High Cutoff Research Articles

Association Between Time-of-Day of Immune Checkpoint Blockade Administration and Outcomes in Metastatic Renal Cell Carcinoma.

Preclinical evidence demonstrating circadian rhythmicity within the immune system provides a rationale for hypothesis that immune checkpoint inhibitor (ICI) infusion time-of-day may serve as an actionable mechanism to improve outcomes. Herein, we explore the association between ICI time of infusion (TOI) and outcomes in metastatic renal cell carcinoma (mRCC). Data from patients with mRCC who received nivolumab or nivolumab/ipilimumab, in first- or second-line were retrospectively collected. Patients who received < 20% of infusions after 16:30 were assigned to the early TOI sub-cohort, while the rest were assigned to the late TOI sub-cohort. Clinical outcomes were compared across the 2 groups. Among 135 patients included, 89 (65.9%) and 46 (34.1%) were assigned to early and late TOI sub-cohorts, respectively. Baseline characteristics were comparable across the 2 sub-cohorts. Objective response rate (ORR) was 36.0% with early TOI versus 29.5% with late TOI (P=.157). Median time to treatment failure (TTF) was 9.5 months in the early TOI sub-cohort versus 4.6 months in the late TOI sub-cohort with a hazard ratio (HR) of 1.405 (95% CI, 0.919-2.149; P=.11) in univariate analysis and 1.694 (95% CI, 1.064-2.698; P=.026) in multivariate analysis. Higher cut offs allocating patients into the late TOI sub-cohort yielded an incremental increase in the HR for TTF and overall survival (OS) that reached statistical significance. In patients with mRCC, early TOI yielded a numerical increase in ORR, TTF and OS, with the TTF difference reaching significance in multivariate analysis. Prospective randomized studies are warranted to examine the impact of chronomodulation on outcomes with ICIs in mRCC.

A Statistical Study on the Acceleration Conditions of Ultrarelativistic Electrons in the Earth's Outer Radiation Belt During Geomagnetic Storms

AbstractUsing the data from Van Allen Probes, we statistically study the acceleration conditions of ultrarelativistic electrons (Ek &gt; 3 MeV) in the Earth's outer radiation belt. Based on the different high energy cutoffs of ultrarelativistic electrons, the acceleration events of ultrarelativistic electrons are divided into the four groups of “3.4 MeV events,” “5.2 MeV events,” “6.3 MeV events,” and “7.7 MeV events.” According to different solar wind and substorm conditions during the recovery stage, we classify solar wind into three categories: no high‐speed flows, short‐duration high‐speed flows, and long‐duration high‐speed flows. Substorms are divided into continuous substorm activity and non‐continuous substorm activity. Our statistical results show that (a) The different solar wind speeds can cause enhancements of ultrarelativistic electrons with different energies. The high solar wind speed is more important in the acceleration of ultrarelativistic electrons with higher energies (7.7 MeV) than lower energies (3.4, 5.2, and 6.3 MeV). (b) The different substorm activities during the recovery stage can cause enhancements of ultrarelativistic electrons with different energies. Continuous intense substorms in the early recovery stage can contribute to the rapid recovery and enhancements of ultrarelativistic electrons. The timing, intensity, and duration of substorms during the recovery stage are important to the acceleration of ultrarelativistic electrons. (c) Relativistic (1 MeV) electrons are the direct “source” of ultrarelativistic electrons (3.4, 5.2, and 6.3 MeV) in the outer radiation belt. These can help us further understand the electron dynamics of the Earth’s outer radiation belt.

Multifunctional composite interfacial layer based on aluminum and boron for single crystal LiNi0.8Co0.1Mn0.1O2 with enhanced electrochemical performance at high voltage and temperature

Nickel-rich cathodes are unable to meet the requirements of widespread commercialization due to rapid capacity decay and poor thermal stability. This work greatly improves the capacity retention of the cathode with high cut-off voltage and high temperature by constructing a multifunctional composite interfacial layer of LiAlO2, LiBO2, Al2O3 and B2O3 on the surface of single crystal LiNi0.8Co0.1Mn0.1O2 (NCM811). The formation of the composite layer consumes the surface residual lithium and reduces the interfacial side reactions, contributing to further formation of a stable cathode-electrolyte interface. The fast ion conductor layer improves Li+ transport pathways and rate performance is enhanced. The oxide layer effectively resists the erosion of HF, inhibits the irreversible phase change and oxygen evolution reaction of the cathode. The thermal stability of the material is significantly improved. Ultimately, modified cathode exhibits excellent capacity retention of 78.4 % and 70.4 % after 100 cycles at high cutoff voltage (4.5 V) and high temperature (55 °C) at a rate of 0.5C, respectively.

One Stone, Three Birds: An Air and Interface Stable Argyrodite Solid Electrolyte with Multifunctional Nanoshells.

Li6 PS5 Cl (LPSC) solid electrolytes, based on Argyrodite, have shown potential for developing high energy density and safe all-solid-state lithium metal batteries. However, challenges such as interfacial reactions, uneven Li deposition, and air instability remain unresolved. To address these issues, a simple and effective approach is proposed to design and prepare a solid electrolyte with unique structural features: Li6 PS4 Cl0.75 -OF0.25 (LPSC-OF0.25 ) with protective LiF@Li2 O nanoshells and F and O-rich internal units. The LPSC-OF0.25 electrolyte exhibits high ionic conductivity and the capability of "killing three birds with one stone" by improving the moist air tolerance, as well as the interface compatibility between the anode or cathode and the solid electrolyte. The improved performance is attributed to the peculiar morphology and the self-generating and self-healing interface coupling capability. When coupled with bare LiCoO2 , the LPSC-OF0.25 electrolyte enables stable operation under high cutoff voltage (≈4.65V vs Li/Li+ ), thick cathodes (25mgcm-2 ), and large current density (800 cycles at 2mAcm-2 ). This rationally designed solid electrolyte offers promising prospects for solid-state batteries with high energy and power density for future long-range electric vehicles and aircrafts.

Fluorinated High-Voltage Electrolytes To Stabilize Nickel-Rich Lithium Batteries.

As state-of-the-art (SOA) lithium-ion (Li-ion) batteries approach their specific energy limit (∼250 Wh kg-1), layer-structured, nickel-rich (Ni-rich) lithium transition metal oxide-based cathode materials, e.g., LiNi0.8Mn0.1Co0.1O2 (NMC811), have attracted great interest owing to their practical high specific capacities (>200 mAhg-1). Coupled with their high average discharge voltages (∼4 V vs Li/Li+), Ni-rich cathode-based lithium batteries possess a great potential to achieve much higher specific energies (>350 Wh kg-1 at the cell level) than the SOA Li-ion counterparts. In addition, Ni-rich oxides are low-cost battery cathode materials due to their low cobalt contents. However, Ni-rich cathode-based lithium batteries suffer quick capacity degradations upon cycling, particularly at high upper cutoff voltages (e.g., ≥4.5 V vs Li/Li+), due to crystal structure changes of the active cathode materials and parasitic side reactions at the electrolyte/electrode interfaces. In this study, a fluorinated-solvent-based, high-voltage stable electrolyte (HVE), i.e., 1 M Li bis(trifluoromethanesulfonyl)imide (LiTFSI) in fluoroethylene carbonate (FEC), bis(2,2,2-trifluoroethyl) carbonate (FDEC), and methyl (2,2,2-trifluoroethyl) carbonate (FEMC) with Li difluoro(oxalate)borate (LiDFOB) additive, was formulated and evaluated in Li/NMC811 battery cells. To the best of our knowledge, this class of electrolyte has not been investigated for Ni-rich cathode-based lithium batteries. Li/NMC811 cells with HVE exhibited a superior long-term cycle performance stability, maintaining ∼80% capacity after ∼500 cycles at a high cutoff voltage of 4.5 V (vs Li/Li+) than a baseline carbonate-solvent-based electrolyte (BE). The superior cycle stability of the Li/NMC811 cells is attributed to the inherently high-voltage stability of HVE, supported by the physical and electrochemical analyses. This conclusion is supported by our density functional theory (DFT) modeling where HVE shows a less tendency of deprotonation/oxidation than BE, leading to the observed cycle stability. The findings in this study are important to help tackle the technical challenges facing Ni-rich cathode-based lithium batteries to realize their high energy density potentials with a long cycle life.

Extracorporeal light-chain elimination in myeloma with simple medium cutoff membrane hemodialysis: a retrospective cohort study.

We determined the efficacy of free light chain (FLC) removal by regular dialysis equipment (high-flux filtration) with medium cutoff (MCO) membrane hemodialysis (HD) as an adjuvant treatment to standard chemotherapy for patients with acute kidney injury complicating multiple myeloma (MM) and its impact on further dialysis dependency. Sixty patients with acute dialysis-dependent renal failure secondary to MM were treated with MCO-HD (55 patients) or HCO (high cutoff)-HD (5 patients) as a control. FLC serum concentration, total protein, immunoglobulins, and LDH were measured throughout the dialysis therapy. The kidney function of the patients was followed up for 1 year. The median age was 69 years; 25 female and 35 male patients were enrolled. HD significantly reduced FLC kappa levels in the MCO/HCO group by 58%/84% (MCO/HCO group; p < 0.05) and FLC lambda by 39%/33% (MCO/HCO group; p < 0.05). Single HD data (MCO) showed a relative reduction of 70% in kappa and 37% in lambda FLC concentration, as expected by the different sizes of the light chains. Renal function improved significantly and continuously from starting creatinine 5.7/3.8 mg/dl (MCO/HCO group) before HD to 1.4/2.0 mg/dl (MCO/HCO group; p < 0.001) after 1 year. No significant alteration of total protein, immunoglobulins, and LDH concentrations by HD (HCO and MCO group) was observed. After 1 year, 37 of 60 patients were alive and 34 of them were off dialysis. FLC elimination with MCO-HD is effective, technically easy, and less cost-intensive as compared with HCO-HD. Kidney function recovery in MM patients is achievable.

Ca-Zr co-doping enabled electrochemical reversibility of O3-type NaCrO2 for sodium-ion batteries with high-voltage characteristics

O3-type NaCrO2 has been researched as a promising cathode material for sodium-ion batteries (SIBs), however, it suffers from serious irreversible phase transitions when charged to 3.8 V, thereby resulting in a severe decline of reversible capacity. To improve the structural stability, small amounts of Ca2+ and Zr4+ ions are introduced into the O3-type NaCrO2 via a facile solid-state reaction in this work. In the voltage range of 1.5–3.8 V, O3-type Na0.94Ca0.03Cr0.97Zr0.03O2 delivers ∼ 120 mAh g−1 with a capacity retention of 64.6% after 500 cycles and a reversible capacity of 76 mAh g−1 at 20C, much better than those of O3-type NaCrO2. The improved performance of O3-type Na0.94Ca0.03Cr0.97Zr0.03O2 is attributed to the better structural reversibility and electrochemical reaction kinetics at the high charge cutoff voltage enabled by Ca and Zr co-doping. Our findings benefit the development of cathode materials with high energy density and high cycling stability for SIBs.

Wavelength scaling of high harmonic yields and cutoff energies in solids driven by mid-infrared pulses.

The effect of driving wavelengths on high harmonic generation (HHG) have long been a fundamental research topic. However, despite of abundant efforts, the investigation of wavelength scaling of HHG in solids is still confined within the scope of theoretical predictions. In this work, we for the first time to the best of our knowledge, experimentally reveal wavelength scaling of HHG yields and cutoff energy in three typical solid media (namely pristine crystals GaSe, CdTe and polycrystalline ZnSe), driven in a broad mid-infrared (MIR) range from 4.0 to 8.7 µm. It is revealed that when the driving wavelength is shorter than 6.5-7.0 µm, HHG yields decrease monotonously with the MIR driving wavelengths, while they rise abruptly by 1-3 orders of magnitude driven at longer wavelength and exhibit a crest at 7.5 µm. In addition, the cutoff energies are found independent on driving wavelengths across the broad MIR pump spectral range. We propose that the interband mechanism dominates the HHG process when the driving wavelength is shorter than 6.5-7.0 µm, and as the driving wavelength increases, intraband contribution leads to an abrupt rise of the HHG yields, which is verified by the HHG polarization measurement driven at 3.0 and 7.0 µm. This work not only experimentally demonstrate the wavelength scaling of HHG in solids, but more importantly blazes the trail for optimizing the HHG performance by choosing a driving wavelength and provides experimental method to distinguish the interband and intraband dynamics.

Modeling Improved Li-Ion Cell Capacity through Suppression of Temperature with Internal Electrolyte Flow

Lithium-ion cells are ubiquitous in portable electronic applications and are growing in popularity for electric vehicles including passenger cars. Yet, a dramatic reduction in global emissions to combat climate change calls for significantly broader adoption of carbon neutral technologies in electric vehicles and in stationary energy storage to complement variable renewable sources and growing electricity demand.1 For lithium-ion batteries, a critical barrier to such broader adoption is the inability to sustain high rate while also accessing the full capacity of cells. In addition to mass transport effects, overheating commonly limits the duration of high-rate discharge or charge due to excessive heat generation and inadequate heat removal.Here, we provide a brief illustrative tutorial of these coupled effects in a pseudo two-dimensional electrochemical model and build on our previous modeling and dimensional analyses2-4 of how internal electrolyte flow across Li-ion cells reduces both mass and thermal transport limitations.First, we describe the intentional and sudden onset of internal electrolyte convection to curb or to avert further temperature rise in a Li-ion cell during high-rate discharge. We examine two modes for introducing electrolyte flow: temperature-triggered (“reactive”) and discharge-rate triggered (“proactive”) modes. In the reactive case, flow is introduced in the simulation when a cell under high-rate discharge reaches a high safety cutoff temperature. In the proactive case, flow begins as the discharge rate is step changed from midrate to high rate. A practical application of proactive mode is that a battery thermal management system could be programmed to initiate electrolyte flow in anticipation of greater heat generation at a higher rate.Next, using the aforementioned continuum modeling with circulation through an external tank, we compare and contrast Li-ion cell thermal responses to the onset of flow in reactive mode versus in proactive mode. In both cases, the threshold flow rate (~μm/s) to suppress temperature rise agrees in order of magnitude with dimensionless group estimates reported in our previous work.4 Namely, temperature rise is suppressed when the heat generation rate becomes lower than the heat removal rate. At the highest electrolyte flow rates simulated (>>μm /s), the heat removal by internal electrolyte flow dominates, and the cell achieves nearly full discharge capacity without prematurely crossing temperature or voltage cutoffs. For low flow rates (<μm /s), the proactive and reactive cases show quantitatively different transient temperature trajectories due to the temperature dependences of heat generation and removal. Heat generation rate decreases with elevated cell temperature due to facile mass transfer and resultant concentration uniformity, optimal electrolyte conductivity, and ease of charge transfer kinetics. Also, heat removal using internal electrolyte flow becomes more effective with high cell temperature relative to ambient inlet temperature. Hence, the flow rate needed to cool a cell that has reached a high safety cutoff temperature (in reactive mode) is lower than the flow rate required to curb temperature rise in a cell just above ambient temperature (in proactive mode) as high-rate discharge starts.

Upcycling of Degraded LiCoO2 Cathodes into High‐Performance Lithium‐Ion Batteries via a Three‐In‐One Strategy

AbstractFaced with the forthcoming tide of retired lithium‐ion batteries (LIBs), it is imperative to explore effective regeneration and upcycling strategies to alleviate the resource shortage, address environmental pollution, and cater to the demand for high‐energy‐density cathode materials. Herein, a facile, non‐constructive, one‐stone‐for‐three‐birds solid‐phase sintering strategy is proposed to regenerate the degraded LiCoO2 (D‐LCO) cathode and even upgrade its stability at high voltages, in which three birds, i.e., lithium supplement, Li2SO4 coating, and Mn doping into Co sites while N, S doping into Li‐O slabs are simultaneously hit with one stone (one‐pot solid‐phase sintering). Benefiting from these favorable characteristics, the upcycled cathode not only yields high discharge‐specific capacity of 188.2 mAh g−1 at 0.2 C, but also delivers superior cycling performance with 92.5% of capacity retention after 100 cycles (86.4% after 300 cycles) at 0.5 C and excellent rate capability at a high cutoff voltage of 4.5 V, superior to a freshly commercial counterpart. This work is expected to provide meaningful guidance for the upcycling of D‐LCO into high‐energy‐density batteries with long‐term cycling stability.

High-harmonic generation in spin and charge current pumping at ferromagnetic or antiferromagnetic resonance in the presence of spin–orbit coupling

One of the cornerstone effects in spintronics is spin pumping by dynamical magnetization that is steadily precessing (around, for example, the z-axis) with frequency ω 0 due to absorption of low-power microwaves of frequency ω 0 under the resonance conditions and in the absence of any applied bias voltage. The two-decades-old ‘standard model’ of this effect, based on the scattering theory of adiabatic quantum pumping, predicts that component of spin current vector is time-independent while and oscillate harmonically in time with a single frequency ω 0 whereas pumped charge current is zero in the same adiabatic limit. Here we employ more general approaches than the ‘standard model’, namely the time-dependent nonequilibrium Green’s function (NEGF) and the Floquet NEGF, to predict unforeseen features of spin pumping: namely precessing localized magnetic moments within a ferromagnetic metal (FM) or antiferromagnetic metal (AFM), whose conduction electrons are exposed to spin–orbit coupling (SOC) of either intrinsic or proximity origin, will pump both spin and charge I(t) currents. All four of these functions harmonically oscillate in time at both even and odd integer multiples of the driving frequency ω 0. The cutoff order of such high harmonics increases with SOC strength, reaching in the one-dimensional FM or AFM models chosen for demonstration. A higher cutoff can be achieved in realistic two-dimensional (2D) FM models defined on a honeycomb lattice, and we provide a prescription of how to realize them using 2D magnets and their heterostructures.

Optically controlled n −Si/p −SeO2/p −SiO2 microwave resonators designed for 5G/6G communication technology

Herein n−Si/p−SiO2 interfaces comprising layers of p-SeO2 are employed as an optically controllable microwave resonators. The stacked layers of SeO2 (500 nm) and SiO2 (50 nm) were deposited onto type Si thin crystals by the thermal evaporation technique under a vacuum pressure of 10−5 mbar. Ytterbium and Au metals were coated onto SiO2 and Si layers, respectively, to form Schottky arms. Energy band diagram analyses were performed to confirm the formation of doubled conduction and valence band offsets. These offsets create energy barriers and potential wells that contribute to the bistable behavior. Photo-impedance spectroscopic measurements were conducted on the device under blue light, demonstrating its ability to function as a light-power tunable microwave resonator and MOS capacitor. In the absence of light, negative capacitance (NC) effects were observed above a driving frequency of 1.07 GHz. As the device was exposed to light and the light power increased, the frequency range of NC effects shifted to higher driving frequencies. Furthermore, the range of NC effects became narrower with increasing light power, indicating a more limited frequency range for the manifestation of negative capacitance. In addition, Si/SeO2/SiO2 microwaves resonators displayed high cutoff frequency exceeding 0.10 THz at driving frequency of 1.07 GHz in the dark. The driving frequency also shifted toward larger values as light power is increased indicating the ability to optically control the cutoff frequency range and value. The high response of the capacitance, conductance, cutoff frequency spectra and the dependence of capacitance–voltage characteristics on incident light power nominate the device as microwave resonators and MOS electro-optic devices suitable for 5G/6G communication technology.

Accurate classification of pulmonary nodules by a combined model of clinical, imaging, and cell-free DNA methylation biomarkers: a model development and external validation study

There is an unmet clinical need for accurate non-invasive tests to facilitate the early diagnosis of lung cancer. We propose a combined model of clinical, imaging, and cell-free DNA methylation biomarkers that aims to improve the classification of pulmonary nodules. We conducted a prospective specimen collection and retrospective masked evaluation study. We recruited participants with a solitary pulmonary nodule sized 5-30 mm from 24 hospitals across 20 cities in China. Participants who were aged 18 years or older and had been referred with 5-30 mm non-calcified and solitary pulmonary nodules, including solid nodules, part solid nodules, and pure ground-glass nodules, were included. We developed a combined clinical and imaging biomarkers (CIBM) model by machine learning for the classification of malignant and benign pulmonary nodules in a cohort (n=839) and validated it in two cohorts (n=258 in the first cohort and n=283 in the second cohort). We then integrated the CIBM model with our previously established circulating tumour DNA methylation model (PulmoSeek) to create a new combined model, PulmoSeek Plus (n=258), and verified it in an independent cohort (n=283). The clinical utility of the models was evaluated using decision curve analysis. A low cutoff (0·65) for high sensitivity and a high cutoff (0·89) for high specificity were applied simultaneously to stratify pulmonary nodules into low-risk, medium-risk, and high-risk groups. The primary outcome was the diagnostic performance of the CIBM, PulmoSeek, and PulmoSeek Plus models. Participants in this study were drawn from two prospective clinical studies that were registered (NCT03181490 and NCT03651986), the first of which was completed, and the second of which is ongoing because 25% of participants have not yet finished the required 3-year follow-up. We recruited a total of 1380 participants. 1097 participants were enrolled from July 7, 2017, to Feb 12, 2019; 839 participants were used for the CIBM model training set, and the rest (n=258) for the first CIBM validation set and the PulmoSeek Plus training set. 283 participants were enrolled from Oct 26, 2018, to March 20, 2020, as an independent validation set for the PulmoSeek Plus model and the second validation set for the CIBM model. The CIBM model validation cohorts had area under the curves (AUCs) of 0·85 (95% CI 0·80-0·89) and 0·85 (0·81-0·89). The PulmoSeek Plus model had better discrimination capacity compared with the CIBM and PulmoSeek models with an increase of 0·05 in AUC (PulmoSeek Plus vs CIBM, 95% CI 0·022-0·087, p=0·001; and PulmoSeek Plus vs PulmoSeek, 0·018-0·083, p=0·002). The overall sensitivity of the PulmoSeek Plus model was 0·98 (0·97-0·99) at a fixed specificity of 0·50 for ruling out lung cancer. A high sensitivity of 0·98 (0·96-0·99) was maintained in early-stage lung cancer (stages 0 and I) and 0·99 (0·96-1·00) in 5-10 mm nodules. The decision curve showed that if an invasive intervention, such as surgical resection or biopsy, was deemed necessary at more than the risk threshold score of 0·54, the PulmoSeek Plus model would provide a standardised net benefit of 82·38% (76·06-86·79%), equivalent to correctly identifying approximately 83 of 100 people with lung cancer. Using the PulmoSeek Plus model to classify pulmonary nodules with two cutoffs (0·65 and 0·89) would have reduced 89% (105/118) of unnecessary surgeries and 73% (308/423) of delayed treatments. The PulmoSeek Plus Model combining clinical, imaging, and cell-free DNA methylation biomarkers aids the early diagnosis of pulmonary nodules, with potential application in clinical decision making for the management of pulmonary nodules. The China National Science Foundation, the Key Project of Guangzhou Scientific Research Project, the High-Level University Construction Project of Guangzhou Medical University, the National Key Research & Development Programme, the Guangdong High Level Hospital Construction "Reaching Peak" Plan, the Guangdong Basic and Applied Basic Research Foundation, the National Natural Science Foundation of China, The Leading Projects of Guangzhou Municipal Health Sciences Foundation, the Key Research and Development Plan of Shaanxi Province of China, the Scheme of Guangzhou Economic and Technological Development District for Leading Talents in Innovation and Entrepreneurship, the Scheme of Guangzhou for Leading Talents in Innovation and Entrepreneurship, the Scheme of Guangzhou for Leading Team in Innovation, the Guangzhou Development Zone International Science and Technology Cooperation Project, and the Science and Technology Planning Project of Guangzhou.

Net reclassification index in comparison of prognostic value of disseminated intravascular coagulation diagnostic criteria by Japanese Society on Thrombosis and Hemostasis and International Society on Thrombosis and Haemostasis: a multicenter prospective cohort study

BackgroundWe compared the prognostic value of the Japanese Society on Thrombosis and Hemostasis (JSTH) disseminated intravascular coagulation (DIC) diagnostic criteria with that of the International Society on Thrombosis and Haemostasis (ISTH) DIC diagnostic criteria for 28-day in-hospital mortality.MethodsWe conducted a multicenter prospective cohort study involving two hematology departments, four emergency departments, and one general medicine department in Japan between August 2017 and July 2021. We assessed three ISTH DIC diagnostic criteria categories using low cutoff levels of D-dimer (low D-dimer), high cutoff levels of D-dimer (high D-dimer), and fibrinogen/fibrin degradation products (FDP) as fibrin-related markers. The main outcome was diagnosis-based category additive net reclassification index (NRI).ResultsA total of 222 patients were included: 82 with hematopoietic disorders, 86 with infections, and 54 with other diseases. The 28-day in-hospital mortality rate was 14% (n = 31). The DIC rates diagnosed by the JSTH, ISTH-low D-dimer, high D-dimer, and FDP DIC diagnosis were 52.7%, 47.3%, 42.8%, and 27.0%, respectively. The overall category additive NRI by JSTH DIC diagnosis vs. ISTH-low D-dimer, high D-dimer, and FDP DIC diagnosis were − 10 (95% confidence interval [CI]: −28 to 8, p = 0.282), − 7.8 (95% CI: −26 to 10, p = 0.401), and − 11 (95% CI: −26 to 3, p = 0.131), respectively.ConclusionsJSTH criterion showed the highest sensitivity for DIC diagnosis that did not improve but reflected the same prognostic value for mortality evaluated using ISTH DIC diagnosis criteria. This finding may help clinicians to use JSTH DIC criterion as an early intervention strategy in patients with coagulopathy.

Artificial intelligence (AI)-powered HER2 quantification continuous score (QCS) and tumor microenvironment (TME) analysis in HER2-amplified metastatic colorectal cancer (mCRC) treated with pertuzumab plus trastuzumab.

34 Background: Pertuzumab plus trastuzumab (per-/tra-) has shown clinical benefits in patients (pts) with HER2-amplified mCRC, but still there is an unmet need of biomarkers to optimize treatment decisions. In this study, we applied AI-powered whole-slide image (WSI) analyzers, to investigate the association of HER2 QCS and TME with clinical outcomes of per-/tra- in pts with HER2-amplified mCRC enrolled in TRIUMPH, a phase II study. Methods: TRIUMPH is a multicenter phase II study to evaluate the efficacy of per-/tra- in pts with mCRC with HER2 amplification confirmed by tumor tissue or circulating tumor DNA (ctDNA) analysis. HER2 immunohistochemistry (IHC) and H&amp;E-stained WSIs from 30 pts enrolled in TRIUMPH were included in the analysis. AI-powered WSI analyzers, Lunit SCOPE HER2 and Lunit SCOPE IO (Lunit, Republic of Korea) detects tumor cells (TC) by HER2 staining intensity (negative, 1+, 2+, or 3+) in HER2-WSI, and detects various class of cells including tumor-infiltrating lymphocytes (TIL), macrophages and fibroblasts in H&amp;E-WSI, respectively. Immune-excluded score (IES) was defined as the proportion of high stromal TIL but low intratumoral TIL area in all analyzable TME. Tumor response was measured by RECIST v1.1, and the primary endpoint was progression-free survival (PFS) assessed by the investigators. Results: All 30 tumor samples had proven HER2-amplification by either HER FISH or ctDNA analysis. The concordance rate between pathologists and AI to examine HER2 IHC was 86.7% (26/30), AI-powered HER2 QCS showed the proportion of HER2 3+ TC was widely distributed (median 73.9%; min-max 11.9%-98.9%) in the samples with HER2 3+ assessed by pathologists. Objective response rates (ORR) of per-/tra- in the whole set and a subgroup of HER2 IHC 3+ assessed by pathologists were 26.7% (8/30) and 34.8% (8/23), respectively. AI-powered HER2 QCS enabled enrichment of responders, as a subgroup of HER2 3+ QCS ≥ 50%, which is a higher cutoff than ASCO/CAP guideline (10%), had 42.1% (8/19) ORR, since all 8 responders harbored HER2 3+ QCS ≥ 50%. PFS and overall survival (OS) were significantly favorable in HER2 3+ QCS ≥ 50% group compared to &lt; 50% group (median PFS [mPFS] 4.4 vs 1.4 m, hazard ratio [HR] 0.12 [95% CI, 0.04-0.38], p = 0.0000994; median OS [mOS] 16.5 vs 4.1 m, HR 0.13 [95% CI, 0.05-0.38], p = 0.000117, respectively). Interestingly, IES and the densities of macrophages and fibroblasts within cancer stroma were correlated with poor response to per-/tra-. Among HER2 3+ QCS ≥ 50% group, 5 pts with high IES (≥ 54%), macrophage density (≥ 26.3/mm2), and fibroblast density (≥ 1790/mm2) had ORR 0%, mPFS 1.3 m, and mOS 4.5 m. Conclusions: AI-powered HER2 QCS and TME analysis may provide additional information to precisely predict per-/tra- response in HER2-positive mCRC.

Developing diagnostic criteria to differentiate fungal foot infections caused by Neoscytalidium dimidiatum and dermatophytes

BackgroundThe predisposing factors and clinical presentations of fungal foot infections caused by non-dermatophytes and dermatophytes are challenging to differentiate. Definite diagnoses of non-dermatophyte infections at first visits facilitate their treatment. ObjectivesThis study aimed to develop diagnostic criteria to differentiate fungal foot infections caused by Neoscytalidium dimidiatum and dermatophytes. MethodsDiagnostic prediction research based on a retrospective, observational, cross-sectional study. The reviewed patients were aged ≥18 and underwent a mycological examination for fungal foot infections. A fungal culture at the initial visit was the gold standard for determining causative organisms. ResultsAnalyses were carried out on the data from 371 patients. N. dimidiatum accounted for 184 (49.6%) infections, and dermatophytes caused the remaining 187 (50.4%) cases. Five significant predefined predictors were used to develop the diagnostic criteria and score. They were immunocompetence status, no family history of fungal infections, the absence of pruritus, the absence of other concurrent fungal skin infections, and agricultural work. The lower score cutoff was <8 (sensitivity 97.8% and specificity 25.7%). The higher cutoff was >11 (sensitivity 83.7% and specificity 57.8%). The score showed an area under the receiver operating characteristic curve of 0.755 and was well calibrated. ConclusionsThe criteria and score show promise for clinical use, with acceptable discriminative performance and good calibration. They will help physicians differentiate the causative organisms in patients with fungal foot infections at the first visit, enabling the determination of appropriate antifungal treatment.

Leptin Levels and Appetite Score in Patients on Hemodialysis Using High Flux or Medium Cutoff Membranes

Chronic kidney disease (CKD) patients on hemodialysis may have a modified appetite due to several factors including a lack of uremic toxins elimination. The use of medium cutoff (MCO) dialysis membranes has been suggested as an alternative to improve the removal of toxins, especially those of medium and high molecular weight. This study aimed to compare the effect of hemodialysis using MCO and high-flux membranes on the appetite and leptin levels of CKD patients. This is a predefined exploratory analysis of a randomized, open study, with a crossover design of 28weeks of follow-up, which compared the effects of MCO and high-flux membranes in 32 CKD patients on hemodialysis. Appetite assessments were performed using the Appetite and Food Satisfaction Questionnaire. The MCO group had an appetite score of 3.00 (1.00-5.50) and 3.00 (1.00-5.00) at the beginning and at the end of the treatment period, respectively, while the high-flux group had 1.00 (0.25-6.00) and 2.00 (0.75-3.25). There were no effects of treatment (P=.573), time (P=.376), and interaction (P=.770) between the MCO and high-flux groups. Leptin levels, at the beginning and at the end of the treatment period, were 2,342.30 (1,156.50-4,091.50) and 2,571.50 (1,619.40-4,036.47) pg/mL in the MCO group, respectively, and 2,183.15 (1,550.67-3,656.50) and 2,685.65 (1,458.20-3,981.08) pg/mL in the high-flux group. There was a time effect (P=.014), showing an increase in leptin levels in both groups, while treatment (P=.771) or interaction (P=.218) effects were not observed. There is no difference between the effects of MCO or high-flux membranes on leptin levels or appetite of CKD patients on hemodialysis.

Assessment of serum microRNA-21 and miRNA-205 as diagnostic markers for stage I and II breast cancer in Indian population.

Current markers (carcinoembryonic antigen [CEA] and carbohydrate antigen 15-3 [CA15-3]) lack sensitivity in diagnosis of breast cancer. The aberrantly expressed circulating miRNAs were shown as diagnostic markers in breast cancer. However, there are very few studies from the Indian population. We studied the diagnostic utility of miRNA-21, miRNA-155 and miRNA-205 compared to CEA and CA15-3 in stage I and II breast cancer patients. Sixty newly diagnosed women with stage I/II breast cancer and 20 healthy controls were recruited. Expression of circulating miRNAs was studied using reverse transcription-polymerase chain reaction, whereas CEA and CA 15-3 were analyzed by enzyme-linked immunosorbent assay. miRNA-21 and miRNA-155 were upregulated, miRNA-205 down-regulated ( P < 0.05) and serum CEA and CA15-3 levels increased in breast cancer patients ( P < 0.001). Receiver operating characteristic curve analysis showed significant area under curve (AUC) for all markers (0.656 to 0.993; P = 0.015 to <0.001) validating their diagnostic potential. Unlike CEA and CA15-3, miRNAs retained their sensitivity even at higher cut-offs (95% CI of mean). Logistic regression analysis showed significant association between disease and marker positivity for miRNA-21 and miRNA-205 but not for miRNA-155. Combining CA15-3 with miRNAs did not improve their diagnostic performance. However, combining CEA with either miRNA-21 (AUC = 0.742; P < 0.001 versus AUC = 0.656; P = 0.018) or miRNA-205 (AUC = 0.733; P < 0.001 versus AUC = 0.700; P < 0.001) increased its diagnostic performance. Our study shows miRNA-21 and miRNA-205, are useful as diagnostic markers for breast cancer in the Indian population and combination of these miRNAs with CEA but not with CA 15-3 improved their diagnostic performance.

The additive value of CA19.9 monitoring in a pancreatic cyst surveillance program.

Surveillance of pancreatic cysts focuses on the detection of (mostly morphologic) features warranting surgery. European guidelines consider elevated CA19.9 as a relative indication for surgery. We aimed to evaluate the role of CA19.9 monitoring for early detection and management in a cyst surveillance population. The PACYFIC-registry is a prospective collaboration that investigates the yield of pancreatic cyst surveillance performed at the discretion of the treating physician. We included participants for whom at least one serum CA19.9 value was determined by a minimum follow-up of 12months. Of 1865 PACYFIC participants, 685 met the inclusion criteria for this study (mean age 67years, SD 10; 61% female). During a median follow-up of 25months (IQR 24, 1966 visits), 29 participants developed high-grade dysplasia (HGD) or pancreatic cancer. At baseline, CA19.9 ranged from 1 to 591kU/L (median 10kU/L [IQR 14]), and was elevated (≥37kU/L) in 64 participants (9%). During 191 of 1966 visits (10%), an elevated CA19.9 was detected, and these visits more often led to an intensified follow-up (42%) than those without an elevated CA19.9 (27%; p<0.001). An elevated CA19.9 was the sole reason for surgery in five participants with benign disease (10%). The baseline CA19.9 value was (as continuous or dichotomous variable at the 37kU/L threshold) not independently associated with HGD or pancreatic cancer development, whilst a CA19.9 of≥133kU/L was (HR 3.8, 95% CI 1.1-13, p=0.03). In this pancreatic cyst surveillance cohort, CA19.9 monitoring caused substantial harm by shortening surveillance intervals (and performance of unnecessary surgery). The current CA19.9 cutoff was not predictive of HGD and pancreatic cancer, whereas a higher cutoff may decrease false-positive values. The role of CA19.9 monitoring should be critically appraised prior to implementation in surveillance programs and guidelines.

NOAC Therapy According to CHA2DS2-VASc Without Atrial Fibrillation: A Systematic Review.

According to Quality-Adjusted Life Expectancy, novel oral anticoagulant therapy is preferred when the stroke risk is higher than 0.9% per year. CHA2DS2-VASc is a tool to select those patients at high risk for stroke due to atherosclerosis and atrial cardiopathy, who could benefit from anticoagulation even in sinus rhythm. Systematic electronic database searches were conducted using Pubmed and Scopus. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses Statement 2020 was followed. Thirteen studies were included, comprising altogether 19,600,104 patients. Data show that the predictive accuracy for stroke of CHA2DS2-VASc among patients with and without atrial fibrillation (AF) is similar, but the benefit of anticoagulation, considering the 1-year risk of stroke for every CHA2DS2-VASc value, starts from higher cutoffs in patients without AF (around CHA2DS2-VASc 4). Atrial fibrillation should no longer be considered a sine qua non for the prevention of thromboembolism in patients at high risk of stroke due to atherosclerosis and atrial disease, but only an additional risk factor to be included in the predictive model used to select patients for novel oral anticoagulant therapy, regardless of the rhythm. CHA2DS2-VASc-AF may be an option. Additional randomized clinical trials are needed.