Despite the high incidence of chronic obstructive pulmonary disease (COPD) in Aboriginal communities in Australia, Aboriginal Health Workers (AHWs) have limited knowledge about effective management.To evaluate an online education program, co-designed with AHWs and exercise physiologists (EPs) or physiotherapists (PTs), to increase knowledge about COPD and its management.AHWs and EPs from four Aboriginal Community Controlled Health Services (ACCHS) were recruited. An Aboriginal researcher and a physiotherapist experienced in COPD management and pulmonary rehabilitation (PR) delivered seven online education sessions. These sessions used co-design principles and an Aboriginal pedagogy framework ‘8 Ways of learning’, which incorporates Aboriginal protocols and perspectives to realign teaching techniques and strengthen learning outcomes. Topics covered were: How the lungs work; What is COPD; Medications and how to use inhalers and COPD Action Plans; Why exercise is important; Managing breathlessness; Healthy eating; Managing anxiety and depression. After each session, AHWs with support from EPs, co-designed education ‘yarning’ resources using Aboriginal ways of learning to ensure topics were culturally safe for the local Aboriginal community and practiced delivering this at the following session. At the end of the program participants completed an anonymous online survey  to assess satisfaction, and a semi-structured interview about their experience of the online education.Of the 12 participants, 11 completed the survey . Most (90%) participants strongly agreed or agreed that the online sessions increased knowledge and skills they needed to support Aboriginal patients with COPD. All (100%) participants felt: their cultural perspectives and opinions were valued and that they were encouraged to include cultural knowledge. Most (91%) reported that delivering their own co-designed yarning scripts during the online sessions improved their understanding of the topics. Eleven participants completed semi-structured interviews about participating in online education to co-design Aboriginal ‘yarning’ resources. Themes identified were: revealing the Aboriginal lung health landscape; participating in online learning; structuring the online education sessions; co-designing with the facilitators.Online education using co-design and 8 Ways of learning was rated highly by AHWs and EPs for improving COPD knowledge and valuing cultural perspectives. The use of co-design principles supported the cultural adaptation of COPD resources for Aboriginal people with COPD.PROSPERO (registration number: CRD42019111405).The online version contains supplementary material available at 10.1186/s12889-023-15508-y. Aboriginal and Torres Strait Islander people, the Indigenous peoples of Australia , have a higher burden of chronic obstructive pulmonary disease (COPD) than other Australians –4, whichAboriginal Community Controlled Health Services (ACCHS) are incorporated organisations, governed by a Board consisting of local Aboriginal community members. ACCHS were established to address the inadequacies of mainstream health services to deliver culturally safe care for Aboriginal people , 12. ACCEnhancing a capable and trained Aboriginal health workforce has shown to improve health care access and outcomes for Aboriginal people and positively contribute to the performance, quality and deliverable outcomes of the Aboriginal primary health sector . ACCHS fDeconstruct/reconstruct ; Community Links (identification of key community stakeholders to be consulted about projects); Learning maps ; Story Sharing ; Symbols and images ; Land links ; Non-verbal ; and Non-linear   that I know that are diagnosed, but I think they should be diagnosed since starting the BE WELL project.” (AHW_05)AHWs and EPs perceived Aboriginal people have low access and limited knowledge of lung health services provided by ACCHS and mainstream health services, such as PR. AHWs perceived an ACCHS would be the first point of contact for Aboriginal people with COPD, but acknowledged their ACCHS had low numbers of existing patients diagnosed with COPD. The ACCHS in the BE WELL project had only recently commenced offering PR and most previous clinical discussions related to lung disease focussed on quitting smoking and nicotine replacement therapy.“And you know, ever since being able to learn more about the lungs and COPD, I'm able to identify the patients when they do come into the clinic.” (AHW_11)Since participating in the BE WELL project several AHWs reported they were now able to identify existing ACCHS patients at risk of COPD and able to refer them to PR.“I don't think they go too often [to hospital]. It's not their meeting place.” (EP_01)EPs mentioned delivering PR by their ACCHS was important, considering mainstream health services struggle to engage Aboriginal people because those services are perceived as culturally unsafe.“The hardest thing for us now [at ACCHS] is to get participants and then get them to regularly attend.” (EP_01)An EP also spoke about needing to work with Aboriginal patients to overcome fear and avoidance of breathlessness during exercise training and maintaining their ongoing participation in an 8-week PR program.EPs also spoke of the need to strengthen the cultural component of lung care by delivering programs on Country away from the clinical environment, spending additional time listening to and allowing Aboriginal people to share their ‘story’, and increasing access to care by improving referral processes within their ACCHS for assessment and management."I think the shorter sessions are probably better." (EP_07)Overall AHWs reported the education sessions were successfully adjusted to an online delivery mode using VoIP technologies. AHWs positively described their experience using VoIP technologies as it enabled the educational content to be packaged into small manageable topics around other work demands. This approach supported thorough explanation of each of the seven COPD topics and enabled AHWs to ask questions and revisit educational material.“I enjoyed it. – [Facilitator] went through the sessions really well. [Facilitator] explained every bit, you know, every detail, bit by bit, in the way that I was able to understand.” (AHW_ 11)AHWs mentioned some technical challenges such as limited Wi-Fi connectivity and using a work computer with a broken camera.“I think particularly for the Aboriginal Health Worker they are a little bit quiet and… felt a bit of shame. I suppose both, you know, when you're talking on video conferencing and particularly in the beginning. In the end, they just opened up completely…I think it was really quite good.” (EP_01)The EPs perception of the use of VoIP technologies varied. Two EPs reported that although online delivery ran smoothly and they got a lot out of the online sessions, their preference would be for face-to-face delivery to enable practical and interactive education. One of these EPs also mentioned they had initially suggested that the education sessions could be provided as a one-day refresher. Positive perspectives about using VoIP technologies were that they were nearly as good as attending in person because information and pictures could be brought up on the computer screen, and questions could always be asked of the facilitators. An EP mentioned using VoIP technologies was better than providing the information quickly face-to-face over two days. From their perspective, the best aspect was having a one week break in between each session to develop yarning scripts. The same EP also reflected on the experience of VoIP technologies for AHWs.“This isn't like a GP just reading off a piece of paper. Look, we made it into a good discussion, but we [AHWs] made it. So there's feedback, there's input to start more yarnings and kind of branch off each other. Yeah, I think yarning will be a good thing.” (AHW_03)All AHWs reported that engaging with the education sessions, preparing their own yarning scripts, applying the stimulus questions and demonstrating how they would deliver their own yarning sessions to colleagues and the facilitators reassured to them they had interpreted the seven COPD topics correctly. The sessions were reported as being a culturally safe and a self-paced learning environment, where AHWs were driving their own knowledge development, enabling them to confidently design their own yarnings. Several AHWs also spoke about the structured, clear and culturally safe way the scripts they developed enabled them to yarn about complex lung health information simply with Aboriginal people.“We worked together and I let her present it [the yarning script], cause it's her mob [Aboriginal community], her program. So I was really supporting her delivering the program.” (EP_01)For the EPs, the education sessions were reported as helpful and more as a refresher, complimenting their existing lung health clinical skills and strengthening their Aboriginal cultural knowledge. Consistently EPs expressed professional respect for the AHWs, emphasising the value of collegiality, shared decision-making and autonomy. An EP observed that an AHW found it confronting initially to allocate time and to prepare yarning scripts. As a result, the EP supported the AHW to better prepare and deliver their yarning scripts. EPs also reported that the education and yarning sessions enabled them to have confidence that AHWs were seeing good examples of patients with lung disease and were aware of what to look out for clinically.“Yeah, especially the medications. That was so far out of my scope at the time.” (AHW_03)Delivering information into manageable topics was reported to increase comprehension and reduce complexity. Subsequently this scaffolding approach was reported as enabling the AHW to make greater sense of the COPD information.“I think, medication wise, that's one for me that I still definitely need a little bit more assistance with, so that was good to be able to go over them again”. (EP_07)EPs consistently reported the topics were pitched appropriately and included the right amount and type of information for AHWs, Aboriginal patients and covered everything they needed to know.‘clear’ and ‘culturally safe’. Resources defined as useful were the pictures, diagrams, booklets, medication charts, PowerPoint slides and videos of the correct use of inhalers and of patients with lung disease. An AHW mentioned practical teaching aides, such as placebo inhalers and spacers were resources that should be used more often in future sessions. Some AHWs stated using videos particularly helped them learn about the symptoms of lung disease.“I have not seen anyone with COPD before. Well, I may have, but I didn't know what it is. So, I thought [using videos of patients with lung disease] was great.” (AHW_03)AHWs provided consistent positive feedback about the range of resources used during the online sessions. Resources were described as All EPs mentioned the resources were useful in their role as supervisors of AHWs. The EPs also perceived the resources as culturally appropriate and helpful. An EP reported the resources had been valuable to their role and ACCHS beyond the BE WELL project and patients with COPD, as the format can be applied across other health programs. Future sessions could be enhanced by incorporating additional resources such as real-life scenarios and videos of patients at the beginning of each session.AHWs and EPs agreed that the number, length and frequency of each topic and the education sessions were broadly right. Short 30-min sessions were preferred as these allowed staff to maintain focus. An EP mentioned the timing of the education sessions made it hard for them to attend and support AHWs, and that over time attending became more of a chore.knowledgeable’ and perceived them as ‘culturally competent’ and ‘professionally respectful’ and ‘understood’ the demands of the AHWs roles and their learning needs. All AHWs felt that their cultural knowledge and perspectives were respected by the facilitators. They also reported the facilitators had created a culturally safe learning environment for Aboriginal organisations and staff to engage in learning by incorporating Aboriginal protocols, such as an Acknowledgement of Country and using resources depicting Aboriginal people.AHWs perspectives of the facilitators were overwhelmingly positive. AHWs consistently described the facilitators as ‘‘unapproachable’. The AHW stated this occurred when minimal staff from their ACCHS attended the first online session which made the session confronting for a lone AHW. The experience resulted in the ACCHS regrouping and identifying how all staff could attend future sessions around clinical responsibilities.AHWs described the facilitator (JA) as explaining information in ways the AHWs could understand, which increased AHWs self-reported knowledge. The facilitator had engaged the AHWs in relaxed discussions and provided feedback about the yarning scripts that the AHWs had created. This allowed AHWs to share their perspective, knowledge and yarning approaches openly and deeply. An AHW reported one occasion when the facilitators seemed “You know, they were really good at facilitating us to create our own yarn, and also our own ideas for how the program should be run.” (EP_01)EPs described the facilitators’ attributes similarly to the AHWs. They felt the facilitators supported their learning and encouraged them to contribute to discussions exploring the applicability and adaptation of the educational content and material and the overall BE WELL program to fit the local Aboriginal community context. The EPs also stated the facilitators were responsive to the EPs and AHWs ideas and ways of being, such as how they and the ACCHS worked with community.“[The facilitators] pretty much gave us free rein…. Well, not to talk us up, but, you know, they [the facilitators] loved what we came up with. So, yeah, like they literally gave us a lot of wriggle room.” (AHW_ 03)Most AHWs described the facilitators’ expectations to attend the online sessions, prepare and present their yarnings as realistic and reasonable. AHWs felt encouraged to make choices and changes to adapt the education sessions.“Because our transport driver called in sick that day, so I had to fill in [and missed a session].” (AHW_08)Two AHWs from different ACCHS highlighted the intensity and demands of the AHW role, while participating in the online education sessions.‘tough’ and agreed with an AHW at their service that expectations were too high."The expectation felt too much on a couple of the health workers, but that's not the facilitator’s fault. That's just, once again time management, and just being super busy, and juggling lots of things. It can just feel like another thing to have to do." (EP_06)Three of the four EPs mentioned the facilitators were flexible, accommodating and did not expect too much when the EPs were attending the session or helping the AHWs prepare their yarning scripts. The other EP acknowledged the role of an AHW is “It [using co-design] was just trying to get it more culturally appropriate. So it's not just going to be like the typical GPs talk. Because that’s when you lose people, that's when your gonna lose community. So it's just a yarn.” (AHW_03)All AHWs and EPs agreed co-design occurred. AHWs reported feeling supported by the facilitators and were able to transform the COPD educational material into their own words to better engage the local Aboriginal community.“We haven't as of yet [included local Aboriginal stories or language], because there was a lot of new information for someone learning about COPD.” (AHW_05)AHWs simplified the clinical information and incorporated local knowledge, terms and phrases, as well as their personal experiences of the local Aboriginal community. This approach made the yarning resources their own and was reported as relieving the pressure and expectation they initially felt co-designing the educational material. However, they felt that there were more Aboriginal cultural references that could be included in the future as they developed their knowledge and confidence and began to deliver yarnings sessions within their respective BE WELL programs.In addition, EPs commented the facilitators asked enquiring questions of the team about the format, session frequency, timing, topics and whether the local BE WELL teams’ needs were being met, which supported co-design and local adaptation.The study aimed to explore the experiences of AHWs and EPs from four ACCHS engaged in online education sessions to build knowledge and skills to co-design education ‘yarning’ material for Aboriginal people with COPD. The quantitative survey highlighted the benefits of the online education sessions to build AHWs and EPs capability to co-design COPD yarning resources. The online sessions were also reported as being helpful in allowing AHWs and EPs to support Aboriginal patients with COPD. Overall, the online learning space that was created in the study allowed AHWs to feel their cultural perspectives and professional opinions were valued and respected. Many findings of the survey were crystalised in the qualitative interviews, supporting triangulation . ParticiAdvancements in technology-enabled learning are revolutionising face-to-face education towards online platforms and classrooms, which has potential to support learning and self-management of patients with COPD, PR programs broadly, as well as how health professionals access and engage with education , 43. TheAHWs and EPs highlighted that the online education sessions were culturally safe spaces to ask questions and seek advice and feedback. AHWs expressed they experienced professional independence and autonomy and collaborated with facilitators and EPs, which supported their knowledge development and facilitated local accountability to confidently co-design their own yarning material. EPs specifically found the online education sessions which used 8 Ways of learning culturally helpful, especially for their supervisory role with AHWs. The sessions also further enhanced their existing clinical knowledge and experience in managing people with COPD.Both-Ways Seeing or Two-Eyed Seeing [The EPs’ cultural competence and support of AHWs was evident. This was important as AHWs within the ACCHS sector have reported negative experiences working with allied health professionals . EPs cond Seeing –50. WhilOverall, the study revealed COPD in Aboriginal communities is poorly understood and could be under-detected and that services for managing COPD, such as PR, are underdeveloped. AHWs and EPs perceived limited COPD health literacy and low access to lung services within ACCHS or mainstream health services by the local Aboriginal community. Although limited studies and no national data are available, it has been reported that Aboriginal people are highly likely to be at risk of poorer health literacy , 52, andConsistently, cultural adaptation occurred around ways of talking and communicating (‘yarning’) to make COPD information and engagement with the material conversational. Developing research skills of AHWs is particularly important during Aboriginal research . AHWs, eThe study highlighted some challenges for implementing online education sessions. Some AHWs and EPs reported pressures participating in the study and attending the online sessions while meeting other work responsibilities, staying engaged over time, and preparing the yarning scripts too far in advance of the ACCHS commencing their BE WELL PR Program. These findings are consistent with Farnbach et al. , which rInitial coding was conducted independently by three researchers . The results represent the experiences of AHWs and EPs by using their voices as study participants. The engagement of Aboriginal and non-Aboriginal members of the research team during the design, delivery and analysis strengthens the inclusion of Aboriginal perspectives and meaning of the data. Two members of the research team (JA and DM) facilitated the online education sessions with close and ongoing involvement with participants. They developed deep knowledge about the insights, benefits and strengths of the study, and identified ‘objective distance’ was required during data collection, because both were close to the study and mindful of the potential positive and negative effects on research quality. To reduce researcher bias, an independent member of the research team (KG) with no contact with the participants during the online education sessions conducted the qualitative interviews using VoIP technologies. It is acknowledged additional research is required to validate the impact of VoIP technologies on the quality of participants’ experiences of qualitative data collection . ParticiFuture research should explore whether online education of AHWs and EPs to develop yarnings about COPD management, improves patient health outcomes, enables behavioural changes and increases access to culturally safe PR. Future researchers should also be conscious of the importance of an iterative and flexible process, with a genuine commitment to establishing and maintaining equal partnerships with participants.Online education using co-design and 8 Ways of learning was rated highly by AHWs and EPs for improving COPD knowledge and valuing cultural perspectives. The use of co-design principles and 8 Ways of learning with AHWs and EPs supported the cultural adaptation of COPD resources for Aboriginal people with COPD. The findings demonstrated that building culturally safe learning environments can provide effective online learning spaces that increase knowledge, skills and confidence and promote effective participation and collaboration. Key to these findings was respect for AHWs’ cultural knowledge and lived experiences and deeply valuing Aboriginal ways of learning and communicating through yarning.Additional file 1. Survey. BE WELL online education participant survey tool.Additional file 2. Interview questions. BE WELL online education participant interview questions.


Central nervous system (CNS) symptoms are frequent after chimeric antigen receptor T-cell therapy (CARTx) and usually attributed to immune effector cell-associated neurotoxicity syndrome (ICANS). Cerebrospinal fluid (CSF) testing to rule out CNS infection is not routinely performed, although ICANS and viral encephalitis have overlapping presentations. Reports of viral encephalitis after CARTx are increasing, but no cohort studies have been performed to understand its epidemiology.This retrospective cohort study included all adults receiving first CARTx for B-cell malignancies at Fred Hutch Cancer Center from July 2013 to December 2022. We computed the cumulative incidence of CSF testing for viruses within 56 days after CARTx.Figure 1). ICANS was diagnosed in 29 (85.3%) of these 34 patients (ICANS grade ≥ 3 in 14), and 26 patients received immunosuppressive treatment. In the remaining five tested patients, the cause of CNS symptoms was vascular (n=1), CNS progressive disease (n=2), metabolic encephalopathy (n=1) or unknown (n=1). CSF testing practices evolved overtime, and testing was performed more frequently before 2018 ; after 2018, all tested patients had ICANS grade ≥ 3. Four patients had a positive CSF PCR test for EBV (n=3) occurring 8–39 days post-CARTx or HHV-6 (n=1) on day 32 post-CARTx. EBV detection in CSF was low-level, of unclear clinical significance, and not treated; all three patients were treated for ICANS. The patient with HHV-6 had low-level detection in CSF and blood; HHV-6 encephalitis was considered, but no antiviral therapy was administered, and symptoms resolved with treatment for ICANS grade 4.626 patients received CARTx during the study period; 552 (88.2%) received CD19 or CD20-targeted CARTx and 74 (11.8%) BCMA-targeted CARTx. Median age was 60.4 (IQR: 50.9–67.6) years, 232 (37.1%) identified as female, and 216 (34.5%) received prior hematopoietic cell transplantation. Thirty-four patients had CSF tested for viruses with PCR in the context of CNS symptoms for a cumulative incidence of 5.7%  : Grant/Research Support|Century Therapeutics: Independent Data Review Committee|Janssen: Advisor/Consultant|Janssen: Honoraria|Juno Therapeutics (a BMS company): Grant/Research Support|Kite Pharma: Advisor/Consultant|Kite Pharma: Honoraria|Legend Biotech: Advisor/Consultant|Legend Biotech: Honoraria|MorphoSys: Advisor/Consultant|MorphoSys: Honoraria|Sobi: Advisor/Consultant|Sobi: Grant/Research Support|Sobi: Honoraria David G. Maloney, MD, PhD, A2 Biotherapeutics: Membership with compensation: member of scientific advisory board|BMS: Advisor/Consultant|BMS: Grant/Research Support|BMS: Honoraria|BMS: Member (compensation): JCAR017 EAP-001 Safety Review Committee, CLL Strategic Council. Without compensation: JCAR017-BCM03 Scientific Steering Committ|Celgene: Advisor/Consultant|Celgene: Grant/Research Support|Celgene: Honoraria|Chimeric Therapeutics: Membership with compensation: member of scientific advisory board|Genentech: Advisor/Consultant|Genentech: Honoraria|Genentech: Membership with compensation: member and chair of the Lymphoma Steering Committee|Gilead Sciences: Membership with compensation: Member Scientific Review Committee, Research Scholars Program in Hematologic Malignancies|ImmPACT Bio: Membership with compensation: Member, Clinical Advisory Board, CD19/CD20 bi-specific CAR-T Cell Therapy Program|Interius: Membership with compensation: member clinical advisory board|Juno Therapeutics: Advisor/Consultant|Juno Therapeutics: Grant/Research Support|Juno Therapeutics: Honoraria|Juno Therapeutics/BMS: Dr. Maloney has the rights to royalties from Fred Hutchinson Cancer Center for patents licensed to Juno Therapeutics/BMS|Kite: Advisor/Consultant|Kite: Grant/Research Support|Kite: Honoraria|Legend Biotech: Grant/Research Support|Navan Technologies: Membership with compensation: member of scientific advisory board Joshua A. Hill, MD, Allovir: Advisor/Consultant|Allovir: Grant/Research Support|Century Therapeutics: Advisor/Consultant|Covance/CSL: Advisor/Consultant|Deverra: Grant/Research Support|Eversana Life Science Services, LLC: Advisor/Consultant|GeoVax: Grant/Research Support|Gilead: Advisor/Consultant|Gilead: Grant/Research Support|Karius: Advisor/Consultant|Karius: Grant/Research Support|Merck: Grant/Research Support|Moderna DSMB: Advisor/Consultant|Octapharma AG: Advisor/Consultant|OptumHealth: Advisor/Consultant|Oxford Immunotec: Grant/Research Support|Pfizer (previously Amplyx/Medpace): Advisor/Consultant|Senti BioSciences, Inc: Advisor/Consultant|Symbio: Advisor/Consultant|Takeda: Advisor/Consultant|Takeda: Grant/Research Support|Up-to-Date: Advisor/Consultant


Several observational studies have found that physical inactivity and sedentary time are associated with idiopathic pulmonary fibrosis (IPF) risk. However, the causality between them still requires further investigation. Therefore, our study aimed to investigate the causal effect of physical activity (PA) and sedentary time on the risk of IPF via two-sample Mendelian randomization (MR) analysis.Multiple genome-wide association study (GWAS) data involving individuals of European ancestry were analyzed. The datasets encompassed published UK Biobank data  and IPF data  from FinnGen Biobank. The inverse variance weighting (IVW) method was the primary approach for our analysis. Sensitivity analyses were implemented with Cochran’s Q test, MR-Egger regression, MR-PRESSO global test, and leave-one-out analysis.Genetically predicted self-reported PA was associated with lower IPF risk . No causal effects of accelerometry-based PA or sedentary time on the risk of IPF were observed.Our findings supported a protective relationship between self-reported PA and the risk for IPF. The results suggested that enhancing PA may be an effective preventive strategy for IPF.The online version contains supplementary material available at 10.1186/s12931-023-02610-3. Idiopathic pulmonary fibrosis (IPF) imposes a significant economic burden on society, with its global incidence steadily rising yearly . PatientThe interplay between PA and IPF has garnered extensive attention in recent years. Various randomized clinical studies have demonstrated the efficacy of PA in ameliorating symptoms and enhancing outcomes in IPF patients . HoweverMendelian randomization (MR) offers an alternative approach for potential causal inference when conducting RCTs is either impractical or unfeasible . MR emplIn this paper, we assess the potential cause-effect between PAs, sedentary time and the risk of IPF via MR analysis. Our investigation relies on large-scale genome-wide association study (GWAS) data. The primary objective of this study is to provide valuable insights into preventive intervention strategies for IPF, informed by the outcomes of our MR analysis.We performed a two-sample MR study to assess the causal effect of PA/sedentary time on IPF using GWAS summary statistics. This instrumental variable (IV) analysis emulates an RCT regarding the random allocation of single nucleotide polymorphisms (SNPs) among offspring, free from confounding factors such as sex and age. In this study, the MR design must adhere to three assumptions  Fig. 1)1).Fig. 1Summary data for self-reported and accelerometer-based PA phenotypes were obtained from the UK Biobank , 20. TheRegarding accelerometry-based PA (“average acceleration”), exercise data were gathered from over 100,000 participants who wore Axivity-AX3 accelerometers on their wrists . After a–8) were included, and SNPs exhibiting significant associations with IPF were excluded. Subsequently, SNPs were clumped . Third, SNPs that could exhibit pleiotropic effects were removed [For the robustness of the MR analysis, it is necessary to consider the effect of vertical and horizontal pleiotropy on MR analysis . Therefo removed , 25. In ariables ; an F stariables . Steigerariables . These cTo prevent participant overlap, genomic data of 2018 cases and 373,064 controls were utilized as outcome variables in the GWAS analysis of IPF from the FinnGen Biobank (R9) . IPF cashttps://www.ebi.ac.uk/gwas/). Additionally, the summary data of IPF can be found at FinnGen Biobank (https://www.finngen.fi/en/access_results). All data were derived from public databases and did not require ethical and moral review.The GWAS summary data of PAs and sedentary time can be accessed at the GWAS Catalog  analysis, which served as the primary analytical method. This approach involves a meta-analysis of each SNP's Wald ratio between the exposure and the outcome . If poteA multistep process was undertaken for sensitivity analysis and assessing the second and third assumptions. Cochran’s Q test initially evaluated heterogeneity among the IVs . SubsequIn our study, 18 SNPs were employed as IVs for self-reported PA, 6 for accelerometry-based PA, and 5 for sedentary time. The F statistics for all genetic instruments exceeded 29.98, indicating no instrument bias   . We usedIn conclusion, through the MR analysis of large-scale GWAS data, our study has bolstered the evidence indicating a causal link between PA and the risk of IPF. Additional research is needed to elucidate the underlying mechanisms connecting PA with IPF. Considering the imperative of preventing IPF, significant emphasis should be placed on lifestyle management, including promoting regular exercise as a relevant strategy for preventing IPF.Additional file 1: Table S1. Instrument variables of Moderate-to-vigorous physical activity. Table S2. Instrument variables of Average acceleration. Table S3. Instrument variables of Sedentary time.Additional file 2: Figure S1. Scatter plot (A), Funnel plot (B), forest plot (C) and leave-one-out analysis (D) for moderate-to-vigorous physical activity on idiopathic pulmonary fibrosis. Figure S2. Scatter plot (A), Funnel plot (B), forest plot (C) and leave-one-out analysis (D) for average acceleration on idiopathic pulmonary fibrosis. Figure S3. Scatter plot (A), Funnel plot (B), forest plot (C) and leave-one-out analysis (D) for sedentary time on idiopathic pulmonary fibrosis.


L265P突变激活造血细胞激酶（HCK），HCK进一步激活布鲁顿酪氨酸激酶（BTK），最终活化核转录因子NF-κB促进淋巴浆细胞的恶性增殖华氏巨球蛋白血症（WM）是一种罕见的分泌IgM的惰性淋巴浆细胞淋巴瘤，在非霍奇金淋巴瘤中占2％1. 病例：回顾性分析2018年1月至2022年8月上海交通大学医学院附属瑞金医院符合治疗指征并接受BTKi单药治疗的58例初诊WM患者。所有患者符合以下WM诊断标准9/L，β2-微球蛋白（β2-MG）>3 mg/L，IgM>70 g/L。低危组：0或1个危险因素且年龄≤65岁；中危组：2个危险因素或年龄>65岁；高危组：2个以上危险因素。2. 危险分层：采用WM国际预后评分系统（ISSWM）进行危险分层L265P和CXCR4突变检测：方法包括一代测序（Sanger）、等位基因特异性聚合酶链反应（AS-PCR）和二代测序（NGS），标本来源包括淋巴结、骨髓和外周血。进行MYD88L265P突变检测的52例患者中，51例（98％）患者采用NGS和（或）AS-PCR方法，47例（90％）患者采用骨髓和（或）淋巴结。骨髓和淋巴结肿瘤组织中基因组DNA通过DNA纯化试剂盒（美国QIAGEN公司产品）提取并定量。外周血和骨髓未经CD19分选。标本留取获得患者知情同意。3. MYD884. 疗效和疾病进展的定义：58例初诊患者均接受BTKi单药治疗，其中有43例接受伊布替尼治疗口服420 mg，每日1次；15例接受泽布替尼治疗口服160 mg，每日2次。采用第7届国际WM工作组（IWWM）制定的标准定义疗效和疾病进展5. 伊布替尼转换为泽布替尼患者：10例初诊患者接受伊布替尼治疗后转换为泽布替尼治疗，2例患者不耐受，其中1例表现为出血，1例表现为乏力伴皮疹；2例是MYD88野生型；2例是MYD88和CXCR4双突变；2例疗效未达PR；2例MYD88突变CXCR4野生型患者获得PR后希望追求更深程度的缓解。10例转换治疗患者转换治疗前的最佳疗效和预后情况纳入伊布替尼组，由于此10例患者非初诊接受泽布替尼治疗，因此未纳入泽布替尼组。6. 随访：通过查看门诊记录、住院病历及电话咨询的方式随访，末次随访日期为2022年10月23日。中位随访时间16（1～55）个月。χ2检验，采用Kaplan-Meier法分析患者的生存情况，P<0.05为差异有统计学意义。7. 统计学处理：采用SPSS 23.0软件进行统计学分析。计数资料用例数（百分比）表示，计量资料用中位数（范围）表示。组间率的比较采用似然比1. 临床特征：58例初诊WM患者的基线临床特征见MUTCXCR4WT）组（26例）MRR为73％，其中伊布替尼组（20例）MRR为70％，泽布替尼组（6例）MRR为83％。MYD88突变CXCR4突变型（MYD88MUTCXCR4MUT）组（9例）MRR为67％，其中伊布替尼组（8例）MRR为63％，泽布替尼组（1例）MRR为100％。MYD88野生型（MYD88WT）组（6例）MRR为67％，均为伊布替尼组，泽布替尼组患者未检测到MYD88WT。2. 疗效：排除3例患者基线IgM<5 g/L，有55例患者可评估疗效，其中伊布替尼组40例，泽布替尼组15例。所有患者中位接受BTKi治疗15（1～55）个月，ORR为87％，MRR为71％，非常好的部分缓解（VGPR）率为7％。其中伊布替尼组中位治疗时间15（1～55）个月，ORR为85％，MRR为70％，VGPR率为10％。泽布替尼组中位治疗时间13（1～30）个月，ORR为93％，MRR为73％，VGPR率为0％。根据患者MYD88和CXCR4基因突变情况（41例）进行分组，MYD88突变CXCR4野生型（MYD883. 由伊布替尼转换为泽布替尼治疗患者的疗效：10例患者由于各种原因由伊布替尼单药治疗转换为泽布替尼单药治疗，接受伊布替尼单药中位治疗时间7.5个月，转换后泽布替尼中位治疗时间3.5个月，转换前、后的ORR分别为90％和100％，MRR分别为80％和80％，VGPR率分别为10％和50％。P＝0.998）（P＝0.371）。4. 预后：所有使用BTKi单药治疗患者中位随访16个月，24个月PFS率为86％。其中伊布替尼组和泽布替尼组中位随访时间均为16个月，24个月PFS率均为86％，所有患者均存活。ISS评分低、中、高危患者PFS的差异无统计学意义（5. 不良反应：BTKi单药引起中性粒细胞减少的总发生率为12％（7/58），其中伊布替尼组为12％（5/43），泽布替尼组为13％（2/15），均未见3级及以上中性粒细胞减少。BTKi单药引起血小板减少的总发生率为10％（6/58），其中伊布替尼组为12％（5/43），3级及以上占5％（2/43）；泽布替尼组为7％（1/15），未见3级及以上血小板减少。其他不良反应均小于3级，伊布替尼组心房颤动发生率为5％（2/43）、心动过速发生率为5％（2/43）、出血发生率为5％（2/43）、皮疹发生率为7％（3/43）；泽布替尼组心动过速发生率为7％（1/15）、出血发生率为7％（1/15）。本研究回顾性分析本中心58例应用BTKi单药的初诊WM患者，根据患者的临床特征，泽布替尼组ISS高危患者比例较高，达60％，而我们的预后分析结果与Treon等研究显示，伊布替尼单药治疗随访5年的MRR为78％，VGPR率为27％L265P突变阳性率88％，与国际临床研究报道的比例相似L265P突变检出率增高可能由于90％初诊患者采用了骨髓液和（或）淋巴结作标本，98％患者通过NGS和（或）AS-PCR方法检测。MYD88和CXCR4的基因分型是BTKi疗效和预后的重要参考，无论是接受伊布替尼还是泽布替尼单药治疗，MYD88MUTCXCR4WT患者疗效较好，MYD88MUTCXCR4MUT其次，MYD88WT较差MUTCXCR4WT亚型MRR最高，为73％，而MYD88MUTCXCR4MUT和MYD88WT的MRR均为67％。Pivotal研究中经治MYD88WT患者接受伊布替尼治疗的MRR为28.6％WT患者接受泽布替尼治疗的MRR为50％WT患者均接受伊布替尼治疗，MRR为67％，一方面可能由于患者为初诊且例数较少，另一方面与MYD88检测方法有关。6例MYD88WT中4例疗效≥PR，其中1例通过Sanger法，另1例通过外周血检测MYD88突变，通过Sanger法和外周血检测可能增加MYD88假阴性率本研究报道初诊WM患者MYD88在不良反应方面，ASPEN研究表明，伊布替尼导致心房颤动和高血压的发生率略高，而泽布替尼导致的粒细胞减少较常见WM患者的治疗进入了靶向药物时代，我们的研究发现，伊布替尼和泽布替尼治疗初诊WM患者均体现出良好的疗效和可耐受的不良反应。新一代BTKi泽布替尼在治疗深度中的优势有待进一步通过延长用药时间和积累更多患者得到证实，这种优势能否最终转换为PFS的优势也需延长随访时间。


In this work, a reconfigurable ultra-wideband transmissive terahertz polarization rotator based on graphene metamaterial is proposed that can switch between two states of polarization rotation within a broad terahertz band by changing the Fermi level of graphene. The proposed reconfigurable polarization rotator is based on a two-dimensional periodic array of multilayer graphene metamaterial structure, which is composed of metal grating, graphene grating, silicon dioxide thin film, and a dielectric substrate. The graphene metamaterial can achieve high co-polarized transmission of a linearly polarized incident wave at the off-state of the graphene grating without applying the bias voltage. Once the specially designed bias voltage is applied to change the Fermi level of graphene, the polarization rotation angle of linearly polarized waves is switched to 45° by the graphene metamaterial at the on-state. The working frequency band with 45-degree linear polarized transmission remaining above 0.7 and the polarization conversion ratio (PCR) above 90% is from 0.35 to 1.75 THz, and the relative bandwidth reaches 133.3% of the central working frequency. Furthermore, even with oblique incidence at large angles, the proposed device retains high-efficiency conversion in a broad band. The proposed graphene metamaterial offers a novel approach for the design of a terahertz tunable polarization rotator and is expected to be applied in the applications of terahertz wireless communication, imaging, and sensing. Terahertz waves, which bridge the gap between macroscopic electronics and nanoscale photonics, are electromagnetic (EM) waves between millimeter waves and infrared light . They haPolarization control is an important aspect of free-space terahertz EM wave propagation. Polarization converters play an important role in terahertz polarization modulation . CompareAs one type of polarization converter, a polarization rotator is a device that can rotate the electric field vector of an incident linearly polarized EM wave by certain degrees. However, most reported metamaterial polarization rotators are passive devices that can’t change the polarization state of a terahertz wave on demand once the geometric parameters are fixed. Compared with passive metamaterial polarization rotators, the reconfigurable metamaterial polarization converter can provide more freedom and enables functional integration ,15,16.For designing reconfigurable devices in the terahertz band, loading active materials is a good candidate. Graphene is a two-dimensional active material with a thickness of one atomic layer, and it has excellent optical and electrical properties ,18. The At present, most reconfigurable polarization rotators mainly realize the conversion of orthogonal polarization waves, but other types of polarization rotation are less studied. In some communication systems, 45° polarized waves are necessary, and in some specific situations, this sort of polarization has more advantages than 0° or 90° polarization, such as symmetric propagation characteristics. As for some terahertz emitters, 45° linear polarization output is also needed in the system . TherefoIn this work, a reconfigurable, high-efficiency, and ultra-wideband polarization rotator is proposed, which has a simple structure and consists of a metal wire grating, graphene gratings, an insulating film, and a dielectric substrate. By changing the bias voltage loaded on the graphene gratings, the polarization rotation angle of the transmitted linearly polarized wave can be easily switched between 0° and 45°. Moreover, the proposed polarization rotator is insensitive to oblique incidence. The proposed graphene-based metamaterial polarization rotator has excellent performance and will have potential applications in the fields of terahertz wireless communication, sensing, and imaging.y-polarized waves to pass through the metal grating with a 45° polarization rotation [rotation .z-axis of the three-dimensional coordinate system, the metal wire gratings, dielectric layer, first graphene grating layer, silicon dioxide insulating layer, and second graphene grating layer are arranged from front to back.The three-dimensional schematic diagram of the reconfigurable polarization rotator unit structure proposed in this paper is shown in x-axis and composed of rectangular metal sheets arranged along the y-axis, with width w1 = 4 μm, thickness mt = 0.2 μm, and mutual interval g1 = 4 μm. The material was gold and has a conductivity σ = 4 × 107 S/m, which is a perfect reflection layer in the terahertz band [In order to pursue the maximization of the PCR, 45-degree linear polarized transmission, and the trade-off between the preservation of the PCR bandwidth in the considered frequency range and the material thinning, the element structure and structural parameters were optimized. The metal wire grating was parallel to the rtz band .pt = 40 μm, and the material was TOPAS polymer with a relative dielectric constant of 2.35, which is an ideal terahertz dielectric substrate material due to its extremely low loss and low birefringence in the terahertz band [x-axis. The graphene width w2 = 1.8 μm, and the mutual interval g2 = 3.8 μm. Between the two layers of graphene gratings was a silicon dioxide insulating isolation layer with height st = 0.1 μm. The thickness of the dielectric substrate layer was rtz band . As showω is the operating angular frequency; FE is the Fermi level; Γ is the scattering rate, Γ= ℏ/2τ; τ is the relaxation time; T is the room temperature (T = 300 K); e is the electron charge; parameter ℏ is the reduced Planck constant; and Bk is the Boltzmann constant. The Fermi–Dirac distribution ζ is energy [μ = 2000 cm2/(Vs), which is derived from the formula: The Kubo formula of the graphene layer can be expressed as follows:s energy ,30. The 1×106m/s . The dis1×106m/s :.(5)ε=ετ of the reconfigurable polarization rotator in this paper was 0.2 ps, which is consistent with the measurement of graphene prepared by chemical vapor deposition (CVD). The Fermi level of graphene can be controlled by the bias voltage applied to it. The relationship between FE and gV can be expressed as [rε = 3.9 [ε0 is the permittivity of vacuum. gV is the bias voltage; e is the electron charge; fv is the Fermi velocity, which is 1.1 × 106 m/s; and st is the thickness of the silicon dioxide insulating layer [The graphene relaxation time essed as :(6)EF≈ℏvεr = 3.9  is the rng layer .FE and the bias voltage gV, FE = 0 when gV = 0, the conductivity of graphene is close to zero, and the graphene grating is in the off-state. As the bias voltage increased, the Fermi level of graphene increased. When the bias voltage was applied to meet the requirement of FE = 1 eV, the graphene grating was in the on-state. We performed a numerical simulation using commercial simulation software, HFSS. A planar periodic structure comprises identical unit cells; therefore, it is evaluated using Floquet ports and master–slave boundary conditions. The master–slave boundary conditions, also recognized as linked boundary conditions, are employed to simulate planar periodic structural surfaces. The graphene modeling approach relies on the zero-thickness modeling of the graphene layer, which is based on the application of an impedance boundary condition that accounts for the electrical response of the single-layer graphene, according to the Kubo formula.According to the relationship between the Fermi level y-polarized incident EM waves illuminating the proposed structure were mostly transmitted into the polymer layer. Then, the transmitted y-polarized wave continued to propagate in the polymer layer with an additional phase factor and then reached the graphene grating layer. Due to the anisotropy of such a graphene grating layer, the EM wave was partially transmitted through the graphene grating, and the transmitted wave contains x- and y-polarized components. Meanwhile, the reflected wave also contained x- and y-polarized components and continued to propagate in the polymer layer until reaching the gold grating layer. Most of the EM wave was reflected again by this gold layer and propagated in the polymer layer. The above process was repeated, and the EM wave shuttled between the gold layer and graphene layer, thus forming multiple transmission and multiple reflection processes. The total transmission coefficient xyt to yyt of the proposed structure can be calculated by summing all cross-polarized and co-polarized transmitted waves.In order to provide a better illustration, the polarization conversion characteristics of the Fabry–Perot-like cavity structure can be quantitatively analyzed using the multiple interference theory (MIT) . As showFor a single interface between two boundary media layers, A and B, the transfer matrix can be applied to describe the relationship between forward and backward propagating fields on either side of the interface, which is as follows:BAM can be expressed as:The transfer matrix x and y denote the polarization states of the EM waves in the medium layers A and B, while the superscripts f and b signify forward and backward propagation. Moreover, r and t represent the reflection and transmission coefficients, respectively. For a structure composed of several interfaces surrounded by homogeneous media, the overall transfer matrix is obtained by cascading multiple transfer matrices. Finally, the total transmission of the x-polarized and y-polarized waves with multiple interferences can be expressed as:j is the number of the roundtrips within the spacer layer.The subscripts FE = 0. When y-polarized linearly polarized waves are incident, the co-polarized waves transmit with high efficiency in the operating frequency band of 0.35–1.75 THz, with a transmission greater than 0.80, whereas the cross-polarized waves transmit with essentially little efficiency and a transmission smaller than 0.30. Thus, most transmitted waves are co-polarized; there is little change in the polarization state of the transmitted waves relative to the incident waves, and the polarization rotator will not work in the off-state of the graphene grating.y-polarized incidence [diffφ = y − φxφ. Parameters yφ and yE represent the phase and electric field intensity of co-polarized transmitted waves with y-polarized incidence, respectively. Parameters xφ and xE represent the phase and electric field intensity of a cross-polarized transmitted wave with y-polarized incidence, respectively. The polarization rotation angle α was adopted to demonstrate the function of the polarization rotator, and the ellipse angle χ was adopted to characterize the linear polarization characteristic [To better illustrate the transmission characteristics in the on-state of the proposed polarization rotator based on graphene, the Stokes parameters were introduced to describe the polarization state of the transmitted wave with ncidence , as follteristic ,39.(11)y-polarized incidence, the Stokes parameters need to adhere to specific numerical conditions. To correspond to the linear polarization features, it is important to keep a value of χ = 0. Therefore, parameter S3 should be zero. In order to obtain the polarization rotation angle of 45°, parameter S1 must be close to 0. Considering the above conditions, to simultaneously achieve S3 = 0, S2 ≠ zero, and S1 = 0, the diffφ should be 0° or 180°; meanwhile, xE and yE should be greater than zero. In addition, to optimize efficiency, it is imperative to ensure that xE and yE are as close to each other as possible while also being as large as possible.In order to meet the requirement of the 45° polarization rotation angle with y-polarized electromagnetic wave is incident on the proposed structure from the −z direction , is described as the angle by which the polarization direction rotates relative to the polarization direction of the incident waves. When the polarization rotator is in the on-state, the polarization rotation angle of transmitted waves with incident xoy coordinate system in uov coordinate system. The transmission amplitude in the xoy coordinate system can be defined as follows:To make it easier to analyze the performance of the polarization rotator, the uov coordinate system, the transmitted wave of y-polarized incidence can be decomposed intoAfter the introduction of the y-polarized incidence in the uov coordinate system can be defined as:Thus, the transmission amplitude with y-polarized incidence, with v polarization being the desired polarization [Therefore, the polarization rotation performance of the device can be characterized by the following polarization conversion ratio (PCR) formula for rization :(18)PCR=y-polarized terahertz waves were rotated into polarized waves parallel to the v-axis, which is in reasonable agreement with theoretically calculated results. The simulated PCR remained above 0.9, within the frequency range of the blue region in vyt remained above 0.7, within the frequency range of the red region. The operating frequency range of the proposed structure with good performance is the intersection of the red and blue regions, ranging from 0.35 to 1.75 THz, with the relative bandwidth reaching about 133.3%. Therefore, the proposed device can achieve a high linear polarization conversion efficiency over a wide operating bandwidth.y-polarized waves, as shown in y-axis compared with the y-polarized incidence.y-polarized terahertz wave is normal incident, the reconfigurable polarization rotator can switch the polarization angle between 0° and 45° by changing the Fermi level, and both operating states demonstrate good efficiency and a broad working band.In conclusion, when a To show the advantages of the proposed polarization rotator, we compared it with some reported reconfigurable ones. The detailed comparison of the polarization converters proposed in the literature is presented in FE = 0 was close to zero when no bias voltage was applied to the graphene grating. Thus, the graphene grating is nearly transparent to terahertz waves. As shown in FE ≥ 0.6 eV, the polarization rotation angle will be 45° over a wider bandwidth. However, an increase in the Fermi level resulted in a corresponding increase in the bias voltage. Too high a voltage cannot guarantee safety, and the Fermi energy levels usually range from −1 to 1 eV. For security and physical reliability, higher Fermi levels are unreasonable. The Fermi level FE = 1 eV, which is marked with a white-dotted line in FE = 1 eV was chosen as the suitable working state for the graphene grating, which is the on-state.The effect of the Fermi level on the performance of a reconfigurable polarization rotator has been investigated. The conductivity of the graphene grating at the Fermi level y-polarized waves as the incident angle varied in the xoz plane, while the graphene grating was in the off-state with y-polarized incidence. When the incident angle was less than 50 degrees, the off-state structure exhibited a high transmittance above 0.7 for y-polarized waves with a frequency range of 0.3–1.75 THz, which is marked with the white-dotted line. When the graphene grating was loaded with a bias voltage, the polarization conversion angle α with different incident angles is shown in FE= 1 eV, as the incident angle θ varied, the polarization rotation angle remained at approximately 45° until the incident angle θ reached 50°, and the linear polarization characteristics remained stable in the working frequency band. When the incident angle θ was greater than 50°, the polarization rotation angle increased to 60°, which no longer met the design goal of the polarization rotator. The PCR in θ was less than 50° in the working band. Considering the periods of the metal and graphene gratings were 8 μm and 5.6 μm, respectively, which are about 0.028λ0 and 0.0196λ0, respectively, and much smaller  than the central working wavelength λ0 of incident terahertz radiation, the reconfigurable polarization rotator had better oblique incidence insensitivity over a relatively wide bandwidth.Terahertz waves encounter oblique incidence more frequently than perpendicular incidence; hence, the insensitivity of the reconfigurable polarization rotator to oblique incidence is also an essential indicator. The proposed reconfigurable polarization rotator based on graphene metamaterials has a simple structure and is a combination of metal gratings and graphene gratings, which can efficiently realize ultra-wideband polarization rotation of terahertz waves from 0.35 to 1.75 THz. Owing to the combination of anisotropic and cavity-like resonance-enhanced effects, the polarization rotation angle can be switched between 0° and 45° by changing the Fermi level of graphene.When the bias voltage is applied to the graphene grating, the polarization rotation angle of the linearly polarized wave can be rotated from 0° to 45°. The relative ultra-wide bandwidth of a high 45-degree linear polarized transmission (above 0.7) and a PCR greater than 90% can reach 133.3% of the central working frequency. In addition, the polarization rotator has a stable and efficient polarization conversion in an ultra-wideband range, with incident angles within 0° to 50°.In summary, the polarization rotator proposed can provide switching polarization rotation of linearly polarized waves in a wide operating frequency band, which has potential application in the fields of terahertz wireless communication and imaging.


Graphene is a 2D material with fruitful electrical properties, which can be efficiently prepared, tailored, and modified for a variety of applications, particularly in the field of optoelectronic devices thanks to its planar hexagonal lattice structure. To date, graphene has been prepared using a variety of bottom–up growth and top–down exfoliation techniques. To prepare high‐quality graphene with high yield, a variety of physical exfoliation methods, such as mechanical exfoliation, anode bonding exfoliation, and metal‐assisted exfoliation, have been developed. To adjust the properties of graphene, different tailoring processes have been emerged to precisely pattern graphene, such as gas etching and electron beam lithography. Due to the differences in reactivity and thermal stability of different regions, anisotropic tailoring of graphene can be achieved by using gases as the etchant. To meet practical requirements, further chemical functionalization at the edge and basal plane of graphene has been extensively utilized to modify its properties. The integration and application of graphene devices is facilitated by the combination of graphene preparation, tailoring, and modification. This review focuses on several important strategies for graphene preparation, tailoring, and modification that have recently been developed, providing a foundation for its potential applications. Graphene is a key material for a new generation of electronic devices with unique electrical properties. In this review, current advances in the preparation, tailoring, and modification of graphene to obtain high‐quality graphene with precisely controlled patterning and specific functional groups are summarized. Physicists and chemists have been drawn to graphene due to its unique properties, such as high mechanical strength, high electrical conductivity, and large surface area. These excellent properties support the use of graphene for various electrical and optical applications. Effective approaches to graphene preparation, tailoring, and modification are required to realize these applications.Graphene, which consists of 2D spstrength,1 high Bottom‐up methods depend upon chemical reactions of precursors and produce large‐area graphene with controlled single layer, which is suitable for building large‐area electronic devices. Top‐down methods, consisting of mechanical exfoliation, liquid‐phase exfoliation, and so on, are proposed based on the unique structure of graphite, where carbon atoms in the sp2 hybrid manner form stable covalent bonds and the adjacent layers are combined through weak van der Waals attraction. Graphene flakes can be peeled from bulk graphite once the van der Waals attraction weakens. Top‐down methods are simpler and more convenient than bottom‐up methods because they do not require complex condition control or expensive equipment. More importantly, top‐down methods are suitable for building high‐performance devices to study the intrinsic characteristics of graphene.Graphene can be produced by both physical and chemical methods. The preparation methods of graphene can be classified into two types: bottom‐up and top‐down methods.10 Bot electron beam lithography (EBL), plasma etching, and so on, have been making great advancement and the precision has been improved to the nanoscale, leading to the rapid progress of microelectronic integrated circuits. However, conventional etching methods cannot achieve atomic‐level precision, which plays a crucial role in the fabrication of devices with uniform edge‐configuration, especially in spintronic devices. Gas etching has been discovered to have the feature of anisotropic etching, which can achieve atomic‐level precision, and may provide opportunities for precise processing.It is necessary to tailor graphene into various shapes in order to process and integrate it into electronic devices. For various functional devices, graphene etching is the primary method for patterning desired shapes and controlling layer numbers. Traditional etching techniques in the semiconductor industry, such as photolithography,25 ele Many organic reactions are applicable to graphene due to the richness of carbon chemistry. Electrophilic substitution reactions, free radical reactions, cycloaddition reactions, and coupling reactions are four main approaches, which are classified according to the types of chemical reactions. In addition, mechanochemical methods mainly make use of ball milling to break the graphic C─C framework and introduce the target groups, which is an effective and controllable method. The modifications are divided into two types based on the reaction sites: edge and surface modifications. Ball‐milling methods and Friedel–Crafts acylation are the most common methods for edge modification. Edge modification has been considered as a reliable way to tune its electronic and mechanical properties without damaging its conjugated π‐electron system. Surface modification of graphene can more effectively adjust the band gap and introduce the band level, resulting in more applications in the nanoelectronics fields. In comparison to pristine graphene, the modified graphene has outstanding characteristics and can be used for a variety of applications.Modification is necessary to endow graphene with various properties and functionalities, including noncovalent and covalent modifications to further realize the functional applications. The noncovalent modification uses π–π interactions to modify graphene surface, while covalent modification uses chemical bonds to decorate both the plane and edge of graphene, becoming a more stable and reliable method.36 ManIn this review, we pay attention to the recent significant development of graphene preparation, tailoring, and modification, supplemented by device fabrication Figure . First, 2The exploration of the property and further application of graphene depends on the development of preparation methods, which can be roughly divided into bottom‐up and top‐down methods, represented by chemical vapor deposition (CVD) and mechanical exfoliation, respectively. High‐density defects and wrinkles in graphene produced by CVD reduce its performance in electronic devices. The mechanical exfoliation method can directly exfoliate bulk graphite layer by layer to produce graphene with high‐quality, which is essential for the discovery of new phenomena and the development of high‐performance devices. Many efforts, such as optimizing deposition conditions, have been made to produce high‐quality graphene via CVD, but there are still challenges in achieving the same high quality as mechanically exfoliated graphene. However, most exfoliation methods produce small, low‐yield graphene flakes, limiting device fabrication efficiency and application possibilities. Mechanical exfoliation can be tweaked to address the aforementioned drawbacks. In the following part, we mainly discuss the improvement of mechanical exfoliation Table  after a 2.1 Under the catalysis of Cu, a typical catalyst for graphene growth, carbon species decomposed from hydrocarbons  nucleate on Cu, and the nuclei further grow into large domains until the surface of Cu foil is completely covered. Large‐area monolayer graphene can be made because of the poor solubility of carbon in Cu. Graphene films are often polycrystalline because of the misalignment of the domains. Moreover, wrinkles arising from the mismatch of thermal expansion coefficient between graphene and Cu are commonly observed. Different from the self‐limiting mechanism on Cu foils, the growth of graphene on Ni is mainly based on the precipitation and segregation of dissolved C atoms because of its better solubility of C and higher catalytical reactivity, which often results in inhomogeneous and multilayer graphene. In combination with the advantages of Cu and Ni, the Cu/Ni alloy has been intensively studied for CVD growth of graphene due to its good and controllable solubility of C. As the Ni content in the alloy increases, single‐crystal bilayer, trilayer, and even multilayer graphene can be prepared. In addition, large‐area and adlayer‐free monolayer graphene can also be achieved on Cu–Ni (111) alloy foils. For the preparation of high‐quality graphene, many factors including substrates, carbon sources, and growth conditions must be carefully considered and controlled. CVD is also widely used to produce large‐scale graphene films to meet the requirements of graphene industrialization for display and sensing applications. Automated transfer processes, such as roll‐to‐roll, are applied to improve transfer efficiency and avoid quality degradation, which is superior to wet etch transfer used in laboratories.CVD has been widely applied to fabricate large‐area graphene films.53 Und Usually, poly(methyl methacrylate) (PMMA) can be served to support graphene as a carrier, and copper foil is etched away by chemical etchant (FeCl3). The PMMA/graphene stack is picked up by a target substrate after floating on the surface of the etchant solution. After PMMA is dissolved with acetone, the graphene remains on the substrate. However, the contacts between PMMA and graphene surfaces are evitable, and there are difficulties in the complete removal of PMMA. For instance, acetone cannot entirely dissolve PMMA, and a thin layer of residues may cause degradation of the carrier mobility in graphene.Graphene grown on Cu foils often needs to be transferred to a target substrate for the fabrication of electronic devices. Wet transfer is the most common transfer method.68 Usu2 and sapphire (Al2O3), is vital for achieving high‐performance graphene‐based devices. Common approaches of direct growth on SiO2/Si require relatively high temperature, typically over 1100°C, resulting in low‐quality graphene due to the instability of SiO2. With the assistance of enhanced plasma, the temperature of graphene growth on SiO2/Si can be effectively lowered. Recently, a sapphire‐based multi‐cycle plasma etching‐assisted CVD method successfully led to the growth of wafer‐scale single‐crystal monolayer graphene, which produces graphene via a sacrificial layer of Cu rather than growing directly on sapphire. After a long annealing process, the copper grains are transformed into a regular orientation through which C atoms diffuse into the interface between Cu (111) and Al2O3 (0001). SiC is also a promising insulated substrate for obtaining graphene. At high temperatures above 1600°C, Si atoms on the SiC surface are sublimated, while C atoms are remained to grow into high‐quality graphene.In order to prevent contaminations and wrinkles introduced during wet transfer, the growth of graphene on insulators and semiconductors, such as SiO of SiO2.73 Wit2.2Mechanical exfoliation, in contrast to stronger in‐plane covalent bonding, relies on the relatively weak interlayer van der Waals forces, resulting in exfoliated flakes with a wide range of thickness and lateral dimensions. Though mechanical exfoliation can avoid defects caused by chemical synthesis and contamination introduced by wet transfer, the thickness, sizes, shapes, and locations of the obtained graphene are usually random, limiting the large‐scale device fabrication. Because of the disadvantages mentioned above, mechanical exfoliation is still a long way from mass production and commercialization, but it remains the best way to obtain high‐quality graphene for fundamental studies.2.2.1 This exfoliation process is illustrated in Figure  First, a piece of graphite is placed on the Scotch tape. After folding the tape in half several times to fully exfoliate the bulk crystal, it is pressed with the proper force on a Si wafer. Finally, single‐layer graphene is obtained by peeling the tape away from the wafer at a slow speed. This method is widely used in laboratories thanks to its advantages of producing high‐quality graphene, and it has also emerged as a promising method for obtaining other 2D materials, especially transition metal dichalcogenides (TMDs).In 2004, Geim and Novoselov et al. first isolated graphene with Scotch tape from highly oriented pyrolytic graphite (HOPG).14 ThiThe mechanical exfoliation depends on two kinds of forces, lateral force and normal force. The lateral force is derived from graphite's ability to self‐lubricate, which aids the movement between adjacent layers. Few‐layer graphene can be obtained by overcoming the van der Waals force between adjacent layers via the normal force. During the process of exfoliation, uneven interactions can cause the breakdown of in‐plane covalent bonds, producing fragmented small‐area graphene.The standard exfoliation method involves repeatedly folding Scotch tape to obtain graphene with random number of layers; thus, graphene quality and exfoliation yield are affected by a number of factors, including the substrate, the tape, the experimenters’ operation, temperature, and humidity. Among these factors, the tape and substrate play a vital role in improving peeling efficiency. The modification of substrate and tape is mostly considered to reduce the influence of uncontrollable factors  and improve the exfoliation yield.2.2.2 The ambient adsorbates are removed via oxygen plasma, and followed by heat treatment to ensure uniform contact with the interface. The oxygen plasma cleaning and mild annealing are considered key steps in this method  is reported.79 Thel Figure . The sha2.2.4 Under a kilovolt voltage, Na2O in the glass substrate decomposes into O2− and Na+ ions at high temperatures. Na+ ions migrate across the substrate under the influence of an electric field due to their relatively high mobility, while O2− ions are static, making the surface negatively charged. Thus, a strong electrical field is created, allowing for close atomic contact between graphite and substrate. The graphite is then cleaved away with an adhesive tape, leaving a few layers of graphene adhered to the substrate. The graphene produced can be hundreds of microns in size. However, this method requires high voltage (1.2−1.7 kV) and temperature (200−400°C), which is unavailable in most laboratories. The strong electrostatic effect makes it hard to transfer to other substrates, which may limit its further applications.The basic idea of anode bonding is to enhance the interaction between the bottom layer of graphite and the substrate via forming a strong electrical field.80 Und2.2.5 named covalent‐like quasi‐bonding, is considered to meet the requirements for mechanical exfoliation, which provides uniform and strong interaction with 2D materials. Only a few metals can help with graphene exfoliation due to differences in binding energies between metals and graphene. Ni can be used to peel graphene off due to its high binding energy. While Au, widely used to peel off TMDs, is less effective for graphene exfoliation due to the low binding energy. Metal‐assisted exfoliation becomes an ideal way to transfer materials tightly bound to the growth substrate, such as graphene grown on the silicon carbide (SiC) surface, due to the strong interactions between metal and the 2D materials.It is difficult to produce large‐area single‐layer graphene with traditional exfoliation method due to uneven interactions between graphite, tape, and substrate. Recently, a noncovalent interaction (∼0.5 eV per unit cell) between some metals and 2D materials,82 nam Due to the strong bonding of graphene to the SiC surface, transferring graphene from SiC is still challenging. A method for separating graphene from SiC has been proposed , the graphene layer is transferred to a SiO2/Si substrate. The exfoliation efficiency depends on the binding energy  and the stress of the metal film. Under the same deposition conditions, Ni has the highest stress and the largest binding energy (γGr‐Ni) among other metals (γGr‐Au < γGr‐Cu < γGr‐Pd < γGr‐SiC < γGr‐Ni), which exceeds γGr‐SiC. When Ni is used, a transfer yield of more than 95% can be achieved, whereas Cu, Pd, and Au peel off graphene with difficulty. Due to the large difference between γGr‐SiC and γGr‐Gr, there are still difficulties in directly separating single‐layer graphene from SiC with a Ni layer.Single‐oriented graphene can be obtained with the decomposition of SiC (0001) surface but is mostly one or two layers.91 Dued Figure .[84] As shown in Figure Gr‐Gr < γGr‐Au < γGr‐Ni, leaving the monolayer graphene on the other side.A single‐layer precision selective exfoliation method is developed according to the difference in binding energy between graphene and metals.84 As  The random conventional exfoliation is transformed into a controllable and deterministic process by deposition of metal films using graphite as the material , which is widely used in traditional etching processes, can also be applied to graphene tailoring. The basic working mechanism of RIE can be described as follows. Under the alternating electric field provided by radio frequency, the gas is excited and ionized, generating highly reactive plasma. The graphene basal plane is bombarded and reacted by ions and free radicals in the plasma. Particularly, physical etching reduces the etch selectivity, resulting in isotropic etching. For the preparation of graphene nanoribbons (GNRs) with a well‐controlled edge configuration, which is important for opening the band gap of graphene, atomic‐level etching is required. However, the required accuracy is still beyond the reach of current state‐of‐the‐art nanolithography techniques.To fabricate functional electronic devices, a variety of techniques have been used to tailor graphene.94 Tra and remote plasma etching, selectively remove C atoms at the edge of graphene owing to the difference in reaction rates between C atoms in zigzag and armchair sites, resulting in anisotropic etching with atomic precision. Metal nanoparticles, such as Ni and Fe, can anisotropically etch graphene when migrating on the basal plane, resulting in a crisscross line‐like etching pattern. However, this kind of etching occurs on the surface of graphene, where metal nanoparticles take random movements, making the etching sites uncontrollable, which cannot be applied to graphene patterning. After a brief introduction to EBL, we will primarily focus on anisotropic etching methods with various gases. The comparison of various anisotropic etching methods, in terms of etchant, substrate, edge configuration, and functional group, are summarized in Table Pure chemical etching methods, such as reactive gas etching99 and3.1 Desired patterns can be drawn directly on the resist, then transferred by etching or evaporation to obtain patterned materials, based on the interaction between electrons and resist such as PMMA. For example, as a top‐down processing method, EBL in combination with oxygen plasma etching can obtain specifically patterned graphene.As a typical top‐down method for micro‐nano processing, EBL can achieve nanometer‐level resolution.103 De The graphene is cut through the window of PMMA by oxygen plasma etching after an indented window on PMMA is obtained by EBL  and armchair graphene nanoribbons (AGNRs) terminated with epoxy oxygen atoms, the epoxy‐terminated armchair edge is more stable than the zigzag edge, which explains the existence of the armchair edge  can the hydrogenation of C atoms at the edge and the breakage of the C─C bonds be satisfied at the same time. Therefore, the reaction rate takes a “volcano type” curve with temperature changes  medium can be achieved at ∼130°C using the “direct” Friedel–Crafts acylation. The reactive C═O+ is generated by protonation of a carbonyl group of the benzoic acid derivatives via PPA. With the benzoic acid or benzamide derivatives, any desired functional groups, such as small molecules or macromolecules, can be attached to the edges of graphene. The C═O+ ion attacks the edges/defects of graphene without destroying the basal plane to preserve the conductivity and integrity of graphene in a mild and controllable way. Various functional wedges are introduced to the edge of graphite, endowing graphene materials with specific functions.As a typical electrophilic aromatic substitution reaction, Friedel–Crafts acylation reaction allows the synthesis of acylated products from the reaction between arenes and electrophiles. The edge‐selective graphene modification in a mild polyphosphoric acid (PPA)/phosphorous pentoxide  is determined by thermogravimetric analysis (TGA) showing ∼36 wt%. The covalent attachment of ABA grafts at the graphene edges has been verified using AFM images. The Friedel‐Crafts acylation reaction can introduce linear and hyperbranched polymers onto the edges of graphitic layers. For example, the para‐poly (ether‐ketone) (pPEK) can be covalently grafted to graphite. A series of characterization can verify the success of modification. The resulting pPEK grafted graphite (LPEK‐g‐graphene) shows better tensile properties than pPEK films. Dendritic macromolecular wedges can also be directly grafted to the edges of graphite via the Friedel–Crafts acylation. The solubility of dendritic macromolecules is improved in comparison with that of linear analogs. In general, graphite is treated with AB2 monomer for hyperbranched poly(ether ketone) (HPEK). According to AFM images, the edge of graphene is higher than its basal plane due to the existence of HPEK. The high degree of exfoliation is estimated using wide‐angle X‐ray diffraction. The cyclic voltammetry experiments results show that the carboxylic acid groups exist. The above‐mentioned aromatic 4‐aminobenzoyl moieties on the edge of AB‐EFG can play a dual role in “C‐welding” and “N‐doping” to obtain N‐graphite films, which have high conductivity, good mechanical properties, and high optical transmittance. N‐doped graphene has tremendous potential applications for its superior performance in field‐effect transistors (FETs).Small molecules, linear and hyperbranched macromolecules, are attached to the edges of graphene, as illustrated in Figure 144 Th In comparison with the graphene modification mentioned above, Friedel–Crafts chlorination happens at the edges/defects of graphene as confirmed by X‐ray single‐crystal analysis, which benefited from the solubility of nanographene to obtain the crystal structure. A series of well‐defined nanographene  are chosen to reflect precise chlorination. Chlorination is achieved at ∼80°C in CCl4 with iodine monochloride and catalyzed by AlCl3. Matrix‐assisted laser desorption/ionization‐time of flight mass spectrometry confirms the elemental composition of chlorinated products. The isotopic distribution pattern of the mass peak is in good agreement with the calculated pattern. The precise edge chlorination can be served as an efficient model for edge‐functionalized graphene materials, providing an efficient way to tune properties of nanographene such as solubility, band gap, and the position of the frontier molecular orbital.A Friedel‐Crafts chlorination reaction for edge chlorination of nanographene is reported as a vital step toward controlled functionalization, resulting in well‐defined chemical functionalized graphene materials.151 In3‒) is prepared by chlorosulfonation and finally reduced to form graphene thiol (G─SH)  of sulfur‐modified samples shows the standard signatures for both sulfonate and thiolate groups, and the S:C atomic ratio of G─SO3− and G─SH is analyzed to be ∼0.3:100. Chemical functionalization of edges and defect sites of basal plane are visible in fluorescent‐labeled graphene under super‐resolution microscopy. It is possible to create the “glycographene” by radical addition, demonstrating the synthetic feasibility of directly linking reaction groups. Edge localization is visualized by epifluorescence microscopy of a lectin‐glycographene bioconjugate with fluorescently tagged.Unlike the Friedel–Crafts acylation, carbonyl groups cannot be introduced by the electrophilic aromatic substitution, which could slow electron transfer between the basal plane and the functional groups. Sulfur is electrophilic to attack electron‐rich graphene, then graphene sulfonate (G─SO) Figure .38]383‒) In this reaction, generated electrophilic ions overcome 2D π–π stacking of graphite and are covalently introduced into the edge of graphite, which ultimately turns to the more stable sulfonated graphene. SEM images of graphite have a flake shape with smooth surfaces, while sulfonated graphene shows an aggregated morphology indicating the presence of H‐bonds among polar sulfonic acid molecules at the graphene edges. The transmission electron microscopy (TEM) images indicate no chemical damage to the basal plane. Graphite can have up to ∼22.5 wt% edge‐selective functionalization.Electrophilic sulfonation is also realized by edge‐selective functionalization with chlorosulfuric acid.152 In4.2.22 carbons to sp3 carbons.Chemical reactions, laser irradiation, and photochemistry can all produce free radicals. Using diazonium salts, benzoyl peroxide, and halogen, free radicals can be added to the basal plane, transforming sp Delocalized electrons are transferred from graphene to aryl diazonium cations, which produce aryl groups of graphene after releasing a molecule of N2. The successful attachment of C6H4─NO2 groups on the graphene sheet can be confirmed by the Fourier transform infrared spectroscopy (FTIR) and time‐of‐flight secondary ion mass spectrometry (TOF‐SIMS) characterizations. The modification of the graphene largely enhances the room temperature resistance and changes the transport properties and electronic structure of graphene. For instance, modified graphene possesses a ∼0.4 eV bandgap. Using diazonium functionalization of graphene, it is possible to modify graphene not protected by PMMA to realize patterning and embroidery. Regular multiply functionalized patterns form molecular graphene embroidery including concentric regions of covalent addend binding. Furthermore, diazonium reaction and thermal treatment to functionalize the spatial structure using EBL on PMMA have been used to achieve reversible covalent patterning of graphene  Figure . F can be further covalently modified on graphene by treating it with the F‐substituted benzyne species, as shown by XPS and FTIR characterizations. Therefore, aryne cycloaddition is a facile and mild approach to obtain aryne functionalized graphene with good dispersibility.The aryne cycloaddition of graphene can be realized under mild reaction conditions. The aryne‐modified graphene sheets are stable and dispersible in a variety of solvents Figure .[163 Various enediynes directly attack sp2 carbon atoms at the surface of graphene. The modified graphene is soluble in many kinds of organic solvents and has excellent electric conductivity. This unique self‐coupling method can also be used to make polymer‐grafted graphite.Bergman cyclization is a cycloaromatization of enediyne‐containing compounds carried out a diradical intermediate Figure .[164 The nitrene addition could not take place only at the sheet's edges, and the resulting structure is similar to graphene oxide. The other method of nitrene addition is photochemical or thermal activation of graphene with perfluorophenyl azide (PFPA), which is converted to the active singlet perfluorophenylnitrene and undergoes C═C addition reactions with the graphene to produce the aziridine adduct. The solubility of graphene can be greatly regulated by chemical functionalization, and the functionalized graphene products disperse well in the corresponding solvents.Graphene nanosheets can be functionalized through nitrene addition of azido‐phenylalanine to exfoliate graphite Figure .[165 Specifically, graphite and graphene are used as dienophiles, both the 9‐methylanthracene and the 2,3‐dimethoxy‐1,3‐butadiene are used as dienes for the D‐A reaction. The carbons in graphene manage to transform from sp2 hybridized to sp3 hybridized through the D‐A chemistry. Attenuated total reflectance FTIR spectroscopy can be used to confirm the generality of graphene D‐A reactions. A solvent‐free D‐A reaction has been carried out by heating a mixture of graphite and typical dienophiles, such as maleic anhydride (MA) and maleimide (MI). Various characterization techniques have confirmed the functionalization of graphite with dienophiles, implying that graphite can be functionalized and delaminated into a few layers of graphitic nanosheets efficiently.Through the Diels–Alder (D‐A) reaction, graphene can be used as diene or dienophile to modify the electronic properties under mild conditions Figure .[167 The addition dichlorocarbene, diarylcarbene, and fluorinated olefins is the focus of most experimental work. The functionalization is operated based on a conventional method which is used to produce the dichlorocarbene. In brief, the graphene is suspended in a mixed solution of chloroform (CHCl3), sodium hydroxide (NaOH), and phase transfer catalyst under reflux.Since carbene functionalization on carbon nanotubes has been studied extensively, it is possible that dichlorocarbene functionalization on graphene will occur naturally Figure .[1694.2.4Mechanochemical methods and microwave assisted methods can cause some small gas molecules to react on the edge of graphene. This method is simple, low‐cost, environmentally friendly, and scalable for mass‐producing graphene nanoplatelets (GnPs) with various functional groups.A variety of functional groups could be grafted to the edge of graphite when mixing the graphene with solids, liquids, or even chemical vapors in a ball‐mill crusher according to the availability of mechanochemical reactions driven by ball milling. During ball milling, the high‐speed rotation of the stainless‐steel balls generates sufficient kinetic energy to break the graphitic C─C framework, and then various functional groups can be introduced at the broken edges of graphite. Edge‐selective functionalized graphene nanoplatelets can be achieved through mechanochemical reactions with hydrogen, carbon dioxide, sulfur trioxide, or carbon dioxide/sulfur trioxide mixture. The gas is captured by mechanochemically produced active carbon species resulting in graphene with edge‐selective functionalization. Active carbon species are formed when the edges of graphite are broken, which are reactive to pick up halogens. The presence of Cl, Br, and I is successfully confirmed by energy dispersive X‐ray spectroscopy with element mapping. Furthermore, it is found that the edge‐halogens cause the edge expansion of XGnPs. Two‐step ball‐milling of graphene yields the graphene nanoplatelets (ISGnPs) with iodine/sulfonic acid functionalized at the edge. First, graphite can be edge functionalized by iodine under ball‐mining to produce IGnPs, followed by ball‐milling with sulfur trioxide to produce ISGnPs. Phosphorus is covalently attached to the edges of graphene nanoplatelets by ball‐milling  is obtained with high yield by ball milling. The generated ECG can be dispersed in a lot of polar solvents to be exfoliated into graphene nanosheets. Because of the hydration induced by ball‐milling, the high‐energy carboxylates turn into carboxylic acids (─COOH), and residual activated carbon species turn into hydroxyl (─OH) and hydroperoxyl (─OOH) by oxygen and moisture in the air. The ball milling process makes the surface area increase to large extents. Carbon disulfide (CS2) can also be introduced to the edges of GnPs with abundant ─C═S/─C─S bonds through mechanochemical reactions with CS2  have been synthesized by mechanochemical reactions in the presence of a halogen gas Figure .[170g Figure .[1722 Figure . The res When further exposed to oxygen and moisture in the air, hydrogen‐GnPs, sulfonic acid‐GnPs, carboxylic acid‐GnPs, or carboxylic acid/sulfonic acid‐GnPs can be generated. They show excellent performance in electrocatalyst and functional device applications.Mechanochemical reactions with hydrogen, sulfur trioxide, carbon dioxide, or a mixture of sulfur dioxide and carbon trioxide can efficiently produce the graphene nanoplatelets (GnPs) with various functional groups on the edge selectively.46 Whe In this case, microwave irradiation may cause the halogen to become slightly ionized, which aids the halogenation reaction. The Cl and Br atoms have been covalently functionalized on the graphene sheet with ∼21% and ∼4% atom percentage. The graphene halides (G─X) can be easily exfoliated into monolayer graphene in organic solvents. After high temperature annealing, the chlorine content is reduced, and the structure of chlorinated graphene (G─Cl) can be restored. As a result, after annealing, the conductivity of the G─Cl film increases significantly. The high solubility and low cost of G─Cl allow it to meet the requirements for large‐area and economical electronic devices such as FETs, photovoltaics, and light‐emitting diodes. For instance, the G─Cl itself can be used as a functional component to prepare FETs. G─X could also be an important versatile precursor and intermediate material to fabricate new composite materials.Chemical synthesis of highly modified graphite can also be accomplished using microwave‐sparks‐assisted halogenation reactions Figure .[175 Under microwave radiation, molecular collisions caused by relatively high‐frequency electromagnetic radiation produce active singlet perfluorophenyl nitrene, which can react with C═C bonds of graphite via cycloaddition. Therefore, graphene can react with PFPA when exposed to microwaves. Any amine‐containing molecules can be covalently attached to the PFPA functionalized graphene. For instance, it can conjugate with glycosyl amine to give carbohydrate‐presenting graphene.PFPA can also be used to functionalize graphene through a microwave‐assisted reaction.176 Un5Graphene has been used in a wide range of applications, since it can be effectively exfoliated, tailored, and modified. Whether in laboratory research or industrial applications, large‐scale, high‐quality, and layer‐controlled graphene with specific functionalities is a worthy goal to pursue.As two parallel roads for graphene preparation, CVD and mechanical exfoliation provide strong support for the availability of large‐area and high‐quality graphene based on their complementary advantages, holding great prospects for the realization of graphene‐based integrated circuits and the exploration of novel phenomenon, such as superconductivity discovered in magic‐angle graphene superlattices. Much effort should be made to improve the quality and size of graphene. In case of CVD, growth conditions are needed to be optimized to obtain high‐quality single‐crystal graphene on metal substrates. Gentle and clean transfer procedures are required to preserve the excellent transport properties of graphene. New methods are needed to be developed to achieve graphene growth directly on dielectric surfaces. Furthermore, mechanism studies of graphene exfoliation are needed to be explored, which is crucial for obtaining large‐area and high‐quality graphene.Etching is a key step to fabricate various structures of graphene, endowing graphene with excellent properties. Traditional organic synthesis is also seen as a complementary choice for producing specific pattern of graphene or other materials, but involves complicated condition control and product post‐processing. In contrast, top‐down etching can effectively control the morphology of graphene over large area in combination with EBL, and anisotropic etching provide scientists with an alternative to studying topological and spin properties of edge states. However, it should be noted that an in‐depth understanding of the etching mechanism and the establishment of the theoretical model are required to study the underlying effects of different etching conditions.Through covalent functionalization, molecular catalysts can be immobilized on the graphene surface to form stable photocatalytic materials. In graphene chemistry, most reactions on graphene originate from the organic reactions of benzene. However, it is not rigorous enough to regard graphene as benzene, so the reaction mechanism on graphene needs to be further studied in the future. It is also necessary to precisely control the modified positions of graphene according to specific requirements, such as opening the bandgap or implementing new mechanisms. Target molecules should be introduced to realize the specific functions of graphene‐based devices.On the basis of improved graphene preparation, tailoring, and modification methods, large‐area and high‐quality graphene with precisely controlled patterns and specific functional groups should be used to fabricate devices. These three parts will invite in‐depth research on the amazing structures and electronic devices of graphene, such as magic‐angle graphene and graphene‐based single‐molecule junctions, to satisfy the exploration of novel properties and applications of graphene. Through delicate design, the processes of preparation, tailoring, and modification should be further combined to fabricate next‐generation electronic devices.The authors declare no conflict of interest.


Defects on graphene over a micrometer in size were selectively blocked using polyvinyl alcohol through the formation of hydrogen bonding with defects. Because this hydrophilic PVA does not prefer to be located on the hydrophobic graphene surface, PVA selectively filled hydrophilic defects on graphene after the process of deposition through the solution. The mechanism of the selective deposition via hydrophilic–hydrophilic interactions was also supported by scanning tunneling microscopy and atomic force microscopy analysis of selective deposition of hydrophobic alkanes on hydrophobic graphene surface and observation of PVA initial growth at defect edges. Polymer–based graphene nanocomposites hold great potential for applications such as sensors, energy harvesting, and gas barrier films because of their superior mechanical, optical, and barrier properties ,3,4,5,6.Furthermore, graphene defects do not occur only in the synthesis process. Defects may also occur in the process of transferring graphene to the target substrate . AlthougA number of graphene healing methods have been reported. For example, since DFT calculations or molecular dynamics could study the interactions of graphene with a variety of molecules, these methods hold great potential to design graphene–defect–healing processes ,26,27. AHere, we report that graphene defects over micrometer could be selectively filled with hydrophilic polymers using hydrophilic–hydrophilic interactions. Although the graphene surface is hydrophobic, graphene defects are generally hydrophilic due to the existence of hydrophilic functional groups such as hydroxyl and carboxyl groups ,36,37. U36H74), Sigma–Aldrich, St. Louis, MO, USA), and heptane  were used without a further purification process. As a solvent, ethanol was purchased from Sigma–Aldrich. The height of PVA in defects on graphene was obtained using AFM  in non–contact mode.Polyvinyl alcohol  method ,23,38. T2 plasma using reactive ion etching (RIE) equipment in order to remove graphene off the back side by inverting the graphene coated with PMMA. To obtain only graphene from CVD–graphene, Cu foil was etched in an aqueous ammonium persulfate (APS) solution for 4 h. Graphene floating on the APS solution was transferred to deionized (DI) water using PET film and the remaining APS solution was rinsed three times. Before graphene was transferred to Si wafer, the Si wafer was cleaned in acetone and isopropyl alcohol (IPA) using sonication for 10 min, respectively. Then, graphene was transferred to the target substrate and dried at room temperature for 30 min in order to prevent water from being trapped between the graphene and the Si wafer substrate. After that, it was put oven for an hour, dried completely, and the PMMA used as a supporting material in acetone for an hour on hot plate at 40 °C was removed. Graphene on Si wafer was rinsed in IPA and extra solvent was blown using nitrogen.Graphene was transferred onto the Si wafer through the wet transfer method using polymethylmethacrylate (PMMA) as a supporting material ,39. The Holes were manufactured using photolithography ,41. A phHTC heptane solution of 1 mM was prepared by ultra–sonicating the HTC and heptane mixture for 1 h at room temperature. For the PVA solution, PVA was dissolved in ethanol with a concentration of 0.1 g/mL by stirring the solution for 30 min at 45 °C.For HTC deposition, the HTC solution in heptane (b.p 98 °C) was dropped on patterned graphene with holes, and the solvent was slowly vaporized at room temperature to obtain multilayer HTC on graphene. For the PVA deposition, the PVA solution in ethanol was dropped on prepared graphene with a hole. Then, the ethanol solvent was slowly vaporized at room temperature and quenched before fully vaporized by blowing the solution to investigate the initial growth of PVA. For the full deposition of PVA, after dropping PVA solution on patterned graphene, the ethanol solvent was slowly and completely vaporized at room temperature. Then, the sample was annealed on a hot plate at 210 °C for 10 min to prepare the selectively deposited PVA films in graphene defects where Tg and Tm of PVA are 74.3 °C and 222.7 °C, respectively.Samples for AFM measurements were created by making artificial defects on CVD–graphene transferred on Si wafer substrate and dropping the HTC or PVA solutions as shown in the experimental methods 2.2, 2.3, 2.4, 2.5, and 2.6 above. The AFM imaging process was conducted in non–contact mode using park system’s NX10 equipment. Images were scanned measuring 10 μm × 10 μm or 20 μm × 20 μm in size. The values of the scan rate for the pristine graphene sample, graphene coated with multilayer HTC, and PVA in defects on graphene were 0.35 Hz, 0.6 Hz, and 0.3 Hz, respectively. The values of Z servo gain for the pristine graphene sample, graphene coated with multilayer HTC, and PVA were 1, 1.5, and 1, respectively.A self–assembled HTC monolayer on CVD–graphene was imaged using STM . The STM tip was created by cutting the tip of a wire made of Pt/Ir  alloy. In order to investigate a self–assembled HTC monolayer at molecular level, HTC was dissolved in 1–phenyloctane for STM study. The HTC solution was replaced with CVD–graphene on copper substrate. The STM tip went into the solution and approached the graphene surface. The self–assembled structure of HTC was mainly scanned at 700~800 mV and 200~300 pA. All image processing was performed using SPIP software.2 surface. The lack of a strong van der Waals interaction between HTC and surface leads to HTC molecules not being nucleated on the amorphous SiO2 surface in the early nucleation stage. Therefore, it was expected that HTC would only be deposited on patterned graphene and not on the amorphous SiO2 surface. This hypothesis is experimentally demonstrated using patterned graphene. The graphene has periodically aligned 5 μm defects as shown in 2 to graphene before the deposition was measured as ~2 nm through the non–contact mode of AFM , were deposited on patterned graphene in order to confirm that hydrophobic molecules prefer to be deposited on only a hydrophobic graphene surface rather than hydrophilic graphene defects as shown in e of AFM b. After In order to prove the hypothesis that hydrophilic–hydrophilic interaction between PVA and defects allows selective deposition, the initial growth of PVA was investigated before completing deposition. As shown in Although various healing methods for graphene defects have been developed, defects over micrometer size are not efficiently healed. Upon considering the hydrophobic surface of graphene and the hydrophilic characteristics of graphene defects, it was demonstrated that hydrophilic polymer could selectively fill graphene defects over micrometer size through hydrogen bonding with functional groups at defect edges. This mechanism study for selective deposition of polymers in graphene defects would provide insights for further development of polymer–graphene composites.