Concurrent self-assembly of RGB microLEDs for next-generation displays.

MicroLED displays have been in the spotlight as the next-generation displays owing to their various advantages, including long lifetime and high brightness compared with organic light-emitting diode (OLED) displays. As a result, microLED technology1,2 is being commercialized for large-screen displays such as digital signage and active R&D programmes are being carried out for other applications, such as augmented reality3, flexible displays4 and biological imaging5. However, substantial obstacles in transfer technology, namely, high throughput, high yield and production scalability up to Generation 10+ (2,940 × 3,370 mm2) glass sizes, need to be overcome so that microLEDs can enter mainstream product markets and compete with liquid-crystal displays and OLED displays. Here we present a new transfer method based on fluidic self-assembly (FSA) technology, named magnetic-force-assisted dielectrophoretic self-assembly technology (MDSAT), which combines magnetic and dielectrophoresis (DEP) forces to achieve a simultaneous red, green and blue (RGB) LED transfer yield of 99.99% within 15 min. By embedding nickel, a ferromagnetic material, in the microLEDs, their movements were controlled by using magnets, and by applying localized DEP force centred around the receptor holes, these microLEDs were effectively captured and assembled in the receptor site. Furthermore, concurrent assembly of RGB LEDs were demonstrated through shape matching between microLEDs and receptors. Finally, a light-emitting panel was fabricated, showing damage-free transfer characteristics and uniform RGB electroluminescence emission, demonstrating our MDSAT method to be an excellent transfer technology candidate for high-volume production of mainstream commercial products.

Fluidic self-assembly for MicroLED displays by controlled viscosity.

Displays in which arrays of microscopic 'particles', or chiplets, of inorganic light-emitting diodes (LEDs) constitute the pixels, termed MicroLED displays, have received considerable attention1,2 because they can potentially outperform commercially available displays based on organic LEDs3,4 in terms of power consumption, colour saturation, brightness and stability and without image burn-in issues1,2,5-7. To manufacture these displays, LED chiplets must be epitaxially grown on separate wafers for maximum device performance and then transferred onto the display substrate. Given that the number of LEDs needed for transfer is tremendous-for example, more than 24 million chiplets smaller than 100 µm are required for a 50-inch, ultra-high-definition display-a technique capable of assembling tens of millions of individual LEDs at low cost and high throughput is needed to commercialize MicroLED displays. Here we demonstrate a MicroLED lighting panel consisting of more than 19,000 disk-shaped GaN chiplets, 45 µm in diameter and 5 µm in thickness, assembled in 60 s by a simple agitation-based, surface-tension-driven fluidic self-assembly (FSA) technique with a yield of 99.88%. The creation of this level of large-scale, high-yield FSA of sub-100-µm chiplets was considered a significant challenge because of the low inertia of the chiplets. Our key finding in overcoming this difficulty is that the addition of a small amount of poloxamer to the assembly solution increases its viscosity which, in turn, increases liquid-to-chiplet momentum transfer. Our results represent significant progress towards the ultimate goal of low-cost, high-throughput manufacture of full-colour MicroLED displays by FSA.

The KEYNOTE-811 trial of dual PD-1 and HER2 blockade in HER2-positive gastric cancer.

Human epidermal growth factor receptor 2 (HER2, also known as ERBB2) amplification or overexpression occurs in approximately 20% of advanced gastric or gastro-oesophageal junction adenocarcinomas1-3. More than a decade ago, combination therapy with the anti-HER2 antibody trastuzumab and chemotherapy became the standard first-line treatment for patients with these types of tumours4. Although adding the anti-programmed death 1 (PD-1) antibody pembrolizumab to chemotherapy does not significantly improve efficacy in advanced HER2-negative gastric cancer5, there are preclinical6-19 and clinical20,21 rationales for adding pembrolizumab in HER2-positive disease. Here we describe results of the protocol-specified first interim analysis of the randomized, double-blind, placebo-controlled phase III KEYNOTE-811 study of pembrolizumab plus trastuzumab and chemotherapy for unresectable or metastatic, HER2-positive gastric or gastro-oesophageal junction adenocarcinoma22 ( https://clinicaltrials.gov , NCT03615326). We show that adding pembrolizumab to trastuzumab and chemotherapy markedly reduces tumour size, induces complete responses in some participants, and significantly improves objective response rate.

Identification of plants' functional counterpart of the metazoan mediator of DNA Damage checkpoint 1.

Induction of DNA damage triggers rapid phosphorylation of the histone H2A.X (γH2A.X). In animals, mediator of DNA damage checkpoint 1 (MDC1) binds γH2A.X through a tandem BRCA1 carboxyl-terminal (tBRCT) domain and mediates recruitment of downstream effectors of DNA damage response (DDR). However, readers of this modification in plants have remained elusive. We show that from the Arabidopsis BRCT domain proteome, BCP1-4 proteins with tBRCT domains are involved in DDR. Through its tBRCT domain BCP4 binds γH2A.X in vitro and localizes to DNA damage-induced foci in an H2A.X-dependent manner. BCP4 also contains a domain that interacts directly with NBS1 and thus acts as a functional counterpart of MDC1. We also show that BCP1, that contains two tBRCT domains, co-localizes with γH2A.X but it does not bind γH2A.X suggesting functional similarity with human PAXIP1. A phylogenetic analysis supports that PAXIP1 and MDC1 in metazoa and their plant counterparts evolved independently from common ancestors with tBRCT domains. Collectively, our study reveals missing components and provides mechanistic and evolutionary insights into plant DDR.

Extremophilic red algae as models for understanding adaptation to hostile environments and the evolution of eukaryotic life on the early earth.

Extremophiles have always garnered great interest because of their exotic lifestyles and ability to thrive at the physical limits of life. In hot springs environments, the Cyanidiophyceae red algae are the only photosynthetic eukaryotes able to live under extremely low pH (0-5) and relatively high temperature (35ºC to 63ºC). These extremophiles live as biofilms in the springs, inhabit acid soils near the hot springs, and form endolithic populations in the surrounding rocks. Cyanidiophyceae represent a remarkable source of knowledge about the evolution of extremophilic lifestyles and their genomes encode specialized enzymes that have applied uses. Here we review the evolutionary origin, taxonomy, genome biology, industrial applications, and use of Cyanidiophyceae as genetic models. Currently, Cyanidiophyceae comprise a single order (Cyanidiales), three families, four genera, and nine species, including the well-known Cyanidioschyzon merolae and Galdieria sulphuraria. These algae have small, gene-rich genomes that are analogous to those of prokaryotes they live and compete with. There are few spliceosomal introns and evidence exists for horizontal gene transfer as a driver of local adaptation to gain access to external fixed carbon and to extrude toxic metals. Cyanidiophyceae offer a variety of commercial opportunities such as phytoremediation to detoxify contaminated soils or waters and exploitation of their mixotrophic lifestyles to support the efficient production of bioproducts such as phycocyanin and floridosides. In terms of exobiology, Cyanidiophyceae are an ideal model system for understanding the evolutionary effects of foreign gene acquisition and the interactions between different organisms inhabiting the same harsh environment on the early Earth. Finally, we describe ongoing research with C. merolae genetics and summarize the unique insights they offer to the understanding of algal biology and evolution.

Proteomic Discovery of Plasma Protein Biomarkers and Development of Models Predicting Prognosis of High-Grade Serous Ovarian Carcinoma.

Ovarian cancer is one of the most lethal female cancers. For accurate prognosis prediction, this study aimed to investigate novel, blood-based prognostic biomarkers for high-grade serous ovarian carcinoma (HGSOC) using mass spectrometry-based proteomics methods. We conducted label-free liquid chromatography-tandem mass spectrometry using frozen plasma samples obtained from patients with newly diagnosed HGSOC (n = 20). Based on progression-free survival (PFS), the samples were divided into two groups: good (PFS ≥18 months) and poor prognosis groups (PFS <18 months). Proteomic profiles were compared between the two groups. Referring to proteomics data that we previously obtained using frozen cancer tissues from chemotherapy-naïve patients with HGSOC, overlapping protein biomarkers were selected as candidate biomarkers. Biomarkers were validated using an independent set of HGSOC plasma samples (n = 202) via enzyme-linked immunosorbent assay (ELISA). To construct models predicting the 18-month PFS rate, we performed stepwise selection based on the area under the receiver operating characteristic curve (AUC) with 5-fold cross-validation. Analysis of differentially expressed proteins in plasma samples revealed that 35 and 61 proteins were upregulated in the good and poor prognosis groups, respectively. Through hierarchical clustering and bioinformatic analyses, GSN, VCAN, SND1, SIGLEC14, CD163, and PRMT1 were selected as candidate biomarkers and were subjected to ELISA. In multivariate analysis, plasma GSN was identified as an independent poor prognostic biomarker for PFS (adjusted hazard ratio, 1.556; 95% confidence interval, 1.073-2.256; p = 0.020). By combining clinical factors and ELISA results, we constructed several models to predict the 18-month PFS rate. A model consisting of four predictors (FIGO stage, residual tumor after surgery, and plasma levels of GSN and VCAN) showed the best predictive performance (mean validated AUC, 0.779). The newly developed model was converted to a nomogram for clinical use. Our study results provided insights into protein biomarkers, which might offer clues for developing therapeutic targets.

Pembrolizumab plus trastuzumab and chemotherapy for HER2-positive gastric or gastro-oesophageal junction adenocarcinoma: interim analyses from the phase 3 KEYNOTE-811 randomised placebo-controlled trial.

BACKGROUND: Evidence for the efficacy of combined PD-1 and HER2 blockade with chemotherapy on progression-free and overall survival in HER2-positive gastro-oesophageal cancer is scarce. The first interim analysis of the randomised, phase 3 KEYNOTE-811 study showed a superior objective response with pembrolizumab compared with placebo when added to trastuzumab plus fluoropyrimidine and platinum-based chemotherapy. Here, we report results from protocol-specified subsequent interim analyses of KEYNOTE-811. METHODS: The randomised, phase 3 KEYNOTE-811 trial involved 168 medical centres in 20 countries worldwide. Patients aged 18 years or older with locally advanced or metastatic HER2-positive gastro-oesophageal junction adenocarcinoma, without previous first-line treatment, were randomly assigned (1:1) by an integrated interactive voice-response and web-response system to intravenous pembrolizumab 200 mg or placebo, both to be combined with standard chemotherapy (fluoropyrimidine and platinum-based therapy) plus trastuzumab every 3 weeks for up to 35 cycles or until disease progression, unacceptable toxic effects, or investigator or participant-initiated withdrawal. Randomisation used a block size of four and was stratified by region, PD-L1 status, and chemotherapy. Dual primary endpoints were progression-free and overall survival, analysed by intention to treat. Safety was assessed in all randomly assigned patients who received at least one dose of study treatment according to the treatment received. KEYNOTE-811 is registered with ClinicalTrials.gov (NCT03615326) and is active but not recruiting. FINDINGS: Between Oct 5, 2018, and Aug 6, 2021, 698 patients were assigned to pembrolizumab (n=350) or placebo (n=348). 564 (81%) were male and 134 (19%) were female. At the third interim analysis, 286 (82%) of 350 patients in the pembrolizumab group and 304 (88%) of 346 in the placebo group who received treatment had discontinued treatment, mostly due to disease progression. At the second interim analysis (median follow-up 28·3 months [IQR 19·4-34·3] in the pembrolizumab group and 28·5 months [20·1-34·3] in the placebo group), median progression-free survival was 10·0 months (95% CI 8·6-11·7) in the pembrolizumab group versus 8·1 months (7·0-8·5) in the placebo group (hazard ratio [HR] 0·72, 95% CI 0·60-0·87; p=0·0002). Median overall survival was 20·0 months (17·8-23·2) versus 16·9 months (15·0-19·8; HR 0·87 [0·72-1·06]; p=0·084). At the third interim analysis (median follow-up 38·4 months [IQR 29·5-44·4] in the pembrolizumab group and 38·6 months [30·2-44·4] in the placebo group), median progression-free survival was 10·0 months (8·6-12·2) versus 8·1 months (7·1-8·6; HR 0·73 [0·61-0·87]), and median overall survival was 20·0 months (17·8-22·1) versus 16·8 months (15·0-18·7; HR 0·84 [0·70-1·01]), but did not meet prespecified criteria for significance and will continue to final analysis. Grade 3 or worse treatment-related adverse events occurred in 204 (58%) of 350 patients in the pembrolizumab group versus 176 (51%) of 346 patients in the placebo group. Treatment-related adverse events that led to death occurred in four (1%) patients in the pembrolizumab group and three (1%) in the placebo group. The most common treatment-related adverse events of any grade were diarrhoea (165 [47%] in the pembrolizumab group vs 145 [42%] in the placebo group), nausea (154 [44%] vs 152 [44%]), and anaemia (109 [31%] vs 113 [33%]). INTERPRETATION: Compared with placebo, pembrolizumab significantly improved progression-free survival when combined with first-line trastuzumab and chemotherapy for metastatic HER2-positive gastro-oesophageal cancer, specifically in patients with tumours with a PD-L1 combined positive score of 1 or more. Overall survival follow-up is ongoing and will be reported at the final analysis. FUNDING: Merck Sharp & Dohme.

CXCR2 antagonist navarixin in combination with pembrolizumab in select advanced solid tumors: a phase 2 randomized trial.

C-X-C motif chemokine receptor 2 (CXCR2) has a role in tumor progression, lineage plasticity, and reduction of immune checkpoint inhibitor efficacy. Preclinical evidence suggests potential benefit of CXCR2 inhibition in multiple solid tumors. In this phase 2 study (NCT03473925), adults with previously treated advanced or metastatic castration-resistant prostate cancer (CRPC), microsatellite-stable colorectal cancer (MSS CRC), or non-small-cell lung cancer (NSCLC) were randomized 1:1 to the CXCR2 antagonist navarixin 30 or 100 mg orally once daily plus pembrolizumab 200 mg intravenously every 3 weeks up to 35 cycles. Primary endpoints were investigator-assessed objective response rate (RECIST v1.1) and safety. Of 105 patients (CRPC, n=40; MSS CRC, n=40; NSCLC, n=25), 3 had a partial response (2 CRPC, 1 MSS CRC) for ORRs of 5%, 2.5%, and 0%, respectively. Median progression-free survival was 1.8-2.4 months without evidence of a dose-response relationship, and the study was closed at a prespecified interim analysis for lack of efficacy. Dose-limiting toxicities occurred in 2/48 patients (4%) receiving navarixin 30 mg and 3/48 (6%) receiving navarixin 100 mg; events included grade 4 neutropenia and grade 3 transaminase elevation, hepatitis, and pneumonitis. Treatment-related adverse events occurred in 70/105 patients (67%) and led to treatment discontinuation in 7/105 (7%). Maximal reductions from baseline in absolute neutrophil count were 44.5%-48.2% (cycle 1) and 37.5%-44.2% (cycle 2) and occurred within 6-12 hours postdose in both groups. Navarixin plus pembrolizumab did not demonstrate sufficient efficacy in this study. Safety and tolerability of the combination were manageable. (Trial registration: ClinicalTrials.gov , NCT03473925).

Lenvatinib plus pembrolizumab for patients with previously treated advanced ovarian cancer: Results from the phase 2 multicohort LEAP-005 study.

OBJECTIVES: The phase 2, multicohort, open-label LEAP-005 study evaluated lenvatinib plus pembrolizumab in patients with previously treated advanced solid tumors. We report outcomes from the ovarian cancer cohort. METHODS: Eligible patients had metastatic/unresectable ovarian cancer and had received 3 previous lines of therapy. Patients received lenvatinib 20 mg/day plus pembrolizumab 200 mg every 3 weeks. Treatment continued until progression, unacceptable toxicity, or (for pembrolizumab) completion of 35 cycles. Primary endpoints were objective response rate (ORR) per RECIST version 1.1 and safety. Secondary endpoints included duration of response (DOR), progression-free survival (PFS), and overall survival (OS). RESULTS: Thirty-one patients were enrolled. 39% had high grade serous ovarian cancer, 23% were platinum-sensitive, 55% were platinum-resistant, 23% were platinum-refractory, and 84% had tumors that had a PD-L1 combined positive (CPS) score ≥1. ORR (95% CI) was 26% (12%-45%) by investigator assessment and 35% (19%-55%) by blinded independent central review (BICR). Per BICR, median DOR was 9.2 (1.5+ to 37.8+) months. ORRs (95% CI) by BICR were 35% (9/26 patients; 17%-56%) for PD-L1 CPS ≥ 1 disease and 50% (2/4 patients; 7%-93%) for PD-L1 CPS < 1 disease. Median (95% CI) PFS by BICR and OS were 6.2 (4.0-8.5) months and 21.3 (11.7-32.3) months, respectively. Treatment-related AEs occurred in 94% of patients (grade 3-4, 77%). One patient died from treatment-related hypovolemic shock. CONCLUSIONS: Lenvatinib plus pembrolizumab demonstrated antitumor activity as fourth line therapy in patients with advanced ovarian cancer, and no unanticipated safety signals were identified. Responses were observed regardless of PD-L1 status.

Mortality after cardiac arrest in children less than 2 years: relevant factors.

BACKGROUND: There are only scant studies of predicting outcomes of pediatric resuscitation due to lack of population-based data. This study aimed to determine variable factors that may impact the survival of resuscitated children aged under 24 months. METHODS: This is a retrospective study of 66 children under 24 months. Cardiopulmonary resuscitation (CPR) with pediatric advanced life support guideline was performed uniformly for all children. Linear regression analysis with variable factors was conducted to determine impacts on mortality. RESULT: Factors with statistically significant increases in mortality were the number of administered epinephrine (p value < 0.001), total CPR duration (p value < 0.001), in-hospital CPR duration of out-hospital cardiac arrest (p value < 0.001), and changes in cardiac rhythm (p value < 0.040). However, there is no statistically significant association between patient outcomes and remaining factors such as age, sex, underlying disease, etiology, time between last normal to CPR, initial CPR location, initial cardiac rhythm, venous access time, or inotropic usage. CONCLUSION: More than 10 times of epinephrine administration and CPR duration longer than 30 minutes were associated with a higher mortality rate, while each epinephrine administration and prolonged CPR time increased mortality. IMPACT STATEMENT: This study analyzed various factors influencing mortality after cardiac arrest in patients under 24 months. Increased number of administered epinephrine and prolonged cardiopulmonary resuscitation duration do not increase survival rate in patients under 24 months. In patients with electrocardiogram rhythm changes during CPR, mortality increased when the rhythm changed into asystole in comparison to no changes occurring in the rhythm.

Second-line chemoimmunotherapy with nivolumab and paclitaxel in immune-related biomarker-enriched advanced gastric cancer: a multicenter phase Ib/II study.

BACKGROUND: We conducted a trial to evaluate the efficacy and safety of nivolumab and paclitaxel as second-line therapy for immune-related biomarker-enriched advanced gastric cancer (AGC). METHODS: This open-label, single-arm, phase Ib/II study was a part of multi-institutional, biomarker-integrated umbrella study conducted in Korea. In phase Ib, patients received nivolumab (3 mg/kg) on Days 1 and 15 and paclitaxel (dose level 1, 70 mg/m2 or dose level 2, 80 mg/m2) on Days 1, 8, 15 every four weeks. In phase II, patients with Epstein-Barr virus-related, deficient mismatch repair or programmed cell death-ligand-1-positive AGC were enrolled. The primary endpoints were recommended phase II dose (RP2D, phase Ib) and progression-free survival (PFS, phase II). Secondary endpoints included objective response rate (ORR), overall survival (OS), safety, and exploratory biomarker analysis. RESULTS: Dose level 2 was selected as RP2D. In phase II, 48 patients were enrolled. The median PFS and OS were 3.9 and 11.2 months, respectively. The ORR was 23.3%, and the median response duration was 16.7 months. Grade 3 or higher treatment-related adverse events, mainly neutropenia, occurred in 20 patients (41.7%). Targeted sequencing revealed that patients with RTK/RAS pathway alterations or the HLA-A02 supertype had better survival. Patients with elevated baseline interleukin-1 receptor antagonist levels had worse survival. CONCLUSIONS: Although the study did not meet its primary end point, nivolumab and paclitaxel for AGC demonstrated a durable response with manageable toxicity profiles. Genomic analysis or plasma cytokine analysis may provide information for the selection of patients who would benefit more from immunotherapy combined with chemotherapy.

Discovery of novel 1H-benzo[d]imidazole-4,7-dione based transglutaminase 2 inhibitors as p53 stabilizing anticancer agents in renal cell carcinoma.

Overexpression of transglutaminase 2 (TGase 2; TG2) has been implicated in the progression of renal cell carcinoma (RCC) through the inactivation of p53 by forming a protein complex. Because most p53 in RCC has no mutations, apoptosis can be increased by inhibiting the binding between TG2 and p53 to increase the stability of p53. In the present study, a novel TG2 inhibitor was discovered by investigating the structure of 1H-benzo[d]imidazole-4,7-dione as a simpler chemotype based on the amino-1,4-benzoquinone moiety of streptonigrin, a previously reported inhibitor. Through structure-activity relationship (SAR) studies, compound 8j (MD102) was discovered as a potent TG2 inhibitor with an IC50 value of 0.35 µM, p53 stabilization effect and anticancer effects in the ACHN and Caki-1 RCC cell lines with sulforhodamine B (SRB) GI50 values of 2.15 µM and 1.98 µM, respectively. The binding property of compound 8j (MD102) with TG2 was confirmed to be reversible in a competitive enzyme assay, and the binding interaction was expected to be formed at the ß-sandwich domain, a p53 binding site, in the SPR binding assay with mutant proteins. The mode of binding of compound 8j (MD102) to the ß-sandwich domain of TG2 was analyzed by molecular docking using the crystal structure of the active conformation of human TG2. Compound 8j (MD102) induced a decrease in the downstream signaling of p-AKT and p-mTOR through the stabilization of p53 by TG2 inhibition, resulting in tumor cell apoptosis. In a xenograft animal model using ACHN cancer cells, oral administration and intraperitoneal injection of compound 8j (MD102) showed an inhibitory effect on tumor growth, confirming increased levels of p53 and decreased levels of Ki-67 in tumor tissues through immunohistochemical (IHC) tissue staining. These results indicated that the inhibition of TG2 by compound 8j (MD102) could enhance p53 stabilization, thereby ultimately showing anticancer effects in RCC. Compound 8j (MD102), a novel TG2 inhibitor, can be further applied for the development of an anticancer candidate drug targeting RCC.

Prediction of outcomes for rescue cerclage in cervical insufficiency: A multicenter retrospective study.

Purpose: Cervical insufficiency is a significant risk factor for preterm birth and miscarriage during the second trimester; cervical cerclage is a treatment option. This study seeks to evaluate the predictive roles of various clinical factors and to develop predictive models for immediate and long-term outcomes after rescue cerclage. Methods: We conducted a multicenter retrospective study on patients who underwent rescue cerclage at 14 to 26 weeks of gestation. Data were collected from the Electronic Medical Record systems of participating hospitals. Outcomes were dichotomized into immediate failure (inability to maintain pregnancy for at least 48 hours post-cerclage, gestational latency < 2 days) and long-term success (maintenance of pregnancy until at least 28 weeks of gestation). Clinical factors influencing these outcomes were analyzed. Results: The study included 98 patients. Immediate failure correlated with longer prolapsed membrane lengths, elevated C-reactive protein levels at admission, and extended operation time. The successful maintenance of pregnancy until at least 28 weeks was associated with earlier gestational age at diagnosis, negative AmniSure test results, longer lengths of the functional cervix, and smaller cervical dilatation at the time of cerclage. Binary logistic regression models for immediate failure and long-term success exhibited excellent and good predictive abilities, respectively (AUROC = 0.912, 95% CI: 0.834-0.989; and AUROC = 0.872, 95% CI: 0.788-0.956). Conclusion: The developed logistic regression models offer a valuable tool for the prognostic assessment of patients undergoing rescue cerclage, enabling informed clinical decision-making.

Finely tuned ionizable lipid nanoparticles for CRISPR/Cas9 ribonucleoprotein delivery and gene editing.

Nonviral delivery of the CRISPR/Cas9 system provides great benefits for in vivo gene therapy due to the low risk of side effects. However, in vivo gene editing by delivering the Cas9 ribonucleoprotein (RNP) is challenging due to the poor delivery into target tissues and cells. Here, we introduce an effective delivery method for the CRISPR/Cas9 RNPs by finely tuning the formulation of ionizable lipid nanoparticles. The LNPs delivering CRISPR/Cas9 RNPs (CrLNPs) are demonstrated to induce gene editing with high efficiencies in various cancer cell lines in vitro. Furthermore, we show that CrLNPs can be delivered into tumor tissues with high efficiency, as well as induce significant gene editing in vivo. The current study presents an effective platform for nonviral delivery of the CRISPR/Cas9 system that can be applied as an in vivo gene editing therapeutic for treating various diseases such as cancer and genetic disorders.

Failure Prediction of High-Flow Nasal Cannula at the Conventional Oxygen Therapy Phase in the Emergency Department.

INTRODUCTION: The use of high-flow nasal cannula (HFNC) in patients with acute hypoxemic respiratory failure has been increasing in the emergency department (ED). However, studies are lacking on the prediction of HFNC failure before therapy initiation in the ED. We investigated whether the existing indices, such as the ratio of pulse oximetry oxygen saturation/fraction of inspired oxygen to respiratory rate (ROX) and ratio of ROX index to heart rate (ROX-HR), can accurately predict HFNC failure at the conventional oxygen therapy phase in the ED. METHODS: This retrospective single-center study included patients treated with HFNC in the ED. The ROX and ROX-HR indices were calculated before initiating HFNC. An estimated fraction of inspired oxygen was used for conventional oxygen therapy. We plotted each index's receiver operating characteristics curve and calculated the area under the curve (AUC) for diagnostic capacity. The optimal cutoff values were assessed using the Youden index. The primary outcome was HFNC failure, defined as intubation in the ED. RESULTS: Among the 97 included patients, 25 (25.8%) failed HFNC therapy in the ED. The ROX and ROX-HR indices measured before initiating HFNC showed AUCs of 0.709 and 0.754, respectively. A ROX index of <5.614 and a ROX-HR index of <6.152 were associated with a high risk of intubation, even after correcting for confounding variables. CONCLUSION: The ROX and ROX-HR indices measured before initiating HFNC provide a relatively fair predictive value of HFNC failure in the ED.

Pediatric Extracorporeal Membrane Oxygenation in Korea: A Multicenter Retrospective Study on Utilization and Outcomes Spanning Over a Decade.

BACKGROUND: Over the last decade, extracorporeal membrane oxygenation (ECMO) use in critically ill children has increased and is associated with favorable outcomes. Our study aims to evaluate the current status of pediatric ECMO in Korea, with a specific focus on its volume and changes in survival rates based on diagnostic indications. METHODS: This multicenter study retrospectively analyzed the indications and outcomes of pediatric ECMO over 10 years in patients at 14 hospitals in Korea from January 2012 to December 2021. Four diagnostic categories (neonatal respiratory, pediatric respiratory, post-cardiotomy, and cardiac-medical) and trends were compared between periods 1 (2012-2016) and 2 (2017-2021). RESULTS: Overall, 1065 ECMO runs were performed on 1032 patients, with the annual number of cases remaining unchanged over the 10 years. ECMO was most frequently used for post-cardiotomy (42.4%), cardiac-medical (31.8%), pediatric respiratory (17.5%), and neonatal respiratory (8.2%) cases. A 3.7% increase and 6.1% decrease in pediatric respiratory and post-cardiotomy cases, respectively, were noted between periods 1 and 2. Among the four groups, the cardiac-medical group had the highest survival rate (51.2%), followed by the pediatric respiratory (46.4%), post-cardiotomy (36.5%), and neonatal respiratory (29.4%) groups. A consistent improvement was noted in patient survival over the 10 years, with a significant increase between the two periods from 38.2% to 47.1% (P = 0.004). Improvement in survival was evident in post-cardiotomy cases (30-45%, P = 0.002). Significant associations with mortality were observed in neonates, patients requiring dialysis, and those treated with extracorporeal cardiopulmonary resuscitation (P < 0.001). In pediatric respiratory ECMO, immunocompromised patients also showed a significant correlation with mortality (P < 0.001). CONCLUSION: Pediatric ECMO demonstrated a steady increase in overall survival in Korea; however, further efforts are needed since the outcomes remain suboptimal compared with global outcomes.

Development of an In-Pipe Inspection Robot for Large-Diameter Water Pipes.

This paper describes the development of an in-pipe inspection robot system designed for large-diameter water pipes. The robot is equipped with a Magnetic Flux Leakage (MFL) sensor module. The robot system is intended for pipes with diameters ranging from 900 mm to 1200 mm. The structure of the in-pipe inspection robot consists of the front and rear driving parts, with the inspection module located centrally. The robot is powered by 22 motors, including eight wheels with motors positioned at both the bottom and the top for propulsion. To ensure that the robot's center aligns with that of the pipeline during operation, lifting units have been incorporated. The robot is equipped with cameras and LiDAR sensors at the front and rear to monitor the internal environment of the pipeline. Pipeline inspection is conducted using the MFL inspection modules, and the robot's driving mechanism is designed to execute spiral maneuvers while maintaining contact with the pipeline surface during rotation. The in-pipe inspection robot is configured with wireless communication modules and batteries, allowing for wireless operation. Following its development, the inspection robot underwent driving experiments in actual pipelines to validate its performance. The field test bed used for these experiments is approximately 1 km in length. Results from the driving experiments on the field test bed confirmed the robot's ability to navigate various curvatures and obstacles within the pipeline. It is posited that the use of the developed in-pipe inspection robot can reduce economic costs and enhance the safety of inspectors when examining aging pipes.

Scannable Dual-Focus Metalens with Hybrid Phase.

Metalenses with two foci in the longitudinal or transverse direction, called bifocal or dual-focus metalenses, are promising building blocks in tomography techniques, data storage, and optical tweezers. For practical applications, relative movement between the beam and specimen is required, and beam scanning is highly desirable for high-speed operation without vibration. However, dual-focus metalenses employ a hyperbolic phase that experiences off-axis aberrations, which is not suitable for beam scanning. Here, we demonstrated a scannable dual-focus metalens by employing a new phase called "hybrid phase". The hybrid phase consists of a hyperbolic phase inside and a quadratic phase outside to reduce off-axis aberrations while maintaining a high numerical aperture. We show that the two foci of the scannable dual-focus metalens move together without severe distortion for incident angles of up to 2.5°. Our design easily extends to the case of multifocusing, which is essential for various applications ranging from imaging to manipulation.

Enhanced gelling property and freeze-thaw stability of potato, tapioca and corn starches modified by mild heating in aqueous ethanol solution.

BACKGROUND: Physically modified starches can be classified as natural ingredients on food labels and clean label products. Thus, the market demand for physically modified starch is increasing. Potato, tapioca and corn starches were physically modified by mild heat treatment in an alcoholic solution to enhance their gelling property and freeze-thaw stability. RESULTS: During mild heating of starch suspension (40% w/w) in 10% ethanol solution at the onset gelatinization temperature, granular swelling of starch occurred, followed by amylose leaching with medication of the surface structure of the starch granules. All treated starches exhibited increased gelatinization and pasting temperatures and decreased breakdown for pasting as a result of improved stability against shear and heat. The treated starches had higher hardness, cohesiveness and springiness of gel than the respective native starches, and these gel properties were more pronounced in potato starch than in tapioca and corn starches. The treated starches showed substantially reduced gel syneresis during freeze-thawing. CONCLUSION: Physical modification of starch by mild heat treatment in an alcoholic solution substantially improved its gelation ability and freeze-thaw stability. © 2024 Society of Chemical Industry.

Efficacy and safety of pembrolizumab monotherapy in patients with advanced thyroid cancer in the phase 2 KEYNOTE-158 study.

BACKGROUND: The authors report results from the thyroid carcinoma cohort of the multicohort phase 2 KEYNOTE-158 study (NCT02628067), which evaluated pembrolizumab monotherapy in patients with previously treated cancers. METHODS: Eligible patients had histologically and/or cytologically confirmed papillary or follicular thyroid carcinoma, failure of or intolerance to prior therapy, and measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Patients received pembrolizumab (200 mg) every 3 weeks for up to 35 cycles. The primary end point was objective response rate (ORR) per RECIST v1.1 by independent central review. RESULTS: A total of 103 patients were enrolled and received pembrolizumab. Median duration from first dose to data cutoff (October 5, 2020) was 49.4 (range, 43.9-54.9) months. ORR was 6.8% (95% confidence interval [CI], 2.8%-13.5%), and median duration of response was 18.4 (range, 4.2-47.2+) months. ORR was 8.7% (95% CI, 2.4%-20.8%) among patients with programmed cell death ligand 1 (PD-L1) combined positive score (CPS) ≥1 (n = 46) and 5.7% (95% CI, 1.2%-15.7%) among patients with PD-L1 CPS <1 (n = 53). Median overall survival and progression-free survival were 34.5 (95% CI, 21.2 to not reached) and 4.2 (95% CI, 3.9-6.2) months, respectively. Treatment-related adverse events occurred in 69.9% of patients (grade 3-5, 14.6%). CONCLUSIONS: Pembrolizumab demonstrated manageable toxicity and durable antitumor activity in a small subset of patients with advanced thyroid cancer. These results provide evidence of modest antitumor activity in this setting regardless of tumor PD-L1 expression. Future studies evaluating immune checkpoint inhibitors in patients with differentiated thyroid cancer should focus on biomarker-driven patient selection or combination of immune checkpoint inhibitors with other agents, in order to achieve higher response rates than observed in this study.