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BackgroundUsing broad range cell-free DNA sequencing (BRcfDNA-Seq), a nontargeted next-generation sequencing (NGS) methodology, we previously identified a novel class of approximately 50 nt ultrashort single-stranded cell-free DNA (uscfDNA) in plasma that is distinctly different from 167 bp mononucleosomal cell-free DNA (mncfDNA). We hypothesize that uscfDNA possesses characteristics that are useful for disease detection.MethodsUsing BRcfDNA-Seq, we examined both cfDNA populations in the plasma of 18 noncancer controls and 14 patients with late-stage nonsmall cell lung carcinoma (NSCLC). In comparison to mncfDNA, we assessed whether functional element (FE) peaks, fragmentomics, end-motifs, and G-Quadruplex (G-Quad) signatures could be useful features of uscfDNA for NSCLC determination.ResultsIn noncancer participants, compared to mncfDNA, uscfDNA fragments showed a 45.2-fold increased tendency to form FE peaks (enriched in promoter, intronic, and exonic regions), demonstrated a distinct end-motif-frequency profile, and presented with a 4.9-fold increase in G-Quad signatures. Within NSCLC participants, only the uscfDNA population had discoverable FE peak candidates. Additionally, uscfDNA showcased different end-motif-frequency candidates distinct from mncfDNA. Although both cfDNA populations showed increased fragmentation in NSCLC, the G-Quad signatures were more discriminatory in uscfDNA. Compilation of cfDNA features using principal component analysis revealed that the first 5 principal components of both cfDNA subtypes had a cumulative explained variance of >80%.ConclusionsThese observations indicate that the distinct biological processes of uscfDNA and that FE peaks, fragmentomics, end-motifs, and G-Quad signatures are uscfDNA features with promising biomarker potential. These findings further justify its exploration as a distinct class of biomarker to augment pre-existing liquid biopsy approaches.

Introduction: The early diagnosis of kidney injury in type 2 diabetes (T2DM) is important to prevent the long-term damaging effects of kidney loss and is decisive for patient outcomes. While SIRT2 is implicated in diabetes pathogenesis, its correlation with diabetic nephropathy remains unexplored. This study was designed to evaluate the association of urine SIRT2 levels with diabetic kidney injury, as well as potential underlying mechanisms. Methods: In T2DM patients, db/db mice, and high glucose plus palmitic acid treated HK2 cell models, ELISA, Immunoturbidimetry, Immunohistochemistry, Western blot, and Quantitative real-time polymerase chain reaction were used to detect SIRT2 levels and kidney damage. According to urinary albumin/creatinine ratio (UACR), 163 T2DM patients were divided into three groups. Spearman correlation analysis was used to investigate the relationship between urinary sirtuin2/creatinine ratio (USCR) and biomarkers of kidney injury. The influencing factors of albuminuria in T2DM patients were analyzed by logistic regression model. Results: In our findings, the Macro group exhibited the highest USCR levels as UACR increased. There was a positive association between USCR and UACR, α1-microglobulin/creatinine ratio (UαCR), β2-microglobulin/creatinine ratio (UβCR), and retinol-binding protein/creatinine ratio (URCR), with a negative correlation observed with eGFR. Logistic ordered multiclassification regression analysis, adjusting for confounding variables, confirmed that USCR remained a significant risk factor for the severity of albuminuria in T2DM patients. In the db/db mice kidney SIRT2 protein level increased significantly. Increased SIRT2 protein levels were also observed in renal tubular epithelial cells treated with high glucose plus palmitic acid. Moreover, SIRT2 promotes the expression of proinflammatory factors TNF-α and IL-6 by modulating the phosphorylation of p38 MAPK and p-JNK in renal tubular cells induced by high glucose and palmitic acid. Conclusion: Urinary SIRT2 is closely related to eGFR, renal tubule injury, and urinary albumin excretion in T2DM patients, which is expected to be an important indicator to comprehensively reflect renal injury.

Abstract Understanding the determinants of biodiversity in fragmented habitats is fundamental for informing sustainable landscape development, especially in urban landscapes that substantially fragment natural habitat. However, the relative roles of landscape and habitat characteristics, as emphasized by two competing frameworks (the island biogeography theory and the habitat diversity hypothesis), in structuring species assemblages in fragmented habitats have not been fully explored. This study investigated bird assemblages at 26 habitat patches (ranging in size from 0.3 to 290.4 ha) in an urban landscape, southwest China, among which habitat type composition and woody plant species composition varied significantly. Through 14 bird surveys conducted over six breeding seasons from 2017 to 2022, we recorded 70 breeding bird species (excluding birds recorded only once and fly-overs, such as raptors, swallows and swifts), with an average of 26 ± 10 (SD) species per patch. We found that patch area had significant direct and indirect effects on bird richness, with the indirect effects mediated by habitat richness (i.e., the number of habitat types). Isolation (measured as the distance to the nearest patch), perimeter to area ratio (PAR), and woody plant richness did not significantly predict variation in bird richness. Furthermore, none of these factors significantly sorted bird species based on their functional traits. However, the overall makeup of bird assemblages was significantly associated with the specific habitat types and woody plant species present in the patches. The results suggest that neither the island biogeography theory nor the habitat diversity hypothesis can fully explain the impacts of habitat fragmentation on bird richness in our study system, with their roles primarily being linked to patch area. The findings that habitat and plant compositions were the major drivers of variation in bird assemblage composition offer valuable insights into urban planning and green initiatives. Conservation efforts should focus not only on preserving large areas, but also on preventing urban monocultures by promoting diverse habitats within those areas, contributing to the persistence of meta-communities.

BackgroundVasculogenic Mimicry (VM) can reduce the efficacy of anti-angiogenesis and promote distant metastasis in hepatocellular carcinoma (HCC). Our previous studies have found that Celastrus orbiculatus extract (COE) can inhibit the VM formation in HCC by reducing EphA2 expression. However the underlying mechanism related to EphA2 in VM formation is unclear.PurposeThis study aimed to confirm that EphA2 is one of the potential targets of COE, and to explore the effect of EphA2 in VM formation in hypoxia context in HCC.MethodsTCM Systems Pharmacology database and proteomics analysis were used to explore the key targets of COE in HCC treatment. CD31-PAS double staining and VE-CAD staining were used to indicate vasculogenic mimicry. The localization of EphA2 and VE-CAD was examined through fluorescent microscopy. CCK8 assay, cell invasion assay, and tube formation assay were used to indicate the formation of VM under hypoxic conditions. The regulatory relationship of EphA2 upstream and downstream molecules were evaluated through COIP and Western Blot. The nude mouse xenograft tumor models were used to observe the VM formation after knocking down or overexpressing EphA2.ResultsEphA2 is identified to the target of COE, and the driving gene of HCC. In HCC surgical specimens, EphA2 expression is closely associated with the VM formation of HCC. COE-regulated EphA2 is involved in hypoxia-induced VM formation in HCC cells in vitro. EphA2 is regulated by HIF directly or indirectly by C-MYC. Overexpression of EphA2 can promote the VM formation of HCC in nude mice, while knocking down EphA2 can inhibit the VM formation.ConclusionEphA2, as a target of COE, plays a crucial regulatory role in the formation of vasculogenic mimicry in HCC, involving upstream HIF/MYC transcriptional promotion and downstream PI3K/FAK/VE-CAD expression regulation.

Lung adenocarcinoma is the most common type of lung cancer. Known risk variants explain only a small fraction of lung adenocarcinoma heritability. Here, we conducted a two-stage genome-wide association study of lung adenocarcinoma of East Asian ancestry (21,658 cases and 150,676 controls; 54.5% never-smokers) and identified 12 novel susceptibility variants, bringing the total number to 28 at 25 independent loci. Transcriptome-wide association analyses together with colocalization studies using a Taiwanese lung expression quantitative trait loci dataset (n = 115) identified novel candidate genes, including FADS1 at 11q12 and ELF5 at 11p13. In a multi-ancestry meta-analysis of East Asian and European studies, four loci were identified at 2p11, 4q32, 16q23, and 18q12. At the same time, most of our findings in East Asian populations showed no evidence of association in European populations. In our studies drawn from East Asian populations, a polygenic risk score based on the 25 loci had a stronger association in never-smokers vs. individuals with a history of smoking (Pinteraction = 0.0058). These findings provide new insights into the etiology of lung adenocarcinoma in individuals from East Asian populations, which could be important in developing translational applications.

Abstract Previous studies on putative neural mechanisms of negative symptoms in schizophrenia mainly used single modal imaging data, and seldom utilized schizophrenia patients with prominent negative symptoms (PNS).This study adopted the multimodal fusion method and recruited a homogeneous sample with PNS. We aimed to identify negative symptoms-related structural and functional neural correlates of schizophrenia. Structural magnetic resonance imaging (sMRI) and resting-state functional MRI (rs-fMRI) were performed in 31 schizophrenia patients with PNS and 33 demographically matched healthy controls.Compared to healthy controls, schizophrenia patients with PNS exhibited significantly altered functional activations in the default mode network (DMN) and had structural gray matter volume (GMV) alterations in the cerebello-thalamo-cortical network. Correlational analyses showed that negative symptoms severity was significantly correlated with the cerebello-thalamo-cortical structural network, but not with the DMN network in schizophrenia patients with PNS.Our findings highlight the important role of the cerebello-thalamo-cortical structural network underpinning the neuropathology of negative symptoms in schizophrenia. Future research should recruit a large sample and schizophrenia patients without PNS, and apply adjustments for multiple comparison, to verify our preliminary findings.

Abstract Examining beta diversity of animal assemblages in fragmented habitats, which measures variation in species composition among different fragments, is important for understanding the impact of habitat fragmentation on biodiversity. However, relying solely on taxonomic composition may not provide a comprehensive understanding. Incorporating measures of functional and phylogenetic diversities is essential for elucidating the ecological mechanisms underlying changes in community composition. In addition, prevailing studies often prioritize the evaluation of landscape characteristics within fragments as determinants of beta diversity, neglecting differences in habitat type and plant community composition. In this study, we surveyed birds in 26 remnant woodlot patches (ranging from 0.3 to 290.4 ha) in an urban landscape, southwest China, during the breeding season from 2017 to 2022. We recorded 70 bird species (excluding those recorded only once and high‐flying birds, including raptors, swallows, and swifts), with the number of species per patch varying from 14 to 56. The overall bird taxonomic and phylogenetic beta diversities were primarily contributed by the turnover component, while functional beta diversity was dominated by the nestedness‐resultant component. Patch area and perimeter area ratio significantly influenced the taxonomic, functional, and phylogenetic beta diversities, primarily mediated through the nestedness‐resultant component, while inter‐patch distance had a significant effect via the turnover component. In addition, there was a considerable correlation of bird taxonomic, functional, and phylogenetic beta diversities with habitat type and woody plant beta diversities, including their respective partitioned turnover and nestedness‐resultant components. Our results suggest that bird assemblages in these patches may be regulated by selective extinction, interspecific competition, and environmental filtering. The findings have significant implications for sustainable landscape planning and habitat restoration. Conserving habitat patches of different sizes and maintaining or enhancing habitat heterogeneity between patches can facilitate the persistence of metacommunities.

Epidermal growth factor receptor exon 20 insertion mutations (EGFRexon20ins) are detected in approximately 2% of patients with non-small cell lung cancer (NSCLC). Due to a lack of effective therapy, the prognosis of these patients is typically poor. Sunvozertinib (DZD9008) was designed as an oral, potent, irreversible, and selective EGFR tyrosine kinase inhibitor, showing activity against EGFRexon20ins and other mutations. In both cell lines and xenograft models, sunvozertinib shows potent antitumor activity. In the two ongoing phase I clinical studies, sunvozertinib was tolerated up to 400 mg once daily. The most common drug-related adverse events included diarrhea and skin rash. Antitumor efficacy was observed at the doses of 100 mg and above in patients with EGFRexon20ins NSCLC across different subtypes, with prior amivantamab treatment as well as with baseline brain metastasis. The median duration of response has not been reached.SignificanceWe report the discovery and early clinical development of sunvozertinib, a potential treatment option for the unmet medical need of EGFRexon20ins NSCLC. This article is highlighted in the In This Issue feature, p. 1599.

Plasma cell-free DNA is being widely explored as a biomarker for clinical screening. Currently, methods are optimized for the extraction and detection of double-stranded mononucleosomal cell-free DNA of ∼160bp in length. We introduce uscfDNA-seq, a single-stranded cell-free DNA next-generation sequencing pipeline, which bypasses previous limitations to reveal a population of ultrashort single-stranded cell-free DNA in human plasma. This species has a modal size of 50nt and is distinctly separate from mononucleosomal cell-free DNA. Treatment with single-stranded and double-stranded specific nucleases suggests that ultrashort cell-free DNA is primarily single-stranded. It is distributed evenly across chromosomes and has a similar distribution profile over functional elements as the genome, albeit with an enrichment over promoters, exons, and introns, which may be suggestive of a terminal state of genome degradation. The examination of this cfDNA species could reveal new features of cell death pathways or it can be used for cell-free DNA biomarker discovery.

Abstract Background Childhood obesity became a severe public health challenge, and insulin resistance (IR) was one of the common complications. Both obesity and IR were considered as the basis of metabolic disorders. However, it is unclear which common key metabolites are associated with childhood obesity and IR. Methods The children were divided into normal weight and overweight/obese groups. Fasting blood glucose and fasting insulin were measured, and homeostasis model assessment of insulin resistance was calculated. Liquid chromatography–tandem mass spectrometry was applied for metabonomic analysis. Multiple linear regression analysis and correlation analysis explored the relationships between obesity, IR, and metabolites. Random forests were used to rank the importance of differential metabolites, and relative operating characteristic curves were used for prediction. Results A total of 88 normal‐weight children and 171 obese/overweight children participated in the study. There was a significant difference between the two groups in 30 metabolites. Childhood obesity was significantly associated with 10 amino acid metabolites and 20 fatty acid metabolites. There were 12 metabolites significantly correlated with IR. The ranking of metabolites in random forest showed that glutamine, tyrosine, and alanine were important in amino acids, and pyruvic‐ox‐2, ethylmalonic‐2, and phenyllactic‐2 were important in fatty acids. The area under the curve of body mass index standard deviation score (BMI‐SDS) combined with key amino acid metabolites and fatty acid metabolites for predicting IR was 80.0% and 76.6%, respectively. Conclusions There are common key metabolites related to IR and obese children, and these key metabolites combined with BMI‐SDS could effectively predict the risk of IR.

This paper investigates a 1.7 mm diameter ultra-weak fiber Bragg grating (UWFBG) hydrophone towed array cable for acoustic direction finding. The mechanism of the underwater acoustic waves received by this integrated-coating sensitizing optical cable is deduced, and it is shown that the amplitude of its response varies with the direction of the sound wave. An anechoic pool experiment is carried out to test the performance of such a hydrophone array. The test array is a selection of six sensing fibers, each of which is coiled into 9 cm diameter fiber ring suspended in the water to receive acoustic signals. An average sensitivity of −141.2 dB re rad/μPa at frequencies from 2.5 kHz to 6.3 kHz was achieved, validating the detection of the azimuth of underwater acoustic waves. The ultra-thin towing cable system, with free structure, high sensitivity, and underwater target-detection capability has demonstrated great potential for future unmanned underwater vehicle (UUV) applications.

The gut microbiome plays a critical role in the pathogenesis of type 2 diabetes mellitus (T2DM). However, the inconvenience of obtaining fecal samples hinders the clinical application of gut microbiome analysis. In this study, we hypothesized that tongue coating color is associated with the severity of T2DM. Therefore, we aimed to compare tongue coating, gut microbiomes, and various clinical parameters between patients with T2DM with yellow (YC) and non-yellow tongue coatings (NYC). Tongue coating and gut microbiomes of 27 patients with T2DM (13 with YC and 14 with NYC) were analyzed using 16S rDNA gene sequencing technology. Additionally, we measured glycated hemoglobin (HbA1c), random blood glucose (RBG), fasting blood glucose (FBG), postprandial blood glucose (PBG), insulin (INS), glucagon (GC), body mass index (BMI), and homeostasis model assessment of β-cell function (HOMA-β) levels for each patient. The correlation between tongue coating and the gut microbiomes was also analyzed. Our findings provide evidence that the levels of Lactobacillus spp. are significantly higher in both the tongue coating and the gut microbiomes of patients with YC. Additionally, we observed that elevated INS and GC levels, along with decreased BMI and HOMA-β levels, were indicative of a more severe condition in patients with T2DM with YC. Moreover, our results suggest that the composition of the tongue coating may reflect the presence of Lactobacillus spp. in the gut. These results provide insights regarding the potential relationship between tongue coating color, the gut microbiome, and T2DM.

Receptor tyrosine-protein kinase ERBB3 (HER3) is expressed in most EGFR-mutated lung cancers but is not a known mechanism of resistance to EGFR inhibitors. HER3-DXd is an antibody-drug conjugate consisting of a HER3 antibody attached to a topoisomerase I inhibitor payload via a tetrapeptide-based cleavable linker. This phase I, dose escalation/expansion study included patients with locally advanced or metastatic EGFR-mutated non-small cell lung cancer (NSCLC) with prior EGFR tyrosine kinase inhibitor (TKI) therapy. Among 57 patients receiving HER3-DXd 5.6 mg/kg intravenously once every 3 weeks, the confirmed objective response rate by blinded independent central review (Response Evaluation Criteria in Solid Tumors v1.1) was 39% [95% confidence interval (CI), 26.0-52.4], and median progression-free survival was 8.2 (95% CI, 4.4-8.3) months. Responses were observed in patients with known and unknown EGFR TKI resistance mechanisms. Clinical activity was observed across a broad range of HER3 membrane expression. The most common grade ≥3 treatment-emergent adverse events were hematologic toxicities. HER3-DXd has clinical activity in EGFR TKI-resistant cancers independent of resistance mechanisms, providing an approach to treat a broad range of drug-resistant cancers. SIGNIFICANCE: In metastatic EGFR-mutated NSCLC, after disease progression on EGFR TKI therapy, treatment approaches include genotype-directed therapy targeting a known resistance mechanism or chemotherapy. HER3-DXd demonstrated clinical activity spanning known and unknown EGFR TKI resistance mechanisms. HER3-DXd could present a future treatment option agnostic to the EGFR TKI resistance mechanism.See related commentary by Lim et al., p. 16.This article is highlighted in the In This Issue feature, p. 1.

(1) Background: Bifidobacterium plays a pivotal role within the gut microbiota, significantly affecting host health through its abundance and composition in the intestine. Factors such as age, gender, and living environment exert considerable influence on the gut microbiota, yet scant attention has been directed towards understanding the specific effects of these factors on the Bifidobacterium population. Therefore, this study focused on 98 adult fecal samples to conduct absolute and relative quantitative analyses of bifidobacteria. (2) Methods: Using droplet digital PCR and the PacBio Sequel II sequencing platform, this study sought to determine the influence of various factors, including living environment, age, and BMI, on the absolute content and biodiversity of intestinal bifidobacteria. (3) Results: Quantitative results indicated that the bifidobacteria content in the intestinal tract ranged from 106 to 109 CFU/g. Notably, the number of bifidobacteria in the intestinal tract of the school population surpassed that of the off-campus population significantly (p = 0.003). Additionally, the group of young people exhibited a significantly higher count of bifidobacteria than the middle-aged and elderly groups (p = 0.041). The normal-weight group displayed a significantly higher bifidobacteria count than the obese group (p = 0.027). Further analysis of the relative abundance of bifidobacteria under different influencing factors revealed that the living environment emerged as the primary factor affecting the intestinal bifidobacteria structure (p = 0.046, R2 = 2.411). Moreover, the diversity of bifidobacteria in the intestinal tract of college students surpassed that in the out-of-school population (p = 0.034). This was characterized by a notable increase in 11 strains, including B. longum, B. bifidum, and B. pseudolongum, in the intestinal tract of college students, forming a more intricate intestinal bifidobacteria interaction network. (4) Conclusions: In summary, this study elucidated the principal factors affecting intestinal bifidobacteria and delineated their characteristics of intestinal bifidobacteria in diverse populations. By enriching the theory surrounding gut microbiota and health, this study provides essential data support for further investigations into the intricate dynamics of the gut microbiota.

The object of the study was to evaluate the suitability and trueness of the removable partial denture (RPD) framework fabricated by polyether ether ketone (PEEK) with the CAD-CAM technology in vitro. Four different types of dentition defects were selected. In each type, five PEEK RPD frameworks were fabricated by the CAD-CAM technology, while five Co-Cr RPD frameworks were made by traditional casting. The suitability of the framework was evaluated by silicone rubber film slice measurement and the three-dimensional image overlay method. The trueness of the PEEK framework was detected by the three-dimensional image overlay method. Data were statistically analyzed with the use of an independent samples t-test (α = 0.05). The suitability values by silicone rubber film slice measurement of the PEEK group were lower than those of the Co-Cr group in four types, with the differences indicating statistical significance (p < 0.05) in type one, type two, and type four. The suitability values using the three-dimensional image overlay method showed no statistical differences (p > 0.05) between the two groups in four types. The trueness values of the PEEK group were within the allowable range of clinical error. The suitability and trueness of the PEEK RPD framework fabricated by CAD-CAM technology met the requirements of the clinical prosthesis.

The study aimed to investigate the dynamic changes of metabolites in beef high rib with different dry-aging periods by non-targeted metabolomics based on ultra-high performance liquid chromatography-mass spectrometry (UPLC-MS). Multivariate statistical analysis and metabolic pathway analysis were performed on the metabolites. The results showed that 41 differential metabolites were identified in dry-aged beef, including 21 amino acids, 16 fatty acids, 2 nucleotides and 2 other metabolites. The types and relative contents of differential metabolites increased significantly with prolonged aging time. Five key metabolic pathways were identified, including purine metabolism; fatty acid degradation; alanine, aspartate and glutamate metabolism; arginine and proline metabolism; and the tricarboxylic acid (TCA) cycle, which could promote the formation of flavor and nutrients in dry-aged beef.

Since the early 1990s, Taiwan has successfully transformed civilian control over its military with its democratisation. Despite some constraints, the elected administrations and congress have influenced on defence affairs, and each of the four elected administrations has demonstrated distinct characteristics. In parallel, the external threat from China has been risen with its military expansion. This paper analyses how civilian leadership in Taipei has addressed the external threats and incorporated non-military factors in defence policies. Distinct national identities between administrations have led to different and inconsistent strategies and disruption of military modernisation. The popularity of various national measures, such as reducing conscription and shifting energy policies, has also eroded Taiwan’s deterrence. With its expanding military inferiority to China, Taiwan has an increasingly narrow margin for making mistakes in its defence policy.

In order to improve the suitability of the fiber hydrophone towing line array, we propose an interferometric hydrophone towed line array with a diameter of 1.7 mm. The line array is an integration of sensitization and package, embedding grating sensors in the composite materials of Kevlar and polyurethane in an additional pultrusion process. The theory and experiment indicate that polymer cladding of pultrusion is an effective way to improve phase sensitivity, increasing mechanical strength and decreasing cable diameter simultaneously. Then, a hydroacoustic detection system, with a quasi-distributed ultra-weak fiber Bragg grating towed line array, based on unbalanced interference is established and its phase sensitivities are tested experimentally. The result is measured by the vibration liquid column method and compared with a standard piezoelectric underwater acoustic detector. Over the frequency range of 200–2000 Hz, the system has a good amplitude–frequency response. We obtain an average phase sound pressure sensitivity of about −147.96 dB (re 1 rad/μPa) and a relative flatness response of 3 dB. The experimental results show that this system provides the possibility of an integrated hydrophone towed linear array with high adaptability and reliability.

IntroductionThe TIGER-3 (NCT02322281) study was initiated to compare the efficacy and safety of rociletinib, a third-generation EGFR tyrosine kinase inhibitor (TKI) that targets EGFR T790M and common EGFR-activating mutations, versus chemotherapy in patients with NSCLC who progressed on first- or second-generation EGFR TKIs.MethodsPatients with advanced or metastatic EGFR-mutated NSCLC with disease progression on standard therapy (previous EGFR TKI and platinum-based chemotherapy) were randomized to oral rociletinib (500 or 625 mg twice daily) or single-agent chemotherapy (pemetrexed, gemcitabine, docetaxel, or paclitaxel).ResultsEnrollment was halted when rociletinib development was discontinued in 2016. Of 149 enrolled patients, 75 were randomized to rociletinib (n = 53: 500 mg twice daily; n = 22: 625 mg twice daily) and 74 to chemotherapy. The median investigator-assessed progression-free survival (PFS) was 4.1 months (95% confidence interval [CI]: 2.6-5.4) in the rociletinib 500-mg group and 5.5 months (95% CI: 1.8-8.1) in the 625-mg group versus 2.5 months (95% CI: 1.4-2.9) in the chemotherapy group. An improved PFS was observed in patients with T790M-positive NSCLC treated with rociletinib (n = 25; 500 mg and 625 mg twice daily) versus chemotherapy (n = 20; 6.8 versus 2.7 mo; hazard ratio = 0.55, 95% CI: 0.28-1.07, p = 0.074). Grade 3 or higher hyperglycemia (24.0%), corrected QT prolongation (6.7%), diarrhea (2.7%), and vomiting (1.3%) were more frequent with rociletinib than chemotherapy (0%, 0%, 1.4%, and 0%, respectively).ConclusionsRociletinib had a more favorable median PFS versus chemotherapy but had higher rates of hyperglycemia and corrected QT prolongation in patients with advanced EGFR-mutated NSCLC who progressed on previous EGFR TKI. Incomplete enrollment prevented evaluation of the primary efficacy end point.

Purpose: The purpose of this study was to evaluate the fit and retention of clasps made of polyether ether ketone (PEEK) or cobalt–chromium alloy (Co–Cr) at different tooth positions in experimental simulations of in vitro wear and removal for 5 years. Methods: Standard crowns of the right mandibular first premolar (44) and first molar (46) were selected, and a circular three-arm clasp was designed, scanned and fabricated. Ten PEEK clasps were used as the experimental group, and 10 Co–Cr clasps were used as the control group. The seating channel was parallel to the side of the abutment base in both groups. The oral environment was simulated, and each clasp was tested in artificial saliva for 7200 cycles while the change in clasp retention force was recorded. The fit before and after the fatigue cycles was measured by the silicone rubber film copying method. Data were statistically analyzed using the independent samples t-test (α = 0.05). Results: Before circulation, the retention forces of the clasps at position 44 were 4.61 ± 0.91 N (PEEK) and 47.50 ± 10.59 N (Co–Cr), and the forces at position 46 were 3.38 ± 0.49 N (PEEK) and 28.79 ± 10.99 N (Co–Cr). After circulation, the retention forces of the clasps at position 44 were 4.15 ± 0.91 N (PEEK) and 13.90 ± 6.59 N (Co–Cr), and the forces at position 46 were 2.93 ± 0.25 N (PEEK) and 11.56 ± 3.93 N (Co–Cr). Before circulation, the fit of each clasp at the reference points (clasp tip, clasp arm, and occlusal rest) was between 41.70 μm and 170.29 μm, and after circulation, they were between 64.05 μm and 182.59 μm. The retention force and fit of the PEEK clasps did not undergo statistically significant changes from before to after circulation (P > 0.05). However, there were statistically significant (P

Electric field-induced release and measurement (EFIRM) is a novel, plate-based, liquid biopsy platform capable of detecting circulating tumor DNA containing EGFR mutations directly from saliva and plasma in both early- and late-stage patients with non-small-cell lung cancer. We investigated the properties of the target molecule for EFIRM and determined that the platform preferentially detects single-stranded DNA molecules. We then investigated the properties of the EFIRM assay and determined the linearity, linear range, precision, and limit of detection for six different EGFR variants (the four most common g.Exon19del variants), p.T790M, and p.L858R). The limit of detection was in single-digit copy number for the latter two mutations, and the limit of detection for Exon19del was 5000 copies. Following these investigations, technical validations were performed for four separate EFIRM liquid biopsy assays, qualitative and quantitative assays for both saliva and plasma. We conclude that EFIRM liquid biopsy is an assay platform that interrogates a biomarker not targeted by any other extant platform (namely, circulating single-stranded DNA molecules). The assay has acceptable performance characteristics in both quantitative and qualitative assays on both saliva and plasma.

Mutations identified in the epidermal growth factor receptor (EGFR) predict sensitivity to EGFR-targeted therapy for non-small cell lung carcinoma (NSCLC). We previously reported that Electric Field-Induced Release and Measurement (EFIRM)-based liquid biopsy could detect EGFR ctDNA with >94% concordance with tissue-based genotyping. A side-by-side comparison of concordance of EFIRM and droplet digital PCR (ddPCR) for the detection of the two front-line actionable EFGR mutations was performed with paired plasma and saliva samples from 13 NSCLC patients. Deep sequencing analysis based on single-strand DNA library preparation was employed to determine the size distributions of EGFR L858R ctDNA in plasma and saliva samples. EFIRM detected both EGFR mutations with 100% sensitivity in both plasma and saliva samples, whereas ddPCR detected EGFR mutations with sensitivities of 84.6% and 15.4%, respectively. In saliva samples, the majority of EGFR L858R ctDNA fragments detected were

Abstract Background While there is growing research considering the experiences of transgender youth whose identities align with the gender binary, especially among young trans women, there are significantly fewer studies that accurately capture data about nonbinary youth, and even fewer studies capturing the experiences of transgender and gender diverse (TGD) youth of color. The purpose of this research was to assess the prevalence of sexual health behaviors, mental health challenges, substance use, and healthcare utilization among Black/African American, Latinx, Asian/Pacific Islander, indigenous and multi-racial/ethnic TGD youth, who have been largely underrepresented in research. Methods A total of 108 TGD youth ages 16–24 were recruited into the Trans Youth of Color Study (TRUTH). Each participant completed a 90-min survey administered by a research assistant with more sensitive information collected using ACASI. In addition to a completing a survey administered by research staff, participants also participated in specimen collection, which included urine sampling to assess recent substance use without a prescription, self-collected rectal/frontal and throat swabs to test for gonorrhea and chlamydia, and a blood draw to test for recent use of drugs, gonorrhea and chlamydia, and syphilis. The sample was recruited at public venues, community outreach and referral, through social media outreach, and via participant referral. Cross-sectional analyses were from a single study visit. Results Compared to rates among their cisgender peers, participants reported experiencing adverse social and structural determinants of health—e.g. food insecurity (61%), housing instability (30%), and limited access to healthcare (26% had no place to go for healthcare)—and elevated rates of illicit drug use (19–85%), mental health problems (e.g. 60% self-reported depression), and involvement in sexual risk-related behaviors (e.g. among those reporting penetrative sex 57–67% reported sex without a condom). Conclusions This study adds descriptions of both mental and sexual health outcomes of a non-clinical sample of TGD youth to the literature, particularly among young transgender men and gender nonbinary youth, who have frequently been excluded from previous studies of sexual health. The findings document experiences and behaviors among TGD youth that contribute to mental and sexual health concerns, including rates of substance use, and healthcare utilization.

Background: Difficult airway conditions represent a substantial challenge for clinicians. Predicting such conditions is essential for subsequent treatment planning, but the reported diagnostic accuracies are still quite low. To overcome these challenges, we developed a rapid, non-invasive, cost-effective, and highly-accurate deep-learning approach to identify difficult airway conditions through photographic image analysis. Methods: For each of 1000 patients scheduled for elective surgery under general anesthesia, images were captured from 9 specific and different viewpoints. The collected image set was divided into training and testing subsets in the ratio of 8:2. We used a semi-supervised deep-learning method to train and test an AI model for difficult airway prediction. Results: We trained our semi-supervised deep-learning model using only 30% of the labeled training samples (with the remaining 70% used without labels). We evaluated the model performance using metrics of accuracy, sensitivity, specificity, F1-score, and the area under the ROC curve (AUC). The numerical values of these four metrics were found to be 90.00%, 89.58%, 90.13%, 81.13%, and 0.9435, respectively. For a fully-supervised learning scheme (with 100% of the labeled training samples used for model training), the corresponding values were 90.50%, 91.67%, 90.13%, 82.25%, and 0.9457, respectively. When three professional anesthesiologists conducted comprehensive evaluation, the corresponding results were 91.00%, 91.67%, 90.79%, 83.26%, and 0.9497, respectively. It can be seen that the semi-supervised deep learning model trained by us with only 30% labeled samples can achieve a comparable effect with the fully supervised learning model, but the sample labeling cost is smaller. Our method can achieve a good balance between performance and cost. At the same time, the results of the semi-supervised model trained with only 30% labeled samples were very close to the performance of human experts. Conclusions: To the best of our knowledge, our study is the first one to apply a semi-supervised deep-learning method in order to identify the difficulties of both mask ventilation and intubation. Our AI-based image analysis system can be used as an effective tool to identify patients with difficult airway conditions. Clinical trial registration: ChiCTR2100049879 (URL: http://www.chictr.org.cn).