding evaluation was conducted for a total of four treatment rooms including Elekta Unity, Varian Halcyon, and Accuray Tomotherapy. The developed program possesses the capability to calculate transmitted dose, maximum treatable patient capacity, and shielding wall thickness based on patient data. The doses were measured for five days using glass dosimeters to compare with the results of program. The IMRT factors and use factors obtained from patient data showed differences of up to 65.0% and 33.8%, respectively, compared to safety management report. The shielding evaluation conducted in each treatment room showed that the transmitted dose at every location was below 1% of the dose limit. The results of program and measurements showed a maximum difference of 0.003 mSv/week in transmitted dose. The ORSE program allows for the shielding evaluation results to the clinical environment of each institution based on patient data.

Asciminib in Newly Diagnosed Chronic Myeloid Leukemia.

BACKGROUND: Patients with newly diagnosed chronic myeloid leukemia (CML) need long-term therapy with high efficacy and safety. Asciminib, a BCR::ABL1 inhibitor specifically targeting the ABL myristoyl pocket, may offer better efficacy and safety and fewer side effects than currently available frontline ATP-competitive tyrosine kinase inhibitors (TKIs). METHODS: In a phase 3 trial, patients with newly diagnosed CML were randomly assigned in a 1:1 ratio to receive either asciminib (80 mg once daily) or an investigator-selected TKI, with randomization stratified by European Treatment and Outcome Study long-term survival score category (low, intermediate, or high risk) and by TKI selected by investigators before randomization (including imatinib and second-generation TKIs). The primary end points were major molecular response (defined as BCR::ABL1 transcript levels ≤0.1% on the International Scale [IS]) at week 48, for comparisons between asciminib and investigator-selected TKIs and between asciminib and investigator-selected TKIs in the prerandomization-selected imatinib stratum. RESULTS: A total of 201 patients were assigned to receive asciminib and 204 to receive investigator-selected TKIs. The median follow-up was 16.3 months in the asciminib group and 15.7 months in the investigator-selected TKI group. A major molecular response at week 48 occurred in 67.7% of patients in the asciminib group, as compared with 49.0% in the investigator-selected TKI group (difference, 18.9 percentage points; 95% confidence interval [CI], 9.6 to 28.2; adjusted two-sided P<0.001]), and in 69.3% of patients in the asciminib group as compared with 40.2% in the imatinib group within the imatinib stratum (difference, 29.6 percentage points; 95% CI, 16.9 to 42.2; adjusted two-sided P<0.001). The percentage of patients with a major molecular response at week 48 was 66.0% with asciminib and 57.8% with TKIs in the second-generation TKI stratum (difference, 8.2 percentage points; 95% CI, -5.1 to 21.5). Adverse events of grade 3 or higher and events leading to discontinuation of the trial regimen were less frequent with asciminib (38.0% and 4.5%, respectively) than with imatinib (44.4% and 11.1%) and second-generation TKIs (54.9% and 9.8%). CONCLUSIONS: In this trial comparing asciminib with investigator-selected TKIs and imatinib, asciminib showed superior efficacy and a favorable safety profile in patients with newly diagnosed chronic-phase CML. Direct comparison between asciminib and second-generation TKIs was not a primary objective. (Funded by Novartis; ASC4FIRST ClinicalTrials.gov number, NCT04971226).

Real-world effectiveness of a single conventional disease-modifying anti-rheumatic drug (cDMARD) plus an anti-TNF agent versus multiple cDMARDs in rheumatoid arthritis: a prospective observational study.

Objective: The objective of this prospective, observational multicenter study (NCT03264703) was to compare the effectiveness of single conventional disease-modifying anti-rheumatic drug (cDMARD) plus anti-tumor necrosis factor (TNF) therapy versus multiple cDMARD treatments in patients with moderate-to-severe rheumatoid arthritis (RA) following cDMARD failure in the real-world setting in South Korea. Methods: At the treating physicians' discretion, patients received single cDMARD plus anti-TNF therapy or multiple cDMARDs. Changes from baseline in disease activity score 28-joint count with erythrocyte sedimentation rate (DAS28-ESR), corticosteroid use, and Korean Health Assessment Questionnaire (KHAQ-20) scores were evaluated at 3, 6, and 12 months. Results: Of 207 enrollees, the final analysis included 45 of 73 cDMARD plus anti-TNF and 91 of 134 multiple-cDMARD recipients. There were no significant between-group differences (BGDs) in ANCOVA-adjusted changes from baseline in DAS28-ESR at 3, 6 (primary endpoint), and 12 months (BGDs -0.18, -0.38, and -0.03, respectively). More cDMARD plus anti-TNF than multiple-cDMARD recipients achieved a >50% reduction from baseline in corticosteroid dosage at 12 months (35.7% vs 14.6%; p=0.007). Changes from baseline in KHAQ-20 scores at 3, 6, and 12 months were significantly better with cDMARD plus anti-TNF therapy than with multiple cDMARDs (BGD -0.18, -0.19, and -0.19 points, respectively; all p≤0.024). Conclusion: In the real-world setting, relative to multiple cDMARDs, single cDMARD plus anti-TNF therapy significantly improved quality-of-life scores and reduced corticosteroid use, with no significant BGD in disease activity, in RA patients in whom previous cDMARD therapy had failed.

Transcriptional Changes in Radiation-Induced Lung Injury: A Comparative Analysis of Two Radiation Doses for Preclinical Research.

In a recent stereotactic body radiation therapy animal model, radiation pneumonitis and radiation pulmonary fibrosis were observed at around 2 and 6 weeks, respectively. However, the molecular signature of this model remains unclear. This study aimed to examine the molecular characteristics at these two stages using RNA-seq analysis. Transcriptomic profiling revealed distinct transcriptional patterns for each stage. Inflammatory response and immune cell activation were involved in both stages. Cell cycle processes and response to type II interferons were observed during the inflammation stage. Extracellular matrix organization and immunoglobulin production were noted during the fibrosis stage. To investigate the impact of a 10 Gy difference on fibrosis progression, doses of 45, 55, and 65 Gy were tested. A dose of 65 Gy was selected and compared with 75 Gy. The 65 Gy dose induced inflammation and fibrosis as well as the 75 Gy dose, but with reduced lung damage, fewer inflammatory cells, and decreased collagen deposition, particularly during the inflammation stage. Transcriptomic analysis revealed significant overlap, but differences were observed and clarified in Gene Ontology and KEGG pathway analysis, potentially influenced by changes in interferon-gamma-mediated lipid metabolism. This suggests the suitability of 65 Gy for future preclinical basic and pharmaceutical research connected with radiation-induced lung injury.