Sequential Plasma Research Articles

Ocular Pharmacokinetics of Faricimab Following Intravitreal Administration in Patients With Retinal Disease.

To characterize faricimab ocular and systemic pharmacokinetics (PK) in patients with neovascular age-related macular degeneration (nAMD) or diabetic macular edema (DME) and to assess the effect of faricimab ocular exposure on clinical endpoints. A population PK (popPK) model was developed using pooled data from phase 1 to 3 studies in patients with nAMD/DME. The dataset included 1095 faricimab aqueous humor (AH) concentrations from 284 patients and 8372 faricimab plasma concentrations from 2246 patients. Following intravitreal administration, faricimab PK was accurately described by a linear three-compartment model with sequential vitreous humor (VH), AH, and plasma compartments. Faricimab VH elimination to AH is the slowest process, with an estimated half-life (t1/2) of 7.5 days. Due to flip-flop kinetics, plasma, AH, and VH concentrations declined in parallel. Disease had no effect on faricimab PK. Plasma exposure was ∼6000-fold lower than VH exposure. Age, anti-drug antibodies, body weight, and sex statistically significantly influenced PK parameters but had no clinically meaningful effect on ocular and systemic exposure. VH t1/2 alone could not explain faricimab dosing frequency. Exposure-response analyses showed similar gains in best-corrected visual acuity across faricimab exposure ranges and dosing regimens. Faricimab ocular and systemic pharmacokinetics were quantified and accurately described by the popPK model, developed using a large dataset from patients with nAMD/DME. Exposure-response analyses suggest that faricimab phase 3 dosing algorithms are appropriate to select the most suitable dosing regimen. The popPK analysis suggested that faricimab dosing frequency was influenced by several factors and not by VH t1/2 alone.

Enhancing Charge Trapping Performance of Hafnia Thin Films Using Sequential Plasma Atomic Layer Deposition.

We aimed to fabricate reliable memory devices using HfO2, which is gaining attention as a charge-trapping layer material for next-generation NAND flash memory. To this end, a new atomic layer deposition process using sequential remote plasma (RP) and direct plasma (DP) was designed to create charge-trapping memory devices. Subsequently, the operational characteristics of the devices were analyzed based on the thickness ratio of thin films deposited using the sequential RP and DP processes. As the thickness of the initially RP-deposited thin film increased, the memory window and retention also increased, while the interface defect density and leakage current decreased. When the thickness of the RP-deposited thin film was 7 nm, a maximum memory window of 10.1 V was achieved at an operating voltage of ±10 V, and the interface trap density (Dit) reached a minimum value of 1.0 × 1012 eV-1cm-2. Once the RP-deposited thin film reaches a certain thickness, the ion bombardment effect from DP on the substrate is expected to decrease, improving the Si/SiO2/HfO2 interface and thereby enhancing device endurance and reliability. This study confirmed that the proposed sequential RP and DP deposition processes could resolve issues related to unstable interface layers, improve device performance, and enhance process throughput.

Sequential DBD plasma-assisted tandem tri-electrodes Fenton process for enhanced antibiotics treatment and denitrification

Ozone generated by dielectric barrier discharge (DBD) plasma has the potential for water treatment; however, its limitations, including water solubility, performance in complex matrices, and resistance to some pollutants. This study explored a sequential DBD plasma assisted by a tandem tri-electrode Fenton (S-PEF) process, using a three-stage treatment approach for degrading antibiotics (sulfamethoxazole, SMX; amoxicillin, AMX; and norfloxacin, NOF) in continuous flow mode for 220-bed volumes. Initially, antibiotics such as SMX and AMX underwent degradation in DBD plasma gas, which housed the mixing chamber. The more resilient NOF was removed by hydroxyl radicals (OH) in the following anodic chamber of the tandem trielectrodes by Fenton assisted oxidation. The continuous cyclic redox regeneration of Fe in tandem trielectrodes prevents secondary Fe sludge pollution. Finally, NO3-N and NO2-N were denitrified into N2 with 95 % selectivity in a cathodic chamber using copper oxide nanowires. This sequential treatment is crucial to mitigating the competitive effects of CO32− and humic acid in wastewater since O3 is less susceptible to them compared to OH. The S-PEF completely degraded all antibiotics regardless of water temperature (10 and 25 °C) compared to sole plasma treatment. Finally, toxicity assessments using an ecological structure–activity relationship (ECOSAR) and E. coli disinfection assays showed a significant reduction in toxicity. This study highlights the promising potential of the S-PEF as an advanced technology for wastewater treatment.

Sequential application of cold plasma in chicken breast: Improvement of meat tenderness and bactericidal mechanism against histamine-producing Raoultella sp.

The feasibility of plasma-activated lactic acid solution (PALA) combined with dielectric barrier discharge (DBD) plasma treatment in chicken breast was evaluated. Results indicated that sequential plasma treatments slowed down the increase in the pH value and TVB-N value of meat during storage. Moreover, PALA treatment weakened the lipid oxidation triggered by DBD plasma treatment. Furthermore, centrifugal loss and shear force of chicken breast in the PALA-DBD group were reduced by 2.88% and 19.4%, respectively, and the myofibril fragmentation index was significantly increased compared to the control group, and PALA treatment increased free water content. Microbiological analyses showed that PALA-DBD treatment disrupted the cell membrane integrity of Raoultella sp., induced oxidative stress and reduced the activity of antioxidant enzymes (catalase and superoxide dismutase), led to the degradation of bacterial proteins and the disruption of α-helical structure.

Longitudinal dynamics of circulating tumor DNA for treatment monitoring in patients with breast cancer recurrence

The prevalence and dynamics of circulating tumor DNA (ctDNA) in patients with breast cancer recurrence or de novo metastatic cancer were examined in a retrospective analysis of a prospective observational cohort. Twenty-three recurrent/metastatic breast cancer cases (8 locoregional, 15 distant metastasis) were enrolled, and sequential plasma samples were obtained. Anchor mutations were selected from the target sequencing of each patient’s primary and/or metastatic tumor. An in-house developed assay (UHS assay) was employed for a tumor-informed ctDNA assay during treatment and follow-up. A median of three (range 1–5) anchor mutations per case were applied for ctDNA detection. ctDNA was detected in 14 (63.6%, 14/22) cases at the time of enrollment and 18 (78.5%, 18/23) cases during follow-up. More anchor mutations and higher tumor burden were significantly related to higher ctDNA positive rates (p-value 0.036, 0.043, respectively). The mean enriched variant allele frequency (eVAF) at each time point was significantly higher for stable or progressive disease responses (ANOVA test p-value < 0.001). Eight patients showed an increase in their ctDNA eVAF prior to clinical progression with a mean lead time of 6.2 months (range 1.5–11 months). ctDNA dynamics measured using personalized assay reflected the clinical course of breast cancer recurrence.

Early circulating tumor DNA changes predict outcomes in head and neck cancer patients under re-radiotherapy.

Local recurrence after radiotherapy is common in locally advanced head and neck cancer (HNC) patients. Re-irradiation can improve local disease control, but disease progression remains frequent. Hence, predictive biomarkers are needed to adapt treatment intensity to the patient's individual risk. We quantified circulating tumor DNA (ctDNA) in sequential plasma samples and correlated ctDNA levels with disease outcome. Ninety four longitudinal plasma samples from 16 locally advanced HNC patients and 57 healthy donors were collected at re-radiotherapy baseline, after 5 and 10 radiation fractions, at irradiation end, and at routine follow-up visits. Plasma DNA was subjected to low coverage whole genome sequencing for copy number variation (CNV) profiling to quantify ctDNA burden. CNV-based ctDNA burden was detected in 8/16 patients and 25/94 plasma samples. Ten additional ctDNA-positive samples were identified by tracking patient-specific CNVs found in earlier sequential plasma samples. ctDNA-positivity after 5 and 10 radiation fractions (both: log-rank, p = .050) as well as at the end of irradiation correlated with short progression-free survival (log-rank, p = .006). Moreover, a pronounced decrease of ctDNA toward re-radiotherapy termination was associated with worse treatment outcome (log-rank, p = .005). Dynamic ctDNA tracking in serial plasma beyond re-radiotherapy reflected treatment response and imminent disease progression. In five patients, molecular progression was detected prior to tumor progression based on clinical imaging. Our findings emphasize that quantifying ctDNA during re-radiotherapy may contribute to disease monitoring and personalization of adjuvant treatment, follow-up intervals, and dose prescription.

Cost-effectiveness of liquid biopsy for molecular profiling of newly diagnosed advanced non-squamous NSCLC in an Asian population.

178 Background: Liquid biopsy is complementary to tissue biopsy for lung cancer profiling, yet evidence of the cost-effectiveness is limited. This could retard implementation and reimbursement in clinical practice. The aim of this study is to estimate the cost-effectiveness of profiling strategies that include liquid biopsy and to identify the optimal profiling approach for newly diagnosed advanced non-squamous non-small cell lung cancer (NSCLC) in an Asian population using Singapore as an example. Methods: A decision tree and partitioned-survival model was developed from the Singapore healthcare system’s perspective to evaluate the cost-effectiveness of five molecular profiling strategies: either tissue or plasma next-generation sequencing (NGS) alone, a concurrent, and two sequential approaches. Model inputs were informed by local data or published literature. Sensitivity analyses and scenario analyses were undertaken to understand the robustness of the conclusions for decision making. The optimal strategy at different willingness-to-pay (WTP) thresholds was presented by cost-effectiveness acceptability frontier and the expected loss curve. Results: The sequential tissue-plasma NGS approach revealed an additional 0.0981 quality adjusted life years (QALYs) for an extra cost of S$3,074 over a 20-year time horizon compared to tissue NGS alone, resulting in an incremental cost-effectiveness ratio (ICER) of S$31,318/QALY and an incremental net monetary benefit of S$1,343 per patient. The findings were sensitive to the costs of pembrolizumab and osimertinib and the probabilities of re-biopsy after tissue NGS. Sequential plasma-tissue NGS and plasma NGS alone were more costly and less effective than alternatives. Conclusions: The sequential tissue-plasma NGS approach generated the highest net monetary benefit and was the optimal testing strategy when WTP was S$45,000/QALY. It retained superiority but understandably with a higher ICER when expensive, non-first line treatments were included. Overall, its routine clinical practice should be proactively considered for newly diagnosed advanced non-squamous NSCLC in an Asian population.

Hard transparent nanogradient coating for ultradurable omniphobic liquid-like surface

Omniphobic liquid-like surface (LLS) offers excellent dynamic liquid repellency owing to the highly mobile polymer chains mediating at the solid–liquid interface. These polymer chains, often achieved by surface grafting, are not durable against abrasion or oxidation, which seriously hinders their practical application. Here we report a new vapor-based approach to create transparent nanogradient coating for LLSs with unprecedented mechanical strength and durability. The nanogradient coating is composed of a sandwich structure with an ultrathin primer, a rigid bulk, and a nanocomposite surface with abundant polydimethylsiloxane-like chains, all of which achieved via sequential plasma polymerization of a linear and a cyclic siloxane. The plasma-polymerized cyclic siloxane enables coating good mechanical strength while the plasma-polymerized linear siloxane confers coating sub-nanometer roughness and excellent dynamic liquid repellency. The resultant coating exhibits contact angle hysteresis < 5° towards many low-surface-energy liquids, as well as good mechanical strength with the hardness exceeding 1 GPa and superior durability enduring 100,000 cycles of abrasion. The coating also survived industrial standard thermal and accelerated UV-aging tests without losing its liquid repellency and transparency. The reported method is facile, scalable, and substrate-independent, offering exciting new opportunities towards industrial fabrication and real-world application of LLS.

Oxidative stress, redox status and surfactant metabolism in mechanically ventilated patients receiving different approaches to oxygen therapy (MecROX): An observational study protocol for mechanistic evaluation.

MecROX is a mechanistic sub-study of the UK-ROX trial which was designed to evaluate the clinical and cost-effectiveness of a conservative approach to oxygen therapy for invasively ventilated adults in intensive care. This is based on the scientific rationale that excess oxygen is harmful. Epithelial cell damage with alveolar surfactant deficiency is characteristic of hyperoxic acute lung injury. Additionally, hyperoxaemia (excess blood oxygen levels) may exacerbate whole-body oxidative stress leading to cell death, autophagy, mitochondrial dysfunction, bioenergetic failure and multi-organ failure resulting in poor clinical outcomes. However, there is a lack of in-vivo human models evaluating the mechanisms that underpin oxygen-induced organ damage in mechanically ventilated patients. The aim of the MecROX mechanistic sub-study is to assess lung surfactant composition and global systemic redox status to provide a mechanistic and complementary scientific rationale to the UK-ROX trial findings. The objectives are to quantify in-vivo surfactant composition, synthesis, and metabolism with markers of oxidative stress and systemic redox disequilibrium (as evidenced by alterations in the 'reactive species interactome') to differentiate between groups of conservative and usual oxygen targets. After randomisation into the UK-ROX trial, 100 adult participants (50 in the conservative and 50 in usual care group) will be recruited at two trial sites. Blood and endotracheal samples will be taken at 0, 48 and 72 hours following an infusion of 3 mg/kg methyl-D 9-choline chloride. This is a non-radioactive, stable isotope of choline (vitamin), which has been extensively used to study surfactant phospholipid kinetics in humans. This study will mechanistically evaluate the in-vivo surfactant synthesis and breakdown (by hydrolysis and oxidation), oxidative stress and redox disequilibrium from sequential plasma and bronchial samples using an array of analytical platforms. We will compare conservative and usual oxygenation groups according to the amount of oxygen administered. Trial registration: ISRCTNISRCTN61929838, 27/03/2023 https://doi.org/10.1186/ISRCTN61929838.

Plasma mutational burden in PIK3CA and TP53 independently predicts early progression in patients with HR+/HER2- metastatic breast cancer (MBC) enrolled in the GEICAM/2014-12 FLIPPER trial.

1029 Background: There is an unmet need for molecular diagnostics to predict therapy outcomes using blood-based biomarker monitoring to guide treatments in HR+/HER2- MBC patients. Here, we report initial results of serial ctDNA analyses in a trial of Fulvestrant (F) + CDK4/6 inhibitor (CDK4/6i) Palbociclib (Pa) vs. F + Placebo (Pl). Endocrine therapy + CDK4/6i are currently the cornerstones of treatment for HR+/HER2- MBC. However, between 10–30% of patients suffer primary resistance. Thus, early identification of HR+/HER2- MBC patients that progress during CDK4/6i treatment is required. Methods: The GEICAM FLIPPER trial (NCT02690480) is a multicenter, double-blind, randomized, phase II study comparing F+Pa vs F+Pl in postmenopausal women with HR+/HER2- MBC. Sequential plasma was collected from 187 patients at baseline, 12, 24, 36, and 48 weeks on treatment and at progression. In total, 903 samples were analyzed using the Plasma-SeqSensei BC IVD kit (Sysmex Inostics) that identifies and quantifies ctDNA mutations in six BC-related genes. The mutant allele frequency (MAF) of PIK3CA and TP53 variants was assessed in baseline samples (median value as cutoff). These variants, identified as the most prevalent, were used as surrogate markers for mutational burden. The Kaplan-Meier method was used to estimate median (m) PFS and overall survival (OS). Hazard ratio (HR) and odds ratio (OR) were calculated with 95% confidence interval (CI) using Cox proportional hazards regression model and logistic regression respectively, unadjusted or adjusted by age, site of disease, disease presentation at study entry and clinical subtype. Results: Previously we showed that F+Pa improved 1-year PFS (83.5% vs. 71.9%, p=0.064) and mPFS (31.8 vs. 22.0 months, p=0.001) vs F+Pl. Here, ctDNA analyses revealed that having ≥1 mutation in PIK3CA + TP53 was prognostic of early (≤12 months) progression (OR 2.37; 95% CI 1.1-5.12, p=0.0274) independent of treatment arm. Furthermore, having ≥2 mutations was associated with treatment resistance (not achieving objective response; OR 3.55; 95% CI 1.28-9.87, p=0.0151). Additionally, worse mPFS and mOS were seen in patients with ≥2 mutations in PIK3CA + TP53 (PFS: HR 3.6; 95% CI 2.25-5.76, p&lt;0.0001; OS: HR 2.92; 95% CI 1.66-5.12, p=0.002) and in patients with high MAF (PFS: HR 2.43; 95% CI 1.6-3.68, p&lt;0.0001; OS: HR 2.83; 95% CI 1.75-4.58, p&lt;0.0001). Finally, having ≥2 mutations in PIK3CA + TP53 was predictive of early progression (OR 22.32; 95% CI 4.12-120.9, p&lt;0.0001) and worse mOS (61.8 vs. 34.79 months) in the F+Pl arm (HR 5.91; 95% CI 2.65-13.16, p&lt;0.0001) but not in the F+Pa arm. Conclusions: Baseline plasma mutational burden in both PIK3CA and TP53 genes was significantly associated with Fulvestrant +/- Palbociclib treatment outcome in HR+/HER2- MBC and appeared to be predictive of Palbociclib benefit. Clinical trial information: NCT02690480 .

Use of liquid biomarker thymidine kinase activity (TKa) to predict outcome and progression in patients with metastatic breast cancer (MBC) in the GEICAM/2014-12 FLIPPER trial.

1028 Background: There is a need for more precise blood-based tumor biomarkers in MBC. TKa is a liquid proliferation biomarker providing prognostic, predictive and monitoring information in MBC. TKa can be measured in blood using the DiviTum TKa assay. Here we report the results of TKa in a trial of endocrine therapy (ET) fulvestrant (F) + the CDK4/6 inhibitor (CDK4/6i) Palbociclib (Pa) vs. F + Placebo (Pl), the GEICAM FLIPPER trial (NCT02690480), a multicenter, double-blind, randomized (1:1) study. F+Pa showed 1-year PFS rates of 83.5% vs. 71.9% (p=0.064) and better median (m)PFS (31.8 vs. 22.0 months, p=0.001) than F+Pl in first line treatment of HR+/HER2- MBC patients. F+Pa also significantly improved ORR and CBR. ET+CDK4/6i are currently the cornerstone of treatment for HR+/HER2- MBC. However, 10-30% of these patients display primary resistance to treatment. Early identification of patient subsets with different risk of progression during treatment with CDK4/6i may help tailor clinical management and disease monitoring. Methods: Sequential plasma was collected from 187 patients (pts) at baseline (BL) and at 12, 24, 36, 48 weeks (w) on treatment, and at progression. 910 samples were analyzed for TKa with the FDA approved and CE labelled DiviTum TKa assay (Biovica, Sweden) using DuA (DiviTum unit of Activity) as measuring unit. The cutoff for categorizing in high vs low is 250 DuA. The Kaplan-Meier method was used to estimate mPFS and mOS. Unadjusted and adjusted hazard ratio (HR) and odds ratio (OR) with 95% confidence interval (CI) were calculated with the Cox proportional hazards regression model and with logistic regression respectively, considering relevant confounders. Results: Low BL TKa predicted better PFS (30.5 months mPFS in low vs 19.8 in high, HR 1.62; 95% CI 1.11-2.35, p=0.011) and OS (HR 1.81; 95% CI 1.15-2.85, p=0.0099). Higher TKa at BL and at 12w was detected in pts that progressed before 12 months. Conversely, low BL TKa, maintained throughout week 12-48, were associated with objective response (HR 2.58; 95% CI 1.38-4.81, p=0.0029) and OS (HR 5.74; 95%CI 2.06-16, p=0.0008). At progression, pts on F+Pa tended to have higher TKa levels than F+Pl (246 vs. 138 DuA), reflecting faster growing tumors, not achieving statistical significance (p=0.0585). TKa monitoring and dynamics from BL and on treatment timepoints (week 12-48) show that the group of pts with low TK at BL that remain low during treatment is enriched with non-progressors and pts that progress after 12 months (p=0.0108). High TKa at BL predicted shorter OS in the F+Pa arm (HR 4.39; 95% CI 2.15-8.99, p&lt;0.0001). Conclusions: Measuring blood TKa levels can monitor and predict efficacy of F+/-Pa at BL and during therapy in MBC. TKa dynamics before and during therapy are associated with PFS and OS. Future studies will provide additional knowledge on the utility of TKa in MBC. Clinical trial information: NCT02690480 .

Oxidative stress, redox status and surfactant metabolism in mechanically ventilated patients receiving different approaches to oxygen therapy (MecROX): An observational study protocol for mechanistic evaluation

Background MecROX is a mechanistic sub-study of the UK-ROX trial which was designed to evaluate the clinical and cost-effectiveness of a conservative approach to oxygen therapy for invasively ventilated adults in intensive care. This is based on the scientific rationale that excess oxygen is harmful. Epithelial cell damage with alveolar surfactant deficiency is characteristic of hyperoxic acute lung injury. Additionally, hyperoxaemia (excess blood oxygen levels) may exacerbate whole-body oxidative stress leading to cell death, autophagy, mitochondrial dysfunction, bioenergetic failure and multi-organ failure resulting in poor clinical outcomes. However, there is a lack of in-vivo human models evaluating the mechanisms that underpin oxygen-induced organ damage in mechanically ventilated patients. Aim The aim of the MecROX mechanistic sub-study is to assess lung surfactant composition and global systemic redox status to provide a mechanistic and complementary scientific rationale to the UK-ROX trial findings. The objectives are to quantify in-vivo surfactant composition, synthesis, and metabolism with markers of oxidative stress and systemic redox disequilibrium (as evidenced by alterations in the ‘reactive species interactome’) to differentiate between groups of conservative and usual oxygen targets. Methods and design After randomisation into the UK-ROX trial, 100 adult participants (50 in the conservative and 50 in usual care group) will be recruited at two trial sites. Blood and endotracheal samples will be taken at 0, 48 and 72 hours following an infusion of 3 mg/kg methyl-D9-choline chloride. This is a non-radioactive, stable isotope of choline (vitamin), which has been extensively used to study surfactant phospholipid kinetics in humans. This study will mechanistically evaluate the in-vivo surfactant synthesis and breakdown (by hydrolysis and oxidation), oxidative stress and redox disequilibrium from sequential plasma and bronchial samples using an array of analytical platforms. We will compare conservative and usual oxygenation groups according to the amount of oxygen administered. Trial registration: ISRCTN ISRCTN61929838, 27/03/2023 https://doi.org/10.1186/ISRCTN61929838.

The cost-effectiveness of including liquid biopsy into molecular profiling strategies for newly diagnosed advanced non-squamous non-small cell lung cancer in an Asian population

ObjectivesLiquid biopsy is complementary to tissue biopsy for lung cancer profiling, yet evidence of the cost-effectiveness is limited. This could retard implementation and reimbursement in clinical practice. The aim of this study is to estimate the cost-effectiveness of profiling strategies that include liquid biopsy and to identify the optimal profiling approach for newly diagnosed advanced non-squamous non-small cell lung cancer (NSCLC) in an Asian population using Singapore as an example. Materials and methodsA decision tree and partitioned-survival model was developed from the Singapore healthcare system’s perspective to evaluate the cost-effectiveness of five molecular profiling strategies: either tissue or plasma next-generation sequencing (NGS) alone, a concurrent, and two sequential approaches. Model inputs were informed by local data or published literature. Sensitivity analyses and scenario analyses were undertaken to understand the robustness of the conclusions for decision making. The optimal strategy at different willingness-to-pay (WTP) thresholds was presented by cost-effectiveness acceptability frontier and the expected loss curve. ResultsThe sequential tissue-plasma NGS approach revealed an additional 0.0981 quality adjusted life years (QALYs) for an extra cost of S$3,074 over a 20-year time horizon compared to tissue NGS alone, resulting in an incremental cost-effectiveness ratio (ICER) of S$31,318/QALY and an incremental net monetary benefit of S$1,343 per patient. The findings were sensitive to the costs of pembrolizumab and osimertinib and the probabilities of re-biopsy after tissue NGS. Sequential plasma-tissue NGS and plasma NGS alone were more costly and less effective than alternatives. ConclusionThe sequential tissue-plasma NGS approach generated the highest net monetary benefit and was the optimal testing strategy when WTP was S$45,000/QALY. It retained superiority but understandably with a higher ICER when expensive, non-first line treatments were included. Overall, its routine clinical practice should be proactively considered for newly diagnosed advanced non-squamous NSCLC in an Asian population.

Conversion of Layered WS2 Crystals into Mixed-Domain Electrochemical Catalysts by Plasma-Assisted Surface Reconstruction.

Electrocatalytic water splitting is crucial to generate clean hydrogen fuel, but implementation at an industrial scale remains limited due to dependence on expensive platinum (Pt)-based electrocatalysts. Here, an all-dry process to transform electrochemically inert bulk WS2 into a multidomain electrochemical catalyst that enables scalable and cost-effective implementation of the hydrogen evolution reaction (HER) in water electrolysis is reported. Direct dry transfer of WS2 flakes to a gold thin film deposited on a silicon substrate provides a general platform to produce the working electrodes for HER with tunable charge transfer resistance. By treating the mechanically exfoliated WS2 with sequential Ar-O2 plasma, mixed domains of WS2, WO3, and tungsten oxysulfide form on the surfaces of the flakes, which gives rise to a superior HER with much greater long-term stability and steady-state activity compared to Pt. Using density functional theory, ultraefficient atomic sites formed on the constituent nanodomains are identified, and the quantification of atomic-scale reactivities and resulting HER activities fully support the experimental observations.

Improvement of tensile strength and toughness in aramid/epoxy composites by sequential air plasma and (3-glycidyloxypropyl) trimethoxysilane treatments

This work explores sequential surface treatments involving atmospheric-air plasma and (3-glycidyloxypropyl) trimethoxysilane (GLYMO) to enhance the tensile properties of aramid/epoxy composites. To prove the technical advantages of this approach, aramid fibers received individual (atmospheric-air plasma or GLYMO) or sequential (plasma followed by GLYMO, and vice versa) surface treatments. Single fiber tensile tests (SFT) and X-ray photoelectron spectroscopy (XPS) were employed to characterize changes in aramid fibers upon the surface modifications. SFT revealed that none of the surface treatments compromised their tensile strength (σ max ). Applying GLYMO, whether individually or in sequence (GLYMO followed by plasma and plasma followed by GLYMO), led to a significant enhancement in the fibers’ elastic modulus (E). Composites with plasma-treated fibers displayed a 5% increase in E and an 8.5% increase in σ max , with no changes in toughness. However, the most notable improvements were achieved through sequential plasma followed by GLYMO treatments, resulting in a ~ 10% increase in σ max and a remarkable ~ 40% improvement in toughness. Plasma introduces oxygen-containing groups to the fiber surface, facilitating GLYMO grafting. Subsequent crosslinking of GLYMO with the epoxy resin strengthens the fiber-matrix interface. This sequential surface modification offers an alternative pathway for fabricating composites with superior toughness and σ max .

Association between left ventricular systolic function parameters and myocardial injury, organ failure and mortality in patients with septic shock

BackgroundLeft ventricular ejection fraction (LVEF) is inconsistently associated with poor outcomes in patients with sepsis. Newer parameters such as LV longitudinal strain (LVLS), mitral annular plane systolic excursion (MAPSE) and LV longitudinal wall fractional shortening (LV-LWFS) may be more sensitive indicators of LV dysfunction, but are sparsely investigated. Our objective was to evaluate the association between five traditional and novel echocardiographic parameters of LV systolic function (LVEF, peak tissue Doppler velocity at the mitral valve (s´), LVLS, MAPSE and LV-LWFS) and outcomes in patients admitted to the Intensive Care Unit (ICU) with septic shock.MethodsA total of 152 patients admitted to the ICU with septic shock from two data repositories were included. Transthoracic echocardiograms were performed within 24 h of ICU admission. The primary outcome was myocardial injury, defined as high-sensitivity troponin T ≥ 45 ng/L on ICU admission. Secondary outcomes were organ support-free days (OSFD) and 30-day mortality. We also tested for the prognostic value of the systolic function parameters using multivariable analysis.ResultsLVLS, MAPSE and LV-LWFS, but not LVEF and s´, differed between patients with and without myocardial injury. After adjustment for age, pre-existing cardiac disease, Simplified Acute Physiology (SAPS3) score, Sequential Organ Failure Assessment (SOFA) score, plasma creatinine and presence of right ventricular dysfunction, only MAPSE and LV-LWFS were independently associated with myocardial injury. None of the systolic function parameters were associated with OSFD or 30-day mortality.ConclusionsMAPSE and LV-LWFS are independently associated with myocardial injury and outperform LVEF, s´ and LVLS. Whether these parameters are associated with clinical outcomes such as the need for organ support and short-term mortality is still unclear.Trial registration NCT01747187 and NCT04695119.

Plasma symmetric dimethylarginine as a metabolite biomarker of severe acute ischemic stroke.

After severe ischemic stroke (IS), circulating levels of symmetric dimethylarginine (SDMA) increase. We investigated the early dynamics of SDMA in stroke to potentially aid with prehospital identification of severe IS from hemorrhagic stroke (HS). We performed targeted mass spectrometry (MS) measurements of SDMA in two sequential acute plasma samples (early and secondary) of 50 IS patients with LVO and 49 HS patients. Secondary samples of 227 IS and 84 HS patients with moderate to severe symptoms (NIHSS ≥ 7) subsequently underwent ELISA validation. The median (IQR) last-known-well (LKW) to sampling times were 43 min (35-67) for early samples in the MS analysis, and 83 min (65-113) for secondary samples in MS and ELISA analyses. No inter-group differences existed in early samples, but IS patients had significantly higher mean (IQR) SDMA levels in secondary samples in both analyses: 5.8 (5.3-6.9) vs. 5.1 (4.2-5.8) A.U. for HS, p < 0.001, with MS; and 0.82 (0.72-1.01) vs. 0.71 (0.58-0.85) nmol/mL for HS, p < 0.001, with ELISA. For IS patients, higher SDMA levels were associated with cardioembolic stroke: 0.84 (0.73-1.09) vs. 0.79 (0.71-0.91) nmol/mL for other etiologies, p = 0.042, and poor outcome: modified Rankin Scale (mRS) 4-6; 0.90 (0.73-1.06) vs. 0.80 (0.72-0.97) nmol/mL for mRS 0-3 (p = 0.045). In a large clinical cohort of stroke patients with moderate to severe symptoms, our data suggest that SDMA can assist in differentiation of IS and HS patients already 1 h and a half after symptom onset. SDMA may prove to have future value in a diagnostic stroke biomarker panel.

(Invited) Modified SAB Methods for Hybrid and All-Cu Bonding for 3D Integration below 200ºC

Two methods of Surface Activated Bonding (SAB) will be proposed to enable low-temperature hybrid bonding for 3D integration.A modified one involves surface activation processes using Ar fast-atom-beam bombardment with simultaneous co-sputtering of Si nano-adhesion layer, followed by sequential plasma irradiation with N2 radicals. These processes combine hydrophilic treatment and bonding in a low-vacuum chamber. The Si nano-adhesion layer and the sequential plasma treatment appear to enhance hydrophilicity, which enables low-temperature bonding of both Si oxides and Cu pads as hybrid bonding. Bonding in a low-vacuum environment helps to avoid void generation caused by air entrainment.The other one is the standard SAB. But we will connect two device wafers not in a hybrid bonding but in all-Cu bonding. A small insulation layer surrounds the area around the Cu electrode on the wafers, while the rest is covered with Cu solid layers. These solid layers constitute the ground layer, power layer, or their paired layers and may contribute to heat dissipation when connected to thermal vias. The two wafers are connected only by bonding on the Cu electrodes and solid layers. The insulating parts around the Cu electrodes do not necessarily have to be bonded, and the gaps may be kept in a vacuum. Of course, the bonded surfaces need to be flattened, and a new division and layout design of the solid electrode will be required.Cu-Cu direct bonding is possible at room temperature by applying the standard SAB directly. Of course, this requires bonding in an ultra-high vacuum condition, which inevitably reduces the throughput. However, room temperature bonding is overwhelmingly advantageous for bonding different types of devices and wafers. It is expected to become a powerful tool for 3D heterogeneous integration of devices in the future. Figure 1

Hydrophilic Bonding of SiO2/SiO2 and Cu/Cu using Sequential Plasma Activation

To meet the increasing market demand for next-generation electronic devices, 3D system integration is getting greater and greater attention. However, traditional methods such as soldering or bump bonding cannot handle high density interconnection. Therefore, hybrid bonding technology, which simultaneously bonds Cu wiring layer and SiO2 dielectric layer, is indispensable. In the hybrid bonding process, hydrophilic bonding is commonly used to bond SiO2 to SiO2. This technique involves bonding of hydrophilic bonding surfaces, followed by post-bonding annealing to achieve a reliable bonding interface. For Cu bonding, it is necessary to break the oxide layer at the Cu bonding interface and allow Cu atoms to diffuse into each other to achieve electrical connection.However, since post-bonding annealing at high temperatures can damage the device or induce residual stress at the bonding interface, low temperature process below 200°C is preferable. Currently, the most widely adopted process is hydrophilic bonding using N2 plasma, which also achieves hybrid bonding through heating at around 350°C to 400°C.In this study, we propose to apply sequential plasma activation bonding (SPAB), which has been shown to be effective for low-temperature bonding of quartz glass, to the bonding of TEOS SiO2 and Cu. SPAB is a technique that forms a highly reactive oxynitrides on the substrate by continuously irradiating the bonding surface with O2 plasma, N2 plasma, and nitrogen radicals. This then adsorbs a large amount of OH groups by reacting with moisture, leading to a strong bond after bonding and post-bonding annealing at 200°C. Since this technique is effective for quartz, it is expected to be effective for TEOS SiO2 as well, and we also investigate its effect on Cu in this study.For this, we investigated the effect of SPAB for blanket TEOS SiO2 and Cu wafer separately. Cu layers were deposited on 4 inch, 525 µm thick Si wafers, and TEOS SiO2 layers on 6 inch, 625 µm thick Si wafers. The Cu layers were deposited by sputtering with a 1 µm thickness, while the SiO2 layers were deposited using plasma-enhanced TEOS process for a 1 µm thickness. Both types of deposited layers were planarized by CMP.The SPAB process was carried out using RIE plasma and microwave radicals of N2 and O2 gas. The bonding surfaces were activated by O2 plasma, N2 plasma, and N radicals sequentially. After the surface activation, the wafers were exposed to ambient air to adsorb water on the surface, followed by bonding in air and post-bonding annealing at 200°C for 2 hours.For comparison, bonding was also carried out using only N2 plasma and only O2 plasma activation, respectively. Results show that when surface activation was performed using only N2 plasma, the bond strength was 0.75 J/m2 for TEOS SiO2 and 0.33 J/m2 for Cu. In the case of O2 plasma activation, the bond strength was 0.57 J/m2 for TEOS SiO2 and 0.98 J/m2 for Cu.On the other hand, the SPAB technique improves the bond strength to 1.13 J/m2 for TEOS SiO2 and 1.03 J/m2 for Cu. Therefore, it can be concluded that the SPAB technique enhances the bond strengths of both TEOS SiO2 and Cu compared to single gas plasma activation. Since the SPAB improves the bond strength of both SiO2 and Cu in the same process condition with annealing temperature of 200°C, this technique will contribute low temperature hybrid bonding applications.

In-Host HEV Quasispecies Evolution Shows the Limits of Mutagenic Antiviral Treatments.

Here, we report the in-host hepatitis E virus (HEV) quasispecies evolution in a chronically infected patient who was treated with three different regimens of ribavirin (RBV) for nearly 6 years. Sequential plasma samples were collected at different time points and subjected to RNA extraction and deep sequencing using the MiSeq Illumina platforms. Specifically, we RT-PCR amplified a single amplicon from the core region located in the open-reading frame 2 (ORF2). At the nucleotide level (genotype), our analysis showed an increase in the number of rare haplotypes and a drastic reduction in the frequency of the master (most represented) sequence during the period when the virus was found to be insensitive to RBV treatment. Contrarily, at the amino acid level (phenotype), our study revealed conservation of the amino acids, which is represented by a high prevalence of the master sequence. Our findings suggest that using mutagenic antivirals concomitant with high viral loads can lead to the selection and proliferation of a rich set of synonymous haplotypes that express the same phenotype. This can also lead to the selection and proliferation of conservative substitutions that express fitness-enhanced phenotypes. These results have important clinical implications, as they suggest that using mutagenic agents as a monotherapy treatment regimen in the absence of sufficiently effective viral inhibitors can result in diversification and proliferation of a highly diverse quasispecies resistant to further treatment. Therefore, such approaches should be avoided whenever possible.