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Alpelisib, a PI3Kα-selective inhibitor and degrader, plus fulvestrant showed efficacy in hormone receptor-positive, HER2-negative, PIK3CA-mutated advanced breast cancer in SOLAR-1; limited data are available in the post-cyclin-dependent kinase 4/6 inhibitor setting. BYLieve aimed to assess alpelisib plus endocrine therapy in this setting in three cohorts defined by immediate previous treatment; here, we report results from cohort A. This ongoing, phase 2, multicentre, open-label, non-comparative study enrolled patients with hormone receptor-positive, HER2-negative, advanced breast cancer with tumour PIK3CA mutation, following progression on or after previous therapy, including CDK4/6 inhibitors, from 114 study locations (cancer centres, medical centres, university hospitals, and hospitals) in 18 countries worldwide. Participants aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 2 or less, with no more than two previous anticancer treatments and no more than one previous chemotherapy regimen, were enrolled in three cohorts. In cohort A, patients must have had progression on or after a CDK4/6 inhibitor plus an aromatase inhibitor as the immediate previous treatment. Patients received oral alpelisib 300 mg/day (continuously) plus fulvestrant 500 mg intramuscularly on day 1 of each 28-day cycle and on day 15 of cycle 1. The primary endpoint was the proportion of patients alive without disease progression at 6 months per local assessment using Response Evaluation Criteria in Solid Tumors, version 1.1, in patients with a centrally confirmed PIK3CA mutation. This trial is registered with ClinicalTrials.gov, NCT03056755. Between Aug 14, 2017, and Dec 17, 2019 (data cutoff), 127 patients with at least 6 months' follow-up were enrolled into cohort A. 121 patients had a centrally confirmed PIK3CA mutation. At data cutoff, median follow-up was 11·7 months (IQR 8·5-15·9). 61 (50·4%; 95% CI 41·2-59·6) of 121 patients were alive without disease progression at 6 months. The most frequent grade 3 or worse adverse events were hyperglycaemia (36 [28%] of 127 patients), rash (12 [9%]), and rash maculopapular (12 [9%]). Serious adverse events occurred in 33 (26%) of 127 patients. No treatment-related deaths were reported. BYLieve showed activity of alpelisib plus fulvestrant with manageable toxicity in patients with PIK3CA-mutated, hormone receptor-positive, HER2-negative advanced breast cancer, after progression on a CDK4/6 inhibitor plus an aromatase inhibitor. Novartis Pharmaceuticals.

A new approach is introduced to significantly improve the performance of thermophotovoltaic (TPV) systems using low-dimensional thermal emitters and photovoltaic (PV) cells. By reducing the thickness of both the emitter and the PV cell, strong spectral selectivity in thermal emission and absorption can be achieved by confining photons in trapped waveguide modes inside the thin-films that act as thermal analogs to quantum wells. Simultaneously, photo-excited carriers travel shorter distances across the thin-films reducing bulk recombination losses resulting in a lower saturation current in the PV cell. We predict a TPV efficiency enhancement with near-field coupling between the thermal emitter and the PV cell up to 38.7% using a thin-film germanium (Ge) emitter at 1000 K and an ultra-thin gallium antimonide (GaSb) cell supported by perfect back reflectors separated by 100 nm. Even in the far-field limit, the efficiency is predicted to reach 31.5%, which is over an order of magnitude higher than the Shockley Queisser limit of 1.6% for a bulk GaSb cell and a blackbody emitter at 1000 K. The proposed design approach does not require nanoscale patterning of the emitter and PV cell surfaces, but instead offers a simple low-cost solution to improve the performance of thermophotovoltaic systems.

: Walking while performing cognitive and motor tasks simultaneously interferes with gait performance and may lead to falls in older adults with mild cognitive impairment (MCI). Executive function, which seems to play a key role in dual-task gait performance, can be improved by combined physical and cognitive training. Virtual reality (VR) has the potential to assist rehabilitation, and its effect on physical and cognitive function requires further investigation. The purpose of this study was to assess the effects of VR-based physical and cognitive training on executive function and dual-task gait performance in older adults with MCI, as well as to compare VR-based physical and cognitive training with traditional combined physical and cognitive training. : Thirty-four community-dwelling older adults with MCI were randomly assigned into either a VR-based physical and cognitive training (VR) group or a combined traditional physical and cognitive training (CPC) group for 36 sessions over 12 weeks. Outcome measures included executive function [Stroop Color and Word Test (SCWT) and trail making test (TMT) A and B], gait performance (gait speed, stride length, and cadence) and dual-task costs (DTCs). Walking tasks were performed during single-task walking, walking while performing serial subtraction (cognitive dual task), and walking while carrying a tray (motor dual task). The GAIT Up system was used to evaluate gait parameters including speed, stride length, cadence and DTCs. DTC were defined as 100 * (single-task gait parameters - dual-task gait parameters)/single-task gait parameters. : Both groups showed significant improvements in the SCWT and single-task and motor dual-task gait performance measures. However, only the VR group showed improvements in cognitive dual-task gait performance and the DTC of cadence. Moreover, the VR group showed more improvements than the CPC group in the TMT-B and DTC of cadence with borderline significances. : A 12-week VR-based physical and cognitive training program led to significant improvements in dual-task gait performance in older adults with MCI, which may be attributed to improvements in executive function.

Background Evaluating outcome reliability is critical in real-world evidence studies. Overall survival is a common outcome in these studies; however, its capture in real-world data (RWD) sources is often incomplete and supplemented with linked mortality information from external sources. Conflicting recommendations exist for censoring overall survival in real-world evidence studies. This simulation study aimed to understand the impact of different censoring methods on estimating median survival and log hazard ratios when external mortality information is partially captured. Methods We used Monte Carlo simulation to emulate a non-randomized comparative effectiveness study of two treatments with RWD from electronic health records and linked external mortality data. We simulated the time to death, the time to last database activity, and the time to data cutoff. Death events after the last database activity were attributed to linked external mortality data and randomly set to missing to reflect the sensitivity of contemporary real-world data sources. Two censoring schemes were evaluated: (1) censoring at the last activity date and (2) censoring at the end of data availability (data cutoff) without an observed death. We assessed the performance of each method in estimating median survival and log hazard ratios using bias, coverage, variance, and rejection rate under varying amounts of incomplete mortality information and varying treatment effects, length of follow-up, and sample size. Results When mortality information was fully captured, median survival estimates were unbiased when censoring at data cutoff and underestimated when censoring at the last activity. When linked mortality information was missing, censoring at the last activity date underestimated the median survival, while censoring at the data cutoff overestimated it. As missing linked mortality information increased, bias decreased when censoring at the last activity date and increased when censoring at data cutoff. Conclusions Researchers should consider the completeness of linked external mortality information when choosing how to censor the analysis of overall survival using RWD. Substantial bias in median survival estimates can occur if an inappropriate censoring scheme is selected. We advocate for RWD providers to perform validation studies of their mortality data and publish their findings to inform methodological decisions better.

The aim of this study was to conduct a comprehensive analysis of the placement of multiple wearable sensors for the purpose of analyzing and classifying the gaits of patients with neurological disorders. Seven inertial measurement unit (IMU) sensors were placed at seven locations: the lower back (L5) and both sides of the thigh, distal tibia (shank), and foot. The 20 subjects selected to participate in this study were separated into two groups: stroke patients (11) and patients with neurological disorders other than stroke (brain concussion, spinal injury, or brain hemorrhage) (9). The temporal parameters of gait were calculated using a wearable device, and various features and sensor configurations were examined to establish the ideal accuracy for classifying different groups. A comparison of the various methods and features for classifying the three groups revealed that a combination of time domain and gait temporal feature-based classification with the Multilayer Perceptron (MLP) algorithm outperformed the other methods of feature-based classification. The classification results of different sensor placements revealed that the sensor placed on the shank achieved higher accuracy than the other sensor placements (L5, foot, and thigh). The placement-based classification of the shank sensor achieved 89.13% testing accuracy with the Decision Tree (DT) classifier algorithm. The results of this study indicate that the wearable IMU device is capable of differentiating between the gait patterns of healthy patients, patients with stroke, and patients with other neurological disorders. Moreover, the most favorable results were reported for the classification that used the combination of time domain and gait temporal features as the model input and the shank location for sensor placement.

•This study employs advanced meta-analytic methods to revisit language production networks and map four key language processing components.•We identified a distinct speech control network separate from the domain-general and high-level language networks.•The left ventral precentral cortex is shown to play a central role in language production, beyond Broca's area.•Our research proposes a novel framework for a language production network.•Propose a two-pathway process, emphasizing the speech control system's central coordination role in language tasks. In recent decades, converging evidence has reached a consensus that human speech production is carried out by large-scale hierarchical network comprising both language-selective and domain-general systems. However, it remains unclear how these systems interact during speech production and the specific contributions of their component regions. By utilizing a series of meta-analytic approaches based on various language tasks, we dissociated four major systems in this study: domain-general, high-level language, motor-perception, and speech-control systems. Using meta-analytic connectivity modeling, we found that while the domain-general system is coactivated with high-level language regions and speech-control networks, only the speech-control network at the ventral precentral gyrus is coactivated with other systems during different speech-related tasks, including motor perception. In summary, this study revisits the previously proposed language models using meta-analytic approaches and highlights the contribution of the speech-control network to the process of speech production independent of articulatory motor.

A p-n junction maintained at above ambient temperature can work as a heat engine, converting some of the supplied heat into electricity and rejecting entropy by interband emission. Such thermoradiative cells have potential to harvest low-grade heat into electricity. By analyzing the entropy content of different spectral components of thermal radiation, we identify an approach to increase the efficiency of thermoradiative cells via spectrally selecting long-wavelength photons for radiative exchange. Furthermore, we predict that the near-field photon extraction by coupling photons generated from interband electronic transition to phonon polariton modes on the surface of a heat sink can increase the conversion efficiency as well as the power generation density, providing more opportunities to efficiently utilize terrestrial emission for clean energy. An ideal InSb thermoradiative cell can achieve a maximum efficiency and power density up to 20.4% and 327 Wm −2 , respectively, between a hot source at 500 K and a cold sink at 300 K. However, sub-bandgap and non-radiative losses will significantly degrade the cell performance.

Alpelisib, a PI3Kα-selective inhibitor and degrader, plus fulvestrant showed efficacy in hormone receptor-positive, HER2-negative, PIK3CA-mutated advanced breast cancer in SOLAR-1; limited data are available in the post-cyclin-dependent kinase 4/6 inhibitor setting. BYLieve aimed to assess alpelisib plus endocrine therapy in this setting in three cohorts defined by immediate previous treatment; here, we report results from cohort A. This ongoing, phase 2, multicentre, open-label, non-comparative study enrolled patients with hormone receptor-positive, HER2-negative, advanced breast cancer with tumour PIK3CA mutation, following progression on or after previous therapy, including CDK4/6 inhibitors, from 114 study locations (cancer centres, medical centres, university hospitals, and hospitals) in 18 countries worldwide. Participants aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 2 or less, with no more than two previous anticancer treatments and no more than one previous chemotherapy regimen, were enrolled in three cohorts. In cohort A, patients must have had progression on or after a CDK4/6 inhibitor plus an aromatase inhibitor as the immediate previous treatment. Patients received oral alpelisib 300 mg/day (continuously) plus fulvestrant 500 mg intramuscularly on day 1 of each 28-day cycle and on day 15 of cycle 1. The primary endpoint was the proportion of patients alive without disease progression at 6 months per local assessment using Response Evaluation Criteria in Solid Tumors, version 1.1, in patients with a centrally confirmed PIK3CA mutation. This trial is registered with ClinicalTrials.gov, NCT03056755. Between Aug 14, 2017, and Jul 29, 2022 (data cutoff), 127 patients with at least 18 months’ follow-up were enrolled into cohort A. 119 patients had a centrally confirmed PIK3CA mutation. At data cutoff, median follow-up was 21·8 months (IQR 10·8–37·6). 64 (53·8%; 95% CI 44·4–63·0) of 119 patients were alive without disease progression at 6 months. The most frequent grade 3 or worse adverse events were hyperglycaemia (37 [29%] of 127 patients), rash (13 [10%]), and rash maculopapular (11 [9%]). Serious adverse events occurred in 37 (29%) of 127 patients. No treatment-related deaths were reported. BYLieve showed activity of alpelisib plus fulvestrant with manageable toxicity in patients with PIK3CA-mutated, hormone receptor-positive, HER2-negative advanced breast cancer, after progression on a CDK4/6 inhibitor plus an aromatase inhibitor. Novartis Pharmaceuticals.

Iron accumulation causes cell death and disrupts tissue functions, which necessitates chelation therapy to reduce iron overload. However, clinical utilization of deferoxamine (DFO), an iron chelator, has been documented to give rise to systemic adverse effects, including ocular toxicity. This study provided the pathogenic and molecular basis for DFO‐related retinopathy and identified retinal pigment epithelium (RPE) as the target tissue in DFO‐related retinopathy. Our modeling demonstrated the susceptibility of RPE to DFO compared with the neuroretina. Intriguingly, we established upregulation of hypoxia inducible factor (HIF) 2α and mitochondrial deficit as the most prominent pathogenesis underlying the RPE atrophy. Moreover, suppressing hyperactivity of HIF2α and preserving mitochondrial dysfunction by α‐ketoglutarate (AKG) protects the RPE against lesions both in vitro and in vivo . This supported our observation that AKG supplementation alleviates visual impairment in a patient undergoing DFO‐chelation therapy. Overall, our study established a significant role of iron deficiency in initiating DFO‐related RPE atrophy. Inhibiting HIF2α and rescuing mitochondrial function by AKG protect RPE cells and can potentially ameliorate patients' visual function. Synopsis Deferoxamine (DFO) stabilizes HIF2α and disrupts mitochondrial oxidative phosphorylation, leading to RPE atrophy. Inhibiting HIF2α and preserving mitochondrial oxidative phosphorylation by α‐ketoglutarate (AKG) mitigate RPE cell death and ameliorate visual impairment in the clinic. DFO primarily acts on RPE and disrupts its iron homeostasis, causing atrophic lesions. DFO upregulates HIF2α and undermines mitochondrial oxidative phosphorylation in the RPE, accounting for its susceptibility to iron depletion. RPE intolerance to HIF2α‐induced anaerobic glycolysis contributes to susceptibility to DFO toxicity. RPE survival is sustained by mitochondrial oxidative phosphorylation. The glycolytic photoreceptor is initially spared from the DFO‐enhanced HIF levels. AKG, an intermediary metabolite of the Krebs cycle, destabilizes HIF2α and preserves mitochondrial respiration capacity, which protect RPE from damage and mitigates visual impairment in the clinic. Graphical Abstract Deferoxamine (DFO) stabilizes HIF2α and disrupts mitochondrial oxidative phosphorylation, leading to RPE atrophy. Inhibiting HIF2α and preserving mitochondrial oxidative phosphorylation by α‐ketoglutarate (AKG) mitigate RPE cell death, and ameliorate visual impairment in the clinic.

In this work, buckypaper composed of multi-walled carbon nanotubes (MWCNT) was prepared through a vacuum filtration process. The effect of MWCNT aspect ratio on the buckypaper performance was investigated. The freestanding and highly flexible buckypaper can be used as a sensor to attach on a complex surface monitoring the strain and temperature at the critical area. The mechanical properties of the buckypaper were examined using the tensile and nanoindentation tests. The strain and temperature sensitivities of the buckypaper were evaluated through the four-point bending and thermal chamber tests, respectively. In addition, the microstructure and thermal stability of the buckypaper were studied by scanning electron microscopy (SEM) and thermogravimetric analyzer (TGA), respectively. Experimental results showed that the mechanical properties such as Young’s modulus, tensile strength, fracture strain, and hardness of the buckypaper made of high aspect ratio MWCNTs were significantly superior to the buckypaper consisted of low aspect ratio MWCNTs, while the strain and temperature sensitivities of the buckypaper composed of low aspect ratio MWCNTs were better than that of the buckypaper made of high aspect ratio MWCNTs.