Factors associated with engraftment success of patient-derived xenografts of breast cancer.

BACKGROUND: Patient-derived xenograft (PDX) models serve as a valuable tool for the preclinical evaluation of novel therapies. They closely replicate the genetic, phenotypic, and histopathological characteristics of primary breast tumors. Despite their promise, the rate of successful PDX engraftment is various in the literature. This study aimed to identify the key factors associated with successful PDX engraftment of primary breast cancer. METHODS: We integrated clinicopathological data with morphological attributes quantified using a trained artificial intelligence (AI) model to identify the principal factors affecting PDX engraftment. RESULTS: Multivariate logistic regression analyses demonstrated that several factors, including a high Ki-67 labeling index (Ki-67LI) (p < 0.001), younger age at diagnosis (p = 0.032), post neoadjuvant chemotherapy (NAC) (p = 0.006), higher histologic grade (p = 0.039), larger tumor size (p = 0.029), and AI-assessed higher intratumoral necrosis (p = 0.027) and intratumoral invasive carcinoma (p = 0.040) proportions, were significant factors for successful PDX engraftment (area under the curve [AUC] 0.905). In the NAC group, a higher Ki-67LI (p < 0.001), lower Miller-Payne grade (p < 0.001), and reduced proportion of intratumoral normal breast glands as assessed by AI (p = 0.06) collectively provided excellent prediction accuracy for successful PDX engraftment (AUC 0.89). CONCLUSIONS: We found that high Ki-67LI, younger age, post-NAC status, higher histologic grade, larger tumor size, and specific morphological attributes were significant factors for predicting successful PDX engraftment of primary breast cancer.

Malignant potential of neuroendocrine microtumor of the pancreas harboring high-grade transformation: lesson learned from a patient with von Hippel-Lindau syndrome.

Pancreatic neuroendocrine microtumor (PNEMT) is a neuroendocrine tumor (NET) < 0.5 cm in diameter, and it is considered benign. We report a PNEMT with high-grade transformation (HGT). A man in his 60s with von Hippel-Lindau syndrome underwent surgical resection of a NET. A second sub-centimeter nodule with a nodule-in-nodule pattern was discovered. The 0.4 cm outer nodule contained clear columnar cells with round nuclei and indistinct nucleoli, while the 0.1 cm inner nodule had eosinophilic cells with an increased nuclear to cytoplasmic ratio, vesicular nuclei, and prominent nucleoli. Tumor cells in the outer and inner nodules were synaptophysin and chromogranin positive. Only the inner nodule was p53 positive, while the outer nodule was exclusively positive for carbonic anhydrase 9 and vimentin. The Ki-67 labeling indices for the outer and inner nodules were 2.1% (grade 1) and 44.3% (grade 3), respectively. This nodule was determined to be a PNEMT with HGT. Our findings suggest that a PNEMT may not always be benign and can undergo HGT.

Inhibition of Glial Activation and Subsequent Reduction in White Matter Damage through Supplementation with a Combined Extract of Wheat Bran, Citrus Peel, and Jujube in a Rat Model of Vascular Dementia.

Vascular dementia (VaD) is the second most common type of dementia after Alzheimer's disease. In our previous studies, we showed that wheat bran extract (WBE) reduced white matter damage in a rat VaD model and improved memory in a human clinical trial. However, starch gelatinization made the large-scale preparation of WBE difficult. To simplify the manufacturing process and increase efficacy, we attempted to find a decoction containing an optimum ratio of wheat bran, sliced citrus peel, and sliced jujube (WCJ). To find an optimal ratio, the cell survival of C6 (rat glioma) cultured under hypoxic conditions (1% O2) was measured, and apoptosis was assessed. To confirm the efficacies of the optimized WCJ for VaD, pupillary light reflex, white matter damage, and the activation of astrocytes and microglia were assessed in a rat model of bilateral common carotid artery occlusion (BCCAO) causing chronic hypoperfusion. Using a combination of both searching the literature and cell survival experiments, we chose 6:2:1 as the optimal ratio of wheat bran to sliced citrus peel to sliced jujube to prepare WCJ. We showed that phytic acid contained only in wheat bran can be used as an indicator component for the quality control of WCJ. We observed in vitro that the WCJ treatment improved cell survival by reducing apoptosis through an increase in the Bcl-2/Bax ratio. In the BCCAO experiments, the WCJ-supplemented diet prevented astrocytic and microglial activation, mitigated myelin damage in the corpus callosum and optic tract, and, consequently, improved pupillary light reflex at dosages over 100 mg/kg/day. The results suggest that the consumption of WCJ can prevent VaD by reducing white matter damage, and WCJ can be developed as a safe, herbal medicine to prevent VaD.

Pathophysiology and Treatment of Gout Arthritis; including Gout Arthritis of Hip Joint: A Literature Review.

Gout is triggered by the accumulation of uric acid in the body, leading to hyperuricemia. Genetic, metabolic, and environmental factors can influence this condition. Excessive uric acid buildup results in the formation of monosodium urate (MSU) crystals, which precipitate in specific areas of the body, including the joints, where they can cause symptoms of gout. While the acute and chronic symptoms of gout have been well-documented, diagnosis of gout affecting the hip joint poses significant challenges. The global incidence of gout, the most prevalent form of inflammatory arthritis, is on the rise. Evaluation of the clinical signs, laboratory results, and imaging results is generally required for diagnosis of gout in cases where MSU crystals have not been detected. Hyperuricemia is considered a primary cause of arthritis symptoms, and comprehensive guidelines for treatment are available. Therefore, the choice of medication is straightforward, and moderate effectiveness of treatment has been demonstrated. Gout is a chronic disease, requiring lifelong uric acid-lowering medications, thus application of a treatment strategy based on the target blood uric acid concentration is necessary. Consequently, cases of gout will likely be observed more frequently by hip surgeons in clinical scenarios in the future. The objective of this review is to provide an overview of the pathophysiology of gout and subsequently examine recent advances in diagnostic methods and therapeutic agents based on an understanding of its underlying mechanisms. In addition, literature on gout-related issues affecting the hip joint, providing a useful reference for hip surgeons is examined.

Intracellular calcium links milk stasis to lysosome-dependent cell death during early mammary gland involution.

Involution of the mammary gland after lactation is a dramatic example of coordinated cell death. Weaning causes distension of the alveolar structures due to the accumulation of milk, which, in turn, activates STAT3 and initiates a caspase-independent but lysosome-dependent cell death (LDCD) pathway. Although the importance of STAT3 and LDCD in early mammary involution is well established, it has not been entirely clear how milk stasis activates STAT3. In this report, we demonstrate that protein levels of the PMCA2 calcium pump are significantly downregulated within 2-4 h of experimental milk stasis. Reductions in PMCA2 expression correlate with an increase in cytoplasmic calcium in vivo as measured by multiphoton intravital imaging of GCaMP6f fluorescence. These events occur concomitant with the appearance of nuclear pSTAT3 expression but prior to significant activation of LDCD or its previously implicated mediators such as LIF, IL6, and TGFß3, all of which appear to be upregulated by increased intracellular calcium. We further demonstrate that increased intracellular calcium activates STAT3 by inducing degradation of its negative regulator, SOCS3. We also observed that milk stasis, loss of PMCA2 expression and increased intracellular calcium levels activate TFEB, an important regulator of lysosome biogenesis through a process involving inhibition of CDK4/6 and cell cycle progression. In summary, these data suggest that intracellular calcium serves as an important proximal biochemical signal linking milk stasis to STAT3 activation, increased lysosomal biogenesis, and lysosome-mediated cell death.

A fluorescent probe for selective detection of lysosomal ß-hexosaminidase in live cells.

Determining the activity of lysosomal ß-hexosaminidase in cells is of great importance for understanding the roles that these enzymes play in pathophysiological events. Herein, we designed the new fluorescent probe, ßGalNAc-Rhod-CM(NEt2), which consisted of a ßGalNAc-linked rhodol unit serving as a ß-hexosaminidase reactive fluorogenic moiety and a N,N'-diethylaminocoumarin (CM(NEt2)) group acting as a fluorescence marker for determining the degree of cell permeabilization. Treatment of ßGalNAc-Rhod-CM(NEt2) with ß-hexosaminidase promoted generation of Rhod-CM(NEt2), thereby leading to an increase in the intensity of fluorescence of Rhod. However, this probe did not respond to the functionally related glycosidase, O-GlcNAcase. The detection limit of ßGalNAc-Rhod-CM(NEt2) for ß-hexosaminidase was determined to be 0.52 nM, indicating that it has high sensitivity for this enzyme. Furthermore, the probe functioned as an excellent fluorogenic substrate for ß-hexosaminidase with kcat and Km values of 17 sec-1 and 22 µM, respectively. The results of cell studies using ßGalNAc-Rhod-CM(NEt2) showed that levels of ß-hexosaminidase activity in cells can be determined by measuring the intensity of fluorescence arising from Rhod and that the intensity of fluorescence of CM(NEt2) can be employed to determine the degree of cell permeabilization of the probe. Utilizing the new probe, we assessed ß-hexosaminidase activities in several types of cells and evaluated the effect of glucose concentrations in culture media on the activity of this enzyme.

Synthesis of Graphitic Carbon Coated ZnPS3 and its Superior Electrochemical Properties for Lithium and Sodium Ion Storage.

Graphitic carbon-coated ZnPS3 is prepared via direct phosphosulfurization and high energy mechanical milling (HEMM) with multiwall carbon nanotubes (MWCNTs) and first introduced as an anode for lithium-ion batteries (LIBs) and sodium-ion batteries (SIBs). The HEMM process with MWCNTs reduces the particle size of as-synthesized ZnPS3 bulk to 100-500 nm and yields the ≈5 nm thick graphitic carbon coated ZnPS3 nanoparticles, which are the nanocomposites of 5 nm sized nanocrystallites embedded in the amorphous matrix. The ZnPS3 electrode undergoes the combined conversion and alloying reactions with Li and Na ions and exhibits high initial discharge and charge capacities in both LIBs and SIBs. The graphitic carbon-coated ZnPS3 electrode exhibits excellent high-rate capability and long-term cyclability. The superior electrochemical properties can be attributed to high electrical conductivity, high Li ion mobility, and high reversibility and structural stability derived from the graphitic carbon-coated nanoparticles. This study demonstrates that the novel graphitic carbon-coated ZnPS3 is a promising anode material for both LIBs and SIBs and the graphitic carbon coating methodology by HEMM is expected to apply to the various metal oxides, sulfides, and phosphides.

Efficient Second-Harmonic Generation from Dielectric Inter-subband Polaritonic Metasurfaces Coupled to Lattice Resonance.

Nonlinear optical metasurfaces offer a possibility to perform frequency mixing without the phase-matching constraints of bulk nonlinear crystals and with control of the local nonlinear response at a sub-wavelength scale. Nonlinear inter-subband polaritonic metasurfaces created by combining the semiconductor heterostructures with quantum-engineered inter-subband nonlinear response and electromagnetically engineered metal-clad nanoresonators offer by far the largest second-order nonlinear response of all condensed matter systems reported to date. However, the nonlinear optical response of these metasurfaces is limited by optical intensity saturation in the nanoresonator hot spots that prevented the achievement of power conversion efficiencies over 0.2% in three-wave mixing experiments. In this study, we propose and experimentally demonstrate dielectric inter-subband polaritonic metasurfaces for second-harmonic generation that achieve 0.37% power conversion efficiency. Our structure is created by a new design approach that combines dielectric resonators inducing Mie resonant modes with a lattice resonance to achieve a uniform and high field enhancement throughout the meta-atom volume.

Structural and Functional Development of Inhibitory Connections from the Medial Nucleus of the Trapezoid Body to the Superior Paraolivary Nucleus.

The medial nucleus of the trapezoid body (MNTB) in the auditory brainstem is the principal source of synaptic inhibition to several functionally distinct auditory nuclei. Prominent projections of individual MNTB neurons comprise the major binaural nuclei that are involved in the early processing stages of sound localization as well as the superior paraolivary nucleus (SPON), which contains monaural neurons that extract rapid changes in sound intensity to detect sound gaps and rhythmic oscillations that commonly occur in animal calls and human speech. While the processes that guide the development and refinement of MNTB axon collaterals to the binaural nuclei have become increasingly understood, little is known about the development of MNTB collaterals to the monaural SPON. In this study, we investigated the development of MNTB-SPON connections in mice of both sexes from shortly after birth to three weeks of age, which encompasses the time before and after hearing onset. Individual axon reconstructions and electrophysiological analysis of MNTB-SPON connectivity demonstrate a dramatic increase in the number of MNTB axonal boutons in the SPON before hearing onset. However, this proliferation was not accompanied by changes in the strength of MNTB-SPON connections or by changes in the structural or functional topographic precision. However, following hearing onset, the spread of single-axon boutons along the tonotopic axis increased, indicating an unexpected decrease in the tonotopic precision of the MNTB-SPON pathway. These results provide new insight into the development and organization of inhibition to SPON neurons and the regulation of developmental plasticity in diverging inhibitory pathways.SIGNIFICANCE STATEMENT The superior paraolivary nucleus (SPON) is a prominent auditory brainstem nucleus involved in the early detection of sound gaps and rhythmic oscillations. The ability of SPON neurons to fire at the offset of sound depends on strong and precise synaptic inhibition provided by glycinergic neurons in the medial nucleus of the trapezoid body (MNTB). Here, we investigated the anatomic and physiological maturation of MNTB-LSO connectivity in mice before and after the onset of hearing. We observed a period of bouton proliferation without accompanying changes in topographic precision before hearing onset. This was followed by bouton elimination and an unexpected decrease in the tonotopic precision after hearing onset. These results provide new insight into the development of inhibition to the SPON.

Types and doses of anti-adhesive agents injected into subacromial space do not have an effect on the clinical and anatomical outcomes after arthroscopic rotator cuff repair.

PURPOSE: Joint stiffness after arthroscopic rotator cuff repair is a major concern for orthopaedic surgeons. Various antiadhesive agents are commonly administered after rotator cuff repair for its prevention. This study aimed to compare the outcomes among patients injected with different types and amounts of anti-adhesive agents after rotator cuff repair. It was hypothesized that the outcomes might differ depending on the use of the anti-adhesive agent and its type and dose. METHODS: A total of 267 patients who underwent arthroscopic rotator cuff repair with or without subacromial injection of anti-adhesive agents were enrolled. The first group (group A; 51 patients) were injected with 3 mL of poloxamer/sodium alginate-based anti-adhesive agent. The second group (group B; 93 patients) were injected with 3 mL of sodium hyaluronate-based anti-adhesive agent. The third group (group C; 82 patients) were injected with 1.5 mL of sodium hyaluronate-based anti-adhesive agent. Finally, the last group (group D; 41 patients) who did not use anti-adhesive agents served as the control. The range of motion (ROM) and pain VAS scores were measured preoperatively and at 5 weeks, 3 months, 6 months, and 1 year postoperatively. Functional outcomes were evaluated using American Shoulder and Elbow Surgeons and Constant scores, whereas cuff integrity was assessed via MRI or ultrasonography at least 6 months postoperatively. RESULTS: All ROM measurements, pain VAS scores, and functional scores were significantly improved regardless of the use, type, and dose of the anti-adhesive agents. In addition shoulder ROM and rotator cuff healing did not significantly differ among the groups (all n.s.). CONCLUSIONS: No significant differences were found in the clinical and anatomical outcomes according to the type and dose of the anti-adhesive agents subacromially injected after rotator cuff repair. LEVEL OF EVIDENCE: III.

Enhancing the reliability of particulate matter sensing by multivariate Tobit model using weather and air quality data.

Low-cost particulate matter (PM) sensors have been widely used following recent sensor-technology advancements; however, inherent limitations of low-cost monitors (LCMs), which operate based on light scattering without an air-conditioning function, still restrict their applicability. We propose a regional calibration of LCMs using a multivariate Tobit model with historical weather and air quality data to improve the accuracy of ambient air monitoring, which is highly dependent on meteorological conditions, local climate, and regional PM properties. Weather observations and PM2.5 (fine inhalable particles with diameters ≤ 2.5 µm) concentrations from two regions in Korea, Incheon and Jeju, and one in Singapore were used as training data to build a visibility-based calibration model. To validate the model, field measurements were conducted by an LCM in Jeju and Singapore, where R2 and the error after applying the model in Jeju improved (from 0.85 to 0.88) and reduced by 44% (from 8.4 to 4.7 µg m-3), respectively. The results demonstrated that regional calibration involving air temperature, relative humidity, and other local climate parameters can efficiently correct the bias of the sensor. Our findings suggest that the proposed post-processing using the Tobit model with regional weather and air quality data enhances the applicability of LCMs.

Intracellular Calcium links Milk Stasis to Lysosome Dependent Cell Death by Activating a TGFß3/TFEB/STAT3 Pathway Early during Mammary Gland Involution.

Involution of the mammary gland after lactation is a dramatic example of coordinated cell death. Weaning causes distension of the alveolar structures due to the accumulation of milk, which, in turn, activates STAT3 and initiates a caspase-independent but lysosome-dependent cell death (LDCD) pathway. Although the importance of STAT3 and LDCD in early mammary involution is well established, it has not been entirely clear how milk stasis activates STAT3. In this report, we demonstrate that protein levels of the PMCA2 calcium pump are significantly downregulated within 2-4 hours of experimental milk stasis. Reductions in PMCA2 expression correlate with an increase in cytoplasmic calcium in vivo as measured by multiphoton intravital imaging of GCaMP6f fluorescence. These events occur concomitant with the appearance of nuclear pSTAT3 expression but prior to significant activation of LDCD or its previously implicated mediators such as LIF, IL6 and TGFß3, all of which appear to be upregulated by increased intracellular calcium. We also observed that milk stasis, loss of PMCA2 expression and increased intracellular calcium levels activate TFEB, an important regulator of lysosome biogenesis. This is the result of increased TGFß signaling and inhibition of cell cycle progression. Finally, we demonstrate that increased intracellular calcium activates STAT3 by inducing degradation of its negative regulator, SOCS3, a process which also appears to be mediated by TGFß signaling. In summary, these data suggest that intracellular calcium serves as an important proximal biochemical signal linking milk stasis to STAT3 activation, increased lysosomal biogenesis, and lysosome-mediated cell death.

Linear conductance update improvement of CMOS-compatible second-order memristors for fast and energy-efficient training of a neural network using a memristor crossbar array.

Memristors are two-terminal memory devices that can change the conductance state and store analog values. Thanks to their simple structure, suitability for high-density integration, and non-volatile characteristics, memristors have been intensively studied as synapses in artificial neural network systems. Memristive synapses in neural networks have theoretically better energy efficiency compared with conventional von Neumann computing processors. However, memristor crossbar array-based neural networks usually suffer from low accuracy because of the non-ideal factors of memristors such as non-linearity and asymmetry, which prevent weights from being programmed to their targeted values. In this article, the improvement in linearity and symmetry of pulse update of a fully CMOS-compatible HfO2-based memristor is discussed, by using a second-order memristor effect with a heating pulse and a voltage divider composed of a series resistor and two diodes. We also demonstrate that the improved device characteristics enable energy-efficient and fast training of a memristor crossbar array-based neural network with high accuracy through a realistic model-based simulation. By improving the memristor device's linearity and symmetry, our results open up the possibility of a trainable memristor crossbar array-based neural network system that possesses great energy efficiency, high area efficiency, and high accuracy at the same time.

Prognostic implications of HER2 changes after neoadjuvant chemotherapy in patients with HER2-zero and HER2-low breast cancer.

BACKGROUND: The transition of human epidermal growth factor receptor 2 (HER2) status after neoadjuvant chemotherapy (NAC) in HER2-low breast cancer has not been thoroughly evaluated. Here, we evaluated the HER2 transition among HER2-zero and HER2-low breast cancer cases post-NAC and its impact on clinical outcomes. METHODS: We included 1288 patients with HER2-low or zero breast cancer who underwent NAC and surgery between 2014 and 2018 and had paired pre- and post-therapeutic HER2 status results. RESULTS: Among patients who were HER2-zero pre-NAC (n = 650), 68% and 29% were HER2-zero and HER2-low, respectively, post-NAC. Among patients who were HER2-low pre-NAC (n = 638), 32% of patients showed HER2 changes (low to zero), and 59% of patients had a constant HER2-low status post-NAC. Patients with constant HER2-low or transitions from HER2-low to zero had a higher proportion of hormone receptor positivity (84% and 79%) than those with changes from HER2-zero to low (77%) or with constant HER2-zero (56%), respectively. Multivariable logistic regression analysis revealed that patients with oestrogen receptor positivity had a higher probability of gaining HER2-low expression than those with oestrogen receptor negativity (odds ratio 2.48). No significant differences were observed in terms of overall survival or disease-free survival between patients with and without HER2-changes according to their hormone receptor status, except in the post-therapeutic HER2-low, hormone receptor-negativity subset. CONCLUSION: Temporal heterogeneity of HER2-low expression is observed in substantial numbers of post-NAC breast cancer patients. Clinical outcomes show no significant associations, except in the post-therapeutic HER2-low, hormone receptor negativity subset. The prognostic implications of HER2 transition in HER2-low breast cancer require further investigation.

The Potency of Abamectin Formulations against the Pine Wood Nematode, Bursaphelenchus xylophilus.

Abamectin offers great protection against Bursaphelenchus xylophilus, a well-known devastating pathogen of pine tree stands. Trunk injection of nematicides is currently the most preferred method of control. This study aimed to evaluate the potency of the commonly used formulations of abamectin against B. xylophilus. Twenty-one formulations of abamectin were evaluated by comparing their sublethal toxicities and reproduction inhibition potentials against B. xylophilus. Nematodes were treated with diluted formulation concentrations in multi-well culture plates. And, populations pre-exposed to pre-determined concentrations of the formulations were inoculated onto Botrytis cinerea culture, and in pine twig cuttings. Potency was contrastingly different among formulations, with LC95 of 0.00285 and 0.39462 mg/ml for the most, and the least potent formulation, respectively. Paralysis generally occurred at an application dose of 0.06 µg/ml or higher, and formulations with high sublethal toxicities caused significant paralysis levels at the tested doses, albeit the variations. Nematode reproduction was evident at lower doses of 0.00053-0.0006 µg/ml both on Botrytis cinerea and pine twigs, with significant variations among formulations. Thus, the study highlighted the inconsistencies in the potency of similar product formulations with the same active ingredient concentration against the target organism, and the need to analyze the potential antagonistic effects of the additives used in formulations.

Exploring the Cutting-Edge Frontiers of Electrochemical Random Access Memories (ECRAMs) for Neuromorphic Computing: Revolutionary Advances in Material-to-Device Engineering.

Advanced materials and device engineering has played a crucial role in improving the performance of electrochemical random access memory (ECRAM) devices. ECRAM technology has been identified as a promising candidate for implementing artificial synapses in neuromorphic computing systems due to its ability to store analog values and its ease of programmability. ECRAM devices consist of an electrolyte and a channel material sandwiched between two electrodes, and the performance of these devices depends on the properties of the materials used. This review provides a comprehensive overview of material engineering strategies to optimize the electrolyte and channel materials' ionic conductivity, stability, and ionic diffusivity to improve the performance and reliability of ECRAM devices. Device engineering and scaling strategies are further discussed to enhance ECRAM performance. Last, perspectives on the current challenges and future directions in developing ECRAM-based artificial synapses in neuromorphic computing systems are provided.

Genomic analysis of plasma circulating tumor DNA in patients with heavily pretreated HER2 + metastatic breast cancer.

We explored accumulated genomic alterations in patients with heavily treated HER2 + metastatic breast cancer enrolled in the KCSG BR18-14/KM10B trial. Targeted sequencing was performed with circulating tumor DNAs (ctDNAs) collected before the treatment of 92 patients. ctDNAs collected at the time of disease progression from seven patients who had a durable response for > 12 months were also analyzed. Sixty-five genes were identified as pathogenic alterations in 99 samples. The most frequently altered genes were TP53 (n = 48), PIKCA (n = 21) and ERBB3 (n = 19). TP53 and PIK3CA mutations were significantly related with shorter progression free survival (PFS), and patients with a higher ctDNA fraction showed a worse PFS. The frequency of homologous recombination deficiency (HRD)-related gene mutations was higher than that in matched tumor tissues, and these mutations tended to be associated with shorter PFS. New pathogenic variants were found at the end of treatment in all seven patients, including BRCA2, VHL, RAD50, RB1, BRIP1, ATM, FANCA, and PIK3CA mutations. In conclusion, TP53 and PIK3CA mutations, as well as a higher ctDNA fraction, were associated with worse PFS with trastuzumab and cytotoxic chemotherapy. The enrichment of HRD-related gene mutations and newly detected variants in ctDNA may be related to resistance to treatment.

Cataract Surgery in the Medicare Merit-Based Incentive Payment System: Episode-Based Cost Measure Development and Evaluation.

Objective: To characterize the development and performance of a cataract surgery episode-based cost measure for the Medicare Quality Payment Program. Design: Claims-based analysis. Participants: Medicare clinicians with cataract surgery claims between June 1, 2016, and May 31, 2017. Methods: We limited the analysis to claims with procedure code 66984 (routine cataract surgery), excluding cases with relevant ocular comorbidities. We divided episodes into subgroups by surgery location (Ambulatory Surgery Center [ASC] or Hospital Outpatient Department [HOPD]) and laterality (bilateral when surgeries were within 30 days apart). For the episode-based cost measure, we calculated costs occurring between 60 days before surgery and 90 days after surgery, limited to services identified by an expert committee as related to cataract surgery and under the influence of the cataract surgeon. We attributed costs to the clinician submitting the cataract surgery claim, categorized costs into clinical themes, and calculated episode cost distribution, reliability in detecting clinician-dependent cost variation, and costs with versus without complications. We compared episode-based cost scores with hypothetical "nonselective" cost scores (total Medicare beneficiary costs between 60 days before surgery and 90 days after surgery). Main Outcome Measures: Episode costs with and without complications, clinician-dependent variation (proportion of total cost variance), and proportion of costs from cataract surgery-related clinical themes. Results: We identified 583 356 cataract surgery episodes attributed to 10 790 clinicians and 8189 with ≥ 10 episodes during the measurement period. Most surgeries were performed in an ASC (71%) and unilateral (66%). The mean episode cost was $2876. The HOPD surgeries had higher costs; geography and episodes per clinician did not substantially affect costs. The proportion of cost variation from clinician-dependent factors was higher in episode-based compared with nonselective cost measures (94% vs. 39%), and cataract surgery-related clinical themes represented a higher proportion of total costs for episode-based measures. Episodes with complications had higher costs than episodes without complications ($3738 vs. $2276). Conclusions: The cataract surgery episode-based cost measure performs better than a comparable nonselective measure based on cost distribution, clinician-dependent variance, association with cataract surgery-related clinical themes, and quality alignment (higher costs in episodes with complications). Cost measure maintenance and refinement will be important to maintain clinical validity and reliability. Financial Disclosures: Proprietary or commercial disclosure may be found after the references.

Electrical Phase Modulation Based on Mid-Infrared Intersubband Polaritonic Metasurfaces.

Electrically reconfigurable metasurfaces that overcome the static limitations in controlling the fundamental properties of scattered light are opening new avenues for functional flat optics. This work proposes and experimentally demonstrates electrically phase-tunable mid-infrared metasurfaces based on the polaritonic coupling of Stark-tunable intersubband transitions in semiconductor heterostructures and electromagnetic modes in plasmonic nanoresonators. In the applied voltage range of -3 to +3 V, the local phase tuning of the light reflects from the metasurface, which enables the electrical control of the polarization state and wavefront of the reflected wave. Electrical beam polarization control, electrical beam diffraction control, and electrical beam steering are experimentally demonstrated as applications for local phase tunability. The proposed electrically tunable metasurfaces can easily tune the operating wavelength and function at relatively low voltages, which will enable various applications in the mid-infrared region.

ELK3-CXCL16 axis determines natural killer cell cytotoxicity via the chemotactic activity of CXCL16 in triple negative breast cancer.

Triple-negative breast cancer (TNBC) is the most challenging subtype of breast cancer because of its aggressive behavior and the limited therapeutic strategies available. In the last decade, immunotherapy has become a promising treatment to prolong survival in advanced solid cancers including TNBC. However, the efficacy of immunotherapy in solid cancers remains limited because solid tumors contain few tumor-infiltrating lymphocytes. Here, we show that targeting an ETS transcription factor ELK3 (ELK3) recruits immune cells including natural killer (NK) cells into tumors via the chemotactic activity of chemokine. ELK3 depletion increases CXCL16 expression level and promotes NK cell cytotoxicity through CXCL16-mediated NK cell recruitment in TNBC. In silico analysis showed that ELK3 is negatively correlated with CXCL16 expression in breast cancer patient samples. Low expression of ELK3 and high expression of CXCL16 were associated with a better prognosis. Low expression of ELK3 and high expression of CXCL16 were associated with increased expression of NK cell-related genes. Our findings demonstrate that the ELK3-CXCL16 axis modulates NK cell recruitment to increase NK cell cytotoxicity, suggesting that targeting the ELK3 gene could be an adjuvant strategy for increasing the efficacy of immunotherapy in TNBC.