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We developed and experimentally realized a scheme of optical nonreciprocity (ONR) by using degenerate two-level atoms embedded in an optical ring cavity. For the degenerate transition F g = 4 ↔ F e = 3, we first studied the cavity-transmission property in different coupling field configurations and verified that under the strong-coupling regime, the single-dark-state peak formed by electromagnetically induced transparency (EIT) showed ONR. The stable ground-state Zeeman coherence for Λ-chains involved in the degenerate two-level system was found to be important in the formation of intracavity EIT. However, different from the three-level atom-cavity system, in the degenerate two-level system, the ONR effect based on intracavity EIT occurred only at a low probe intensity, because the cavity-atom coupling strength was weakened in the counter-propagating probe and coupling field configuration. Furthermore, ONR transmission with a high contrast and linewidth-narrowing was experimentally demonstrated.

Smart electromagnetic interference (EMI) shielding materials are of great significance in coping with the dynamic performance demands of cutting-edge electronic devices. However, smart EMI shielding materials are still in their infancy and face a variety of challenges (e.g., large thickness, limited tunable range, poor reversibility, and unclear mechanisms). Here, we report a method for controllable shielding electromagnetic (EM) waves through subwavelength structure changes regulated by the customized structure via a direct printing route. The highly conductive MXene ink is regulated with metal ions (Al 3+ ions), giving superb metallic conductivity (∼5000 S cm -1 ) for the printed lines without an annealing treatment. The reversible tunability of EMI shielding effectiveness (SE) ranging from 8.2 dB ("off" state) to 34 dB ("on" state) is realized through the controllable modulation of subwavelength structure driven by stress. This work provides a feasible strategy to develop intelligent shielding materials and EM devices.

There are substantial disease and health-related quality-of-life (HRQoL) burdens for many patients with myasthenia gravis (MG), especially for those whose disease symptoms are not well controlled. HRQoL measures such as the Myasthenia Gravis Quality of Life 15-item revised (MG-QOL15r) and EuroQoL 5-Dimensions 5-Levels (EQ-5D-5L) are vital for evaluating the clinical benefit of therapeutic interventions in patients with MG, as they assess the burden of disease and the effectiveness of treatment, as perceived by patients. The phase 3 ADAPT study (NCT03669588) demonstrated that efgartigimod-a novel neonatal Fc receptor inhibitor-was well tolerated and that acetylcholine receptor antibody-positive (AChR-Ab+) participants who received efgartigimod had statistically significant improvements in MG-specific clinical scale scores. The ancillary data reported here, which cover an additional treatment cycle, show that these participants had similar significant improvements in HRQoL measures, the MG-QOL15r and EQ-5D-5L utility and visual analog scales, and that these improvements were maintained in the second treatment cycle. Positive effects on HRQoL were rapid, seen as early as the first week of treatment in both treatment cycles, and maintained for up to 4 weeks in the follow-up-only portion of treatment cycles. The pattern of improvements in HRQoL paralleled changes in immunoglobulin G level, and correlational analyses show that improvements were consistent across HRQoL measures and with clinical efficacy measures in the ADAPT study. The substantial and durable improvements in HRQoL end points in this study demonstrate the broader benefit of treatment with efgartigimod beyond relief of immediate signs and symptoms of gMG., (© 2023. The Author(s).)

Introduction: For patients with generalized myasthenia gravis (gMG), the association between symptom severity, often measured with the Myasthenia Gravis Activities of Daily Living (MG-ADL) instrument, and utility values is unknown., Methods: Data was analyzed from the phase 3 ADAPT trial, which included adult patients with gMG randomly assigned to treatment with efgartigimod + conventional therapy (EFG + CT) or placebo + CT (PBO + CT). MG-ADL total symptom scores and the EQ-5D-5L, a measure of health-related quality of life (HRQoL), were collected biweekly up to 26 weeks. Utility values were derived from the EQ-5D-5L data with the United Kingdom value set. Descriptive statistics were reported for MG-ADL and EQ-5D-5L at baseline and follow-up. A normal identity-link regression model estimated the association between utility and the eight MG-ADL items. A generalized estimating equations (GEE) model was estimated to predict utility based on the patient's MG-ADL score and treatment received., Results: A total of 167 patients (84 EFG + CT, 83 PBO + CT) contributed 167 baseline and 2867 follow-up measurements of MG-ADL and EQ-5D-5L. EFG + CT-treated patients experienced more improvements than PBO + CT-treated patients in most MG-ADL items and EQ-5D-5L dimensions, with the largest improvements observed in chewing, brushing teeth/combing hair, eyelid droop (MG-ADL); self-care, usual activities, mobility (EQ-5D-5L). The regression model indicated that individual MG-ADL items contributed differently to utility values, with the largest impact from brushing teeth/combing hair, rising from a chair, chewing, and breathing. The GEE model showed that each unit improvement in MG-ADL led to a statistically significant utility increase of 0.0233 (p < 0.001). In addition, a statistically significant improvement of 0.0598 (p = 0.0079) in utility was found for patients in the EFG + CT group compared to the PBO + CT group., Conclusion: Among patients with gMG, improvements in MG-ADL were significantly associated with higher utility values. MG-ADL scores alone were not sufficient to capture the utility gained from efgartigimod therapy., (© 2023. The Author(s).)

Pathologic complete response (pCR) following neoadjuvant therapy has been associated with improved event-free survival (EFS) and overall survival (OS) in early-stage breast cancer. The magnitude of this association varies by breast cancer subtype, yet further research focusing on subtype-specific populations is limited. Here we provide an updated and comprehensive evaluation of the association between pCR and survival outcomes in triple-negative breast cancer (TNBC). A literature review identified neoadjuvant studies, including clinical trials, real-world cohort studies, and studies that pooled multiple trials or cohorts, which reported EFS/OS results by pCR in patients with early-stage TNBC. Meta-analyses were performed to evaluate the association between pCR and EFS/OS and to predict long-term survival outcomes based on pCR status. Sensitivity analyses were conducted to assess the impact of cross-study variations. Twenty-five studies with over 4,000 patients with TNBC were identified. A synthesis of evidence from these studies suggested substantial improvement in EFS and OS for pCR versus non-pCR [EFS HR (95% confidence interval): 0.24 (0.20-0.29); OS: 0.19 (0.15-0.24)]; consistent results were reported in sensitivity analyses. Collectively, our findings suggest that adjuvant therapy is associated with improved EFS/OS in patients with TNBC who received neoadjuvant therapy, regardless of pCR status., (©2020 American Association for Cancer Research.)

Purpose: To investigate the changes of plasma 25(OH)D levels in type 2 diabetes mellitus (T2DM) patients and explore its role in the dysfunction of glucose and lipid metabolism and cognition., Methods: One hundred and thirty-two T2DM patients were enrolled and the demographic and clinical data were collected. The plasma concentration of 25(OH)D was detected and the patients were divided into two groups including a Vitamin D insufficient (VDI) group and a normal VD group according to the clinical diagnostic criterial of VDI with the plasma 25(OH)D level less than 29 ng/mL. The glycolipid metabolic and routine blood biochemical indices were detected, the plasma concentrations of C-reactive protein (CRP), interleukin-6 (IL-6), soluble myeloid soluble trigger receptor 1 (sTREM1) were measured. The cognitive function was assessed using the Behavior Rating Inventory of Executive Function-Adult Version (BRIEF-A). The depressive symptomatology was assessed using the Center for Epidemiological Survey Depression Scale (CES-D). Sleep quality was assessed using the Pittsburgh sleep quality index (PSQI)., Results: There were 70 T2DM patients with VDI (70/132, 53.03%) in this study. The plasma concentrations of glycated hemoglobin (HbA1c), fasting plasma glucose (FPG), postprandial blood glucose (PBG), IL-6, and sTREM1 were remarkably increased in T2DM patients with VDI as compared with that with the normal VD, accompanied with an elevated BRIEF-A scores. There was no significant difference between groups with regard to the indices of blood lipid, liver function, and scores in CES-D and PSQI. Moreover, results of Pearson correlation test showed that the plasma 25(OH)D levels were negatively correlated with HbA1c, FPG, PBG, CRP, IL-6, sTREM1, CES-D sum scores, and PSQI sum scores, but positively correlated with the plasma levels of Serum creatinine (Scr). Furthermore, result of Receiver Operating Characteristic (ROC) curve analysis showed a predictive role of VDI levels in discriminating T2DM patients with higher cognitive impairments, with the sensitivity and specificity being 62.12% and 62.12%, respectively., Conclusion: VDI is harmful for T2DM patients with a significant relation with the hyperglycosemia and cognitive dysfunction., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Sun, Yu, Gao, Wei, Qi, Ma, Xu, Xu and Ge.)

Objective: To evaluate real-world utilization patterns of intravenous immunoglobulin (IVIg) among patients with generalized myasthenia gravis (gMG) over 3 years post-IVIg initiation., Methods: Patients with gMG who initiated IVIg treatment were identified from a United States claims database (Symphony Health's Integrated Dataverse [IDV]®, January 1, 2014 - December 31, 2019). The frequency of subsequent IVIg treatment and associated cost during the year post-IVIg initiation were analyzed. Usage patterns of IVIg and concomitant gMG treatments during the year preceding and 3 years post-IVIg initiation were compared., Results: Among 1225 patients with gMG who initiated IVIg treatment, 706 patients (57.6%) received 1 to 5 IVIg treatment courses (intermittent IVIg users), and 519 patients (42.4%) received ≥6 IVIg treatment courses (chronic IVIg users) within the subsequent year. Mean annual medical cost per patient was nearly 2.5-fold higher for chronic vs. intermittent IVIg users ($161,478 vs. $64,888, p < 0.001). The proportion of patients using corticosteroids and nonsteroidal immunosuppressive treatments (NSISTs) was not reduced over the 3-year follow-up period following IVIg initiation, even for patients who continued annual chronic IVIg for 3 consecutive years post-initiation., Conclusions: Nearly half of patients with gMG received chronic and multiple IVIg treatment courses within the first year once initiating IVIg treatment, indicating higher usage than expected. For all IVIg initiators, the proportion of patients using corticosteroids and NSISTs did not decrease over 3 years despite IVIg initiation., (Copyright © 2022. Published by Elsevier B.V.)

Introduction: To examine the prevalence rates of biosimilar discontinuation and switchback to the originator tumor necrosis factor alpha (TNF) inhibitors following non-medical switch (NMS) in patients., Methods: Real-world studies reporting biosimilar discontinuation and switchback rates following NMS published between January 2012 and August 2018 were identified through a systematic literature review. A meta-analysis estimated the annualized discontinuation and switchback rates. A subsequent meta-analysis assessed annualized incremental discontinuation rate among studies reporting both discontinuation rates in patients who underwent an NMS (switchers) and patients who remained on originators (non-switchers)., Results: A total of 66 publications were identified: 31 in gastroenterology, 32 in rheumatology, and 3 in both. Half of the studies reported switchback rates; only 9 studies reported discontinuation rates for both switchers and non-switchers. Across studies, the mean/range sample size of the NMS patient population was 136/9-1641; mean/range follow-up was 10/3-24 months. Annualized biosimilar discontinuation rate was 21% (95% confidence interval [CI] 18%, 25%). Switchback rate was 14% (95% CI 10%, 17%) among all NMS patients and 62% (95% CI 44%, 80%) among discontinuers. The mean/range sample size of switchers and non-switchers was 344/89-1621 and 768/19-2870, respectively; mean/range follow-up was 11/6-18 and 12/6-8 months, respectively. Annualized incremental biosimilar discontinuation rate was 18% (95% CI 4%, 31%)., Conclusion: Biosimilar discontinuation was found to be prevalent among patients who underwent an NMS from an originator TNF inhibitor to its biosimilar(s) in the real world. In addition, switchback to the originator TNF inhibitors was common following biosimilar discontinuation. Careful consideration is necessary when switching patients already on an originator TNF inhibitor to its biosimilar(s). Main limitations included the heterogeneity of the studies and the limited comparability of the data., (© 2022. This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.)

The treat-to-target strategy, which defines clinical remission as the primary therapeutic goal for rheumatoid arthritis (RA), is a widely recommended treatment approach in clinical guidelines. Achieving remission has been associated with improved clinical outcomes, quality of life, and productivity. These benefits are likely to translate to reduced economic burden in terms of lower healthcare costs and resource utilization. As such, a literature review was conducted to better understand the economic value of remission. Despite the large heterogeneity found in RA-related economic outcomes across studies, patients in remission consistently had lower direct medical and indirect costs, less healthcare resource utilization, and greater productivity compared to those without remission. Remission was associated with 19-52% savings in direct medical costs and 37-75% savings in indirect costs. The economic value of remission should thus be considered in economic analyses of RA therapies to inform treatment and reimbursement decisions., (© 2021. The Author(s).)

BACKGROUND: Patients with relapsed or refractory (R/R) acute myeloid leukemia (AML) and confirmed feline McDonough sarcoma (FMS)-like tyrosine kinase 3 gene mutations ( FLT3 mut+ ) have a poor prognosis and limited effective treatment options. Gilteritinib is the first targeted therapy approved in the United States and Europe for R/R FLT3 mut+ AML with significantly improved efficacy compared with existing treatments. OBJECTIVE: To evaluate gilteritinib against salvage chemotherapy (SC) and best supportive care (BSC) over a lifetime horizon among adult patients with R/R FLT3 mut+ AML from a US third-party payer's perspective. METHODS: The model structure of this cost-effectiveness analysis included a decision tree to stratify patients based on their hematopoietic stem cell transplantation (HSCT) status, followed by 2 separate 3-state partitioned survival models to predict the long-term health status conditional on HSCT status. The ADMIRAL trial data and literature were used to predict probabilities of patients being in different health states until a conservative cure point at year 3. Afterwards, living patients followed the survival outcomes of long-term survivors with AML. Model inputs for utilities, medical resource use, and costs were based on the ADMIRAL trial, published literature, and public sources. All costs were inflated to 2019 US dollars (USD). Total incremental costs (in 2019 USD), life-years (LYs), quality-adjusted LYs (QALYs), and incremental cost-effectiveness ratios (ICERs) were calculated. Deterministic sensitivity analyses and probabilistic sensitivity analyses were performed. RESULTS: This work was supported by Astellas Pharma, Inc., which was involved in all stages of the research and manuscript development. Garnham, Pandya, and Shah are employees of Astellas and hold stock/stock options. Zeidan consulted and received personal fees/honoraria and research funding from Astellas. Zeidan also has received research funding from Celgene/BMS, Abbvie, Astex, Pfizer, Medimmune/AstraZeneca, Boehringer-Ingelheim, Trovagene/Cardiff Oncology, Incyte, Takeda, Novartis, Amgen, Aprea, and ADC Therapeutics; has participated in advisory boards; has consulted with and/or received honoraria from AbbVie, Otsuka, Pfizer, Celgene/BMS, Jazz, Incyte, Agios, Boehringer-Ingelheim, Novartis, Acceleron, Daiichi Sankyo, Taiho, Seattle Genetics, BeyondSpring, Cardiff Oncology, Takeda, Ionis, Amgen, Janssen, Syndax, Gilead, Kura, Aprea, Lox Oncology, Genentech, Servier, Jasper, Tyme, and Epizyme; has served on clinical trial committees for Novartis, Abbvie, Geron, Gilead, Kura, Lox Oncology, BioCryst, and Celgene/BMS; and has received travel support for meetings from Pfizer, Novartis, and Cardiff Oncology. Qi and Yang are employees of Analysis Group, Inc., which received consulting fees from Astellas for work on this study. Part of this material was presented at the American Society of Hematology (ASH) Annual Meeting; December 7-10, 2019; Orlando, FL.CONCLUSIONS: Gilteritinib is a cost-effective novel treatment for patients with R/R FLT3 mut+ AML in the United States. DISCLOSURES: This work was supported by Astellas Pharma, Inc., which was involved in all stages of the research and manuscript development. Garnham, Pandya, and Shah are employees of Astellas and hold stock/stock options. Zeidan consulted and received personal fees/honoraria and research funding from Astellas. Zeidan also has received research funding from Celgene/BMS, Abbvie, Astex, Pfizer, Medimmune/AstraZeneca, Boehringer-Ingelheim, Trovagene/Cardiff Oncology, Incyte, Takeda, Novartis, Amgen, Aprea, and ADC Therapeutics; has participated in advisory boards; has consulted with and/or received honoraria from AbbVie, Otsuka, Pfizer, Celgene/BMS, Jazz, Incyte, Agios, Boehringer-Ingelheim, Novartis, Acceleron, Daiichi Sankyo, Taiho, Seattle Genetics, BeyondSpring, Cardiff Oncology, Takeda, Ionis, Amgen, Janssen, Syndax, Gilead, Kura, Aprea, Lox Oncology, Genentech, Servier, Jasper, Tyme, and Epizyme; has served on clinical trial committees for Novartis, Abbvie, Geron, Gilead, Kura, Lox Oncology, BioCryst, and Celgene/BMS; and has received travel support for meetings from Pfizer, Novartis, and Cardiff Oncology. Qi and Yang are employees of Analysis Group, Inc., which received consulting fees from Astellas for work on this study. Part of this material was presented at the American Society of Hematology (ASH) Annual Meeting; December 7-10, 2019; Orlando, FL.

Purpose: To assess the cost-effectiveness and cost-effective price of tisagenlecleucel, a novel, effective chimeric antigen receptor T-cell therapy, versus salvage chemotherapy (SC) for the treatment of relapsed or refractory diffuse large B-cell lymphoma (r/r DLBCL) using a willingness-to-pay (WTP) threshold of $150,000 per quality-adjusted life year (QALY) gained from a US third-party payer's perspective., Methods: A three-state (progression-free survival, progressive disease, and death), responder-based partitioned survival model with a lifetime horizon and 3% annual discount rate was developed. Overall survival (OS) and progression-free survival of tisagenlecleucel were estimated separately for patients with and without an overall response (OR), using data from JULIET ( Study of Efficacy and Safety of CTL019 in Adult DLBCL Patients). OS of SC was informed by SCHOLAR-1 (Retrospective Non-Hodgkin Lymphoma Research). Mixture cure models were used to inform the survival of tisagenlecleucel responders, supported by JULIET. The median OS was 11.1 months in all tisagenlecleucel-treated patients but not reached for responders; no progression or death occurred among responders since month 22 of treatment. For tisagenlecleucel nonresponders and SC, survival was based on standard parametric models until month 60and the survival of DLBCL long-term survivors thereafter. The model prediction validated well against the observed trial data. Costs and utilities were from the literature; utilities depended on health states and were used to estimate QALYs. Total costs, QALYs, and incremental cost per QALY gained were estimated. A cost-effective price range was estimated for all tisagenlecleucel-treated patients, OR responders, and complete response (CR) responders. Deterministic sensitivity and scenario analyses and a probabilistic sensitivity analysis were performed. All costs were reported in or inflated to 2020 US dollars., Findings: Tisagenlecleucel was associated with 3.35 QALYs gained versus SC.,The estimated incremental costs per QALY gained versus SC were $78,652 using the wholesale acquisition cost of $373,000 for tisagenlecleucel. The estimated cost-effective price of tisagenlecleucel in all treated patients was $612,270 at the WTP threshold of $150,000. Tisagenlecleucel OR and CR responders had an increase of 7.82 and 9.34 QALYs versus SC, with cost-effective prices estimated at $1,281,456 and $1,551,974, respectively. Sensitivity analysis results supported the base case findings., Implications: Tisagenlecleucel is a cost-effective treatment versus SC for r/r DLBCL from the perspective of a US third-party payer. The estimated cost-effective prices ranged from $612,270 (all tisagenlecleucel-treated patients) to up to $1.5 million (patients achieving CR). Limitations include the use of single-arm trials due to data availability., (Copyright © 2021 Elsevier Inc. All rights reserved.)

There are limited treatment options and substantial unmet needs for adult patients with relapsed or refractory diffuse large B cell lymphoma (r/r DLBCL) in Japan. In 2019, tisagenlecleucel, a CD19-directed chimeric antigen receptor T cell therapy, was approved for r/r DLBCL in Japan. The efficacy and safety of tisagenlecleucel were demonstrated in the pivotal phase II single-arm JULIET trial. The objective of the current study was to assess the cost-effectiveness of tisagenlecleucel treatment strategy versus current standard of care (salvage chemotherapy treatment strategy) for the treatment of patients with r/r DLBCL in Japan. A three-state partitioned survival model was constructed from a Japanese public healthcare payer's perspective, with the following three health states: progression-free survival, progressive/relapsed disease, and death. Because the tisagenlecleucel arm included patients who did or did not receive the infusion, a decision-tree structure was used to partition patients based on their infusion status. Treatment efficacy and costs were based on tisagenlecleucel-infused patients for those who received the infusion; for non-infused patients, they were based on standard salvage chemotherapy. The efficacy inputs for tisagenlecleucel-infused patients and salvage chemotherapy were based on observed data in the JULIET trial and the international SCHOLAR-1 meta-analysis, respectively, before year 3. Afterward, all patients were assumed to have no further progression and to incur the mortality risk of long-term DLBCL survivors. The base case analysis explored a lifetime horizon (44 years), with costs and effectiveness discounted 2.0% annually, and it used a monthly model cycle. Direct costs were considered in the base case, composed of pretreatment costs, treatment costs, adverse events management costs, follow-up costs before progression, subsequent SCT costs, post-progression costs, and terminal care costs. Total incremental costs, life years (LYs), and quality-adjusted life years (QALYs) were compared for tisagenlecleucel versus salvage chemotherapy. The incremental cost-effectiveness ratio (ICER) was estimated as the costs per QALY gained, and a threshold of ¥7.5 million was used to assess whether tisagenlecleucel is cost effective. Deterministic and probabilistic sensitivity analyses were performed. The total LYs (discounted) for tisagenlecleucel and salvage chemotherapy were 7.24 and 4.35 years, respectively; the corresponding QALYs were 5.42 and 2.57 years, respectively. The discounted incremental LYs and QALYs comparing tisagenlecleucel to salvage chemotherapy were estimated as 2.89 and 2.85 years, respectively. Over a lifetime horizon, the model estimated that tisagenlecleucel had a total incremental cost of ¥15,590,335 (discounted) versus salvage chemotherapy. Tisagenlecleucel was associated with an ICER of ¥5,476,496 per QALY gained compared to salvage chemotherapy. Extensive sensitivity analyses supported the base-case findings. Tisagenlecleucel is a cost-effective treatment strategy for r/r DLBCL compared to salvage chemotherapy treatment strategy from a Japanese public healthcare payer's perspective., (Copyright © 2021 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Until recently, treatment options were relatively limited for children and young adults with relapsed or refractory (r/r) acute lymphoblastic leukemia (ALL). Tisagenlecleucel is a chimeric antigen receptor T cell (CAR-T) immunotherapy with promising efficacy and manageable safety that was approved in Japan in 2019 for the treatment of CD19-positive r/r B cell ALL (B-ALL). However, there is no publication assessing the cost-effectiveness of CAR-T in Japan. The objective of this study was to assess the cost-effectiveness of a tisagenlecleucel treatment strategy compared to a blinatumomab treatment strategy and a clofarabine combination treatment strategy (i.e., clofarabine + cyclophosphamide + etoposide) in Japan for pediatric and young adult patients up to 25 years of age with r/r B-ALL. A partitioned survival model with a lifetime horizon and monthly cycle was constructed from a Japanese public healthcare payer's perspective. Patients were distributed across the following partitioned health states: event-free survival (EFS), progressive disease, and death, which were informed by the EFS and overall survival (OS) data of respective clinical trials before year 5. For the tisagenlecleucel arm, a decision-tree structure was used to partition patients based on the infusion status; those who discontinued prior to receiving infusion were assigned efficacy and cost inputs of blinatumomab and those who received infusion were assigned efficacy and costs inputs based on tisagenlecleucel-infused patients. As trial data for blinatumomab and clofarabine ended before year 5, matching-adjusted indirect comparisons were used to extrapolate OS between the end of trial observation and up to year 5. All surviving patients followed the mortality risk of long-term ALL survivors without additional risk of disease relapse after year 5, regardless of initial treatment strategies. The model accounted for pretreatment costs, treatment costs, adverse event costs, follow-up costs, subsequent allogeneic hematopoietic stem cell transplantation costs, and terminal care costs. Incremental cost-effectiveness ratios (ICERs) per life-years (LYs) gained and ICERs per quality-adjusted life-years (QALYs) gained were evaluated using a 2% discount rate, and a threshold of ¥7.5 million was used to assess cost-effectiveness. Deterministic and probabilistic sensitivity analyses were performed. The total LYs (discounted) for tisagenlecleucel, blinatumomab, and clofarabine combination treatment strategies were 13.3, 4.0, and 2.7 years, respectively; the corresponding QALYs were 11.6, 3.1, and 2.1 years, respectively. The ICERs per QALY gained for tisagenlecleucel were ¥2,035,071 versus blinatumomab and ¥2,644,702 versus clofarabine combination therapy. Extensive sensitivity analyses supported the findings. Tisagenlecleucel is a cost-effective treatment strategy for pediatric and young adult patients with r/r B-ALL from a Japanese public healthcare payer's perspective., (Copyright © 2021 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Aims: To estimate the economic impact of the introduction of gilteritinib for the treatment of relapsed/refractory (R/R) FLT3 mutation-positive ( FLT3 mut+ ) acute myeloid leukemia (AML) from a US payer's perspective., Methods: A budget impact model (BIM) was developed to evaluate the 3-year total budgetary impact of treating adults with R/R FLT3 mut+ AML eligible for gilteritinib in a hypothetical US health plan. Total costs (drugs/administration, hospitalization, monitoring, adverse events, transfusions, subsequent hematopoietic stem cell transplantation, post-progression, and FLT3 testing) were estimated before and after gilteritinib entry. The budget impact was the total cost difference between the two scenarios. The target population size and cost inputs were based on public data or published literature, drug market share was informed by market research data, and the model included recommended treatments for R/R FLT3 mut+ AML per clinical guidelines. Deterministic sensitivity analyses (DSAs) and scenario analyses varying key model inputs and assumptions were conducted to test for robustness., Results: In a hypothetical health plan with 1 million members, 20.9 adults with R/R FLT3 mut+ AML were estimated to be eligible for gilteritinib. Of these, it was assumed 30.0% would be treated with gilteritinib in Year 1 following gilteritinib entry, increasing the total plan budget by $663,795 and the per-member-per-month (PMPM) cost by $0.055. In Years 2-3, the market share of gilteritinib increased to 45.0%, increasing the total plan budget impact by $1,078,371 and $1,087,230, and the PMPM cost by $0.090 and $0.091, respectively. The model results remained robust in DSAs and scenario analyses, with the largest impact observed when the projected uptake of gilteritinib was changed., Limitations: The results of this BIM are contingent upon the model's assumptions and inputs., Conclusions: Adding gilteritinib to the formulary for the treatment of adults with R/R FLT3 mut+ AML had a minimal budget impact from a US payer's perspective.

Aims: This study estimated the total costs associated with tisagenlecleucel treatment in adult patients with relapsed/refractory (r/r) diffuse large B-cell lymphoma (DLBCL) based on the JULIET trial from a United States hospital's perspective. Methods: An economic model was developed to assess the total costs associated with tisagenlecleucel treatment (from leukapheresis to two months post-infusion) in adults (aged ≥18 years) with r/r DLBCL using a fee-for-service approach. Costs were considered during the pre-treatment, tisagenlecleucel infusion, and follow-up periods, and were estimated based on the health resource utilization and safety data from the JULIET trial. Cost components included leukapheresis, lymphodepleting chemotherapy, tisagenlecleucel infusion/administration, inpatient and intensive care unit (ICU) admission, medical professional visits, lab tests/procedures, and management of adverse events (AEs). The base-case model estimated the total costs using observed hospitalization, ICU, and AE data from JULIET, while scenario analyses varied key assumptions related to AEs and hospitalization. Results: The estimated overall cost associated with tisagenlecleucel treatment from leukapheresis to two months post-infusion was $437,927/patient, of which $64,784 (14.8%) was additional to tisagenlecleucel's list price ($373,000) and the associated administration cost ($143). The top three key drivers of the additional cost were AE management ($30,594; 47.2%), inpatient/ICU not attributed to AEs ($24,285; 37.5%), and lab tests/procedures ($5,443; 8.4%). In the scenario analyses, total costs ranged from $382,702 (no AEs, no hospitalization) to $469,006 (cytokine release syndrome and B-cell aplasia, hospitalization). Limitations : This analysis was limited to two months of follow-up after tisagenlecleucel infusion, which cannot capture long-term safety outcomes associated with the treatment and may underestimate AE costs. Conclusions: The total cost of tisagenlecleucel administration from leukapheresis to two months was estimated at $437,927. In addition to tisagenlecleucel's price, the main drivers were AE management costs and inpatient/ICU costs. Future studies based on real-world, long-term use of tisagenlecleucel are warranted.

Background: Tisagenlecleucel was approved for the treatment of pediatric and young adult patients with relapsed/refractory (r/r) B-cell acute lymphoblastic leukemia (ALL) based on the pivotal ELIANA trial., Objective: To comprehensively evaluate the total costs associated with tisagenlecleucel treatment, including costs from pre- to postinfusion periods of tisagenlecleucel in addition to the cost of tisagenlecleucel., Methods: An economic model was developed to estimate total costs associated with tisagenlecleucel treatment from the time of leukapheresis to 2 months postinfusion from a U.S. hospital's perspective. Costs were estimated based on resource use and safety management from the ELIANA trial and were considered during the pretreatment, tisagenlecleucel infusion, and follow-up periods of treatment. Cost components included leukapheresis, lymphodepleting chemotherapy, tisagenlecleucel infusion and hospital administration, inpatient and intensive care unit admissions, medical professional visits, laboratory tests and procedures, and management of major adverse events. Scenario analyses were conducted by varying key assumptions related to adverse events and hospitalization., Results: The total cost associated with tisagenlecleucel treatment among pediatric and young adult patients with r/r ALL was estimated to be $612,779, of which $137,636 (22.5%) was in addition to the list price of tisagenlecleucel ($475,000) and the associated administration cost of $143.08. The top 3 drivers of the additional cost were adverse event management ($70,968; 51.6%), inpatient and intensive care unit admissions not attributed to adverse events ($57,952; 42.1%), and laboratory tests and procedures ($5,209; 3.8%). The costs incurred during the pretreatment, infusion, and follow-up periods were $29,002, $476,659, and $107,118, respectively. In the scenario analyses, the total costs ranged from $483,169 (tisagenlecleucel treatment in the outpatient setting without adverse events) to $672,373 (tisagenlecleucel treatment in the inpatient setting with grade 3/4 cytokine release syndrome and B-cell aplasia)., Conclusions: In this economic model, tisagenlecleucel treatment among pediatric and young adult patients with r/r ALL was estimated to cost $612,779. The cost of care in addition to the price of tisagenlecleucel accounted for 22.5% of the total, with adverse event management and inpatient and intensive care unit admissions being main drivers. Further studies are warranted to assess the cost of tisagenlecleucel treatment in the context of current standards of care in real-world clinical practice., Disclosures: This study was supported by Novartis. The study sponsor was involved in several aspects of the research, including the study design, the interpretation of data, the writing of the manuscript, and the decision to submit the manuscript for publication. Hao is an employee of Novartis and has stock/stock options. Yang, Chai, Qi, and Wu are employees of Analysis Group, which received consulting fees from Novartis for work on this study. Part of the material in this manuscript was presented at the American Society of Hematology Annual Meeting held December 7-10, 2019, in Orlando, FL.

Background: Pathologic complete response (pCR) is a common efficacy endpoint in neoadjuvant therapy trials for triple-negative breast cancer (TNBC). Previous studies have shown that pCR is strongly associated with improved long-term survival outcomes, including event-free survival (EFS) and overall survival (OS). However, the trial-level associations between treatment effect on pCR and long-term survival outcomes are not well established. This study sought to evaluate these associations by incorporating more recent clinical trials in TNBC., Methods: A literature review identified published randomized controlled trials (RCTs) of neoadjuvant therapy for TNBC that reported results for both pCR and EFS/OS. Meta-regression models were performed to evaluate the association of treatment effect on pCR and EFS/OS. Sensitivity analyses were conducted to assess the impact of divergent study designs., Results: Ten comparisons from 8 RCTs (N=2,478 patients) were identified from the literature review. The log (odds ratio) of pCR was a significant predictor of the log (hazard ratio) of EFS (P=.003), with a coefficient of determination of 0.68 (95% CI, 0.41-0.95). There was a weaker association between pCR and OS (P=.18), with a coefficient of determination of 0.24 (95% CI, 0.01-0.77). Consistent results were found in the exploratory analysis and sensitivity analyses., Conclusions: This is the first study that has shown a trial-level association between pCR and survival outcomes in TNBC. By incorporating the most up-to-date RCTs, this study showed a significant trial-level association between pCR and EFS. A positive association between pCR and OS was also recorded.

Introduction: Janus kinase (JAK) inhibitors are a class of targeted therapies for rheumatoid arthritis (RA) with established clinical efficacy. However, little is known about their efficacy compared with each other. This network meta-analysis (NMA) estimated the comparative efficacy of JAK inhibitors currently approved for RA., Methods: A targeted literature review was conducted for phase III randomized controlled trials (RCTs) evaluating the efficacy of three approved JAK inhibitors (tofacitinib, baricitinib, and upadacitinib) as monotherapy or combination therapy among patients with moderate-to-severe RA who had inadequate response to conventional synthetic disease-modifying antirheumatic drugs (csDMARD-IR). Using Bayesian NMA, American College of Rheumatology (ACR) 20/50/70 responses and clinical remission (defined as DAS28-CRP < 2.6) were evaluated separately at 12 and 24 weeks., Results: Eleven RCTs were identified and included in the NMA. All JAK inhibitors demonstrated significantly better efficacy than csDMARD. Among combination therapies, upadacitinib 15 mg had the highest 12-week ACR50 responses (median [95% credible interval]: 43.4% [33.4%, 54.5%]), followed by tofacitinib 5 mg (38.7% [28.6%, 49.8%]), baricitinib 2 mg (37.1% [25.0%, 50.6%]), and baricitinib 4 mg (36.7%, [27.2%, 47.0%]). Similar results were observed for ACR20/70 and at week 24. Upadacitinib 15 mg + csDMARD was also found to have the highest clinical remission rates at week 12 (29.8% [16.9%, 47.0%]), followed by tofacitinib 5 mg (24.3%, [12.7%, 40.2%]), baricitinib 4 mg (22.8%, [11.8%, 37.5%]), and baricitinib 2 mg (20.1%, [8.6%, 37.4%]). Similar results were seen at week 24. Among monotherapies, upadacitinib had a higher ACR50 response (38.5% [25.3%, 53.2%]) than tofacitinib (30.4% [18.3%, 45.5%]). The differences in efficacy measures were not statistically significant between the JAK inhibitors., Conclusions: The NMA found that upadacitinib 15 mg once daily had numerically higher efficacy in terms of ACR response and clinical remission among approved JAK combination therapies and monotherapies for csDMARD-IR patients with RA.

Solid acids have been widely used as heterogeneous catalysts in developing green and sustainable chemistry. However, it remains a challenge to improve the mass transport properties and acid strength of solid acids simultaneously. Herein, we report a class of two dimensional (2D) layered hybrid solid acids with outstanding mass transfer and extremely high acid strength by incorporating sulfonated polymers in-between montmorillonite layers. The 2D layered structure and broad distribution of pore sizes allow for highly efficient mass transport of substrate molecules into and out of the solid acids. The acid strength of these solid acids was found to be stronger than that of 100% H 2 SO 4 , H 3 PW 12 O 40 and any other reported solid acids to date, as determined by 1 H and 31 P solid-state NMR. These 2D solid acids show extraordinary catalytic performance in biomass conversion to fuels, superior to that of H 3 PW 12 O 40 , HCl and H 2 SO 4 . Theoretical calculations and control experiments reveal that H-bond based interactions between the polymer and montmorillonite facilitate the unusually high acid strengths found in these samples.

Oxaziridine-based redox sulfur imidation provides a breakthrough strategy for selective modification at methionine in proteins. The chemoselectivity of imidization (N-transfer) over oxidation (O-transfer) of the thioether functionality of methionine, and the modification selectivity of methionine over other amino acids, are the key features of this strategy. To elucidate the detailed reaction mechanism and the origin of the reported chemoselectivity, a theoretical investigation on the oxaziridine-based methionine modification reaction is reported. It is found that both the N-transfer and O-transfer pathways occur in a concerted mechanism. Distortion/interaction-activation strain model analysis indicates that the N-transfer chemoselectivity is mainly controlled by the interaction energy. Orbital and charge analysis further supports that the interaction energy resulting from the orbital interaction favors the N-transfer pathway at the early stage of the reaction. The calculated reactivity of eight potential amino acid competitors with the oxaziridine shows excellent selectivity for methionine modification, consistent with the experimental observations. The scarcity of active species in neutral aqueous solution leads to the weak reactivity of tyrosine, lysine, and arginine. The stronger charge-transfer interactions between methionine and the oxaziridine compared with that for the other amino acids also play vital roles in the modification selectivity.

People with cognitive deficits or executive dysfunction are often overweight or obese. Several human neuroimaging studies have found that executive function (EF) predicts food intake and weight gain; however, fewer studies have investigated the relationship between EF and weight loss. The Stroop task is a classic measure of EF that is used in many neuroimaging studies. In the present work, functional near infrared spectroscopy (fNIRS) data were collected during performance of the Stroop task from a sample of overweight or obese adolescents and young adults (n=31) who participated in a summer fitness and weight loss camp. We assessed the Stroop effect by interference in the reaction time (RT) to visual challenges, and by alterations in levels of oxygenated hemoglobin, as detected by fNIRS. In line with previous studies, we found that the Stroop effect was successfully induced by different visual task conditions among obese/overweight individuals. Moreover, our results reveal that better Stroop task performance is correlated with greater weight loss over a4-weekfitness intervention. Indeed, behavioral data demonstrated that reduced RT interference predicted a greater percentage of weight loss. Moreover, overweight/obese individuals with a greater hemodynamic response in the left ventrolateral and bilateral dorsolateral prefrontal cortex due to the Stroop effect lost more weight during the short-term fitness intervention than participants with lower levels of activation of these neural regions. Overall, our results support a role for prefrontal cortex-mediated EF in influencing food intake and weight loss outcomes in a population of a previously unstudied age., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Density functional theory calculations have been carried out to study the mechanism of the gold-catalyzed highly selective hydroamination of alkylidenecyclopropanes. Two main mechanisms (i.e., double-bond activation-first and three-membered-ring activation-first mechanisms) have been examined. The double-bond activation-first mechanism results in the alkene hydroamination product, and it mainly consists of three steps: C-N bond formation, C-C bond rotation, and protodeauration (rate-determining step). Meanwhile, the three-membered-ring activation-first mechanism finally produces allylic amines, and it occurs via the ring-opening (rate-determining step), C-N bond formation, and protodeauration steps. The calculation results show good agreement with the experimental outcomes on the chemo-, regio-, and diastereoselectivity. On this basis, we found that the regioselectivity is caused by the C-C bond rotation step, while the diastereoselectivity is determined by both the C-C bond rotation and the protodeauration steps in the double-bond activation-first mechanism.

Characters, which are man-made symbols composed of strokes arranged in a certain structure, could provide semantic information and play an indispensable role in our daily life. In this paper, we try to make use of the intrinsic characteristics of characters and explore the stroke and structure-based methods for character recognition. First, we introduce two existing part-based models to recognize characters by detecting the elastic strokelike parts. In order to utilize strokes of various scales, we propose to learn the discriminative multi-scale stroke detector-based representation (DMSDR) for characters. However, the part-based models and DMSDR need to manually label the parts or key points for training. In order to learn the discriminative stroke detectors automatically, we further propose the discriminative spatiality embedded dictionary learning-based representation (DSEDR) for character recognition. We make a comparative study of the performance of the tree-structured model (TSM), mixtures-of-parts TSM, DMSDR, and DSEDR for character recognition on three challenging scene character recognition (SCR) data sets as well as two handwritten digits recognition data sets. A series of experiments is done on these data sets with various experimental setup. The experimental results demonstrate the suitability of stroke detector-based models for recognizing characters with deformations and distortions, especially in the case of limited training samples.

Introduction: The objective of the study was to assess the cost-effectiveness of EVE+EXE versus endocrine monotherapies in the treatment of postmenopausal women with HR(+), HER2(-) ABC after failure of treatment with nonsteroidal aromatase inhibitors from a US third-party payer perspective., Materials and Methods: A Markov model was developed to evaluate the costs and effectiveness associated with EVE+EXE, exemestane (EXE), fulvestrant (FUL), and tamoxifen (TAM) over a 10-year time horizon. The model included 3 health states: responsive/stable disease, progression, or death. Monthly transition probabilities were estimated based on the BOLERO-2 (Breast cancer trials of OraL EveROlimus-2) data and network meta-analyses. Costs included drug acquisition and administration costs, medical costs associated health states, and costs for managing adverse events (AEs). Utilities for each health state and disutilities for AEs were derived from the literature. Incremental costs per quality-adjusted life year (QALY) were estimated by comparing EVE+EXE with each endocrine monotherapy. One-way and probabilistic sensitivity analyses were performed., Results: In the base case, EVE+EXE was associated with 1.99 QALYs and total direct costs of $258,648 over 10 years. The incremental cost per QALY of EVE+EXE was $139,740 compared with EXE, $157,749 compared with FUL, and $115,624 compared with TAM. At a willingness-to-pay threshold of $130,000/QALY or above, EVE+EXE appeared to be the most cost-effective treatment among all drugs., Conclusions: Everolimus with EXE demonstrated QALY improvements compared with 3 other endocrine monotherapies. Benchmarked by the economic value of other novel cancer therapies, EVE+EXE might be considered a cost-effective option compared with endocrine therapies for HR(+)/HER2(-) ABC., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Biological motion perception is an essential part of the cognitive process. Stress can affect the cognitive process. The present study explored the intrinsic ERP features of the effects of acute psychological stress on biological motion perception. The results contributed scientific evidence for the adaptive behavior changes under acute stress. After a mental arithmetic task was used to induce stress, the paradigm of point-light displays was used to evaluate biological motion perception. Longer reaction time and lower accuracy were found in the inverted walking condition than in the upright walking condition, which was called the "inversion effect". The P2 peak amplitude and the LPP mean amplitude were significantly higher in the local inverted perception than in the local upright walking condition. Compared to the control condition, the stress condition induced lower RT, shorter P1 peak latency of biological motion perception, lower P2 peak amplitude and LPP mean amplitude, and higher N330 peak amplitude. There was an "inversion effect" in biological motion perception. This effect was related to the structural characteristics of biological motion perception but unrelated to the state of acute psychological stress. Acute psychological stress accelerated the reaction time and enhanced attention control of biological motion perception. Attention resources were used earlier, and less attentional investment was made in the early stage of biological motion perception processing. In the late stage, a continuous weakening of inhibition was shown in the parieto-occipital area. [ABSTRACT FROM AUTHOR]

As a sport conducted in dynamically changing natural environments, orienteering places high demands on athletes' cognitive processing abilities and visual search efficiency. However, previous studies on orienteering have been primarily limited by the use of fixed stimulus materials on computer screens, which are unable to fully simulate authentic sports scenarios. To better understand the sports expertise of orienteering athletes in terms of their real scene image recognition performance and visual search characteristics, this study recruited 40 orienteering athletes, both experts and novices, as participants. By utilizing eye-tracking technology and setting observation points in real-world scenarios to conduct image recognition task tests, the ecological validity of the experiment was further enhanced. The results showed that the experts demonstrated a high level of accuracy and a short response time, with visual search characteristics including few saccade counts, low fixation frequency, concentrated fixation points, simple and clear fixation paths, and higher visual search efficiency. This study further reveals that long-term specialized training will lead to the formation of a unique cognitive structure related to the specific knowledge and long-term memory required by expert orienteering athletes, thereby promoting the development of expert advantage. [ABSTRACT FROM AUTHOR]

Background/Aim: The aim of the study was to investigate whether it is possible to evaluate the axilla after treatment without performing sentinel lymph node biopsy (SLNB) in breast cancer patients with biopsy-proven axillary lymph node metastases who received neoadjuvant chemotherapy (NAC). Patients and Methods: This prospective, randomized, clinically designed study included patients with clinical T1-3 and biopsy-proven N1 breast cancer. Prior to the surgery scheduled after NAC, the patients were randomized into two groups. A biopsy sample was obtained from the clipped axillary lymph node, which was preoperatively known to be metastatic, using fine needle aspiration (FNAB) in the first group and core needle biopsy (CNB) in the second group. The predictive ability of the two biopsy methods for the SLNB results was evaluated. Results: The study included 50 female patients with breast cancer, with a mean age of 48.4±10.72 years. In both groups, metastasis was detected in nine patients, and no metastasis was seen in 14 patients. In intergroup comparisons, all patients with metastasis in the FNAB group also had metastasis according to SLNB, while 21.4% of the cases without metastasis in this group were metastatic according to SLNB. In the CNB group, metastasis was observed in all patients with metastasis according to SLNB, while no metastasis was detected in those who were reported to have no metastasis by SLNB. The accuracy, specificity, and sensitivity values for the prediction of SLNB results were all found to be 100% for CNB, whereas they were 87%, 100%, and 75%, respectively, for FNAB. Conclusion: Both CNB and FNAB could potentially replace SLNB due to their high accuracy rates in evaluating the axilla after NAC. The sensitivity and accuracy of CNB were determined to be higher. [ABSTRACT FROM AUTHOR]

Background: Sucrose invertase is an important catalytic enzyme that is widely distributed in plants and can irreversibly hydrolyze sucrose into fructose and glucose. Daylily is an important perennial flower worldwide and a traditional vegetable in East Asia. Previous studies have suggested that sucrose invertase is involved in the aging of daylily flowers. However, knowledge about the number, physicochemical properties, and expression patterns of daylily sucrose invertases is still lacking. Identifying the daylily sucrose invertase family genes in the genome is highly important for understanding phylogenetic evolution and determining the genetic function of sucrose invertase. Methods: To obtain basic knowledge about the number, classification, sequence composition, and physicochemical properties of sucrose invertases in daylily, bioinformatics software was used to analyze the genome of Hemerocallis citrina (H. citrina), and the basic properties of sucrose invertase genes and proteins were obtained. Then, combined with transcriptome data from flower organs at different developmental stages, the expression patterns of each gene were clarified. Finally, the reliability of the transcriptome data was verified by quantitative real-time polymerase chain reaction (PCR). Results: Through software analysis, 35 sucrose invertases were identified from the H. citrina genome and named HcINV1-HcINV35; these enzymes belong to three subfamilies: cell wall invertases, vacuolar invertases, and chloroplast invertases. The amino acid composition, motif types, promoter composition, gene structure, protein physicochemical properties, gene chromosomal localization, and evolutionary adaptability of daylily invertases were determined; these results provided a comprehensive understanding of daylily invertases. The transcriptome expression profile combined with fluorescence quantitative reverse transcription-polymerase chain reaction (RT‒PCR) analysis suggested that almost all daylily invertase genes were expressed in flower organs, but even genes belonging to the same subfamily did not exhibit the same expression pattern at different developmental stages, suggesting that there may be redundancy or dissimilation in the function of daylily sucrose invertases. [ABSTRACT FROM AUTHOR]

Background: Machine learning classifiers are increasingly used to create predictive models for pathological complete response (pCR) in breast cancer after neoadjuvant therapy (NAT). Few studies have compared the effectiveness of different ML classifiers. This study evaluated radiomics models based on pre- and post-contrast first-phase T1 weighted images (T1WI) in predicting breast cancer pCR after NAT and compared the performance of ML classifiers. Methods: This retrospective study enrolled 281 patients undergoing NAT from the Duke-Breast-Cancer-MRI dataset. Radiomic features were extracted from pre- and post-contrast first-phase T1WI images. The Synthetic Minority Oversampling Technique (SMOTE) was applied, then the dataset was randomly divided into training and validation groups (7:3). The radiomics model was built using selected optimal features. Support vector machine (SVM), random forest (RF), decision tree (DT), k-nearest neighbor (KNN), extreme gradient boosting (XGBoost), and light gradient boosting machine (LightGBM) were classifiers. Receiver operating characteristic curves were used to assess predictive performance. Results: LightGBM performed best in predicting pCR [area under the curve (AUC): 0.823, 95% confidence interval (CI) [0.743–0.902], accuracy 74.0%, sensitivity 85.0%, specificity 67.2%]. During subgroup analysis, RF was most effective in pCR prediction in luminal breast cancers (AUC: 0.914, 95% CI [0.847–0.981], accuracy 87.0%, sensitivity 85.2%, specificity 88.1%). In triple-negative breast cancers, LightGBM performed best (AUC: 0.836, 95% CI [0.708–0.965], accuracy 78.6%, sensitivity 68.2%, specificity 90.0%). Conclusion: The LightGBM-based radiomics model performed best in predicting pCR in patients with breast cancer. RF and LightGBM showed promising results for luminal and triple-negative breast cancers, respectively. [ABSTRACT FROM AUTHOR]

It is necessary to study the propagation path of cracks in concrete materials and its influence on the loading capacity of specimens. The phase-field method for fracture offers a distinct benefit in simulating the crack propagation behavior of brittle materials, which is achieved by implementing a phase field that continuously fluctuates to approximate the crack configuration, abolishing the need for mesh reconstruction and tracking the cracks. In this paper, we have implemented a phase field model using ABAQUS, whose reliability is verified through a tensile test. Then, the splitting test of Brazilian disc is simulated and the results are similar to those of the laboratory experiment. Furthermore, the crack configuration of the prefabricated cracked discs with different tilt angles and different initial lengths is explored. The two important parameters of the phase field method, Gc and l0, are discussed in the Discussion section. A larger Gc value means a larger material toughness and a larger failure load, and a larger l0 value means a larger crack smear range as well as a smaller failure load. [ABSTRACT FROM AUTHOR]

The size-dependent nonlinear vibration model of the magneto-electro-elastic (MEE) sandwich nanobeam on Winkler-Pasternak foundation is built based on nonlocal elasticity theory and Reddy's third-order shear deformation theory. Employing the Hamilton variational principle and von Karman's geometrically nonlinear theory, the nonlinear governing equation system of MEE sandwich nanobeam is deduced. The expressions of nonlinear frequency ratio and critical external electric and magnetic potential are derived with the perturbation method. Several cases are studied in order to show the influence of nonlocal parameter, Winkler and Pasternak elastic foundation, stacking sequence, external electric and magnetic potential on size-dependent nonlinear vibration behaviors of MEE simply supported sandwich nanobeam. [ABSTRACT FROM AUTHOR]

Objective: To compare outcomes of metastatic renal cell carcinoma (mRCC) patients treated with everolimus, temsirolimus, and sorafenib following initial treatment with a tyrosine kinase inhibitor (TKI) in community and academic practices throughout the US., Research Design and Methods: Medical records of mRCC patients who received everolimus, temsirolimus or sorafenib as their second therapy following a TKI were retrospectively reviewed from a nationally representative panel of oncologists. Overall survival (OS) and progression-free survival (PFS) of second targeted therapies were compared using multivariable Cox proportional hazard models, with adjustment for demographics, disease severity and prior treatments., Results: A total of 233, 178, and 123 mRCC patients receiving everolimus, temsirolimus, and sorafenib, respectively, as second targeted therapies were included. Eighty-six percent used sunitinib and the remainder used sorafenib or pazopanib as their initial TKI. After adjusting for baseline characteristics, everolimus was associated with significantly prolonged OS (hazard ratio [HR] 0.60; CI 0.42-0.85; p = 0.004) and PFS (HR 0.73; CI 0.54-0.97; p = 0.032) compared to temsirolimus. Everolimus was associated with significantly longer OS (HR 0.66; CI 0.44-0.99; p = 0.045) and numerically longer PFS compared to sorafenib. No significant differences were observed between temsirolimus and sorafenib., Limitations: Despite adjustment for multiple patient characteristics, comparisons between treatment groups may be confounded by unobserved factors in this retrospective observational study. Tolerability outcomes were not collected., Conclusions: In this retrospective, non-randomized study of mRCC patients with prior TKI treatment, everolimus was associated with significantly prolonged OS and PFS compared to temsirolimus and significantly prolonged OS compared to sorafenib.

Purpose: To compare of the morphological ultrastructure of the 7th generation self-etching adhesive Adper Easy One and two-step total etch adhesive Adper Singlebond 2 after being bonded with the composite resin., Methods: Buccal and lingual box-like holes were made in 20 isolated human molars (5mm in diameter, 3mm in depth), and cuted to pieces from surface of middle part of root (5mm in length, 3mm in width). They were equally divided into 2 groups with 10 root slices and 10 crowns each. The cavities of crown and root pieces were respectively bonded with adhesives of Adper Singlebond 2 and Adper Easy One, and were vertically cuted open from the midline after filling with composite resin to get 20 specimens in each group. Ten specimens of root and crown were randomly selected from each group for 5000 times of thermocycling, and the remaining specimens were soaked in distilled water at room temperature for 1 month. Then all the specimens were polished with sand paper, fixed dehydrated, vacuum dried and sprayed, and the bonding interfaces of the filling edge of profile were scanned by scanning electron microscope(SEM)., Results: SEM photos showed that in the group of total etching Adper Singlebond 2 bonding placed at room temperature, the enamel, cementum and the resin bonded closely with the adhesive after thermocycling. In the group of self etching Adper Easy One bonding placed at room temperature, the adhesive bonded to the enamel, small cracks were occasionally seen, and resin penetration blend within the resin in dentinal tubules, and enamel bonded well to the cementum. The specimens after thermocycling bonded enamel loosely with distinct cracks,while the dentinal tubules and resin penetration integrated and cementum bonded well to the dentin., Conclusions: Ultra-micro structure observation by SEM shows that Adper Singlebond 2 total etch adhesive has better bonding to enamel than the self-etching adhesive Adper Easy One, but the bonding to dentin and cementum has no significant difference.

Granular models are key for understanding many phenomena in seismology, geophysics and geotechniques. Investigations of granular matters have shown that the scale of activated force chains decreases and a transition from solid-like behavior to liquid-like behavior occurs with the increase of shearing rate, and that at a low shearing rate viscosity is almost inversely proportional to maximal sliding velocity. At present, mechanical models describing the aforementioned behavior of granular matter are still lacking. Here we proposed a mechanical model of granular matter with internal length scale, reflecting the fact that the loading of granular matter is caused by shearing, and the stress relaxation is caused by shear band propagation. In combination with the constancy of shear band propagation speed, relationship between the length of activated force chains and shearing rate is obtained, the inverse proportionality of viscosity to shearing rate is interpreted, and the solid-to-liquid behavior transition shearing rate is predicted very well. This model can provide an effective approach to describe force chain evolution and the transition of granular matter from solid-like behavior to liquid-like behavior. [ABSTRACT FROM AUTHOR]

Background: Chimeric antigen receptor (CAR) T-cell therapy is a novel cell therapy for treating non-Hodgkin lymphoma. The development of CAR T-cell therapy has transformed oncology treatment by offering a potential cure. However, due to the high cost of these therapies, and the large number of eligible patients, decision makers are faced with difficult funding decisions. Our objective was to assess the cost-effectiveness of tisagenlecleucel for adults with relapsed/refractory diffuse large B-cell lymphoma in Canada using updated survival data from the recent JULIET trial. Methods: We developed an individual-simulated discrete event simulation model to assess the costs and quality-adjusted life-years (QALY) of tisagenlecleucel compared with salvage chemotherapy. Survival estimates were obtained from a published clinical trial and retrospective analysis. If patients remained progression free for 5 y, they were assumed to be in long-term remission. Costing and utility data were obtained from reports and published sources. A Canadian health care payer perspective was used, and outcomes were modeled over a lifetime horizon. Costs and outcomes were discounted at 1.5% annually, with costs reported in 2021 Canadian dollars. A probabilistic analysis was used, and model parameters were varied in 1-way sensitivity analyses and scenario analyses. Results: After we incorporated the latest clinical evidence, tisagenlecleucel led to an additional cost of $503,417 and additional effectiveness of 2.48 QALYs, with an incremental cost-effectiveness ratio of $202,991 compared with salvage chemotherapy. At a willingness-to-pay threshold of $100,000/QALY, tisagenlecleucel had a 0% likelihood of being cost-effective. Conclusions: At the current drug price, tisagenlecleucel was not found to be a cost-effective option. These results heavily depend on assumptions regarding long-term survival and the price of CAR T. Real-world evidence is needed to reduce uncertainty. Highlights: For patients with diffuse large B-cell lymphoma who failed 2 or more lines of systemic therapy, CAR T was not found to be a cost-effective treatment option at a willingness-to-pay threshold of $100,000. These results heavily depend on the expected long-term survival. The uncertainty in the model may be improved using real-world evidence reported in the future. [ABSTRACT FROM AUTHOR]

Some novel beta-biarylacryl ferrocene derivatives were synthesized via Pd-catalytic Suzuki cross-coupling reactions of beta-(2-bromophenyl)acrylferrocene and arylboronic acids. The structures were determined with elemental analyses, IR spectra, and (1)H-NMR spectra.

Background: Predicting tumor responses to neoadjuvant chemotherapy (NAC) is critical for evaluating prognosis and designing treatment strategies for patients with breast cancer; however, there are no reliable biomarkers that can effectively assess tumor responses. Therefore, we aimed to evaluate the clinical feasibility of using extracellular vesicles (EVs) to predict tumor response after NAC. Methods: Drug-resistant triple-negative breast cancer (TNBC) cell lines were successfully established, which developed specific morphologies and rapidly growing features. To detect resistance to chemotherapeutic drugs, EVs were isolated from cultured cells and plasma samples collected post-NAC from 36 patients with breast cancer. Results: Among the differentially expressed gene profiles between parental and drug-resistant cell lines, drug efflux transporters such as MDR1, MRP1, and BCRP were highly expressed in resistant cell lines. Drug efflux transporters have been identified not only in cell lines but also in EVs released from parental cells using immunoaffinity-based EV isolation. The expression of drug resistance markers in EVs was relatively high in patients with residual disease compared to those with a pathological complete response. Conclusions: The optimal combination of drug-resistant EV markers was significantly efficient in predicting resistance to NAC with 81.82% sensitivity and 92.86% specificity. [ABSTRACT FROM AUTHOR]

In backfill mining, surrounding rock damaged by impact loading (e.g. blasting) is immersed in backfill water after backfilling, and the instability of the impact-damaged and water-soaked (IDWS) surrounding rock can occur under blasting loads. To study the dynamic mechanical properties and the size effect of rock under such working conditions, triaxial dynamic compression tests were conducted on four groups (four length-to-diameter ratios) of first impact-damaged and then water-soaked sandstone specimens using an improved split Hopkinson pressure bar device. The test results show that, at a similar strain rate (approximately 10 s−1), the peak strength and elastic modulus of IDWS specimens are lower than those of the intact specimens, whereas the peak strain is higher than that of the intact specimens. Both the peak strength and peak strain of the IDWS specimens increase with strain rate, exhibiting a strong strain rate dependency. The peak strength, peak strain, and elastic modulus all display a size effect. This size effect varies over different strain rate ranges. When the strain rate is approximately 10 s−1, the peak strength decreases as the length-to-diameter ratio increases. In contrast, at a strain rate of approximately 30 s−1, the peak strength increases with an increase in the length-to-diameter ratio. There is a linear relationship between the incident energy and absorbed energy of the intact and IDWS specimens. Under the same incident energy, the IDWS specimens show higher absorbed energy than the intact specimens. This relationship is independent of the length-to-diameter ratio of rock specimens. [ABSTRACT FROM AUTHOR]

A strategy for catalyst-free domino reaction of 4-aminopyridin-2(1H)-ones, arylglyoxal hydrates and different 1,3-dicarbonyl compounds in water has been established. The mild and efficient procedure afforded pyrrolo[3,2-c]pyridine derivatives with 76-94% yields after simple crystallization. The present procedure shows promising characteristics, such as readily available starting materials, the use of water as reaction media, simple and efficient one-pot operation, and avoiding the need for any hazardous or expensive catalysts., (© 2021. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Background: The evidence base of tisagenlecleucel is uncertain. Objective: To evaluate the cost-effectiveness of tisagenlecleucel. To conduct expected value of perfect information (EVPI) and partial EVPI (EVPPI) analyses. Study design: A three-state partitioned survival model. A short-term decision tree partitioned patients in the tisagenlecleucel arm according to infusion status. Survival was extrapolated to 5 years; general population mortality with a standardised mortality ratio was then applied. EVPI and EVPPI were scaled up to population according to the incidence of the decision. Setting: Irish healthcare payer. Participants: Patients with relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL). Interventions: Tisagenlecleucel versus Salvage Chemotherapy (with or without haematopoietic stem cell transplant). Main Outcome Measure: Incremental cost-effectiveness ratio (ICER). Population EVPI and EVPPI. Results: At list prices, the ICER was €119,509 per quality-adjusted life year (QALY) (incremental costs €218,092; incremental QALYs 1.82). Probability of cost-effectiveness, at a €45,000 per QALY threshold, was 0%. Population EVPI was €0.00. Population EVPI, at the price of tisagenlecleucel that reduced the ICER to €45,000 per QALY, was €3,989,438. Here, survival analysis had the highest population EVPPI (€1,128,053). Conclusion: Tisagenlecleucel is not cost-effective, versus salvage chemotherapy (with or without haematopoietic stem cell transplant), for R/R DLBCL in Ireland. At list prices, further research to decrease decision uncertainty may not be of value. [ABSTRACT FROM AUTHOR]

Highlights: MXene-based macrostructure development and EMI shielding mechanisms are reviewed. Various structural design strategies for MXene-based EMI shielding materials are highlighted and discussed. Current challenges and future directions for MXenes in electromagnetic interference shielding are outlined. There is an urgent demand for flexible, lightweight, mechanically robust, excellent electromagnetic interference (EMI) shielding materials. Two-dimensional (2D) transition metal carbides/nitrides (MXenes) have been potential candidates for the construction of excellent EMI shielding materials due to their great electrical electroconductibility, favorable mechanical nature such as flexibility, large aspect ratios, and simple processability in aqueous media. The applicability of MXenes for EMI shielding has been intensively explored; thus, reviewing the relevant research is beneficial for advancing the design of high-performance MXene-based EMI shields. Herein, recent progress in MXene-based macrostructure development is reviewed, including the associated EMI shielding mechanisms. In particular, various structural design strategies for MXene-based EMI shielding materials are highlighted and explored. In the end, the difficulties and views for the future growth of MXene-based EMI shields are proposed. This review aims to drive the growth of high-performance MXene-based EMI shielding macrostructures on basis of rational structural design and the future high-efficiency utilization of MXene. [ABSTRACT FROM AUTHOR]

To figure out the influence of soft-hard layer thickness ratio on specimens' mechanical properties evolution and microcracking mechanism, combined with digital image correlation technology and acoustic emission facility, uniaxial compression tests were conducted on soft-hard interbedded rock-like materials considering seven bedding dip angles and two soft-hard layer thickness ratios. The results are as follows: 1) The failure mode and failure pattern of layered rock masses are mainly determined by the bedding dip angle α and are less related to the soft-hard thickness ratio. With the increase of dip angle, the failure strength curve of the specimen is approximately U-shaped, and the soft-hard layer thickness ratio affects the U-shaped. The decrease in soft-hard layer thickness ratio will reduce the uniaxial compressive strength of specimens with low dip angles (α≦30°), cause differences in the evolution path of local strain fields of layered rock masses and reduce the horizontal displacement of the main crack. 2) The increase of the proportion of soft layer in the soft-hard layer thickness ratio will reduce the proportion of tensile cracks in the tensile failure specimens and shear cracks in the shear failure specimens, complicating the process of cracks of the layer rock mass. 3) Increasing the proportion of soft layers in the soft-hard layers thickness ratio promotes the generation of secondary cracks in layered rock masses and further reduces the integrity of specimens. Finally, through the findings in this paper, it can provide a reference for analyzing the crack propagation behavior of layered rock. [ABSTRACT FROM AUTHOR]