This study aimed to bring together people who smoke or vape, people who do not smoke and healthcare professionals to identify and agree priorities for electronic cigarette research in the UK. We carried out a priority setting partnership, guided by the methodology developed by the James Lind Alliance involving five key stages: initiation, consultation, collation, prioritisation and dissemination. A total of 765 people submitted 1887 questions that they wanted answered by research. Questions were organised into themes, merged and rewritten as summary questions, with 52 unique questions going forward to the prioritisation survey. Participants then ranked their top 10 questions. Following this ranking exercise, the top 26 were identified by selecting the most frequently prioritised questions adjusting for representative stakeholder group. These were put forward for discussion in the final prioritisation workshop, whereby the top 10 electronic cigarette research questions were agreed. The list of priorities identified will be of interest to researchers and funders of electronic cigarette research and will hopefully direct future research and funding calls. These priorities provide insight into the questions that matter to people who are using or concerned about e-cigarettes, including frontline professionals. Smoking is the leading cause of preventable morbidity and premature death. In the UK, 15% of the population smoke , and appE-cigarette research is a relatively new topic; therefore, it is essential to identify and address research priorities that are relevant to people who smoke or vape, and healthcare and public health professionals (HCPHP). Typically, academic researchers decide the questions that are addressed and investigated, but their priorities may not match those of patients and carers. There is often a mismatch between the types of interventions patients and clinicians wish to see evaluated. There is a need to ensure research is informed and guided by the needs of patients to avoid waste in terms of inadequate focus and outcomes . Given tThe Cochrane Tobacco Addiction Group (TAG) conducted a priority-setting stakeholder engagement project to identify where further research is needed in the areas of tobacco control and smoking cessation . E-cigarThe e-cigarette PSP took place between June-2018 and September-2019. The JLA method (outlined in the JLA guidebook ) is openThe people who take part in the surveys and priority setting stages of the work are not research participants. Thus, there is no requirement for ethics approval. The University of Nottingham Research Ethics Committee deemed this work not to require ethical approval. Completion of the surveys implied consent for submitted information to be included. Principles of ethical research were followed such as confidentiality.A steering group was convened with ”patients” (representing people who smoke and/or vape) and HCPHP. A typical PSP uses the term ”patient”; however, the steering group felt it was more appropriate to refer to people who smoke and/or vape as consumers. The steering group comprised four HCPHPs ), five consumers, three academics, and was chaired by a JLA advisor who supported the group throughout the process to understand the steps required. Each member of the Steering Group completed a ‘Steering Group Interests and Privacy form’, to create a culture of transparency in the group and help the JLA Advisor manage potential bias. Each member of the steering group brought with them knowledge of the topic, an understanding of the patient and clinician populations and access to networks of patients and clinicians. The role of the steering group was to coordinate the PSP and was responsible for a number of tasks, including publishing the initiative, overseeing the checking and collating of uncertainties and taking the final priorities to research funders. The steering group met face-to-face on three occasions with another four teleconferences during key stages of the study.”What questions about electronic cigarettes would you like to see answered by research?” In order to keep the survey as succinct as possible to encourage completion, we did not include further questions such as educational background or participants’ health literacy or understanding of research. It was felt that this information would not be necessary as we did not ask them to consider how a question would be answered or how a study may be designed, only to consider what the priority questions would be. Participants could submit as many questions as they wanted. Participants could contact the lead investigator if they wanted to be involved in the subsequent prioritisation stage.Uncertainties about e-cigarettes were collected via a survey which consisted of an explanation of the study, basic demographic questions , self-reported smoking status , whether they were a HCPHP and an open-ended question: The survey was circulated via steering group members, partner organisations , Action on Smoking and Health, National Centre for Smoking Cessation and Training, Royal College of Physicians, New Nicotine Alliance), and was available on the UK Centre for Tobacco and Alcohol Studies (UKCTAS) website. It was promoted on Facebook and Twitter. Efforts were made to disseminate the survey to target groups—for example, paper versions of the survey were taken to a local homeless centre. In addition to submitted uncertainties, we searched reviews of e-cigarettes for highlighted research uncertainties.Uncertainties gathered in the consultation stage were reviewed, and out-of-scope questions were removed. A list was created of indicative uncertainties . The data were categorised using themes identified in the raw data. This process was managed by the lead investigator (with input from four steering group members) to ensure consistency in dealing with interrelated questions. Those that were difficult to assign to a theme were discussed with the steering group. Uncertainties that could be answered by published systematic reviews were removed from the process; these were identified by searching the Cochrane Library, Prospero and NHS Centre for Reviews and Dissemination databases. Uncertainty was confirmed if there was no review, an out-of-date review (over three years old) or a recent review with an equivocal answer. The collation process was closely monitored by the JLA advisor to ensure transparency and minimization of bias.www.optimalworkshop.com) was used to create an online survey whereby the list of indicative questions was presented in a randomised sequence for each participant. Participants read all questions and selected (drag and drop) the 10 questions they thought were most important for research, and ranked them in order of preference. To facilitate the process of identifying their top 10 questions, an intermediate ”questions of interest” box was included as a holding pen for questions they wished to consider. Participants could swap and change questions as often as they liked before submitting their final top 10. Participants could contact the lead investigator to express an interest in taking part in the final workshop.The long list of indicative uncertainties was reduced into a more manageable list by asking participants to rank the questions according to those most important to them. Interactive card sorting software  consumers/public, 168 (22%) HCPHPs) submitted 1887 uncertainties at the consultation stage. These could be anything they deemed important, including safety, effectiveness, different populations, supply or accessibility of e-cigarettes, environmental issues and related products such as snus and heated tobacco. Submitted questions per person ranged from one to 16. Participants ranged in age from 17 to 88 years old (mean age 47 years). Just over half of the participants were male (57.1%). Participants indicated their smoking status see  and coulHCPHP represented 168 participants. A fifth of these were stop smoking advisors. Other professions included nursing and midwifery, public health, medicine, dentistry, healthcare workers, mental health, pharmacy, physiotherapy, paramedics, occupational therapy, optics, audiology and social work.(“does vaping cause popcorn lung?”). This left 52 indicative uncertainties that progressed to the ranking stage, representing 12 broad themes . The subthemes for each of these overarching themes can be seen in Some submissions were just comments or statements with no underlying question, and these were excluded. After removal of out-of-scope submissions, nonquestions or statements, 1632 uncertainties remained. These were represented by 53 indicative uncertainties; however, the steering group agreed to remove one of these as it was not considered to be a true uncertainty based on the evidence The steering group agreed this was a suitably representative and manageable sized list to take forward to the next stage of the process. No other uncertainties were resolved by evidence of recent published systematic reviews.The ranking stage involved 415 participants  prioritising their top 10 from the list of 52 indicative uncertainties. Again, participants indicated their smoking status see . This tiFor the interim prioritisation, participants chose their top 10 questions from the list of 52 and ranked them in order of preference. These 52 questions and the frequency they were highly prioritised can be seen in It was important to ensure the final indicative questions for the prioritisation workshop were representative of all groups—i.e., of equal significance to votes from across both stakeholder groups. The top 15 questions for HCPHPs, and the top 15 questions for consumers/public gave us a top 21 as nine of these questions were common in both groups. Each group had six questions that did not feature in the other group’s top 15. The steering group then voted for their top five questions from the next 10 most popular questions. This gave us a total of 26 questions for discussion in the final prioritisation workshop see .The final workshop to agree the top 10 research priorities  had 23 pDuring the workshop, each participant was given the opportunity to express their views on which questions they thought should be prioritised and to hear other people’s perspectives. Participants were able to debate and change their minds throughout the day. The research team observed that participants were keen to include as many topics as possible within the top 10 priorities—for example, ensuring there was a question related to pregnancy, and a question related to mental health within the top 10.“Will prescribing e-cigarettes to pregnant smokers encourage smoking cessation, and reduce risk of relapse?”. This word change was agreed with the lead investigator who felt this wording still represented the original respondents’ intent.One change to the wording of a question was made following discussion and agreement from the workshop participants: the word ”prescribing” was changed to ”providing” in the question: The top 10 priorities, , were diThis PSP was conducted according to an independent and transparent process to identify and prioritise questions for research in which people who smoke or vape, people who do not smoke and HCPHPs were successfully brought together. To our knowledge, this is the first prioritisation exercise focusing specifically on e-cigarettes as a therapeutic aid.The top ten research priorities include questions on long term safety; effectiveness for quitting smoking; policy; risks, benefits, barriers and facilitators to use in different populations including pregnancy and those with mental health issues; ingredients and testing; and the effects of second hand vape. This process has demonstrated numerous uncertainties surrounding e-cigarettes; such widespread uncertainty is likely to have an impact on the consistency of advice and information given by HCPHPs, and therefore patients’ confidence in this advice, as evidenced by the literature ,11,12,13Most of the top 10 priorities of this PSP also align with those identified by the Cochrane Tobacco Addiction Group (TAG) . Their pCRUK  have alsIt is reassuring, in this new field of research in e-cigarettes, consumers, HCPHPs and the research establishment are all on the same page when it comes to identifying priorities for future research. However, the 10th priority question in our PSP concerned the safety around second hand vape. This was not identified as a priority for TAG or CRUK, but it highlights the concerns the public and HCPHPs have and are perhaps seeking more assurance and evidence that second hand vape is harmless.Our PSP has shown that there is a lack of research on e-cigarettes and many safety concerns among HCPHPs and consumers . HCPHPs There were no questions on supply or availability of e-cigarettes. Within the original uncertainties submitted, there were questions on how people access vaping equipment, including children and young people, and what the preferred sources are. However, these questions were ranked very low in the prioritisation survey, and therefore, were not discussed in the final workshop. However, the supply of e-cigarettes still remains an uncertainty, and preferred sources for accessing vaping equipment warrant further research.With regard to other products such as heated tobacco, Swedish snus or shisha, there was one question asking what the risks and benefits of these products are and whether they should be treated the same as e-cigarettes (question asked by a vaper). However, this question was not ranked high enough in the prioritisation survey to be discussed in the workshop.All submitted questions were verified against the evidence, but were still considered to be uncertainties, except one question on popcorn lung. The steering group agreed there was enough evidence that there is no risk of popcorn lung from vaping . HoweverFor the other questions, there was often no systematic review evidence, or where there was a systematic review it lacked relevant studies to answer the question. For some questions, there were individual randomised controlled trials, and some participants in the final workshop argued that a question had already been answered because of available data from one trial. However, the JLA process requires a stronger evidence base, such as systematic review data, because a single trial can vary in quality and context, and a subsequent trial may report different results.In order to keep the survey succinct to encourage responses, we did not ask many personal questions, so it is not possible to ascertain if we had responses from a wide range of ethnic populations, from areas of deprivation, or from specific populations—e.g., pregnant women, homeless population, prison population, those with mental health conditions or people suffering from other health conditions such as chronic obstructive pulmonary disease or lung cancer. However, efforts were made to ensure participants were as representative as possible to achieve a wide range of questions. The survey was distributed via the steering group’s broad network, to heads of maternity services, and to the general population via social media. Efforts were made to try to reach different populations—e.g., we succeeded in visiting a homeless shelter, but we faced difficulty reaching the prison population. Furthermore, we did not notice any difference in the types of questions submitted based on smoking status, besides the fact that some vapers asked questions specific to the devices, whereas non-smokers and smokers did not.Additionally, this PSP was concerned with questions relevant to the UK population and organisations. However, many individuals from around the world submitted uncertainties, with 25 other countries represented. These questions were included if they were applicable to the UK. Nonetheless, it is likely that many of the questions will be applicable to an international audience—e.g., questions about safety and effectiveness including in different populations, long-term effects, effects on physical health and second hand vape. However, it is worth noting that there are wide variations in regulatory environments for e-cigarettes around the world. At least 14 countries have banned the sale and use of e-cigarettes, including Thailand, Brazil and Singapore. In the USA, at least five states have banned flavoured e-cigarettes . Therefore, some questions may be dependent on national policy or regulatory environments and may vary by country . Nonetheless, all questions in the top 10 will be relevant to an international audience but may need to be answered differently according to each country’s regulatory environment.A recent publication has highlighted how JLA PSPs have transformed research, and the impact they have had . One sigThe list of priorities identified here will be of interest to researchers and funders of e-cigarette research and will hopefully direct future research and funding calls. These priorities provide insight into the questions that matter to people who are using or concerned about e-cigarettes, including front line professionals. Furthermore, many of these priorities also align with the issues identified by Cochrane TAG and CRUK.


Four possible azimuth steering angles were designed for −26.7°, 0°, 13°, and 42.4°. Measured far-field patterns show good agreement with simulation results.Low-cost and conformal phased array antennas (PAAs) on flexible substrates are of particular interest in many applications. The major deterrents to developing flexible PAA systems are the difficulty in integrating antenna and electronics circuits on the flexible surface, as well as the bendability and oxidation rate of radiating elements and electronics circuits. In this research, graphene ink was developed from graphene flakes and used to inkjet print the radiating element and the active channel of field effect transistors (FETs). Bending and oxidation tests were carried out to validate the application of printed flexible graphene thin films in flexible electronics. An inkjet-printed graphene-based 1 × 2 element phased array antenna was designed and fabricated. Graphene-based field effect transistors were used as switches in the true-time delay line of the phased array antenna. The graphene phased array antenna was 100% inkjet printed on top of a 5 mil flexible Kapton Digital beamforming phased array antennas (PAAs) with distributed control and processing electronics offer numerous advantages for radio frequency (RF) communications, such as electronically controllable beamforming and steering, high average transmitted power and efficiency, flexible sub-arraying to provide multiple communication links simultaneously, reconfigurable high-gain patterns, and increased reliability through reconfiguring redundant array elements. Low-cost and conformal PAAs on flexible substrates are of particular interest in many applications, such as space communications, train antennas, car radio antennas, and cellular base station antennas. The major deterrent to producing flexible PAA systems is the difficulty in integrating antenna and electronics circuits on the flexible surface. One of the major integration methods is to attach and interconnect electronic chips onto the antenna surface . Due to Previously, a prototype PAA was designed, using carbon nanotubes (CNTs) as the active material in the digital switching device and nanosilver ink as interconnect and antenna element material ,5. This Graphene is a 2D material for electronics and photonics, with remarkable electronic, optical, mechanical, and thermal properties. Graphene is being investigated and applied in many fields ,13,14,15High-performance graphene powder suitable for inkjet printing has been grown through chemical vapor deposition (CVD) . A singlCompared to conventional printing techniques, such as offset lithography, gravure printing, flexography, and screen printing, inkjet printing is an ideal solution for high-resolution, low-cost, high-speed printed electronics, due to low material consumption, low equipment and setup costs, and the possibility for mass customization. It is also a non-contact printing technique which does not require any template preparation. The wide application of printed electronics includes organic photodiodes, photovoltaic cells, high-frequency micro-electro-mechanical-switches (MEMS), electronic paper displays, foldable thermochromic displays, and high-performance organic thin-film transistors ,25,26,27Traditional rigid microstrip antennas mainly use copper as the radiating material, due to the cost. However, inks made of nanocopper particles are not mature, and special equipment is needed for the sintering process. The majority of current printed flexible antennas is based on nanosilver particle inks. In this paper, a fully printed 1 × 2 graphene-based PAA is presented. Graphene FETs are used as switches on the TTD lines with on/off ratio of 38 and on-current of 32 µA. Patch antenna elements were also printed with graphene ink. The far-field patterns are characterized and agree well with simulation results. The performance of the graphene-based antenna is compared with the silver-based counterpart. The devices were produced in a room-temperature environment, with thermal curing processes used to anneal the inks which can be substituted with a room-temperature photosintering process. Such a low-temperature processing method permits us to use any flexible substrate with regular transparency, as demonstrated in this paper.To prepare the ink, terpineol was added to cyclohexanone in a volumetric ratio of 15:85. Then, ethyl cellulose was added to the mixture and thereafter placed in an ultrasonic bath (Branson model 2510), which provided mild mechanical vibration and a steady temperature environment for the reaction until all the white powder was completely dissolved. This process takes 1–2 h. Next, the graphene nanoflakes were dispersed in the mixture. For uniform and homogenous dispersion, the nanoflakes were added gradually, at intervals, while the mixture was still in an ultrasonic bath. After the addition of the graphene nanoflakes, the mixture was kept under mild vibration, in the ultrasonic bath, for 10–20 h, and, thereafter, the mixture was centrifuged at 5000 RPM for 20 min, to obtain a homogeneous solution . Finally, the homogeneous dispersant was collected, and the residues were recycled. R2 = 0.9967, which is above the minimum regression coefficient of 0.98 that we required for reliable viscosity measurements. This 5.51 cP viscosity at room temperature is compatible with the inkjet printer we used for the whole fabrication process which can jet out ink or solution only if the viscosity of the ink/solution is within the range of 2–12 cP.After the preparation of the homogeneous solution of graphene, the viscosity of the solution was measured at different shear rates, using a RheoSense m-VROC viscometer  In the conjugated software module (version: 3.1.4), we entered the sample size in mL and an estimated viscosity for an ink from the literature. Then the software provided an estimated calculation for minimum and maximum flow rate. We set five different flow rates within the displayed range and measurement times, and then we dispersed the sample through the measurement sensor. ® flexible substrate. After the viscosity measurement, the contact angle and surface tension between graphene ink and the substrate were also checked. A KRÜSS drop-shape analyzer (DSA-1000)  was used to determine these two parameters. Contact angle is a crucial characterization to check before any printing technique, including inkjet, aerosol jet, or spray coating. The result of contact angle determines how much resolution we can achieve with an ink, and surface tension determines the bonding between ink and substrate. It is recommended to have a surface tension between 25 and 45 mN/m to achieve good bonding between materials in printing techniques. ® substrate. The contact angle was found to be between 20 and 21 °C. This contact angle also represents the wettability of the ink with the substrate. The surface tension was found to be 28.75 mN/m, meaning that the ink has a good bonding with flexible KaptonA DoD Fujifilm Dimatix (model DMP-2800) inkjet printer  was used to print all the thin films and devices. It was equipped with a Dimatix materials cartridge (DMC-11610) . The cartridge head has 16 piezoelectric jetting nozzles with a diameter of 21.5 µm each. The nozzles can dispense a droplet of the nominal volume of 10 pL from the cartridge head. The optimum drop spacing for the graphene ink was 30 µm, and six nozzles were used to print these inks. There was no delay between subsequent printing passes, except for a 0.3 s purge in every ten printing passes. Additionally, to avoid the coffee-ring effect, the platen temperature was set at 60 °C ,30. The The selection of an appropriate waveform is important in order to achieve a good printed pattern. Graphene ink is still a new ink concept, and so there are few waveforms available from different vendors, and they do not work perfectly all the time. Thus, the default waveform of Fujifilm Dimatix Model Fluid is a good waveform to start with for any newly formulated ink. After investigating the jetting of the nozzles, 5–8 nozzles were chosen to print the antenna. To avoid nozzle clogging, nozzles were cleaned after every 30 min of printing. The final voltage setting for each nozzle was 25 V with 4.5 meniscus setting point. Printing frequency can be selected as low as 1 kHz and as high as 5 kHz. Lower printing frequency increases the printing time, and higher frequency decreases the printing time. However, higher printing frequency is also responsible for significantly increasing the ink spreading all over the substrate. Thus, in our work, the cutoff printing frequency was selected to be 2 kHz, to avoid the ink spreading. The printer head was set at 1.5 mm above the platen, to provide sufficient clearance after placing the substrate. Due to the very low percentage (less than 1%) of solid loading of graphene ink, it was necessary to use multiple printing passes. In this work, it was found that, after a minimum of 40 printing passes, graphene could create enough percolation network with good coverage to be conductive. To achieve a good conductive film, thermal annealing was performed after every 10 layers. The current–voltage measurements of the transistors were performed with the Keysight B1500A semiconductor device analyzer . In the far-field pattern measurements, the under-test antenna (UTA) was mounted onto a rotational stage, and a standard gain horn antenna was mounted onto a stage with adjustable angles with far-field distance between the two antennas. A vector network analyzer was used to determine S-parameters and provide the RF signal to the UTA. While the UTA was rotated by the rotational stage, a microwave signal analyzer was used to detect the signal from the receiving standard horn antenna, to get the radiation pattern. Graphene thin film was used to substitute for the widely used silver nanoparticles thin film, due to graphene’s flexibility and anti-oxidization. Graphene nanopowder (Product NP-AO3)  of 12 nm lateral size was used to prepare printable graphene ink . The priThe flexibility of the printed graphene and silver patches with the same thickness of one micron were investigated by performing resistance measurements on a homemade bendable system. Valley bend of 90° for 2000 bending cycles was conducted first, followed by 2000 bending cycles of >135° valley bend, 1000 bending cycles of 90° mountain bend, and 500 bending cycles of >135° mountain bend. The resistance of the silver patch increased around 1993% after 5500 bending cycles, while the printed graphene patch increased around 15%. ® substrate. However, the measured resistance data show less of an effect of bending on graphene film. These results indicate that this kind of printed graphene holds a possible pathway for flexible and bendable electronic devices.The oxidation test was carried out on a hot plate, in air. Each patch was first heated to 120 °C for one hour. Resistance measurements were taken, and then the process was repeated for 10 °C hourly increases up to 290 °C. θ is the beam steering angle. The delay line length interval for adjacent antenna elements can be calculated as follows [The time delay between adjacent elements of a PAA can be calculated as follows :(1)t = d follows :LintervaUsing the above equations, we designed a true-time delay network for a PAA radiating at 4 GHz (within S band). Element distance was designed as half wavelength, to avoid grating lobes. ® FPC polyimide film, source and drain electrodes were inkjet printed, using a Fujifilm Dimatix DMP-2800 materials deposition system. Silver nanoparticle ink   was used for electrodes. The printed electrodes were followed by thermal annealing at 130 °C for 30 min. Then, the graphene active layer, prepared as in 2 monolayer/multilayer dispersion [The top-gate schematic structure of the proposed graphene FET is shown in spersion . Ion gelspersion . To demonstrate the azimuth beam steering, ® FPC polyimide film, using a Fujifilm Dimatix DMP-2831 inkjet-printing system. Using electronic grade graphene solution, we fabricated an FET with an on–off ratio of 38. The true-time delay lines incorporated with the FET switches were proven to work well through the beam-steering experiments of the PAA. The devices were produced in a room-temperature environment, with thermal curing processes used to anneal the inks which can be substituted with a room-temperature photosintering process. The fully printed graphene PAA technology will greatly help the advancement of conformal communication antennas.In this study, an all-inkjet-printed graphene-based 2-bit 2-element PAA was fabricated on a DuPont™ KaptonCompared with the mainstream of silver-based printed antennas, graphene antennas take a longer time to be fabricated. Due to very low percentage (less than 1%) of solid loading of graphene ink, it was necessary to continue 40 printing passes in this work, while only three printing passes were needed for our previous silver-based antenna system. To achieve a good conductive graphene film, we performed thermal annealing after every 10 layers, further increasing the fabrication time and process complexity.


EGFR-mutated non-small cell lung cancer (NSCLC) to EGFR-targeted therapy. We retrospectively evaluated patients who received first-line treatment with EGFR-TKIs for advanced NSCLC with EGFR mutations. Pre-treatment plasma concentrations of PD-L1 and on-treatment (1 month after treatment initiation) plasma concentrations of PD-L1 were measured using the R-plex Human PD-L1 assay. The association between the sPD-L1 level and the clinical outcome was analyzed. Among 66 patients who were eligible for the study, patients with high pre-treatment or on-treatment sPD-L1 levels had decreased objective response rate (ORR) compared with that of patients with low sPD-L1 levels . A high baseline sPD-L1 level was associated with a shortened progression-free survival (PFS) rate . Both univariate and multivariate analyses showed that a high baseline sPD-L1 level was an independent factor associated with the PFS . Our study revealed that the sPD-L1 level was strongly related to the outcome of EGFR-TKIs in NSCLC patients harboring EGFR mutations.Programmed cell death ligand 1 (PD-L1) expressed on tumor tissues is a vital molecule for immune suppression and its impact on the response to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) has been reported. The significance of soluble PD-L1 (sPD-L1) for lung cancer patients remains unknown. This study investigated whether sPD-L1 could predict the response of  EGFR mutations  pathway, which leads to exhausted T-cells and continuous cancer growth, has been identified as the most critical mechanism of tumor evasion . PD-1/PDhibitors . Recent hibitors . High lehibitors , 14. TheEGFR mutations.Evaluating PD-L1 expression in tumor tissue is challenging. First, it is not easy to obtain sufficient tumor samples for analysis from inoperable patients. Furthermore, the test results of PD-L1 expression may differ according to the anti-PD-L1 antibodies applied . And theEGFR mutation (defined as 19DEL or L858R), a treatment-naïve status regarding EGFR-TKIs and a thorough documentation of the response evaluation for patients. The treatment response was evaluated every 2–3 months using computerized tomography according to the Response Evaluation Criteria in Solid Tumors version 1.1.  according to the manufacturer's instructions. All the samples were tested in duplicate.Continuous data were summarized as medians and ranges. When assessing changes in sPD-L1 levels, for each patient with available blood sample, we estimated the difference between levels at baseline and at 1 month after initiating an EGFR-TKI. Patients with a change in sPD-L1 level that was lower than the median difference for the entire population were considered to have a reduction in sPD-L1 levels, whereas others were considered to have no reduction in sPD-L1 levels. For pre-treatment and on-treatment sPD-L1 levels, values that were lower than the median concentration for the entire population were considered to be low, whereas those above or equal to the median concentration were considered to be high.t-test or Mann-Whitney U-test was used for comparing continuous data according to the data distribution determined by the Kolmogorov-Smirnov test. Kaplan-Meier curves and the log-rank test were used to compare survival times across different patient groups. The Cox proportional hazards regression analysis was performed, and HRs and 95% confidence intervals (CIs) were calculated to determine the survival difference. Variables were included in the multivariate analysis if they were statistically significant (p < 0.10) in the univariate analysis. All statistical analyses were performed using GraphPad Prism software  and SPSS statistical software . Results were considered statistically significant at a two-sided p < 0.05.The relationship between categorical parameters was determined using a chi-square test or Fisher's exact test. The student's In total, 66 patients met the inclusion criteria and were enrolled in this study. On-treatment blood samples were collected for 46 of these patients. The distributions of pre-treatment and on-treatment plasma sPD-L1 concentrations are shown in n = 62) and had an ECOG PS status of 0–1 . Fifty-six patients (84.8%) were at stage IIIB to IV at the time of diagnosis, and 10 patients (15.2%) were with recurred disease. A majority of patients were non-smokers , and 16 patients (24.2%) were current or former smokers. Regarding the baseline EGFR mutation status, 33 patients (50.0%) harbored the exon 19 deletion and 33 patients (50.0%) had the exon 21 L858R point mutation . A majority of patients were treated with first-line EGFR-TKIs  and two patients received afatinib treatment. As for the metastasis status, there were 22 patients (33.3%) with brain metastases, 24 patients (36.4%) with bone metastases, and four patients with liver metastases at diagnosis. Among all patients, 38 patients received the EGFR T790M test at progression; 22 of these patients harbored an EGFR T790M mutation when they became resistant to first-line EGFR-TKIs.The demographic and clinical characteristics are demonstrated in EGFR mutation status, type of EGFR-TKI treatment received, metastasis status or T790M mutation at progression between the low sPD-L1 expression group and high sPD-L1 expression group.The patient cohort was divided into two groups based on the level of sPD-L1 before treatment had been initiated. There were no significant differences in gender, age, histological status, ECOG PS status, stage, smoking status, p = 0.026). Meanwhile, a higher on-treatment sPD-L1 level was also associated with a poor response to EGFR-TKIs. The ORR was 73.9% in patients with low on-treatment sPD-L1 levels, but the ORR was only 43.5% in patients with high on-treatment sPD-L1 levels. There were no differences in the treatment response between patients with or without a reduction of sPD-L1 levels. Other clinical characteristics, including gender, age, ECOG PS score, tumor stage, smoking status, EGFR status, and type of EGFR-TKI received were not associated with the therapeutic response.Clinical characteristics of patients and distributions of sPD-L1 concentrations according to the therapeutic response to EGFR-TKIs are listed in We next compared both the pre-treatment and on-treatment sPD-L1 concentrations in patients who achieved a PR and patients who had a best response of stable disease (SD) or progressive disease (PD). The PR group demonstrated significantly lower levels of pre-treatment plasma sPD-L1 compared with the SD+PD group. As for the on-treatment plasma sPD-L1 levels, although the finding was marginally significant, the PR group also showed a lower level of sPD-L1. In whole patient group and subgroups divided by treatment response, the levels of sPD-L1 were not significantly changed by EGFR-TKIs treatment .p-value was 0.005. Although it was not statistically significant, a shorter PFS rate was also observed in patients with higher on-treatment sPD-L1 concentrations . The change in sPD-L1 levels was not correlated with the PFS rate of patients treated with EGFR-TKIs, however.The median progression-free survival (PFS) in the whole patient group was 12.5 months (95% CI: 9.7–15.2 months). As demonstrated in EGFR driver mutation type, brain metastasis status, sPD-L1 concentration, and T790M status at progression were included in the Cox regression analysis. A worse outcome for patients with high sPD-L1 levels before EGFR-TKI treatment was also found for the PFS rate in the Cox regression model with an HR of 2.56 . No clinicopathological factors were associated with the PFS rate .To further evaluate the potential impact of clinical variables on the therapeutic efficacy of treatment with first-line EGFR-TKIs, we performed both univariate and multivariate analyses on the whole patient cohort. Typical factors of age, sex, smoking history, stage, PFS rate , but theEGFR-mutant NSCLC patients with low plasma sPD-L1 levels than in those with high sPD-L1 levels. Furthermore, a prolonged PFS rate was significantly associated with a lower pre-treatment sPD-L1 level. Our results suggested that the plasma PD-L1 concentration could be a promising marker for determining the efficacy of EGFR-TKIs for NSCLC patients harboring EGFR mutations.A growing number of studies have demonstrated that sPD-L1 might play a crucial role in the prediction of the treatment response of PD-1/PD-L1 inhibitors and also the prognosis of cancer patients , 21, 24.The underlying mechanisms of generation and regulation of the soluble forms of PD-L1 are still unclear. One possible source is spliced variant. Zhou et al. showed that alternative splicing of PD-L1 occurred in all melanoma cell lines and splice variants could result in the secretion of sPD-L1 . BesidesEGFR-mutant lung adenocarcinoma patients, PD-L1 represented a favorable biomarker for the response to EGFR-TKIs and outcomes of these patients  for the publication of any potentially identifiable images or data included in this article.YJ, XL, and CZho designed this study and drafted the manuscript. YJ, XL, CZha, FZ, and JL reviewed the patient record, collected patient samples, and conducted the relevant experiments. YJ, CZha, GG, and WL performed the statistical analyses. SR and CS provided critical comments and revised the manuscript. All authors read and approved the final version of the manuscript.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.


BC from wood burning (BCwb) was significantly higher at non-EJ communities. Correlation analysis indicated that the six HAPs were predominantly from fossil fuel combustion sources, not from wood burning. The HAPs were moderately variable across sites (coefficient of divergence (COD) range of 0.07 for carbon tetrachloride to 0.28 for m- and p-xylenes), while BCff and BCwb were highly variable . The BCwb was well correlated with levoglucosan (R2 of 0.68 to 0.95), indicating that BCwb was a robust indicator for wood burning. At the two permanent monitoring sites, wood burning comprised 29–39% of the fine particulate matter (PM2.5) on nights when PM2.5 concentrations were forecasted to be high. Phone survey data were consistent with study measurements; the only significant difference in the survey results among communities were that non-EJ residents burn with indoor devices more often than EJ residents.Ambient air monitoring and phone survey data were collected in three environmental justice (EJ) and three non-EJ communities in Sacramento County during winter 2016–2017 to understand the differences in air toxics and in wood smoke pollution among communities. Concentrations of six hazardous air pollutants (HAPs) and black carbon (BC) from fossil fuel (BC The resultant high-concentration PM2.5 events over the course of an evening can have acute health impacts [Wood smoke from residential burning is the largest source of wintertime particulate matter with aerodynamic diameter less than 2.5 microns , secondarily formed organic mass, and a wide range of gaseous species ,9,10,11.wb) and from fossil fuel combustion (BCff) [While there are thousands of chemicals emitted from residential biomass burning, unique chemicals are emitted from the combustion of wood lignin, namely, levoglucosan and other anhydrous sugars; therefore, levoglucosan was used as the main tracer for wood burning emissions. Levoglucosan is emitted during combustion of wood cellulose , and itsn (BCff) ; this men (BCff) ,27,28,292.5 and cancer risk. This study focused on three such communities—South Natomas, Arden, and South Sacramento—and paired them with nearby non-EJ communities—T Street, Del Paso Manor, and Colonial Heights. Since wood smoke from residential burning is the largest single source of wintertime PM2.5 in Sacramento, and is typically due to local rather than urban- or regional-scale sources, we investigated the levels of PM2.5, hazardous air pollutants (HAPs), and wood smoke contributions to HAPs in these EJ and non-EJ communities, as well as the burning behavior of residents in these communities.Pollution can be higher in environmental justice (EJ) areas which are typically lower-income areas with a higher proportion of minority residents compared to non-EJ areas ,31,32,332.5 was used as the environmental index which in EJ Screen is a fusion of annual average monitored data and modelled data. The PM2.5 concentration in each census block is estimated by the EPA’s Office of Research and Development using a Bayesian space–time downscaling fusion model approach [Ambient air was monitored in three EJ and three non-EJ communities. The EJ communities were determined using the EPA’s EJ Screen tool . In EJ Sapproach ,35. Fina2.5 in the highest 10% nationally as EJ locations, and those in the lowest 50% EJ Index as non-EJ locations; see 2.5. The nearby community (within 5 miles) of Colonial Heights was selected as the non-EJ community to pair with the South Sacramento community. Sacramento Metropolitan Air Quality Management District (SMAQMD) then conducted public outreach through local community groups, neighborhood associations, and its Board Members and staff in a search of volunteers to host monitoring equipment.This results in a rank of the EJ Index for each US census block relative to all other census blocks. A higher EJ index indicates more potential for exposure/risk/proximity to certain facilities and/or a higher percentage minority population. Here, we identified communities with an EJ Index for PMThe HAPs and BC were measured at one site in each of the six communities. Quartz fiber filter samples for quantifying levoglucosan were collected at Del Paso Manor, T Street, and South Sacramento. PM was measured at all sites using low-cost sensors; details can be found in Mukherjee et al. . Details2.5 concentrations would be high on a particular day. Daytime (06:00 or 18:00) and nighttime (18:00 to 06:00) samples were taken, since mobile source emissions are relatively higher in daytime, and residential wood burning emissions are higher in nighttime [The HAPs were collected at a site in each community using five-liter Summa stainless-steel canisters at each site. Samples were collected for four sequential 12 h durations starting at either 06:00 or 18:00 PST on days when forecasts indicated that PMighttime ,26,37. T2.5, and BC data to assess whether there were any covariates that would indicate similar emissions sources.Canisters were shipped to Eastern Research Group (ERG) for analysis by EPA Method TO-15  using a Quartz fiber filters  were collected at Del Paso Manor, T Street, and a South Sacramento site on a forecast basis, generally at the same time as the nighttime HAP samples . Filters were analyzed for organic carbon (OC), elemental carbon (EC), and levoglucosan. Two daytime (06:00 to 18:00 PST) filters were also collected at each of these three sites during January 2017 to evaluate the difference between daytime and nighttime wood smoke concentrations, since residential wood smoke emissions generally occur in the evening when ambient temperatures begin to decrease. At the Del Paso Manor and T Street sites, Thermo Scientific 2025i sequential filtration samplers were used, with a sampling rate of 16.7 L/min. At the South Sacramento site, an AirMetrics mini-vol sampler was used, with a sampling rate of 5 L/min. Sample flow was evaluated before and after each sampling event. Five collocated filters were collected at South Sacramento to evaluate precision. Prior to sampling, filters were pre-baked for 12 h at 500 °C to remove residual organic compounds.Levoglucosan was determined using a Dionex DX-500 series ion chromatograph with detection via an ED-50/ED-50A electrochemical cell. This cell includes two electrodes: a pH-Ag/AgCl (silver/silver chloride) reference electrode and a “standard” gold working electrode. For the separation, a sodium hydroxide gradient and a Dionex CarboPac PA-1 column (4 × 250 mm) were used. The complete run time was 59 min with an injection volume of 100 µL. More details on the method can be found in Sullivan et al. ,44,45.wb and BCff. This method assumes that there are no other sources of BC such as coal dust. In the Sacramento emissions inventory, there is little to no impact from coal combustion emissions, so mobile sources and wood burning emissions are the main sources of BC.Magee Scientific model AE33 Aethalometers were deployed at a site in each community to measure BC. The AE33 collects ambient aerosol onto a filter tape, and then every five minutes measures the absorbance of the material deposited on the tape at 7 wavelengths, ranging from 370 to 960 nm. The BC concentration is from the 880 nm channel. While BC absorbs uniformly across all wavelengths at which absorbance is measured, brown carbon, which is produced by combustion of wood or other biomass, absorbs primarily in the lower wavelengths of the measured range ,47. A cowb and BCff, the model described by Sandradewi et al. [wb and BCff are then calculated by multiplying the BC value from the 880 nm channel by the percentages obtained in the previous step. The calculation is based on a model in which the total BC can be divided into pure black and pure brown carbon using the spectral dependence of the absorbing properties of each material. The spectral dependence is described by the Angstrom exponent (α). From the Beer–Lambert Law, the following equations can be obtained: abs(λ)x is the absorption coefficient for the BC type x (wb or ff) at wavelength λ (470 or 950).To calculate BCi et al.  and summi et al.  was usedwb measurements were compared to levoglucosan to assess the quality of the BCwb calculation.The Sandradewi method requires input values for the Angstrom exponents for pure black and pure brown carbon. For this study, an Angstrom component of 1 for the pure black carbon and a value of 2 for the pure brown carbon were used. These are the default values used by the Aethalometer ,49 and h2.5 mass and meteorological data were obtained from EPA’s air quality system (AQS) for the pre-existing routine monitoring sites at Del Paso Manor and T Street. At both sites, a MetOne beta attenuation monitor (BAM) 1020 collected hourly PM2.5 data, and an R&P 2025 sequential filter sampler was operated as the 24 h Federal Reference Method (FRM) for PM2.5 mass. The FRM filters were collected daily, and PM2.5 mass was determined by gravimetric analysis. Temperature, RH, wind speed, and wind direction data were collected at both sites using R.M. Young instrumentation. Dew point was calculated from temperature and RH measurements. Instrumentation and operations at these sites followed national guidance set by EPA on operations and methods. Wind and temperature data were used for the analysis of BC data. Each site with Aethalometer and canister measurements was assigned meteorological data from the weather station closest to that monitoring site. The Arden and Del Paso Manor communities were closest to the Del Paso Manor weather station, while the T Street, South Natomas, South Sacramento, and Colonial Heights communities were closest to the T Street weather station.Hourly PMp-value of a Student’s t-test is less than 0.05, i.e., significant at a 95% confidence level.Statistical methods used here included conditional bivariate probability function plots ,52, notcff, and BCwb existed across communities, a Kruskal–Wallis rank sum test was performed on HAP concentrations among the communities. The Kruskal–Wallis test was selected to assess how similar the distribution of data was among sites. Post-hoc Nemenyi tests were applied for pairwise comparisons of BC data between each community to determine which communities’ measurements differed significantly from each other; this test is useful for determining whether multiple groups of data are similar or not when there is a large amount of data [To determine whether significant differences in measured concentrations of BC, BC of data .m is the number of samples with a concentration greater than the specified percentile, n is the total number of samples, θ is a wind direction sector, and j is the wind speed interval, the following equation is used to determine CBPF.To identify potential sources of black carbon, a conditional bivariate probability function (CBPF) analysis  was usedThe CBPF is able to determine whether certain combinations of wind speed and wind direction have a high probability of producing concentrations above the specified percentile of data. By providing a greater degree of granularity to the analysis, CBPF facilitates the identification of sources that might not be detected by traditional CPF and can also be used to evaluate the characteristics of a source.wb, and BCff concentrations based on the 80th percentile of the concentrations of each pollutant. The calculations, including the 80th percentile threshold, were performed individually for each site, and radial plots displaying the probability of exceeding the 80th percentile relative to wind speed and direction were created.The polarPlot function available in the openair R package ,54 was uwb) and fossil fuel  combustion [x- and y-axis, e.g., benzene/2,2,4-trimethylpentane versus toluene/2,2,4-trimethylpentane. We examined all possible combinations of the 12 h HAPs relative to the wood smoke indicator BCwb or the mobile source indicator 2,2,4-trimethylpentane to determine under which indicator species the HAPs varied the most. Differences in how ratios change depending on the indicator species in the denominator can indicate which source  most affects the species in the numerator [Ratio:ratio plots were used to assess how individual species relationships changed as a function of known tracers of wood smoke  assess wood burning behavior; (2) evaluate wood burning activity by type of device used to burn; and (3) compare wood burning activity between EJ and non-EJ communities. Telephone interviews were completed with 900  Sacramento County residents who owned a wood or pellet burning device (other than an outdoor barbecue) either inside or outside their home. Addresses in each community were matched with listed landline and mobile phone numbers, then selected at random for interviewing.The margin of error associated with a sample of 900 completed interviews is ±3.3% at the 95% confidence level. That is, there is a 95% chance that the true population parameters lie within 3.3% of the sample statistics. For example, if a response category to a question was chosen by 50% of sample respondents, there is a 95% chance that if the entire county population were surveyed, that same response category would be selected by 46.7–53.3% of all residents (50% ± 3.3%). For the EJ communities, with 444 completed interviews, the margin of error at the 95% confidence level is ±4.7%, while that for the non-EJ communities, with 456 completed interviews, is ±4.6%.Most of the questions were asked in a closed-ended format which were categorized for quantitative analysis; responses to open-ended questions were not used in quantitative analysis. Interviews took approximately 8 min on average to administer. Respondents were screened for age (18+) and ownership of a wood or pellet burning device, and to confirm residency in Sacramento County. Interviewing took place from 2 December through 19 December 2016, and from 6 January through 22 January 2017. Surveys were not conducted on holidays because response rates are typically lower on those days. A full list of the survey questions is provided in the The precision of HAP measurements was determined using ten collocated  samples at T Street. Precision was calculated using the following formula, where A and B are the concentrations from the two collocated samples.R2 value of the collocated measurements when plotted on a scatter plot was 0.99, indicating high precision.The National Air Toxics Trends Station’s (NATTS) goal for high-precision data is ±15% . As showwb compared to PM2.5 from wood burning estimated from levoglucosan measurements. If BCwb has a strong relationship with levoglucosan, it can be used to determine wood burning PM concentrations from Aethalometer measurements. Levoglucosan was compared to BCwb concentrations when the filters were collected as shown in wb (R2 = 0.95). There were moderate correlations between BCwb and levoglucosan concentrations at the South Sacramento (R2 = 0.68) and T Street (R2 = 0.80) sites.Levoglucosan is a unique tracer for wood burning. It is typically collected via multi-hour filter measurements, so it cannot be measured continuously; significant labor and equipment are required to collect and chemically analyze the filters. The Aethalometer provides a calculated value of wood burning on an hourly basis and can run with little maintenance at multiple sites but requires validation that the wood burning calculation is correct. With both filter and Aethalometer measurements collected at the Del Paso Manor, South Sacramento, and T Street sites, we assessed how Aethalometer BC2.5 at the three sites where filters were collected. Filter results are summarized by site in 2.5 from wood burning was also calculated using hourly PM2.5 measurements. Median levoglucosan concentrations across sites ranged from 0.86 μg/m3 at T Street to 1.84 μg/m3 at Del Paso Manor; the highest measured levoglucosan concentration was 5.8 μg/m3 at Del Paso Manor on the night of 19 December, when PM2.5 averaged 69 μg/m3 during the 12 h of sampling. Overall, levoglucosan and wood burning PM concentrations were highest at the Del Paso Manor site; concentrations at T Street and South Sacramento sites were similar. At the Del Paso Manor site, 39% of the PM2.5  during the filter sampling periods was from wood burning. At the T Street site, wood burning accounted for 29% of the PM concentrations . At the South Sacramento site, the median concentration of wood burning PM2.5 was similar to that at the T Street site (6.8 μg/m3 at the South Sacramento site and 6.3 μg/m3 at the T Street site), and about half of the median concentration at the Del Paso Manor (13.5 μg/m3) site. These results suggest that wood burning emissions are higher around the Del Paso Manor site than around the other sites but are still responsible for a significant amount of the PM2.5 at T Street and South Sacramento.Levoglucosan was used to estimate wood burning PM2.5 is well distributed across these three sites during the daytime and is elevated around Del Paso Manor during the nighttime.Nighttime concentrations were compared to two daytime samples collected at each site. As discussed later in the results of the phone survey, residential burning occurs predominantly in the evening or nighttime, not during the day, so levoglucosan found during the daytime is likely carried over from the prior night. On 28 and 29 January 2017, samples were collected at 06:00 and 18:00 PST at each site to provide a rough comparison of daytime concentrations to nighttime concentrations. p < 0.05) at EJ communities compared to non-EJ communities. For example, benzene concentrations were 0.65 µg/m3 in EJ communities and 0.58 µg/m3 in non-EJ communities, on average. There was no significant difference between individual EJ/non-EJ site pairs for any species  when comparing individual site locations. The HAPs that were significantly higher in EJ communities were typically from mobile sources, including 2,2,4-trimethylpentane, an indicator for mobile sources [2.5 in the highest (worst) decile of the entire United States, predominantly due to the fact of mobile source emissions.Concentrations of 2,2,4-trimethylpentane, acrolein, benzene, ethylbenzene, m- and p-xylenes, and toluene were significantly higher , a very long-lived HAP that is no longer emitted in the US, were examined. It was phased out as part of the Montreal Protocol to ban chlorofluorocarbons (CFCs) to repair the ozone hole; because it has a very long residence time in the atmosphere, it is very homogeneous, and concentrations should be approximately 0.085 ppb everywhere in the United States [First, the day/night trends of carbon tetrachloride  rather than consistent robust differences in emissions on Wednesday and Thursday compared to other days.In Sacramento, the T Street site has a typical urban diurnal pattern with elevated morning BC, while the other sites have a nighttime peak in BC that is higher than the BC morning peak. For all sites, BCwb, and BCff measurements were combined with meteorological data to try to identify the likely source of these pollutants. The CBPF was used to identify wind speeds and directions associated with the highest quintile of concentrations. For all sites in this study, the highest quintile of concentrations of BC, BCff, and BCwb occurred at very low wind speeds associated with stable and stagnant conditions . This finding indicates that wood burning had little relation to HAPs at any site. As expected, carbon tetrachloride had little correlation with any other HAP (R2 < 0.12), since its concentration levels are representative of global background concentrations. The HAPs that are typically from fossil fuel combustion  had high correlations among themselves at every site (R2 > 0.70). This means that all of these species were from the same type of source, i.e., mobile source emissions.The association of individual HAPs with BCmbustion ,74,75,762.5. The relative importance of the two sources can be found by plotting the ratio of each species relative to tracers of wood smoke (represented by BCwb) or fossil fuel combustion . High correlation in a ratio:ratio plot indicates that there is little impact from the applied tracer on the species in question, whereas low correlation indicates a high effect from the tracer. Examples are given in wb, the HAPs were highly correlated on the ratio:ratio plots, but when divided by 2,2,4-trimethylpentane, the results clustered together tightly. These relationships indicate that a singular source of emissions dominated the species shown in the figures. Similar results were seen for most of the hydrocarbons . However, the oxygenated, nitrogenated, and chlorinated compounds, such as acetonitrile and acrolein, did not display this characteristic relationship when divided by either BCwb or 2,2,4-trimethylpentane, indicating that these compounds were not associated with BCwb or 2,2,4-trimethylpentane or were not measured due to the difficulty in measuring such compounds via canisters.Ratio:ratio plots were used to help understand the relative contribution of wood smoke and fossil fuel combustion to HAPs, OC, EC, and PMOverall, the survey results show no significant differences between EJ and non-EJ communities in the type of device owned, fraction of homes burning with fireplaces, fraction of homes burning day and night, fraction of homes burning only at night, or fraction of homes with EPA-certified burning devices. The only significant differences are that homes in non-EJ communities burn with an indoor device more often than homes in EJ communities do and, thus, have a higher relative number of burn days than EJ communities. Specifically, the most commonly owned device was an indoor fireplace, owned by 79–80% of all respondents in non-EJ and EJ communities; other devices, such as pellet stoves, accounted for less than 10% of responses. Those respondents who do burn with any device do so between one and two days per week. This frequency increases with the more devices a respondent owns. Of all respondents owning an indoor fireplace, those in non-EJ communities burn significantly more than those in EJ communities . Among respondents who burn with fireplaces, those in non-EJ communities are burning significantly more often than respondents in EJ communities .wb results. Non-EJ communities have more burning device usage than EJ communities and, thus, a significantly higher relative number of burn days. This difference in the number of burn days likely means there are more emissions from wood burning in non-EJ communities which corresponds with the significantly higher observed BCwb in non-EJ communities. However, HAPs have an opposite relationship; for example, in the EJ communities where less wood burning occurs than in non-EJ communities, concentrations of multiple HAPs are higher. These results support all other analyses of the ambient data showing that wood burning has little impact on ambient HAP concentrations.ff were significantly higher at EJ communities than at non-EJ communities. Even though wood smoke emissions can contribute to HAPs, results from this study consistently showed that wood burning has little influence on the ambient levels of HAPs and that fossil fuel combustion was the main source of HAPs. The BCwb had a very high correlation with collocated measurements of the wood burning tracer levoglucosan (R2 across three sites of 0.68 to 0.95), on the high end of reported literature values, indicating that BCwb was a robust indicator for wood burning in Sacramento. Thus, Aethalometer BCwb data could be used from all sites to assess wood burning contributions. Wood burning accounted for 29–39% of the nighttime PM2.5 at the two sites with hourly PM2.5 and filter measurements (T Street and Del Paso Manor). The BCwb concentrations were significantly higher at non-EJ communities than at EJ communities. As shown in the phone survey results, the higher BCwb concentrations in non-EJ communities were mostly likely due to the more burning with indoor fireplaces in the non-EJ communities. Wood burning was not a significant source of HAPs. The HAPs and BCff were higher in EJ communities compared to non-EJ communities, indicating mobile source emissions were likely higher in EJ communities.In this first detailed community monitoring study during the winter in Sacramento County, we found that concentrations of six HAPs  and BC


The study on durability of carbon fiber reinforced plastics (CFRP) in complex environments is critical because of its wide applications. Herein, mechanical behavior of carbon fiber reinforced epoxy composites in the fatigue process were investigated under different humidity via molecular dynamics (MD) simulation method. Transversely isotropic atom based models were established to simulate the structure of CFRP at the atomistic level. Owing to the weak performance in vertical fiber direction, mechanical behavior in a 90° orientation was investigated. Mean stress and energy were both employed to describe the evolution of mechanical performance while mean squared displacement (MSD), radius of gyration (Rg), and free volume were performed to describe the evolution of structural change during the fatigue process. The results show that the humidity led to a weakened interfacial adhesive performance. Free volume became larger under cyclic load, which caused the water molecules to diffuse into the inside of epoxy resin. The distance between the matrix and fiber became larger in the dry system while it reduced because of the diffusion of water molecules in wet system. The rate of performance degradation decreased with the increase in humidity because of poor initial performance at high humidity.  Owing to their excellent material performance such as extremely high specific modulus, large specific strength, and great conductive properties, carbon fiber reinforced plastics (CFRP) are widely used in the aerospace, civil, construction, power, shipping, and other industries. Therefore, several researchers have proposed that it is necessary to study the fatigue properties of CFRP because of its specific applications and complex fatigue behavior. CFRP can be used in the moving structures such as airplanes and helicopters . When itTill now, the fatigue performance analysis has primarily been experimental. The general procedures for fatigue tests are similar. The evolution of specimen stiffness is monitored by the response of stress or strain and the microstructural transformation can be observed by checking the sliced samples under electronic microscope . The strMa et al.  investigHowever, unexpected problems arise in our study on influence of humidity on fatigue performance of CFRP in laboratory. The performance of the specimens varied so much that more parallel experiments were required to eliminate data volatility. Also, from our experience with fatigue testing, the occasional power break, machine failure, and other reasons have different degrees of impact on the experimental data. All of these problems lead to a significant increase in the time and money requirements. Otherwise, only structural changes are observed at the micrometer scale and the observation is discontinued. With the development of computer science and theory of molecular simulation, the molecular dynamics (MD) method has been widely used in the field of computational materials science. Materials behavior can be simulated by the partial movement based on Newton’s theory of motion and potential function based on quantum mechanics. The MD method is widely used in studying the basic performance of materials, such as tensile properties, shear properties, Young’s modulus , glass tHerein, we have studied the performance degradation in vertical fiber orientation and explored the influence of humidity on the fatigue performance of composites via MD method. Besides, some of the phenomenon during fatigue are explained at atomic scale. Multilayer molecular model is widely used to simulate the composites ,30,31 anThe consistent-valence force field (CVFF) was used in the simulation of graphene-epoxy nanocomposites . CVFF cobK, θK, ΦK, and χK are the force constants. b0, θ0, Φ0, and χ0 are the equilibrium bond length, bond angle, torsion angle, and improper angle, while n is the periodicity parameter. ijA and ijB are the square root of product between iA with jA and iB with jB. C and ε are the energy-conversion constant and permittivity, while ijr is the distance between the atom i and j with charges iq and jq. Herein, an all-atom model was employed as it is easy to implement. The model employed in Yu’s research  is used There are two methods to build epoxy resin models. Yu et al.  compared3 is shown in An amorphous cell composed of 30 representative molecules can be obtained by using the method chosen above. The crosslinking model with an initial density of 0.8 g/cmThe method of constructing graphene reinforced epoxy resin is using the Build Layer module in the commercial software Materials Studio. The build Layer module was used to build multi-layers graphene and epoxy resin as a multi-layered system. Polymer-water-graphene-water-polymer model was used to simulate the system with humidity to make the modeling more intuitive and simple. The model for water molecule was TIP3P. Parameters of TIP3P are listed in The moisture content of systems with different humidity are listed in Before performing the strain-control fatigue cyclic loading, an equilibrium system should be first set-up. The Langevin thermostat was applied on the initial structure within NVE ensemble for 2 ns at 298 K to perform Brownian dynamics simulation of a molten polymer. The system was then equilibrated at the NPT ensemble for 2 ns at 298 K with the time step of 0.5 fs. Finally, a stable model was obtained. The NPT ensemble was controlled by the Nose-Hoover thermostat and Nose-Hoover barostat. The time integration of the motion equations was conducted using Velocity-Verlet integration. Final density of equilibrium systems with different humidity are listed in Molecular models with different humidity are shown in −6/ fs and the time step was 1 fs. Stress calculation method was based on the Virial theory that is widely used in the atomic scale. The whole process was completed using open source software LAMMPS. Herein, we primarily investigated the impact of humidity on the fatigue performance and ignored other factors which can be considered in further work. Before applying the fatigue loading, the model was monotonically deformed to the initial strain within the NPT ensembles. The pressure in the unloaded direction was kept at 1 atm. Strain rate was a constant value of 10The stress-strain curves are shown in ε0 is the initial strain, B is the amplitude, t is the time, and T is the period. Herein, ε0, B, and T were 5%, 0.5%, and 1000 fs, respectively. Mean stress [minσ and maxσ are the minimum stress and maximum stress per cycle. Some researchers have predicted the long-term performance using short-term performance with a certain function. Mallick et al. [S is the mean stress per cycle, N is the cyclic number, and a and b are the constant values. Notably, b can be regarded as the speed of the performance degradation and a can be regarded as the initial performance. Fatigue load controlled by strain was applied to the system and herein, primarily, the fatigue behavior was studied in vertical fiber direction (90°). Fatigue cyclic loading was performed using sinusoidal function in the loading direction, the pressure in the unloaded direction was kept at 1 atm. The loading curve can be expressed as:n stress  is widelk et al.  found thk et al.  used an k et al.  employedAs shown in Comparing value a and b in each model with increase in humidity in For the composites, the total performance and interfacial performance are equally important. Evolution of energy can be used to characterize some microscopic phenomena. In this section, total potential energy and interfacial energy were relatively studied. Total energy includes bond, angle, dihedral, improper, van der Waals, and coulomb energy. Among them, bond, angle, dihedral and improper belong to the bond energy, van der Waals and coulomb belong to non-bond energy. The cause of performance degradation can be analyzed by analyzing the evolution of energy. Herein, systems with different humidity were studied. The results of systems with humidity were almost the same as those of the system without humidity. Therefore, we have only displayed the results of the dry system to avoid figures too jumble. The evolution of individual potential energy is shown in From Interfacial energy can reflect the change in distance between the epoxy resin and graphene. The evolution of interfacial energy is shown in As It is critical to investigate the change in structure because macroscopic mechanical response and microscopic energy change are both dependent on the microscopic structural change. In this section, we primarily studied the radius of gyration (Rg), mean-squared displacement (MSD), and free volume fraction (FVF). ir(t) is the current position of the atom i in the group and ir(0) is the original position of the atom i in the group. The x, y, and z components of the mean-squared displacement tensor can be determined using the same formula.The mean-squared displacement was calculated as the root mean square distance between its centre of mass position of fracture and each monomer position in this fracture:As shown in gR2 value in the formula below:M is the total mass of fracture and cmr is the center of mass position of the fracture. The x, y, and z components of the radius of the gyration tensor can be determined using the same formula. This property indicates the level of deformation. To further clarify the results, the initial value of the radius of gyration was set to 0 and relative mean value of radius of gyration was employed to describe the structural change during the fatigue process. The radius of gyration was a measure of the size of the group of atoms, and was computed as the square root of the As per Free volume fraction which reflects the porosity in a molecular system was explored to study the diffusion conditions of water molecules. A molecular model consisting of pure epoxy resin was established and same fatigue cyclic loading method was applied to the pure epoxy system as before. The number of representative units here was same as it was in the composites molecular model above. The free volume fraction was calculated using Multiwfn, an open source software package. (1)Presence of water in the polymer-graphene interface weakened the stiffness and interfacial adhesive performance in the vertical fiber direction. Higher humidity led to a weakened stiffness and adhesive performance.(2)During the process of transversal fatigue, molecular fragments tended to align along the loading direction leading to performance degradation. With regards to microscopic energy, this phenomenon is primarily reflected by the decline of van der Waals, while in terms of macroscopic performance, it is mainly reflected by the decrease in mean stress. (3)During the process of fatigue, interfacial energy of dry system decreased with the cycle numbers. This phenomenon indicates that the distance became larger. However, different results and increase in interfacial energy were observed in the wet system. To understand this phenomenon, another molecular model consisting of pure epoxy resin was established and the free volume of the model before fatigue and after fatigue were relatively calculated. Free volume amplified slightly after fatigue. Increase in the free volume in epoxy resin made it easy for the water molecules to diffuse into the inside of epoxy resin. The diffusion of water molecules reduced the water layer in the polymer-graphene. The thinner water layer led to a stronger interfacial adhesion properties. This conclusion can be confirmed by the evolution of interfacial energy and the mean squared displacement of the epoxy resin and water molecules during fatigue. Besides, interfacial energy of the dry system decreased with the cycle numbers. This phenomenon indicates that the distance became larger. (4)Higher humidity led to a slower rate of performance degradation during fatigue as the performance degraded fast in first several cycles and less prominently in the last several cycles. The performance of composites with high humidity was so poor that no more significant degradation occurred. However, performance continues to decrease because molecular arrangement is the main cause of the performance degradation, even if the interfacial performance improved slightly. In addition, initial performance and rate of performance degradation show a linear relationship with the change of moisture content.Molecular dynamics simulations were used to assess the effect of humidity on the fatigue performance of composites. Four molecular models of composites with different moisture contents were formulated, and for comparison, a molecular model without moisture content was also established. Mean stress was calculated to describe the change in mechanical performance. Interfacial energy was used to describe the interfacial adhesive performance. Mean square displacement and radius of gyration were both used to explain the microstructural change in the process of fatigue. Main conclusions are as follows:This research can provide reference for prospective anti-fatigue design for composites in humidity environment.


Such non-linearly enhanced strain exceeds the values predicted for harmonic vibrations with the same root mean square (RMS) amplitude by more than one order of magnitude. Our work holds promise for dynamical strain engineering and dynamical strain-mediated control of light-matter interactions in 2D materials and related heterostructures.Graphene and related two-dimensional (2D) materials associate remarkable mechanical, electronic, optical and phononic properties. As such, 2D materials are promising for hybrid systems that couple their elementary excitations  to their macroscopic mechanical modes. These built-in systems may yield enhanced strain-mediated coupling compared to bulkier architectures, e.g., comprising a single quantum emitter coupled to a nano-mechanical resonator. Here, using micro-Raman spectroscopy on pristine monolayer graphene drums, we demonstrate that the macroscopic flexural vibrations of graphene induce dynamical optical phonon softening. This softening is an unambiguous fingerprint of dynamically-induced tensile strain that reaches values up to ≈4 × 10 Here, the authors use Raman spectroscopy on circular graphene drums to demonstrate dynamical softening of optical phonons induced by the macroscopic flexural motion of graphene, and find evidence that the strain in graphene is enhanced under non-linear driving. These efforts triggered the study of 2D resonators beyond graphene, made for instance from transition metal dichalcogenide layers18 and van der Waals heterostructures21. In suspended atomically thin membranes, a moderate out-of-plane stress gives rise to large and swiftly tunable strains, in excess of 1%23, opening numerous possibilities for strain-engineering24. These assets also position 2D materials as promising systems to achieve enhanced strain-mediated coupling28 of macroscopic flexural vibrations to quasiparticles  and/or degrees of freedom . Such developments require sensitive probes of dynamical strain. Among the approaches employed to characterise strain in 2D materials, micro-Raman scattering spectroscopy29 stands out as a local, contactless and minimally invasive technique that has been extensively exploited in the static regime to quantitatively convert the frequency softening or hardening of the Raman active modes into an amount of tensile or compressive strain, respectively33. Recently, the interplay between electrostatically-induced strain and doping has been probed in the static regime in suspended graphene monolayers34. Dynamically-induced strain has been investigated using Raman spectroscopy in bulkier micro electro-mechanical systems36, including mesoscopic graphite cantilevers37 but remains unexplored in resonators made from 2D materials.Since the first demonstration of mechanical resonators made from suspended graphene layers38 and dynamical strain-mediated control of light-matter interactions.In this article, using micro-Raman scattering spectroscopy in resonators made from pristine suspended graphene monolayers, we demonstrate efficient strain-mediated coupling between "built-in” quantum degrees of freedom  of the 2D resonator, and its macroscopic flexural vibrations. The dynamically-induced strain is quantitatively determined from the frequency of the Raman-active modes and is found to attain anomalously large values, exceeding the levels of strain expected under harmonic vibrations by more than one order of magnitude. Our work introduces resonators made from graphene and related 2D materials as promising systems for hybrid opto-electro-mechanics2 substrate. The resulting graphene drum is capacitively driven using a time-dependent gate bias Vac ≪ Vdc and Ω/2π the drive frequency. The DC component of the resulting force  and integrated intensity of a Raman feature42 . Biaxial strain is expected around the centre of circular graphene drums22 and the large Grüneisen parameters of graphene 32 allow detection of strain levels down to a few 10−5. The characteristic slope 42. This difference allows a clear disambiguation between strain and doping (see “Methods” section for details).The Raman spectrum of graphene displays two main features: the G mode and the 2D mode, arising from one zone-centre  phonon and from a pair of near-zone edge phonons with opposite momenta, respectively see Fig. 29. Both 0/2π ≈ 33.8 MHz for Vdc = −6 V . At Vdc = −9 V, the 4 ± 0.5 cm−1 2D-mode downshift relative to its value near εs = 3 ± 0.3 × 10−4 that agrees qualitatively well with the value εs = 2 ± 0.2 × 10−4 estimated from the gate-induced upshift of Ω0 , with Vac increasing from 0 to 150 mV and applied at a drive frequency that tracks the Vac-dependent non-linear softening of the mechanical resonance frequency zrms. The correlation plot between ω2D and ωG reveals a linear slope near 2 ; in our experimental geometry they indicate an equilibrium position upshift Δξeq by up to ≈12 nm  and arises from the time-averaged resonant vibrations of the graphene drum. Starting from a reference recorded at Vdc = −8 V and Vac = 0 mV, εd recorded under resonant driving at Vac = 150 mV (where zrms ≈ 9 nm) is as high as the static strain εs induced when ramping Vdc from 0 V to  −8 V (where ξ ≈ 60 nm). Along these lines, the small yet observable broadenings ΔΓG,2D of the Raman features  under Vdc = −6 V with and without resonant driving. Very similar results are observed when performing a line-scan along the perpendicular direction  SiN membranes51 showing RMS displacement saturation similar to Fig. 44, geometrical52 or electrostatically-induced53) may lead to internal energy transfer towards harmonics of the driven mode  are rectified under strong non-linear driving, an effect that further increases the discrepancy between the time-averaged εd we measure and The large values of entclass1pt{minimaentclass1pt{minima,2D Fig.  is smallεd may require microscopic models that may go beyond elasticity theory54 and explicitly take into account the ultimate thinness and atomic structure of graphene56.Combining multi-mode opto-mechanical tomography and hyperspectral Raman mapping on larger graphene drums  would allow us to test whether localisation of harmonics occurs in graphene and to possibly correlate this phenomenon to the dynamically-induced strain field. More generally, unravelling the origin of the anomalously large −4. Realistic improvements of our setup, including phase-resolved Raman measurements36 could permit to probe dynamical strain in finer detail, including in the linear regime, where the effective coupling strength28 could be extracted. For this purpose, larger resonant displacements may be achieved at cryogenic temperatures. In addition, graphene drums, as a prototypical non-linear mechanical systems, can be engineered to favour mode coupling and frequency mixing, which in return can be readout through distinct modifications of their spatially-resolved Raman scattering response.Concluding, we have unveiled efficient coupling between intrinsic microscopic degrees of freedom  and macroscopic non-linear mechanical vibrations in monolayer graphene resonators. Room temperature resonant mechanical vibrations with  ≈10 nm RMS amplitude induce unexpectedly large time-averaged tensile strains up to  ≈ 4 × 1033 could be used as invaluable probes of in-plane and out-of-plane dynamical strain, respectively. Strain-mediated coupling could also be employed to manipulate the rich excitonic manifolds in transition metal dichalcogenides57, as well as the single photon emitters they can host59. More broadly, light absorption and emission could be controlled electro-mechanically in nanoresonators made from custom-designed van der Waals heterostructures60. Going one step further, with the emergence of 2D materials featuring robust magnetic order and topological phases61, that can be probed using optical spectroscopy, we foresee new possibilities to explore and harness phase transitions using nanomechanical resonators based on 2D materials63.Our approach can be directly applied to a variety of 2D materials and related van der Waals heterostructures. In few-layer systems, rigid layer shear and breathing Raman-active modes2/Si substrates, using a thermally assisted mechanical exfoliation scheme as in ref. 64. The pattern is created by optical lithography followed by reactive ion etching and consists of hole arrays (5 and 6 μm in diameter and 250 ± 5 nm in depth) connected by  ~1 μm-wide venting channels. Ti(3 nm)/Au(47 nm) contacts are evaporated using a transmission electron microscopy grid as a shadow mask34 to avoid any contamination with resists and solvents. Our dry transfer method minimises rippling and crumpling effects65, resulting in graphene drums with intrinsic mechanical properties (see ref. 31 and Supplementary Note Monolayer graphene flakes were deposited onto pre-patterned 285 nm-SiO−5 mbar). The drums are capacitively driven using the Si wafer as a backgate and a time-dependent gate bias a is the drum radius, ϵ0 the vacuum dielectric constant, ξ the static displacement, dvac the graphene-SiO2 distance in the absence of any gate bias, 2 layer. This force contains a static component proportional to ξ and a harmonic driving force proportional to Electrically connected graphene drums are mounted into a vacuum chamber , with m0 the pristine mass of the graphene drum. As discussed in details in Supplementary Note 66, as expected for a resist-free fabrication process.A 632.8 nm HeNe continuous wave laser with a power of  ~0.5 mW is focused onto a  ~1.2 μm-diameter spot and is used both for optomechanical and Raman measurements. Unless otherwise stated,  and charge inhomogeneity67. Considering our experimental geometry, we estimate a gate-induced doping level near 3 × 1011 cm−2 at the largest 66. In the dynamical regime, the RMS modulation of the doping level induced by the application of Vac is typically two orders of magnitude smaller than the static doping level and can safely be neglected. Similarly, the reduction of the gate capacitance induced by equilibrium position upshifts discussed in Figs. The Raman scattered light is filtered using a combination of a dichroic mirror and a notch filter. Raman spectra are recorded using a 500 mm monochromator equipped with 300 and 900 grooves/mm gratings, coupled to a cooled CCD array. In addition to electrostatically-induced strain, electrostatically-induced doping might in principle alter the Raman features of suspended graphene≲1011 cm− and char68 is more than three orders of magnitude shorter than the mechanical oscillation period, Raman scattering processes provide an instantaneous measurement of εd. However, since our Raman measurements are performed under continuous wave laser illumination, we are dealing with time-averaged dynamical shifts and broadenings of the G-mode and 2D-mode features. Raman G-mode and 2D-mode spectra are fit using one Lorentzian and two modified Lorentzian functions, as in refs. 67, respectively ps68 is mSupplementary InformationPeer Review File