Differential HBV replicative markers and covalently closed circular DNA transcription in immune-active chronic hepatitis B with and without HBeAg.

BACKGROUND AND AIMS: Molecular processes driving immune-active chronic hepatitis B (CHB) with and without hepatitis B e antigen (HBeAg) remain incompletely understood. This study aimed to investigate expression profiles of serum and intrahepatic HBV markers and replicative activity of HBV in CHB patients with or without HBeAg. METHODS: This study recruited 111 untreated immune-active CHB (60 HBeAg-positive and 51 HBeAg-negative) patients and quantified intrahepatic covalently closed circular DNA (cccDNA), pre-genomic RNA (pgRNA), total HBV DNA (tDNA), and replicative intermediates as well as serum HBV markers (HBV DNA, hepatitis B surface antigen, hepatitis B core-related antigen). Correlations between HBV markers and clinico-virological factors influencing expression levels of HBV markers were analysed. RESULTS: Levels of all serum markers and intrahepatic cccDNA/tDNA as well as cccDNA transcriptional activity and virion productivity were significantly reduced in HBeAg-negative patients compared to those in HBeAg-positive patients. Additionally, correlations between intrahepatic cccDNA/pgRNA and serum markers were impaired in HBeAg-negative individuals. Aminotransferase levels were positively correlated with cccDNA transcriptional activity in HBeAg-positive patients, but not in HBeAg-negative patients. Notably, among HBeAg-positive patients, there was a progressive decline in pgRNA level, transcriptional activity, and serum HBV markers as liver fibrosis advanced, which was not observed in HBeAg-negative patients. CONCLUSIONS: HBeAg loss is correlated with diminished intrahepatic HBV reservoirs and cccDNA transcription, leading to decreased serum HBV marker levels. Circulating HBV markers are not reliable indicators of intrahepatic HBV replicative activity for HBeAg-negative patients. Our findings reveal distinct disease phenotypes between immune-active CHB with and without HBeAg, highlighting the need to establish optimal surrogate biomarkers that can accurately mirror intrahepatic viral activity to aid in decision-making for antiviral therapy for immune-active CHB.

Development of a Risk Prediction Model for Adverse Skin Events Associated with TNF-α Inhibitors in Rheumatoid Arthritis Patients.

Background: Rheumatoid arthritis (RA) is a chronic inflammatory disorder primarily targeting joints, significantly impacting patients' quality of life. The introduction of tumor necrosis factor-alpha (TNF-α) inhibitors has markedly improved RA management by reducing inflammation. However, these medications are associated with adverse skin reactions, which can vary greatly among patients due to genetic differences. Objectives: This study aimed to identify risk factors associated with skin adverse events by TNF-α in RA patients. Methods: A cohort study was conducted, encompassing patients with RA who were prescribed TNF-α inhibitors. This study utilized machine learning algorithms to analyze genetic data and identify markers associated with skin-related adverse events. Various machine learning algorithms were employed to predict skin and subcutaneous tissue-related outcomes, leading to the development of a risk-scoring system. Multivariable logistic regression analysis identified independent risk factors for skin and subcutaneous tissue-related complications. Results: After adjusting for covariates, individuals with the TT genotype of rs12551103, A allele carriers of rs13265933, and C allele carriers of rs73210737 exhibited approximately 20-, 14-, and 10-fold higher incidences of skin adverse events, respectively, compared to those with the C allele, GG genotype, and TT genotype. The machine learning algorithms used for risk prediction showed excellent performance. The risk of skin adverse events among patients receiving TNF-α inhibitors varied based on the risk score: 0 points, 0.6%; 2 points, 3.6%; 3 points, 8.5%; 4 points, 18.9%; 5 points, 36.7%; 6 points, 59.2%; 8 points, 90.0%; 9 points, 95.7%; and 10 points, 98.2%. Conclusions: These findings, emerging from this preliminary study, lay the groundwork for personalized intervention strategies to prevent TNF-α inhibitor-associated skin adverse events. This approach has the potential to improve patient outcomes by minimizing the risk of adverse effects while optimizing therapeutic efficacy.

High-Efficiency In Vitro Root Induction in Pear Microshoots (Pyrus spp.).

Extensive research has been conducted on the in vitro mass propagation of pear (Pyrus spp.) trees through vegetative propagation, demonstrating high efficiency in shoot multiplication across various pear species. However, the low in vitro rooting rates remain a significant barrier to the practical application and commercialization of mass propagation. This study aims to determine the favorable conditions for inducing root formation in the in vitro microshoots of Pyrus genotypes. The base of the microshoots was exposed to a high concentration (2 mg L-1) of auxins (a combination of IBA and NAA) for initial root induction at the moment when callus formation begins. The microshoots were then transferred to an R1 medium (1/2 MS with 30 g L-1 sucrose without PGRs) to promote root development. This method successfully induced rooting in three European pear varieties, one Asian pear variety, and a European-Asian hybrid, resulting in rooting rates of 66.7%, 87.2%, and 100% for the European pear (P. communis), 60% for the Asian pear (P. pyrifolia), and 83.3% for the hybrid pear (P. pyrifolia × P. communis) with an average of 25 days. In contrast, the control group (MS medium) exhibited rooting rates of 0-13.3% after 60 days of culture. These findings will enhance in vitro root induction for various pear varieties and support the mass propagation and acclimatization of pear. The in vitro root induction method developed in this study has the potential for global commercial application in pear cultivation.

Achyranthis radix Extract Enhances Antioxidant Effect of Placenta-Derived Mesenchymal Stem Cell on Injured Human Ocular Cells.

Age-related ocular diseases such as age-related macular degeneration, glaucoma, and diabetic retinopathy are major causes of irreversible vision impairment in the elderly. Conventional treatments focus on symptom relief and disease slowdown, often involving surgery, but fall short of providing a cure, leading to substantial vision loss. Regenerative medicine, particularly mesenchymal stem cells (MSCs), holds promise for ocular disease treatment. This study investigates the synergistic potential of combining placenta-derived MSCs (PD-MSCs) with Achyranthis radix extract (ARE) from Achyranthes japonica to enhance therapeutic outcomes. In a 24-h treatment, ARE significantly increased the proliferative capacity of PD-MSCs and delayed their senescence (* p < 0.05). ARE also enhanced antioxidant capabilities and increased the expression of regeneration-associated genes in an in vitro injured model using chemical damages on human retinal pigment epithelial cell line (ARPE-19) (* p < 0.05). These results suggest that ARE-primed PD-MSC have the capability to enhance the activation of genes associated with regeneration in the injured eye via increasing antioxidant properties. Taken together, these findings support the conclusion that ARE-primed PD-MSC may serve as an enhanced source for stem cell-based therapy in ocular diseases.

Diagnostic accuracy of the Fibrosis-4 index for advanced liver fibrosis in metabolic dysfunction-associated steatotic liver disease with type 2 diabetes: A systematic review and meta-analysis.

Background/Aims: The Fibrosis-4 index (FIB-4) is a non-invasive test widely used to rule out advanced liver fibrosis (AF) in patients with metabolic dysfunction-associated steatotic liver disease (MASLD). However, its diagnostic accuracy in MASLD patients with type 2 diabetes mellitus (T2DM) are controversial due to the high prevalence of AF in this population. Methods: Research focusing on the diagnostic accuracy of FIB-4 for liver fibrosis as validated by liver histology in MASLD patients with T2DM was included, and 12 studies (n=5,624) were finally included in the meta-analysis. Sensitivity, specificity, hierarchical summary receiver operating characteristic (HSROC), positive predictive values (PPVs), and negative predictive values (NPVs) at low cutoffs (1.3-1.67) and high cutoffs (2.67-3.25) for ruling in and out AF, were calculated. Results: At low cutoffs, the meta-analysis revealed a sensitivity of 0.74, specificity of 0.62, and HSROC of 0.75. At high cutoffs, the analysis showed a sensitivity of 0.33, specificity of 0.92, and HSROC of 0.85, suggesting FIB-4 as useful for identifying or excluding AF. In subgroup analyses, high mean age and F3 prevalence were associated with lower sensitivity. The calculated NPV and PPV were 0.82 and 0.49 at low cutoffs, whereas the NPV was 0.28 and the PPV was 0.70 at high cutoffs. There were insufficient estimated NPVs <0.90 at a hypothesized prevalence of AF >30% at an FIB-4 cutoff range of 1.3-1.67. Conclusions: Collectively, FIB-4 has moderate diagnostic accuracy for identifying or excluding AF in MASLD patients with T2DM, but more evidence must be accumulated due to the limited number of currently reported studies and their heterogeneity.

Etiology and Outcomes of Patients with Extreme Hyperbilirubinemia in Korea: A Retrospective Cohort Study.

Background/Aim: Extreme hyperbilirubinemia is occasionally observed in intensive care unit (ICU) and non-ICU settings. This study examined the etiologies of extreme hyperbilirubinemia (bilirubin level ≥12 mg/dL) and the factors associated with the 30-day mortality. Methods: This retrospective observational cohort study identified 439 patients with extreme hyperbilirubinemia at the Gyeongsang National University Changwon Hospital between 2016 and 2020. The patients were classified into three groups and 11 diseases according to their etiology. The risk factors associated with 30-day mortality at the baseline were investigated using the Cox proportional hazards model. Results: Of 439 patients with extreme hyperbilirubinemia, 287, 78, and 74 were in the liver cirrhosis/malignancy group, the ischemic injury group, and the benign hepatobiliary-pancreatic etiological group, respectively, with corresponding 30-day mortality rates of 42.9%, 76.9%, and 17.6%. The most common disease leading to hyperbilirubinemia was a pancreatobiliary malignancy (28.7%), followed by liver cirrhosis (17.3%), hepatocellular carcinoma (10.9%), and liver metastases (8.4%). The etiologies of hyperbilirubinemia, obstructive jaundice, infection, albumin level, creatinine level, and prothrombin time-international normalized ratio were independently associated with the 30-day mortality. Conclusions: This study suggests three etiologies of extreme hyperbilirubinemia in the ICU and non-ICU settings. The prognosis of patients with extreme hyperbilirubinemia depends largely on the etiology and the presence of obstructive jaundice.

Risk Assessment of Hepatitis B virus-related Hepatocellular Carcinoma Development Using Transient Elastography: Systematic Review and Meta-analysis.

Background and Aims: Liver stiffness measurement (LSM) using transient elastography (TE) can assess fibrotic burden in chronic liver diseases. The systematic review and meta-analysis was conducted to determine whether LSM using TE can predict the risk of development of hepatocellular carcinoma (HCC) in chronic hepatitis B (CHB) patients. Methods: A systematic literature search of the Ovid-Medline, EMBASE, Cochrane, and KoreaMed databases (from January 2010 to June 2023) was conducted. Of the 1,345 individual studies identified, 10 studies that used TE were finally registered. Hazard ratios (HRs) and the 95% confidence interval (CIs) were considered summary estimates of treatment effect sizes of ≥ 11 kilopascal (kPa) standard for HCC development. Meta-analysis was performed using the restricted Maximum Likelihood random effects model. Results: Among the ten studies, data for risk ratios for HCC development could be obtained from nine studies. When analyzed for the nine studies, the HR for HCC development was high at 3.33 (95% CI, 2.45-4.54) in CHB patients with a baseline LSM of ≥ 11 kPa compared to patients who did not. In ten studies included, LSM of ≥ 11 kPa showed the sensitivity and specificity for predicting HCC development were 61% (95% CI, 50-71%) and 78% (95% CI, 66-86%), respectively, and the diagnostic accuracy was 0.74 (95% CI, 0.70-0.77). Conclusions: The risk of HCC development was elevated in CHB patients with TE-determined LSM of ≥11 kPa. This finding suggests that TE-determined LSM values may aid the risk prediction of HCC development in CHB patients.

Transient elastography for significant fibrosis in treatment-naïve CHB patients: A systematic review and meta-analysis.

Background and Aims: Accurate diagnosis of significant liver fibrosis in patients with chronic hepatitis B (CHB) is crucial when determining whether to initiate antiviral treatment (AVT). We conduct a meta-analysis to assess the diagnostic performance of transient elastography (TE) for significant liver fibrosis in AVT-naïve CHB patients with serum alanine transaminase (ALT) levels within 5-fold the upper limit of normal (ULN). Methods: The Ovid-Medline, EMBASE, Cochrane, and KoreaMed databases were searched to identify studies that compared the performance of TE and liver biopsy (reference standard) when diagnosing significant liver fibrosis (≥ F2) in AVT-naïve CHB patients with ALT within 5-fold the ULN. A hierarchical summary receiver operating characteristic curve (HSROC) and bivariate model were performed to evaluate the diagnostic performance of TE in the meta-analysis. Results: Eight studies (2,003 patients) were included. The summary sensitivity and specificity for diagnosis of significant liver fibrosis were 0.78 [95% confidence interval (CI), 0.66-0.86] and 0.72 (95% CI, 0.60-0.82), respectively. The HSROC for the diagnosis of significant liver fibrosis was 0.81 (95% CI, 0.72-0.86). The optimal cut-off value of TE for diagnosis of significant liver fibrosis was 7.7 kPa with a sensitivity of 0.64 (95% CI, 0.50-0.76) and specificity of 0.83 (95% CI, 0.72-0.90). Conclusions: Our study demonstrated that TE has an acceptable diagnostic performance for significant liver fibrosis in AVT-naïve CHB patients with ALT within 5-fold the ULN.

Reliability and Validity of a Tablet-Based Neuropsychological Test (the Hellocog) for Screening Dementia.

OBJECTIVE: To address the gap in timely diagnosis of dementia due to limited screening tools, we investigated the validity and reliability of the Hellocog, computerized neuropsychological test based on tablets for screening dementia. The higher the probability score on the Hellocog, the higher the likelihood of dementia. METHODS: This study included 100 patients with dementia and 100 individuals with normal cognition who were aged 60 years or older and free of other major psychiatric, neurological, or medical conditions. They administered the Hellocog on a tablet under the supervision of a neuropsychologist. To determine test-retest reliability, 20 took the Hellocog again after 4 weeks. Diagnostic performance was assessed using the receiver operator characteristics (ROC) analysis. RESULTS: The Hellocog showed adequate internal consistency (Cronbach's alpha=0.69) and good test-retest reliability (intraclass correlation coefficient=0.86, p<0.001). Participants with dementia scored higher on the Hellocog than those with normal cognition (p<0.001), confirming its high criterion validity. Strong correlations with the Mini-Mental Status Examination (MMSE) score and the total score of the Consortium to Establish a Registry for Alzheimer's Disease Neuropsychological Assessment Battery (CERAD-TS) highlight the concurrent validity of the Hellocog. The area under the ROC curve for dementia of the Hellocog was excellent (0.971) and comparable to that of the MMSE and CERAD-TS. The sensitivity and specificity for dementia were 0.945 and 0.872%, respectively, which were slightly better than those of the MMSE and CERAD-TS. CONCLUSION: Hellocog stands out as a valid and reliable tool for self-administered dementia screening, with promise for improving early detection of dementia.

The Spectrum of Isolated Retinal Artery Occlusion Secondary to Giant Cell Arteritis.

We systematically reviewed the literature to investigate the clinical features of isolated arteritic retinal artery occlusion (A-RAO) associated with giant cell arteritis (GCA). The four primary types of A-RAO were central retinal artery occlusion (CRAO), hemi-central retinal artery occlusion (hCRAO), branch retinal artery occlusion (BRAO), and cilioretinal artery occlusion (CLRAO). The most reported presentation was unilateral CRAO, followed by bilateral CRAO, unilateral CLRAO, and bilateral BRAO. Most RAOs were accompanied by typical GCA signs and symptoms, which can help distinguish them from non-arteritic RAOs. When reported, temporal artery biopsy confirmed GCA in most cases. Patients with GCA may present with a broad spectrum of isolated unilateral and bilateral A-RAOs. [Ophthalmic Surg Lasers Imaging Retina 2024;55:XX-XX.].

White matter microstructural integrity as a key to effective propagation of gamma entrainment in humans.

Gamma entrainment through sensory stimulation has the potential to reduce the pathology of Alzheimer's disease in mouse models. However, clinical trials in Alzheimer's disease (AD) patients have yielded inconsistent results, necessitating further investigation. This single-center pre-post intervention study aims to explore the influence of white matter microstructural integrity on gamma rhythm propagation from the visual cortex to AD-affected regions in 31 cognitively normal volunteers aged ≥ 65. Gamma rhythm propagation induced by optimal FLS was measured. Diffusion tensor imaging was employed to assess the integrity of white matter tracts of interest. After excluding 5 participants with a deficit in steady-state visually evoked potentials, 26 participants were included in the final analysis. In the linear regression analyses, gamma entrainment was identified as a significant predictor of gamma propagation (p < 0.001). Furthermore, the study identified white matter microstructural integrity as a significant predictor of gamma propagation by flickering light stimulation (p < 0.05), which was specific to tracts that connect occipital and temporal or frontal regions. These findings indicate that, despite robust entrainment of gamma rhythms in the visual cortex, their propagation to other regions may be impaired if the microstructural integrity of the white matter tracts connecting the visual cortex to other areas is compromised. Consequently, our findings have expanded our understanding of the prerequisites for effective gamma entrainment and suggest that future clinical trials utilizing visual stimulation for gamma entrainment should consider white matter tract microstructural integrity for candidate selection and outcome analysis.

Consistent efficacy of hepatic artery infusion chemotherapy irrespective of PD­L1 positivity in unresectable hepatocellular carcinoma.

Atezolizumab/bevacizumab is the first line of treatment for unresectable hepatocellular carcinoma (HCC), combining immune checkpoint inhibitor and anti-VEGF monoclonal antibodies. Hepatic arterial infusion chemotherapy (HAIC) is administered when the above-described combination fails to confer sufficient clinical benefit. The present study aimed to explore the association between tumor programmed cell death-ligand 1 (PD-L1) positivity and HAIC response. A total of 40 patients with HCC who had undergone HAIC with available biopsy samples obtained between January 2020 and May 2023 were retrospectively enrolled. Tumor response, progression-free survival (PFS), disease control rate (DCR) and overall survival (OS) were evaluated. PD-L1 expression in tumor samples was assessed using a combined positivity score. The response rates of HAIC-treated patients with advanced HCC after failure of atezolizumab/bevacizumab combination therapy were recorded. OS (P=0.9717) and PFS (P=0.4194) did not differ between patients with and without PD-L1 positivity. The objective response rate (P=0.7830) and DCR (P=0.7020) also did not differ based on PD-L1 status. In conclusion, the current findings highlight the consistent efficacy of HAIC, regardless of PD-L1 positivity.

Effect of Biliary Drainage on the Prognosis of Patients with Hepatocellular Carcinoma and Bile Duct Invasion.

Background/Aims: Bile duct invasion (BDI) is rarely observed in patients with advanced hepatocellular carcinoma (HCC), leading to hyperbilirubinemia. However, the efficacy of pretreatment biliary drainage for HCC patients with BDI and obstructive jaundice is currently unclear. Thus, the aim of this study was to assess the effect of biliary drainage on the prognosis of these patients. Methods: We retrospectively enrolled a total of 200 HCC patients with BDI from multicenter cohorts. Patients without obstructive jaundice (n=99) and those who did not undergo HCC treatment (n=37) were excluded from further analysis. Finally, 64 patients with obstructive jaundice (43 subjected to drainage and 21 not subjected to drainage) were included. Propensity score matching was then conducted. Results: The biliary drainage group showed longer overall survival (median 10.13 months vs 4.43 months, p=0.004) and progression-free survival durations (median 7.00 months vs 1.97 months, p<0.001) than the non-drainage group. Multivariate analysis showed that biliary drainage was a significantly favorable prognostic factor for overall survival (hazard ratio, 0.42; p=0.006) and progression-free survival (hazard ratio, 0.30; p<0.001). Furthermore, in the evaluation of first response after HCC treatment, biliary drainage was beneficial (p=0.005). Remarkably, the durations of overall survival (p=0.032) and progression-free survival (p=0.004) were similar after propensity score matching. Conclusions: Biliary drainage is an independent favorable prognostic factor for HCC patients with BDI and obstructive jaundice. Therefore, biliary drainage should be contemplated in the treatment of advanced HCC with BDI to improve survival outcomes.

Avelumab in Combination With Lorlatinib or Crizotinib in Patients With Previously Treated Advanced NSCLC: Phase 1b/2 Results From the JAVELIN Lung 101 Trial.

Introduction: The JAVELIN Lung 101 phase 1b/2 trial evaluated avelumab (immune checkpoint inhibitor) combined with lorlatinib or crizotinib (tyrosine kinase inhibitors) in ALK-positive or ALK-negative advanced NSCLC, respectively. Methods: Starting doses of lorlatinib 100 mg once daily or crizotinib 250 mg twice daily were administered with avelumab 10 mg/kg every 2 weeks. Primary objectives were assessment of maximum tolerated dose (MTD) and recommended phase 2 dose in phase 1 and objective response rate in phase 2. Primary end points were dose-limiting toxicity (DLT) and confirmed objective response per Response Evaluation Criteria in Solid Tumors, version 1.1. Results: In the avelumab plus lorlatinib group (ALK-positive; n = 31; 28 in phase 1b; three in phase 2), two of 28 assessable patients (7%) had DLT, and the MTD and recommended phase 2 dose was avelumab 10 mg/kg every 2 weeks plus lorlatinib 100 mg once daily. In the avelumab plus crizotinib group (ALK-negative; n = 12; all phase 1b), five of 12 assessable patients (42%) had DLT, and the MTD was exceeded with avelumab 10 mg/kg every 2 weeks plus crizotinib 250 mg twice daily; alternative crizotinib doses were not assessed. Objective response rate was 52% (95% confidence interval, 33%-70%) with avelumab plus lorlatinib (complete response, 3%; partial response, 48%) and 25% (95% confidence interval, 6%-57%) with avelumab plus crizotinib (all partial responses). Conclusions: Avelumab plus lorlatinib treatment in ALK-positive NSCLC was feasible, but avelumab plus crizotinib treatment in ALK-negative NSCLC could not be administered at the doses tested. No evidence of increased antitumor activity was observed in either group. ClinicalTrialsgov identifier: NCT02584634.

"Hard" Emulsion-Induced Interface Super-Assembly: A General Strategy for Two-Dimensional Hierarchically Porous Metal-Organic Framework Nanoarchitectures.

Two-dimensional (2D) hierarchically porous metal-organic framework (MOF) nanoarchitectures with tailorable meso-/macropores hold great promise for enhancing mass transfer kinetics, augmenting accessible active sites, and thereby boosting performance in heterogeneous catalysis. However, achieving the general synthesis of 2D free-standing MOF nanosheets with controllable hierarchical porosity and thickness remains a challenging task. Herein, we present an ingenious "hard" emulsion-induced interface super-assembly strategy for preparing 2D hierarchically porous UiO-66-NH2 nanosheets with highly accessible pore channels, tunable meso-/macropore sizes, and adjustable thicknesses. The methodology relies on transforming the geometric shape of oil droplet templates within appropriate oil-in-water emulsions from conventional zero-dimensional (0D) "soft" liquid spheres to 2D "hard" solid sheets below the oil's melting/freezing point. Subsequent surfactant exchange on the surface of 2D "hard" emulsions facilitates the heterogeneous nucleation and interfacial super-assembly of in situ formed mesostructured MOF nanocomposites, serving as structural units, in a loosely packed manner to produce 2D MOF nanosheets with multimodal micro/meso-/macroporous systems. Importantly, this strategy can be extended to prepare other 2D hierarchically porous MOF nanosheets by altering metal-oxo clusters and organic ligands. Benefiting from fast mass transfer and highly accessible Lewis acidic sites, the resultant 2D hierarchically porous UiO-66-NH2 nanosheets deliver a fabulous catalytic yield of approximately 96% on the CO2 cycloaddition of glycidyl-2-methylphenyl ether, far exceeding the yield of approximately 29% achieved using conventional UiO-66-NH2 microporous crystals. This "hard" emulsion-induced interface super-assembly strategy paves a new path toward the rational construction of elaborate 2D nanoarchitecture of hierarchical MOFs with tailored physicochemical properties for diverse potential applications.

Longitudinal Analyses of Circulating-Tumor DNA for Detection of EGFR Mutation-Positive Advanced Non-Small Cell Lung Cancer Progression During Treatment: Data From FLAURA and AURA3.

INTRODUCTION: Epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI)-sensitizing and -resistance mutations may be detected in plasma via circulating tumor DNA (ctDNA). ctDNA level changes reflect alterations in tumor burden and could be a dynamic indicator of treatment effect. This analysis aimed to determine whether longitudinal EGFR-mutation ctDNA testing could detect progressive disease (PD) before radiologic detection. METHODS: This was a retrospective, exploratory ctDNA analysis in two phase 3 trials (FLAURA, NCT02296125; AURA3, NCT02151981). Patients had treatment-naïve (FLAURA) or EGFR-TKI pre-treated (AURA3) advanced non-small cell lung cancer (NSCLC) with EGFR mutations and on-study PD (RECIST), with a baseline ctDNA result and EGFR-mutation ctDNA monitoring beyond Cycle 3 Day 1. Patients received osimertinib versus comparator EGFR-TKIs (FLAURA) or chemotherapy (AURA3). Outcomes included time from ctDNA PD to RECIST PD, and to first subsequent treatment (FST; FLAURA only). RESULTS: ctDNA PD preceded/co-occurred with RECIST-defined PD in 93/146 (64%) patients in FLAURA and 82/146 (56%) in AURA3. Median time from ctDNA PD to RECIST-defined PD (months) was 3.4 and 2.6 in the osimertinib and comparator EGFR-TKI arms (FLAURA) and 2.8 and 1.5 in the osimertinib and chemotherapy arms (AURA3). In FLAURA, median time from ctDNA PD to FST (months) was 6.0 and 4.7 in the osimertinib (n = 51) and comparator EGFR-TKI arms (n = 70). CONCLUSIONS: Among patients with EGFR mutation-positive advanced NSCLC receiving EGFR-TKI or chemotherapy with ctDNA data and RECIST-defined PD, ctDNA PD preceded/co-occurred with RECIST-defined PD in approximately 60% of cases. Longitudinal ctDNA monitoring may detect PD before radiologic PD.

The incidence of periungual desquamation and thrombocytosis in Kawasaki disease and the importance of systematic observation in the subacute phase.

Background: Periungual desquamation and thrombocytosis are characteristic of the subacute phase of Kawasaki disease (KD). However, accurate observations of periungual desquamation and thrombocytosis are lacking. Methods: This retrospective study included patients with acute-phase KD who received treatment at seven affiliated university hospitals in Korea between 2015 and 2017. Data were extracted from an anonymized registry established by the Korean Society of Kawasaki Disease. We investigated whether the findings of patients observed according to a set protocol until the subacute stage (group I) were different from those of patients observed without the use of a protocol (group II). Results: A total of 879 patients with KD were included in the analysis. Periungual desquamation was observed in 85% and 12.7% of patients in groups I and II, respectively. Thrombocytosis was observed in 76.7% and 44.7% of patients in groups I and II, respectively. Furthermore, compared to the initial test, the platelet counts of patients increased 100% and 67.9% in group I and II, respectively. When incomplete KD was defined only by the main symptoms during the acute stage and the diagnostic criterion of periungual desquamation during the subacute stage was excluded, the significant difference in the incidence of incomplete KD between groups I and II was no longer apparent. Conclusion: Performing regular and detailed observations has resulted in a higher incidence of periungual desquamation and thrombocytosis during the subacute phase of KD than those reported in recent studies. This indicates that until now, we have been neglecting the observation of symptoms and signs during the subacute phase. Regular monitoring during this period can also aid in differentiating suspected cases of KD and facilitate appropriate follow-up of complications.

Seasonal influences on the efficacy of anti-programmed cell death (ligand) 1 inhibitors in lung cancer.

BACKGROUND: Seasonal variations in systemic immunity have been reported. This study aimed to evaluate whether seasonality affects the efficacy of anticancer immunotherapy. METHODS: A total of 604 patients with lung cancer receiving single anti-programmed cell death (ligand) 1 (anti-PD-[L]1) inhibitors from two prospective observational cohorts were screened. Primary outcomes were progression-free survival (PFS) and overall survival (OS). Patients were classified into two groups according to the season when the treatment started: winter (November-February) and other seasons (March-October). Kaplan-Meier analysis and Cox proportional hazards models were fitted to evaluate the impact of seasonality on survival. For validation, propensity score matching was performed. RESULTS: A total of 484 patients with advanced non-small cell lung cancer were included. In an unmatched population, multivariable analysis demonstrated that the winter group (n = 173) had a significantly lower risk of progression or death from immunotherapy than the other group (n = 311) (PFS: hazard ratio [HR], 0.77 [95% confidence interval (CI), 0.62-0.96]; p = .018; OS: HR, 0.77 [95% CI, 0.1-0.98]; p = .032). In a propensity score-matched population, the winter group (n = 162) showed significantly longer median PFS (2.8 months [95% CI, 1.9-4.1 months] vs. 2.0 months [95% CI, 1.4-2.7 months]; p = .009) than the other group (n = 162). The winter group's median OS was also significantly longer than that of the other group (13.4 months [95% CI, 10.2-18.0 months] vs. 8.0 months [95% CI, 3.6-8.7 months]; p = .012). The trend toward longer survival in the winter group continued in subgroup analyses. CONCLUSIONS: Starting an anti-PD-(L)1 inhibitor in winter was associated with better treatment outcomes in patients with lung cancer compared to other seasons.

The Description and Analysis of the Complete Genome of Dermacoccus barathri FBCC-B549 Strain.

Dermacoccus barathri is the first reported pathogen within the Dermacoccus genus to cause a catheter-related bloodstream infection, which occurred in 2015. In this study, the complete genome assembly of Dermacoccus barathri was constructed, and the complete genome of Dermacoccus barathri FBCC-B549 consists of a single chromosome (3,137,745 bp) without plasmids. The constructed genome of D. barathri was compared with those of two closely related species within the Dermacoccus genus. D. barathri exhibited a pattern similar to Dermacoccus abyssi in terms of gene clusters and synteny analysis. Contrary to previous studies, biosynthetic gene cluster (BGC) analysis for predicting secondary metabolites revealed the presence of the LAP biosynthesis pathway in the complete genome of D. barathri, predicting the potential synthesis of the secondary metabolite plantazolicin. Furthermore, an analysis to investigate the potential pathogenicity of D. barathri did not reveal any antibiotic resistance genes; however, nine virulence factors were identified in the Virulence Factor Database (VFDB). According to these matching results in the VFDB, despite identifying a few factors involved in biofilm formation, further research is required to determine the actual impact of D. barathri on pathogenicity. The complete genome of D. barathri is expected to serve as a valuable resource for future studies on D. barathri, which currently lack sufficient genomic sequence information.

Micropropagation and Shoot Tip Cryopreservation of 'Sunny Gold' Freesia.

Cryopreservation is a promising method for the long-term preservation of plant germplasm, especially for vegetatively propagated species like freesias. In this study, we investigate streamlining the cryopreservation process for 'Sunny Gold' Freesia, starting from effective in vitro initiation and proliferation using various plant growth regulator combinations. We also assess the impact of subculture on regrowth rates after cryopreservation. The shoot tips were successfully initiated in vitro after sterilization. The shoots were multiplied an average of three times in media containing N6-benzyladenine and kinetin. The regrowth rates of non-cryopreserved shoot tips excised from different subculture cycles did not differ significantly, with rates of 44% observed for plants from more than five subcultures and 47% for those from three subcultures. However, only the shoot tips excised from cultures subjected to three subculture cycles were able to recover after cryopreservation, with a regrowth rate of 31%. Our findings lay the groundwork for the development of an efficient cryopreservation protocol for freesias in the future.