Gastro-oesophageal reflux disease (GORD) is associated with idiopathic pulmonary fibrosis (IPF) in observational studies. It is not known if this association arises because GORD causes IPF or because IPF causes GORD, or because of confounding by factors, such as smoking, associated with both GORD and IPF. We used bidirectional Mendelian randomisation (MR), where genetic variants are used as instrumental variables to address issues of confounding and reverse causation, to examine how, if at all, GORD and IPF are causally related.A bidirectional two-sample MR was performed to estimate the causal effect of GORD on IPF risk and of IPF on GORD risk, using genetic data from the largest GORD (78 707 cases and 288 734 controls) and IPF (4125 cases and 20 464 controls) genome-wide association meta-analyses currently available.GORD increased the risk of IPF, with an OR of 1.6 . There was no evidence of a causal effect of IPF on the risk of GORD, with an OR of 0.999 .We found that GORD increases the risk of IPF, but found no evidence that IPF increases the risk of GORD. GORD should be considered in future studies of IPF risk and interest in it as a potential therapeutic target should be renewed. The mechanisms underlying the effect of GORD on IPF should also be investigated. This bidirectional two-sample Mendelian randomisation study provides strong evidence that gastro-oesophageal reflux disease (GORD) increases the risk of idiopathic pulmonary fibrosis (IPF), but found no evidence that IPF increases the risk of GORDhttps://bit.ly/3Lde737 Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic lung disease characterised by a usual interstitial pneumonia pattern on thorax computed tomography or biopsy in the absence of a recognised cause . The incvice versa [GORD is defined by nonphysiological aspiration of gut contents associated with troublesome symptoms and/or complications such as oesophagitis . GORD hace versa . This isce versa , 10.Unlike observational associations, genetic associations are not affected by classical confounding or reverse causation, as genes are randomly allocated at conception. A Mendelian randomisation (MR) approach that uses genetic variants known to affect GORD as its proxies  can therefore provide indirect evidence for a causal effect of GORD on the risk of IPF, if its underlying assumptions hold , 12. LikHere we describe a bidirectional, two-sample MR study to estimate the causal effect of GORD on the risk of IPF and of IPF on the risk of GORD. We used data from the largest available genome-wide association meta-analyses for both GORD  and IPF For both our analyses of the effect of GORD on IPF risk and of the effect of IPF on GORD risk we used two-sample MR where summary statistics (effect estimates and standard errors) for the gene–exposure (G–X) and gene–outcome (G–Y) associations were obtained from separate studies. A graphical overview of the two MR analyses is provided in nget al. [nget al. [For the MR of the effect of GORD on IPF risk, instruments were selected from the largest available genome-wide association study (GWAS) meta-analysis on GORD by Oget al. . For eacget al. . Summaryget al. .llenet al. [Similarly, for the MR of the effect of IPF on GORD risk, instruments were selected from the largest available GWAS meta-analysis on IPF by Anet al. . For eacnet al. .supplementary material.Here we provide an overview of the MR methods used, with a more detailed description of these methods, their underlying assumptions, relevant references and the code used for the analyses reported in the We estimated the causal effect of GORD on IPF risk  and of Ii.e. variants chosen as instruments for the exposure cannot affect the outcome through any other independent pathways. Pleiotropy can bias MR findings and we therefore investigated its possible presence through assessment of the heterogeneity in the MR estimates across SNPs, using the I2-index and Cochran's Q heterogeneity test.We used the IVW-FE method for our main MR analyses as this is the most powerful method, but it assumes absence of pleiotropy, In the presence of pleiotropy, possible pleiotropic SNPs were identified graphically based on their contribution to the overall heterogeneity (Cochran's Q-statistic) and we repeated the IVW-FE analysis after removing the pleiotropic SNPs. We also performed MR analyses on all SNPs using methods that can account for pleiotropy under different assumptions about its nature. In particular, we considered the following methods: inverse variance weighted random effect, weighted median, weighted mode-based and MR-Egger, with the simulation extrapolation (SIMEX) method to correct for measurement error (dilution bias) used if needed.www.phenoscanner.medschl.cam.ac.uk) to check if instruments used were associated with potential confounders for the effect of GORD on IPF and of IPF on GORD. We performed a leave-one-out analysis to check if any individual SNP was driving the observed association for both GORD on IPF and IPF on GORD.To provide additional assurance regarding pleiotropy we used PhenoScanner  SNPs, based on a total sample of 78 707 GORD cases and 288 734 controls, with replication of findings in 462 753 cases and 1 484 025 controls [The GWAS on GORD by Oget al.  identificontrols . The sami.e. SNP with linkage disequilibrium (LD) r2≥0.8 with the SNP of interest) was used instead (supplementary table S1). All SNPs used in the MR analysis were “strong” instruments with an F-statistic >10 [supplementary table S1). PhenoScanner results for the SNPs used showed that none were associated with potential confounders for the effect of GORD on IPF (in bold in supplementary table S3). However, none of these possibly pleiotropic instruments had an impact on the results, as demonstrated by a negative leave-one-out analysis .Of the 59 SNPs, two were missing in the IPF GWAS meta-analysis dataset and a proxy .2 of 0% (95% CI 0–31%) and a heterogeneity p-value of 0.52.There was no statistical evidence of pleiotropy, with an Illenet al. [The GWAS meta-analysis on IPF by Anet al.  includednet al. –19 plus The GWAS meta-analysis included a total of 4125 IPF cases and 20 464 controls of White European ancestry. IPF cases were defined using the joint American Thoracic Society/European Respiratory Society guidelines .2>0.8) was used (supplementary table S2). Data for the remaining six, for which a satisfactory proxy could not be identified, were obtained from the authors. Individual F-statistics ranged from 30 to 1721 (supplementary table S2). PhenoScanner results for the SNPs used showed that none were associated with potential confounders for the effect of IPF on GORD (supplementary table S4).Of the 19 SNPs, 15 were missing in the GORD GWAS meta-analysis database. For nine a proxy .2 of 63% (95% CI 40–77%) and a heterogeneity p-value of 0.00016. We identified five possible pleiotropic SNPs, shown in 2=0%; heterogeneity p=0.944) and the results remained null . Similar null findings were obtained when using robust methods that adjust for pleiotropy, as shown in We found evidence of pleiotropy, with an IWe undertook a bidirectional two-sample MR study to investigate the causal relationship between GORD and IPF. We found evidence of a causal effect of GORD on IPF, but not of IPF on GORD.2=86%; heterogeneity p<0.00001). The authors reported that confounding by smoking was likely for two reasons. First, a post-hoc meta-regression that controlled for smoking found the association was no longer significant . Second, the effect sizes tended to be larger in studies where a higher proportion of cases, and a lower proportion of controls, smoked. There was significant correlation between the ratio of the proportion of smokers (and ex-smokers) in IPF cases over the proportion in controls and the log odds ratio for the association of GORD and IPF. Our findings using an MR approach overcome confounding by smoking and any other (known or unknown) confounding of observational analyses to indicate a causal effect of GORD on IPF risk. As genetic predisposition to GORD is present from birth, MR estimates the effect of an individual's lifelong predisposition to GORD on the risk of IPF and our findings are therefore also independent of any current nutritional or pharmacological treatment for GORD.The odds of IPF were 1.6 times higher in the presence of GORD, although there was substantial uncertainty around the estimate (95% CI 1.04–2.49) and, in general, the magnitude of the causal effect obtained from MR studies should be interpreted with caution . MoreoveThe underlying mechanism explaining how GORD may increase IPF risk is unknown; however, aspiration of gastric contents can cause chemical pneumonitis or aspiration pneumonia . One stuMUC5B promoter variant rs35705950, which increases airway expression of MUC5B, is the strongest common identified risk factor for IPF. The odds of developing pulmonary fibrosis are 5 times higher for individuals carrying one copy of the disease allele, rising to 20 times higher for individuals with two copies, when compared with individuals carrying no copies of the disease allele. The frequency of the disease allele is around 9% in European ancestry populations [While direct chemical or bacterial epithelial insult may initiate or promote fibrosis, another possibility is by indirect means. For example, GORD may increase IPF risk through airway acidification secondary to aspiration disrupting mucin 5B (MUC5B) function and impairing innate immunity. The ulations , 30. Whiulations , and hasulations . The strulations , 34 and ulations .The theoretical possibility of reverse causation, whereby the association between IPF and GORD is driven by IPF, rather than GORD, is well described . RestricA major strength of our MR work, in contrast to previous observational work examining GORD–IPF relations, is that MR is not affected by classical confounders, such as smoking, or by reverse causation. Our work therefore overcomes these limitations of observational studies to establish GORD as a risk factor for IPF.Our study also has some limitations. One major problem of MR is that while it is not vulnerable to classical confounding or reverse causation, it is affected by pleiotropy. We found evidence for pleiotropy in our MR of IPF on GORD but adjusting for it did not alter our results. Our study had more power for finding an effect of GORD on IPF than IPF on GORD as a consequence of GORD being more common, and there being many more genotyped GORD patients than IPF patients available. Nevertheless, our confidence interval for the GORD on IPF effect is wide and a future study when larger GWAS data are available would be helpful. We cannot exclude that a small effect of IPF on GORD might be found in a future MR study performed on data from a larger IPF sample.In interpreting the finding of a causal effect of GORD on IPF, we need to consider the potential impact of the overlap of participants in the control group, as UK Biobank contributed controls to both the GORD and the IPF GWAS meta-analyses. With participant overlap in a two-sample MR, any weak instrument bias would bias the results away from the null, unlike with completely independent samples where the bias is towards the null . HoweverClinicalTrials.gov: NCT04965298).GORD should be taken into account in future studies of IPF risk and interest in it as a potential therapeutic target should be renewed. Treatment of GORD is not well established to be of benefit in IPF; a recent systematic review found no evidence that treating GORD with antacids, or fundoplication, improved outcomes in IPF . There iWe have assessed the risk of developing IPF in GORD, which is not amenable to indirect assessment by an RCT of GORD treatment, given how rare IPF is an outcome. It could be that GORD has also an independent effect on IPF disease progression; this could be investigated in a future study when sufficient genetic data become available. Understanding the mechanism for increased IPF risk in GORD is now necessary to understand which patients may benefit from existing treatments and for identification of novel therapeutic targets.By means of a bidirectional two-sample MR study we have overcome limitations inherent to observational studies and shown that GORD causes an increased risk of IPF, while we found no evidence that IPF causes an increased risk of GORD. GORD should be considered in future studies of IPF risk and interest in it as a potential therapeutic target should be renewed. The mechanisms underlying the effect of GORD on IPF should also be investigated.10.1183/13993003.01585-2022.Supp1Please note: supplementary material is not edited by the Editorial Office, and is uploaded as it has been supplied by the author.ERJ-01585-2022.TablesSupplementary tables ERJ-01585-2022.MethodsSupplementary methods 10.1183/13993003.01585-2022.Shareable1This one-page PDF can be shared freely online.ERJ-01585-2022.ShareableShareable PDF


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.


Caenorhabditis elegansis considered a useful model for studying the molecular mechanisms underlying TDP-43 toxicityin vivo. Here, we assessed different neuronal systems through established behavioral assays and extended the phenotypic characterisation of aC. elegansmodel expressing wildtype humanTDP-43(hTDP-43) pan-neuronally. Our data show that neuronal expression of hTDP-43 inC. elegansdisrupts chemotaxis and decreases fecundity. The basal slowing response, on the other hand, appears to be preserved in the presence of hTDP-43.Cytoplasmic inclusions consisting of transactive response DNA-binding protein 43 (TDP-43) are a key hallmark of TDP-43 proteinopathies like amyotrophic lateral sclerosis (ALS). Figure 3A). To investigate chemotaxis behavior, we assayed the CI towards both benzaldehyde and diacetyl in hTDP-43 worms . At 20 °C and 25 °C, hTDP-43 worms exhibit a significant reduction of the CI towards both attractants compared with the control strain. At 25 °C, however, the CI was highly confounded by a high paralysis rate which is reflected by a large fraction of hTDP-43 worms that did not enter a test quadrant at all . Nevertheless, our results generally indicate that the circuit required for chemotaxis is affected by neuronal expression of hTDP-43.Given the clear proteotoxicity of TDP-43 in the neuromuscular system , we subsequently investigated other characteristic neuronal controlled behaviors. Two pairs of amphid sensory neurons, AWC and AWA, and multiple interneurons are required for chemotaxis to volatile odors like benzaldehyde and diacetylFigure 3D). The ‘basal slowing response’ refers to the observation that well-fed animals transferred to plates containing bacteria normally move more slowly than those transferred to assay plates without bacteriaFigure 2C), we only assayed worms raised at 20 °C. We measured the average speed of hTDP-43 and control worms on plates with and withoutE. coliand found that both groups significantly reduced their speed on bacteria . The slowing effect was, however, less pronounced in hTDP-43 worms as evidenced by the log2 fold-change in speed  . The reduced food-slowing effect may represent a true biological finding or, due to a lower empty-plate based speed, could be a mere consequence of the reduced response-window for food-slowing of hTDP-43 worms . The latter is not unlikely given the comparable speed of hTDP-43 and controls worms on food . Thus, our results show that hTDP-43 worms can functionally slow on food, though with a smaller drop in locomotion speed than control worms.Next, we assayed the basal slowing response, which relies on dopaminergic neurons that transduce a mechanosensory stimulus through interneurons and motoneurons to effect slowing of the locomotory rate (C. elegansto take up exogenously applied serotonin (5-HT) we conducted a 5-HT-induced egg-laying paradigm to determine whether serotonergic neurotransmission is affected by hTDP-43 expressionFigure 3E). 5-HT had a reduced effect on the egg-laying rate of hTDP-43 worms . To assess whether the altered response to 5-HT could be partially due to lower fecundity, we followed hTDP-43 worms and their controls over time and counted the number of hatched offspring. We found that hTDP-43 worms produce less offspring than control animals and that this effect was enhanced at 25 °C . When the results of the egg-laying paradigm are corrected for the observed decrease in fecundity (i.e. hatched offspring) the differences between control and hTDP-43 worms are no longer significant . It should, however, be noted that there is a clear difference between the 'total eggs laid' and 'hatched offspring', as some eggs may never hatch. Therefore, the corrected 5-HT egg-laying should be interpreted with caution, as differences in the ratio eggs laid:hatched offspring were not specifically quantified in hTDP-43 versus control worms.Normally, when food-deprived worms are transferred to bacteria they display a dramatically enhanced slowing response. This experience-dependent response is mediated by serotoninergic neurotransmissionTaken together, our results show that hTDP-43 disrupts chemotaxis, decreases fecundity and potentially modifies the rate of egg-laying. The dopamine-dependent basal slowing was also observed, although the reduction was not as large when compared to control animals. Thus, proteotoxicity of hTDP-43 seems not to be limited to the neuromuscular system.Strains and maintenanceC. eleganspropagation at 20 °COP50before being tested, unless stated differently.Standard conditions were used forHatched offspringOP50at 20 °C. Adulthood Day 1 worms were serially transferred (at either 20 °C or 25 °C) to fresh 6-cm NGM plates every 24 h until being sterile. 2-3 d after the eggs were laid, the hatched progeny was counted. In each experiment, 15 adult worms per condition were assessed.Synchronized worms were cultured on standard NGM plates seeded withSerotonin-induced egg layingEgg-laying experiments were performed as previously described by Carnell et al., 2005. In short, age-matched adults  were placed into 50 μL of M9 buffer with or without 12.5 mM 5-HT (Sigma-Aldrich). The number of eggs laid in each well was counted after 90 minutes. Each experiment represents the average number of eggs laid per 90 minutes of 15 individual worms.Basal slowing responseFood-slowing was performed as previously described by Sawin et al., 2000. In short, well-fed animals were placed at either an empty assay plate (‘control’ condition) or an assay plate with a ring-shaped bacterial lawn (‘food-slowing’ condition). After 5 minutes of acclimatization worms were recorded for 1 minute  with the WF-NTPChemotaxisThe chemotaxis assay protocol was adapted from Margie et al., 2013. Briefly, the assay was performed in 6 cm Petri dishes containing 8 ml of NGM. These plates were divided into four equal quadrants and an inner circle of approximately 1 cm in diagonal. In two opposing diagonal quadrants a test solution of either 0.5% benzaldehyde  or 0.5% diacetyl  + 0.25M sodium azide (in ethanol) was pipetted. Ethanol mixed with sodium azide was used as control in the other quadrants. Then, worms were transferred in the middle circle and allowed to roam. After 60 minutes pictures were taken and the number of worms per quadrant were counted. Animals were excluded from the analysis if they failed to clear the inner circle or were sitting on the marked lines. The chemotaxis index (CI) was calculated for each strain and experiment using the following formula: CI = /. 150-250 worms per assay were used.Table 1: Strains used


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.