A real-world cohort study of first-line afatinib in patients with EGFR-mutant advanced non-small cell lung cancer in Vietnam.

BACKGROUND: This study aimed to evaluate the efficacy and side effects of first-line afatinib treatment in a real-world setting in Vietnam. METHODS: This retrospective study was conducted across nine hospitals in Vietnam. Advanced epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) patients who received afatinib as first-line therapy between April 2018 and June 2022 were included, and patient medical records were reviewed. Key outcomes were overall response rate (ORR), time-to-treatment failure (TTF), and tolerability. RESULTS: A total of 343 patients on first-line afatinib were eligible for the study. EGFR exon 19 deletion (Del19) alone was detected in 46.9% of patients, L858R mutation alone in 26.3%, and other uncommon EGFR mutations, including compound mutations, in 26.8%. Patients with brain metastases at baseline were 25.4%. Patients who received 40 mg, 30 mg, and 20 mg as starting doses of afatinib were 58.6%, 39.9%, and 1.5%, respectively. The ORR was 78.1% in the overall population, 82.6% in the Del19 mutation subgroup, 73.3% in the L858R mutation subgroup, and 75.0% in the uncommon mutation subgroup (p > 0.05). The univariate and multivariate analyses indicate that the ORR increased when the starting dose was 40 mg compared to starting doses below 40 mg (83.9% vs. 74.3%, p = 0.034). The median TTF (mTTF) was 16.7 months (CI 95%: 14.8-18.5) in all patients, with a median follow-up time of 26.2 months. The mTTF was longer in patients in the common EGFR mutation subgroup (Del19/L858R) than in those in the uncommon mutation subgroup (17.5 vs. 13.8 months, p = 0.045) and in those without versus with brain metastases at baseline (17.5 vs. 15.1 months, p = 0.049). There were no significant differences in the mTTF between subgroups based on the starting dose of 40 mg and < 40 mg (16.7 vs. 16.9 months, p > 0.05). The most common treatment-related adverse events (any grade/grade ≥ 3) were diarrhea (55.4%/3.5%), rash (51.9%/3.2%), paronychia (35.3%/5.0%), and stomatitis (22.2%/1.2%). CONCLUSIONS: Afatinib demonstrated clinical effectiveness and good tolerability in Vietnamese EGFR-mutant NSCLC patients. In our real-world setting, administering a starting dose below 40 mg might result in a reduction in ORR; however, it might not have a significant impact on TTF.

Spectrum and antimicrobial resistance in acute exacerbation of chronic obstructive pulmonary disease with pneumonia: a cross-sectional prospective study from Vietnam.

BACKGROUND: Respiratory infections have long been recognized as a primary cause of acute exacerbation of chronic obstructive pulmonary disease (AE-COPD). Additionally, the emergence of antimicrobial resistance has led to an urgent and critical situation in developing countries, including Vietnam. This study aimed to investigate the distribution and antimicrobial resistance of bacteria in patients with AE-COPD using both conventional culture and multiplex real-time PCR. Additionally, associations between clinical characteristics and indicators of pneumonia in these patients were examined. METHODS: This cross-sectional prospective study included 92 AE-COPD patients with pneumonia and 46 without pneumonia. Sputum specimens were cultured and examined for bacterial identification, and antimicrobial susceptibility was determined for each isolate. Multiplex real-time PCR was also performed to detect ten bacteria and seven viruses. RESULTS: The detection rates of pathogens in AE-COPD patients with pneumonia were 92.39%, compared to 86.96% in those without pneumonia. A total of 26 pathogenic species were identified, showing no significant difference in distribution between the two groups. The predominant bacteria included Klebsiella pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, and Streptococcus pneumoniae, followed by Acinetobacter baumannii and Streptococcus mitis. There was a slight difference in antibiotic resistance between bacteria isolated from two groups. The frequency of H. influenzae was notably greater in AE-COPD patients who experienced respiratory failure (21.92%) than in those who did not (9.23%). S. pneumoniae was more common in patients with stage I (44.44%) or IV (36.36%) COPD than in patients with stage II (17.39%) or III (9.72%) disease. ROC curve analysis revealed that C-reactive protein (CRP) levels could distinguish patients with AE-COPD with and without pneumonia (AUC = 0.78). CONCLUSION: Gram-negative bacteria still play a key role in the etiology of AE-COPD patients, regardless of the presence of pneumonia. This study provides updated evidence for the epidemiology of AE-COPD pathogens and the appropriate selection of antimicrobial agents in Vietnam.

Physical Trace Gas Identification with the Photo Electron Ionization Spectrometer (PEIS).

Chemosensor technology for trace gases in the air always aims to identify these compounds and then measure their concentrations. For identification, traceable methods are sparse and relate to large appliances such as mass spectrometers. We present a new method that uses the alternative traceable measurement of the ionization energies of trace gases in a way that can be miniaturized and energetically tuned. We investigate the achievable performance. Since tunable UV sources are not available for photoionization, we take a detour via impact ionization with electrons, which we generate using the photoelectric effect and bring to sharp, defined energies on a nanoscale in the air. Electron impact ionization is thus possible at air pressures of up to 900 hPa. The sensitivity of the process reaches 1 ppm and is equivalent to that of classic PID. With sharpened energy settings, substance identification is currently possible with an accuracy of 30 meV. We can largely explain the experimental observations with the known quantum mechanical models.

Spin Torque Study of the Spin Hall Conductivity and Spin Diffusion Length in Platinum Thin Films with Varying Resistivity.

We report measurements of the spin torque efficiencies in perpendicularly magnetized Pt/Co bilayers where the Pt resistivity ρ_{Pt} is strongly dependent on thickness t_{Pt}. The dampinglike spin Hall torque efficiency per unit current density ξ_{DL}^{j} varies significantly with t_{Pt}, exhibiting a peak value ξ_{DL}^{j}=0.12 at t_{Pt}=2.8-3.9 nm. In contrast, ξ_{DL}^{j}/ρ_{Pt} increases monotonically with t_{Pt} and saturates for t_{Pt}>5 nm, consistent with an intrinsic spin Hall effect mechanism, in which ξ_{DL}^{j} is enhanced by an increase in ρ_{Pt}. Assuming the Elliott-Yafet spin scattering mechanism dominates, we estimate that the spin diffusion length λ_{s}=(0.77±0.08)×10^{-15} Ω·m^{2}/ρ_{Pt}.

Dual Ionic Pathways in Semi-Solid Electrolyte based on Binary Metal-Organic Frameworks Enable Stable Operation of Li-Metal Batteries at Extremely High Temperatures.

The rapid development of the electronics market necessitates energy storage devices characterized by high energy density and capacity, alongside the ability to maintain stable and safe operation under harsh conditions, particularly elevated temperatures. In this study, a semi-solid-state electrolyte (SSSE) for Li-metal batteries (LMB) is synthesized by integrating metal-organic frameworks (MOFs) as host materials featuring a hierarchical pore structure. A trace amount of liquid electrolyte (LE) is entrapped within these pores through electrochemical activation. These findings demonstrate that this structure exhibits outstanding properties, including remarkably high thermal stability, an extended electrochemical window (5.25 V vs Li/Li+), and robust lithium-ion conductivity (2.04 × 10-4 S cm-1), owing to the synergistic effect of the hierarchical MOF pores facilitating the storage and transport of Li ions. The Li//LiFePO4 cell incorporating prepared SSSE shows excellent capacity retention, retaining 97% (162.8 mAh g-1) of their initial capacity after 100 cycles at 1 C rate at an extremely high temperature of 95 °C. It is believed that this study not only advances the understanding of ion transport in MOF-based SSSE but also significantly contributes to the development of LMB capable of stable and safe operation even under extremely high temperatures.

Electrochemical Degradation of Molecularly Imprinted Polymers for Future Applications of Inflammation Sensing in Cochlear Implants.

After cochlear implant (CI) insertion, there is a possibility of postoperative inflammation, which may involve proinflammatory markers such as interleukin-6. Detecting this inflammation promptly is crucial for administering anti-inflammatory drugs, if required. One potential method for detecting inflammation is using molecular imprinted polymers (MIPs). These MIPs, which can be deposited on the CI electrode, provide readout employing impedance measurements, a feature already available on the CI circuit. MIPs designed for this purpose should possess biocompatibility, conductivity, and degradability. The degradability is crucial because there is a limitation on the number of electrodes available, and once the inflammation sensor degrades after the acute inflammation period, it should remain usable as a regular electrode. In this work, conductive poly(3,4-ethylenedioxythiophene) polystyrenesulfonate-based MIPs were synthesized against biotin as a surrogate target marker. Specific biotin binding with MIPs was determined before and after degradation using electrochemical impedance spectroscopy (EIS) and compared with the control nonimprinted polymers (NIPs). Subsequently, MIPs were electrochemically degraded by EIS with different potentials, wherein a potential dependence was observed. With decreasing potential, fewer dissolved polymers and more monomer molecules were detected in the solution in which degradation took place. At a potential of 0.205 V a negligible amount of dissolved polymer in addition to the dissolved monomer molecules was measured, which can be defined as the limiting potential. Below this potential, only dissolved monomer molecules are obtained, which enables renal clearance. Biocompatibility testing revealed that both the polymer and the solution with dissolved monomer molecules do not exceed the ISO 10993-5 cytotoxicity threshold. Based on these findings, we have developed conductive, biocompatible, and controllably degradable MIPs capable of detecting biotin. This research work paves the way for the advancement of CIs, where inflammation can be detected using molecular imprinting technology without compromising the stability and biosafety of the product.

The Discovery of MORF-627, a Highly Selective Conformationally-Biased Zwitterionic Integrin αvß6 Inhibitor for Fibrosis.

Inhibition of integrin αvß6 is a promising approach to the treatment of fibrotic disease such as idiopathic pulmonary fibrosis. Screening a small library combining head groups that stabilize the bent-closed conformation of integrin αIIbß3 with αv integrin binding motifs resulted in the identification of hit compounds that bind the bent-closed conformation of αvß6. Crystal structures of these compounds bound to αvß6 and related integrins revealed opportunities to increase potency and selectivity, and these efforts were accelerated using accurate free energy perturbation (FEP+) calculations. Optimization of PK parameters including permeability, bioavailability, clearance, and half-life resulted in the discovery of development candidate MORF-627, a highly selective inhibitor of αvß6 that stabilizes the bent-closed conformation and has good oral PK. Unfortunately, the compound showed toxicity in a 28-day NHP safety study, precluding further development. Nevertheless, MORF-627 is a useful tool compound for studying the biology of integrin αvß6.

Real-world analysis of afatinib as a first-line treatment for patients with advanced stage non-small-cell lung cancer with uncommon EGFR mutations: a multicenter study in Vietnam.

Background: Afatinib is indicated for advanced-stage non-small-cell lung cancer (NSCLC) with Epidermal Growth Factor Receptor (EGFR) and uncommon mutations. However, real-world studies on this topic are limited. This study aimed to evaluate afatinib as first-line therapy for locally advanced and metastatic NSCLC with uncommon EGFR mutations. Patients and methods: A retrospective study included 92 patients with advanced NSCLC with uncommon and compound EGFR mutations, treated with afatinib as first-line therapy. Patients were followed up and evaluated every 3 months or when symptoms of progressive disease arose. The endpoints were objective response rate (ORR), time-to-treatment failure (TTF), and adverse events. Results: The G719X EGFR mutation had the highest occurrence rate (53.3% for both monotherapy and the compound). By contrast, the compound mutation G719X-S768I was observed at a rate of 22.8%. The ORR was 75%, with 15.2% of patients achieving complete response. The overall median TTF was 13.8 months. Patients with the G719X EGFR mutation (single and compound) had a median TTF of 19.3 months, longer than that of patients with other mutations, who had a median TTF of 11.2 months. Patients with compound EGFR mutations (G719X and S768I) demonstrated a median TTF of 23.2 months compared to that of 12.3 months for other mutations. Tolerated doses of 20 or 30 mg achieved a longer median TTF of 17.1 months compared to 11.2 months with 40 mg. Median TTF differed between patients with and without brain metastasis, at 11.2 and 16.9 months, respectively. Rash (55.4%) and diarrhea (53.3%) were the most common adverse events, primarily grades 1 and 2. Other side effects occurred at a low rate. Conclusion: Afatinib is effective for locally advanced metastatic NSCLC with uncommon EGFR mutations. Patients with G719X, compound G719X-S768I mutations, and tolerated doses of 20 or 30 mg had a longer median TTF than those with other mutations.

Computational Modeling of Diffusion-Based Delamination for Active Implantable Medical Devices.

Delamination at heterogeneous material interfaces is one of the most prominent failure modes in active implantable medical devices (AIMDs). A well-known example of an AIMD is the cochlear implant (CI). In mechanical engineering, a multitude of testing procedures are known whose data can be used for detailed modeling with respect to digital twins. Detailed, complex models for digital twins are still lacking in bioengineering since body fluid infiltration occurs both into the polymer substrate and along the metal-polymer interfaces. For a newly developed test for an AIMD or CI composed of silicone rubber and metal wiring or electrodes, a mathematical model of these mechanisms is presented. It provides a better understanding of the failure mechanisms in such devices and their validation against real-life data. The implementation utilizes COMSOL Multiphysics®, consisting of a volume diffusion part and models for interface diffusion (and delamination). For a set of experimental data, the necessary diffusion coefficient could be derived. A subsequent comparison of experimental and modeling results showed a good qualitative and functional match. The delamination model follows a mechanical approach. The results of the interface diffusion model, which follows a substance transport-based approach, show a very good approximation to the results of previous experiments.

Synergetic Effect of Li-Ion Concentration and Triple Doping on Ionic Conductivity of Li7La3Zr2O12 Solid Electrolyte.

Li7La3Zr2O12 (LLZO) is a promising and safe solid electrolyte for all-solid-state batteries. To achieve high ionic conductivity of LLZO, stabilizing the cubic phase and reducing Li loss during the sintering process is essential. Therefore, reducing the sintering temperature, which increases the sintering time for high-density pellets, is necessary. Herein, we investigate the change in the crystal structure, morphology, and Li ionic conductivity of LLZO pellets by triple doping with Al, Ga, and Ta and modulating the variation in initial Li concentrations. Interestingly, the proportion of the conductive cubic phase increased with increasing Li stoichiometry by 1.1 times, and this tendency was further accelerated by triple doping. The synergetic effects of triple doping and Li concentration also minimized Li loss during sintering. Accordingly, it provided a high-quality LLZO pellet with good ionic conductivity (3.6 × 10-4 S cm-1) and high relative density (97.8%). Notably, the LLZO pellet was obtained using a very short sintering process (40 min). Considering that the most time-consuming step is the sintering process for LLZO, this study can provide guidelines for the fast production and commercialization of LLZO electrolytes with high ionic conductivity.

Metallacyclophanes of 1,6-bis(diphenylphosphino)pyrene: excimeric emission and effect of oxygen on stability of the rings.

1,6-Bis(diphenylphosphino)pyrene (L) was reacted with Ag(I) and Cu(I) ions to form metallacyclophanes [Ag(2)L(2)(OTf)(2)] (1), [Cu(2)L(2)(MeCN)(4)](2+) (2), and [Cu(2)L(2)I(2)] (3) which consisted of two cofacial pyrenyl rings. 1 and 2 exhibited intramolecular excimeric emissions which along with the UV-vis absorption were invoked in understanding the solution dynamics of the metallocyclophanes. The metallacyclophanes were stable toward ring-opening dissociation at concentration as low as 10(-7) M. However, air oxidation of the dangling PPh(2) groups arising from metal-ligand bond dissociation drove the equilibrium toward dissociation and produced the oxidized phosphine 1,6-bis(diphenylphosphine oxide)pyrene.

Symmetry-aware reservoir computing.

We demonstrate that matching the symmetry properties of a reservoir computer (RC) to the data being processed dramatically increases its processing power. We apply our method to the parity task, a challenging benchmark problem that highlights inversion and permutation symmetries, and to a chaotic system inference task that presents an inversion symmetry rule. For the parity task, our symmetry-aware RC obtains zero error using an exponentially reduced neural network and training data, greatly speeding up the time to result and outperforming artificial neural networks. When both symmetries are respected, we find that the network size N necessary to obtain zero error for 50 different RC instances scales linearly with the parity-order n. Moreover, some symmetry-aware RC instances perform a zero error classification with only N=1 for n≤7. Furthermore, we show that a symmetry-aware RC only needs a training data set with size on the order of (n+n/2) to obtain such a performance, an exponential reduction in comparison to a regular RC which requires a training data set with size on the order of n2^{n} to contain all 2^{n} possible n-bit-long sequences. For the inference task, we show that a symmetry-aware RC presents a normalized root-mean-square error three orders-of-magnitude smaller than regular RCs. For both tasks, our RC approach respects the symmetries by adjusting only the input and the output layers, and not by problem-based modifications to the neural network. We anticipate that the generalizations of our procedure can be applied in information processing for problems with known symmetries.

Cryogenic Memory Architecture Integrating Spin Hall Effect based Magnetic Memory and Superconductive Cryotron Devices.

One of the most challenging obstacles to realizing exascale computing is minimizing the energy consumption of L2 cache, main memory, and interconnects to that memory. For promising cryogenic computing schemes utilizing Josephson junction superconducting logic, this obstacle is exacerbated by the cryogenic system requirements that expose the technology's lack of high-density, high-speed and power-efficient memory. Here we demonstrate an array of cryogenic memory cells consisting of a non-volatile three-terminal magnetic tunnel junction element driven by the spin Hall effect, combined with a superconducting heater-cryotron bit-select element. The write energy of these memory elements is roughly 8 pJ with a bit-select element, designed to achieve a minimum overhead power consumption of about 30%. Individual magnetic memory cells measured at 4 K show reliable switching with write error rates below 10-6, and a 4 × 4 array can be fully addressed with bit select error rates of 10-6. This demonstration is a first step towards a full cryogenic memory architecture targeting energy and performance specifications appropriate for applications in superconducting high performance and quantum computing control systems, which require significant memory resources operating at 4 K.

Photooxidation of a platinum-anthracene pincer complex: formation and structures of Pt(II)-anthrone and -ketal complexes.

Irradiating the cyclometalated pincer complex Pt(II)(DPA)Cl (1, DPA = 1,8-bis(diphenylphosphino)anthracene) in the presence of O(2) led to three sequential oxidations of the anthracenyl ring. The first photoproduct, a Pt(II)-9,10-endoperoxide complex, was converted photochemically to a Pt(II)-9-hydroxyanthrone complex A which was further oxygenated to a Pt(II)-hemiketal (B). The oxidation of A, which could be accelerated by light irradiation, probably involved a Pt(II)-anthraquinone intermediate. B underwent acid-catalyzed ketalization to form a binuclear Pt(II)(2)-diketal (B1). The photolysis was followed by UV-vis absorption and NMR spectroscopy, and the structures of A and B1 were characterized by single crystal X-ray diffraction.