Flimma (https://exbio.wzw.tum.de/flimma/) addresses this issue by implementing the state-of-the-art workflow limma voom in a federated manner, i.e., patient data never leaves its source site. Flimma results are identical to those generated by limma voom on aggregated datasets even in imbalanced scenarios where meta-analysis approaches fail.Aggregating transcriptomics data across hospitals can increase sensitivity and robustness of differential expression analyses, yielding deeper clinical insights. As data exchange is often restricted by privacy legislation, meta-analyses are frequently employed to pool local results. However, the accuracy might drop if class labels are inhomogeneously distributed among cohorts. The online version contains supplementary material available at (10.1186/s13059-021-02553-2). The identification of differentially expressed genes or transcripts, e.g., in diseases or in response to treatment, is a standard but important task in molecular systems medicine.Differential gene expression analysis compares the expression profiles of two or more groups of samples to reveal genes with significant differences between the groups. Technologies for high-throughput gene expression profiling include microarrays and RNA sequencing, the latter being more widely used in clinical research today. Both are intrinsically different, e.g., signal- vs. count-based measurement, and their results subject to platform-specific biases , 2. ManyOne major challenge of differential expression studies is the lack of robustness due to the high technical and biological variability of the data –15, whicp-values or effect sizes may not be realistic. Furthermore, meta-analysis largely ignores possible differences between cohorts  [To control the exchange of sensitive molecular profiling data from, e.g., next-generation sequencing experiments, databases, such as dbGaP  or EGA , restricbutions)  or data butions) , which mbutions) .privacy-aware [privacy-preserving  , differecy-aware  designate.g., DP ), if it FL has become increasingly popular in bioinformatics for GWAS , 43, surDP perturbs the data or results by adding noise to them. Although DP is privacy-preserving and complementary to FL, it might dramatically impact the accuracy of the results. HE performs computation on the encrypted data from the participants. It suffers from two practical disadvantages : it suppFL is a promising alternative to SMPC and HE in terms of performance and scalability. Unlike HE, it does not increase computational cost much compared to the centralized method, and unlike SMPC, it transfers only a small number of model parameters through the network. Similar to HE, SMPC, and meta-analyses, FL is not privacy-preserving like DP, i.e., the server might reconstruct the raw data using the model parameters obtained from the clients –51. HoweThe privacy of federated methods can be enhanced by applying HE or SMPC on the shared model parameters. In comparison to purely SMPC- or HE-based methods, hybrid approaches are computationally efficient because heavy computations are distributed across the clients. Additionally, they offer enhanced privacy compared to pure FL, because the original values of the local parameters remain hidden from the server, and only global parameters are revealed to the server and the clients.Flimma (federated limma), a novel federated privacy-aware tool for the identification of differentially expressed genes called Flimma. Our new tool represents a federated implementation of the popular differential expression analysis workflow limma voom [limma voom among other popular count-based methods, because it is comparably fast without sacrificing accuracy [Flimma could be easily modified for handling microarray data, since the limma method was originally designed for such data [voom [In this paper, we introduce mma voom , one of accuracy . Besidesuch data  and onlyta [voom .Flimma is based on HyFed [limma voom, Flimma enhances the privacy of the data in the cohorts since the expression profiles never leave the local execution sites and only aggregated parameters are revealed to the server and the other local sites. In contrast to meta-analysis approaches, Flimma is particularly robust against heterogeneous distributions of data (in particular of confounders and class labels) across the different cohorts, which makes it a powerful alternative for multi-center studies where patient privacy is a key concern.on HyFed , a hybriFlimma and four meta-analyses approaches on two real-world datasets: a breast cancer expression dataset from TCGA [Flimma’s power, we model the multi-party setting by randomly partitioning both datasets into virtual cohorts, while introducing different levels of imbalance w.r.t. target class labels and covariate distributions. For both datasets, we simulated three realistic scenarios leading to different levels of sample distribution heterogeneity between local cohorts. We split the breast cancer dataset such that three virtual cohorts yield different frequencies of the LumA subtype to simulate an imbalanced distribution of disease subtypes collected at different clinical centers  with the results obtained by running limma voom on the combined dataset. For the privacy-aware approaches, we computed the root mean square error (RMSE), the precision, the recall, the F1 score, the Pearson and the Spearman correlation w.r.t. the results of the aggregated analysis with limma voom, which we treated as ground truth.We compared negative log-transformed Flimma produces the same p-values as the aggregated analysis with limma voom in all scenarios, including the imbalanced ones. This implies that Flimma is robust against heterogeneous data distributions across the clients. However, this is not the case for the meta-analysis approaches. In general, their RMSEs increase (and Pearson correlations decrease) as the scenarios become more imbalanced, and they introduce false positives and false negatives even in the balanced scenario. In spite of the difference in p-values calculated by all meta-analysis methods, their gene rankings were quite similar to the ranking produced by the aggregated limma voom .As shown in Fig. p-value  and difs [edgeR , DESeq2  [DESeq2 , or sleu [sleuth ) exist aComBat or RUVSeq [Flimma effectively handles batch effects, other analyses of expression data such as clustering or classification might require transformed data.Another prospective direction for future work is the development of accessory tools for gene expression analysis. This includes for example, federated principle component Analysis (PCA), useful for quality control, or federated batch effect correction methods, such as r RUVSeq . Althouglimma has been initially developed for differential gene expression analysis, it is widely used for the analysis of various omics data types, e.g., proteomics [Flimma modifications suitable for the analysis of other omics data types in the future.Although oteomics , 70, metoteomics , and micoteomics . TherefoFlimma is a privacy-aware tool for the federated identification of differentially expressed genes. It is user-friendly and publicly available at https://exbio.wzw.tum.de/flimma/including tutorials and a video documentation on its principle and application to real data. While Flimma results are mathematically equivalent to limma voom, Flimma operates on distributed cohorts without the disclosure of sensitive data. To enhance data privacy, Flimma uses a hybrid federated approach, where the local parameters of the clients are hidden from the server and only global parameters resulting from the aggregation are disclosed. In contrast to meta-analysis approaches, Flimma is robust against heterogeneous distribution of data across the different sites and to technical batch effects. In summary, Flimma is a promising alternative to meta-analysis methods for multi-center gene expression projects, as it enhances patient privacy while providing the same results as a centralized analysis.limma voom is the state-of-the-art method for differential expression analysis. Initially designed for microarrays [voom function, which removes the mean-variance trend from RNA-seq data and makes it suitable for analysis by limma [limma published an updated guideline on the recommended limma voom workflow [filterByExpr function from the edgeR package, conversion of raw read counts to log2-transformed counts per million (log-CPM), and normalization of gene expression distributions. We only differ from this workflow by using the upper-quartile (UQ) normalization [voom computes precision weights, which compensate for the mean-variance bias that is typical for RNA-seq data and thus makes them suitable for use in limma.roarrays , it was by limma . Recentlworkflow . Data prlization  instead lization , since tlization , 74. Sinlization , 76, we Flimma is based on HyFed (https://github.com/tum-aimed/hyfed) [HyFed comprises four software components: an aggregator server, a compensator server, a client app, and a web interface.d/hyfed) , a hybrid/hyfed) . HyFed cHyFed, clients mask their local parameters with noise before sending them to the aggregator to enhance the data privacy. The noise matrix has the same shape as the parameter matrix and contains random numbers. The approach to random number generation depends on the data type of the masked matrix and is described in detail in the next section. The noise matrix is sent to the compensator server, which aggregates the noise received from all clients and shares the global noise matrix with the aggregator. The aggregator calculates noisy global parameters and denoises them, by subtracting the global noise matrix provided by the compensator from the noisy global parameters. The proposed hybrid approach provides improved privacy, because a reconstruction attack would require compromising two servers in this case. The aggregator and compensator server components should run in separate machines at distant physical locations. Ideally, to minimize the risk of reconstruction attacks, they should be controlled by third-party organizations not connected to any of the study participants. Currently, the publicly available Flimma web tool is using the aggregator running at the Chair of Experimental Bioinformatics, Technical University of Munich (Germany), while the compensator is hosted at the Department of Mathematics and Computer Science at the University of Southern Denmark (Denmark).To start the project, the coordinating user signs into the web interface, creates the project, sets its parameters , and invites the participants. Each participant receives a token and a project ID from the coordinator and locally runs the client app to join the study and to select the local dataset. The computations are orchestrated by the aggregator server, which coordinates the clients, aggregates their local model parameters to global parameters, and returns global parameters to clients. Unlike in FL, with limma voom, each Flimma client accepts a matrix of read counts and a design matrix, specifying class labels and covariates for each sample. Flimma outputs a table with p-values, fold-changes, and moderated t statistics for each gene.As the original Flimma is publicly available at https://exbio.wzw.tum.de/flimma/. The “HowTo” page provides a quick-start guide for Flimma along with test data and describes input file formats.Flimma employs the local parameter masking approach of HyFed, which treats non-negative integer-valued parameters and real-valued parameters differently. For masking non-negative integers, it applies the standard additive secret sharing scheme based on modular arithmetic over the finite field p is a prime number [Ni are drawn from Mi using modular addition over M=(M′−N) mod p.e number . The eleReal-valued parameters are protected by the secret sharing approach based on Gaussian distribution , 79. NoiMi) given the knowledge of another random variable  [Flimma and the methodology of its evaluation are described in AIMe registry [https://aime-registry.org/report/v6v9dj.To avoid manual execution of /flimma)  and at Z/flimma)  under thregistry  at httpslog(FC)|>1, and BH-adjusted p-value < 0.05. For the results produced by each method, we computed the RMSE, the precision, the recall, the F1 score, the Pearson, and the Spearman correlation. Since only a small number of the most significantly differentially expressed genes is of interest for some research tasks, we have also investigated how the performance of the methods varies with the numbers of top-ranked genes selected.For each method, we considered a gene determined as differentially expressed, if it has |https://gdac.broadinstitute.org/runs/stddata__2016_01_28/data/BRCA/20160128. 850 expression profiles classified as luminal, or basal-like subtypes and annotated with the age of diagnosis and tumor stage were kept. Although breast cancer samples are classified into 4–6 subtypes [Unprocessed read counts summarized to gene-level and clinical annotations of samples were downloaded from subtypes –96, we fsubtypes , 94 . Expression profiles of sun-exposed and non-sun-exposed skin samples annotated with mean ischemic time and sex were kept. The resulting dataset comprises 1277 expression profiles of 677 sun-exposed and 600 non-sun-exposed skin samples, also annotated with sex and ischemic time. In contrast to the TCGA-BRCA dataset, a smaller fraction of genes was differentially expressed between sun-exposed and non-exposed skin samples . ARCHS4 collected raw reads from publicly available human and mouse GEO datasets and uniformly preprocessed them. Raw reads from each human-derived sample were pseudo-aligned against the GRCh38 human reference genome and quantified by kallisto [genefu R package [Raw read counts for three breast cancer cohorts from GSE129508 , GSE14924  (https:/kallisto . Since i package . Same asAdditional file 1 Table S1.Additional file 2 Table S2Additional file 3 Table S3Additional file 4 Supplementary Text and Figures S1-S3Additional file 5 Table S4Additional file 6 Table S5Additional file 7 Table S6Additional file 8 Table S7Additional file 9 Review history.


Objective: Attention deficit hyperactivity disorder (ADHD) is a commonly diagnosed neuropsychiatric disorder in children, which is characterized by inattention, hyperactivity and impulsivity. Using resting-state functional magnetic resonance imaging (R-fMRI), the alterations of static and dynamic characteristics of intrinsic brain activity have been identified in patients with ADHD. Yet, it remains unclear whether the concordance among indices of dynamic R-fMRI is altered in ADHD.Methods: R-fMRI scans obtained from 50 patients with ADHD and 28 healthy controls (HC) were used for the current study. We calculated the regional dynamic changes in brain activity indices using the sliding-window method and compared the differences in variability of these indices between ADHD patients and HCs. Further, the concordance among these dynamic indices was calculated and compared. Finally, the relationship between variability/concordance of these indices and ADHD-relevant clinical test scores was investigated.Results: Patients with ADHD showed decreased variability of dynamic amplitude of low-frequency fluctuation (dALFF) in the left middle frontal gyrus and increased one in right middle occipital gyrus, as compared with the HCs. Besides, ADHD patients showed decreased voxel-wise concordance in the left middle frontal gyrus. Further, lower voxel-wise concordance in ADHD’s left middle frontal gyrus was associated with more non-perseverative errors in Wisconsin Card Sorting Test, which reflects worse cognitive control.Conclusion: Our findings suggest that variability and concordance in dynamic brain activity may serve as biomarkers for the diagnosis of ADHD. Further, the decreased voxel-wise concordance is associated with deficit in cognitive control in ADHD patients. Attention deficit hyperactivity disorder (ADHD) is characterized by inattention, hyperactivity and impulsivity. It is one of the most commonly diagnosed childhood neurodevelopmental disorder, whose prevalence in school-age children and adolescents is estimated at 7.2% . This diMaladaptive in the intrinsic brain activity of ADHD was frequently reported in previous studies. Many of these findings were derived from resting-state functional magnetic resonance imaging (R-fMRI), which measures the blood oxygen level dependent (BOLD) signal without task or stimulation and further characterizes the spatiotemporal organization of brain activities . In specThese R-fMRI indices have been used to characterize the maladaptive brain functions in patients with ADHD. For example, children with ADHD exhibited increased ALFF in the occipital cortex and globus pallidus , and decAlthough these studies provided insights into the neural basis of ADHD, they failed to capture the dynamic changes in brain activities. Recent evidence demonstrated the temporal dynamic in brain activity patterns  and founIn addition, the concordance, i.e., temporal and spatial coupling, among multiple dynamic brain activity indices shows stable individual difference . StudiesThe current study aimed to bridge this gap. In specific, we compared the variability of dynamic R-fMRI indices and concordance among them between patients with ADHD and healthy controls, and further correlated the variability/concordance with the clinical test scores. Based on the results of previous studies, we hypothesized that ADHD patients would exhibit abnormalities in dynamic brain activity and its concordance, and this concordance would be related to its clinical manifestations. Our study may enhance the understanding of the neural mechanism underlying ADHD.Fifty-eight drug-naïve ADHD patients were recruited from the Out-patient Clinic of the First Affiliated Hospital of Wenzhou Medical University. Meanwhile, 31 healthy controls matched in gender, age and IQ were recruited from local schools. The diagnosis of ADHD was performed by three experienced psychiatrists according to the Fifth Edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-V). For all the participants, the exclusion criteria were: (1) conduct disorder, oppositional defiant disorder, or any other psychotropic disorder besides ADHD; (2) history of major neurological or physical illness; (3) current or history use of psychotropic drugs; (4) intelligence quotient (IQ) lower than 80; (5) MR scanning contraindications. This study was approved by the Ethics Committee of the First Affiliated Hospital of Wenzhou Medical University. All participants were well informed and written informed consent was obtained before the test.The revised version of Conners’ Parent Rating Scale (CPRS)  was usedThe computerized Wisconsin Card Sorting Test (WCST)  was usedImages were acquired in a 3T GE Sigma HDX 3.0 scanner  with the following parameters: repetition time (TR) = 2,000 ms, echo time (TE) = 30 ms, 31 axial slices, slice thickness = 4 mm, slice gap = 0.2 mm, flip angle = 90°, matrix size = 64 × 64, field of view (FOV) = 192 × 192 mm, and 240 volumes. High-spatial-resolution T1-weighted 3D images were obtained axially using the following parameters:162 axial slices, repetition time (TR) = 7,200 ms, echo time (TE) = 2.2 ms, flip angle = 7°, section thickness = 1 mm, gap = 0, field of view (FOV) = 256 × 256 mm, data matrix = 256 × 256. During the scanning, sponge earplugs were used to reduce scanner noise, and foam cushions were used to minimize head movement. The subjects were required to be relax, stay still, close their eyes, and stay awake.Data Processing and Analysis for Brain Imaging (DPABI)  was usedR-fMRI indices were calculated with following procedures:ALFF  of each index across the time series from each voxel was calculated and normalized across the voxels to measure the variability in these dynamic R-fMRI indices. Finally, the normalized SD maps of each dynamic R-fMRI index were smoothed (FWHM = 4 mm) to improve the signal-to-noise ratio.In particular, dynamics of these R-fMRI indices were analyzed using Temporal Dynamic Analysis (TDA) toolkits based on DPABI . SpecifiN = number of voxels) voxel-wise concordance values.The concordance of five dynamic R-fMRI indices  were calculated. In specific, volume-wise and voxel-wise concordance was measured by Kendall’s W among these indices . The volImportantly, we validated the results with the window length of 48 and 64 TR.t-tests. Meanwhile, gender distributions were compared using chi-square test. These statistical analyses were performed with SPSS 23.0.We compared age, IQ, ADHD-relevant clinical variables between ADHD patients and healthy controls using two-sample t-test, and the whole-brain gray mask was applied, and the results were corrected by multiple comparisons using Gaussian random field theory . Meanwhile, the volume-wise concordance was compared using analysis of covariance (ANCOVA). Further, Pearson or Spearman partial correlation was used to quantify the associations between dynamic indices and ADHD-relevant clinical test scores. Note that the age, gender, IQ, and head motions are controlled as covariates.The dynamic R-fMRI indices and voxel-wise concordance were compared using two-sample P = 0.014).The characteristics of samples were summarized in p < 0.001, cluster-wise p < 0.05, two-tailed; see Compared with HCs, the ADHD group exhibited increased dALFF variability in right middle occipital gyrus and decreased dALFF variability in left middle frontal gyrus (GRF, voxel-wise p < 0.001, cluster-wise p < 0.05, two-tailed; see The ANCOVA results indicated no significant differences in volume-wise concordance between the ADHD group and HC group. However, ADHD patients showed decreased voxel-wise concordance in left middle frontal gyrus (GRF, voxel-wise r = −0.367, p = 0.012; see r = 0.099, p = 0.646; see No significant correlations were found between the CPRS scores and altered dALFF variability for the ADHD group. However, the abnormal voxel-wise concordance of the left middle frontal was negatively correlated with the non-perseverative errors in WCST of patients with ADHD (Pearson partial correlation, The validation results with the window length of 48 and 64 TR showed good agreement with the results mentioned above .Abnormality in intrinsic brain activities is tightly associated with ADHD. This study systematically compared the dynamic changes in resting-state brain activities of patients with ADHD with HCs. Specifically, we calculated the temporal variability, spatial and temporal concordance of dynamic R-fMRI indices including ALFF, ReHo, DC, VMHC, and GSC in both groups. These properties were then compared between groups and correlated with the clinical variables, in which both the alterations and correlations were identified.Specifically, for the variability, ADHD patients exhibited increased dALFF variability in right middle occipital gyrus and decreased one in left middle frontal gyrus, which may reflect the hyper-activation in visual cortex and hypo-activation in frontal cortex. This is consistent with a previous study in which decreased ReHo was found in frontal and increased ReHo and ALFF was found in visual cortex .The development of the frontal lobe is essential for the acquisition, execution and control of a wide range of functions . And froStructural and functional alterations in occipital were also reported in previous studies. For example, reduced gray matter volume in the right middle occipital gyrus  and hypeAlterations in concordance among the dynamic R-fMRI indices were also identified in patients with ADHD. A recent study found that R-fMRI regional indices was high concordant in brain cortical and subcortical areas across the time window , and theIn addition, we found that the voxel-wise concordance change in left middle frontal gyrus was negatively correlated with non-perseverative errors in WCST of ADHD group. Whereas, we did not find a correlation between them in the HCs. WCST is widely used to assess executive function, including cognitive flexibility, working memory, continuous attention and response inhibition . Non-perOur findings highlighted the role of frontal lobe in the neuropathological mechanism of ADHD, and demonstrated that concordance of R-fMRI indices can serve as a biomarker to indicate the deficit in frontal lobe. To date, the diagnosis of ADHD is still based on symptom scores from clinical interviews, which can be subjective and can be influenced by many factors, such as the experience, stereotype, and cultural differences. Neuropsychiatric biomarkers can help to build a standard and objective diagnosis system, which can benefit the patients. R-fMRI is among the neuropsychiatric tools that have the potential to find the biomarkers . Such biFurther, the behavioral dysfunction may be too subtle to be measured, just like the non-perseverative errors that failed to be capture by the current study. However, as mentioned above, the R-fMRI indices as proposed by the current study are able to evaluated the maladaptive of brain functions.This study has several limitations. First, no significant differences were found among some dynamic indices, which may be due to the relatively small sample size. A larger sample size is needed to validate the alterations in dynamic brain function in ADHD and examine the relationship between dynamic variables and psychological data. Second, the current study only focus on the BOLD signal from gray matter. However, previous studies have demonstrated the white matter signals also provide valuable information ,b. HenceThe current study investigated the variability and concordance of a range of commonly used R-fMRI indices in ADHD. We found that patients with ADHD exhibited increased dALFF variability in right middle occipital gyrus and decreased dALFF variability in left middle frontal gyrus. Meanwhile, we found that voxel-wise concordance of a series of R-fMRI indices in patients with ADHD was decreased in frontal lobe, and a greater decrease was related to worse WSCT performance. These findings suggest that dynamic analysis and functional concordance may provide new insights into the neuropathological mechanism of ADHD.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by the Ethics Committee of the First Affiliated Hospital of Wenzhou Medical University. Written informed consent to participate in this study was provided by the participants’ legal guardian/next of kin.FL and JT analyzed the data and wrote the manuscript. RZ analyzed the data. SC and AQ collected the MRI data. CY, XZ, and BC evaluated the subjects. ZH and MW designed and supervised the experiment, and finalized the manuscript. All authors reviewed the manuscript and made significant contribution to this manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


The COVID-19 pandemic has devastated the global community with nearly 4.9 million deaths as of October 2021. While organ transplant (OT) recipients (OTr) may be at increased risk for severe COVID-19 due to their chronic immunocompromised state, outcomes for OTr with COVID-19 remain disputed in the literature. This review will examine whether OTr with COVID-19 are at higher risk for severe illness and death than non-immunocompromised individuals.Embase.com) will be searched from December 2019 to October 2021 for observational studies (including cohort and case-control) that compare COVID-19 clinical outcomes in OTr to those in individuals without history of OT. The primary outcome of interest will be mortality as defined in each study, with possible further analyses of in-hospital mortality, 28 or 30-day mortality, and all-cause mortality versus mortality attributable to COVID-19. The secondary outcome of interest will be the severity of COVID-19 disease, most frequently defined as requiring intensive care unit admission or mechanical ventilation. Two reviewers will independently screen all abstracts and full-text articles. Potential conflicts will be resolved by a third reviewer and potentially discussion among all investigators. Methodological quality will be appraised using the Newcastle-Ottawa Scale. If data permit, we will perform random-effects meta-analysis with the Sidik-Jonkman estimator and the Hartung-Knapp adjustment for confidence intervals to estimate a summary measure of association between histories of transplant with each outcome. Potential sources of heterogeneity will be explored using meta-regression. Additional analyses will be conducted to explore the potential sources of heterogeneity  considering least minimal adjustment for confounders.MEDLINE (via Ovid and PubMed) and EMBASE  registration DOI: 10.17605/osf.io/4n9d7.The online version contains supplementary material available at 10.1186/s13643-021-01854-8. The first cases of infection from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes coronavirus disease 2019 (COVID-19), were identified in Wuhan, China, in December 2019 [p = 0.038) [Empiric studies comparing outcomes of OTr with COVID-19 to those of the general  patient population have yielded mixed results. Early reports, such as a matched case-control study by Caillard et al. (2020), reported a substantially higher risk of death in hospitalized OTr with COVID-19  .This rapid review will examine whether OTr with COVID-19 are at higher risk for severe illness and death than non-immunocompromised individuals. Compared to that of a traditional systematic review, the methodology of a rapid review is well-suited to summarize emergent evidence for patients, clinicians, and policymakers in a resource-efficient, succinct manner . This inosf.io/4n9d7) and is being reported in accordance with the reporting guidance provided in the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols (PRISMA-P) statement [This rapid review will compare clinical outcomes of COVID-19 between OTr and patients without a history of transplant (controls). The review protocol has been registered within the Open Science Framework database Comparison: Patients with no history of transplant (studies must contain a control group to be included)Outcomes:Primary: mortality as defined in each study, with possible further analyses of in-hospital mortality, 28 or 30-day mortality, and all-cause mortality versus that which is attributable to COVID-19;-Secondary: severity of COVID-19 disease, most frequently defined as requiring intensive care unit admission or mechanical ventilation-Study design: Observational studies (cohort and case-control design)Timing: Published between December 1, 2019, and October 31, 2021Setting: No restrictionLanguage: Written in EnglishEmbase.com) for articles published between December 1, 2019, and October 31, 2021. The search strategy will be peer-reviewed by a research librarian in accordance with the Peer Review of Electronic Search Strategies (PRESS) 2015 Guideline Statement [Database searches will be conducted in MEDLINE (via Ovid and PubMed) and EMBASE , transplant-specific characteristics (organ type and respective number of transplants), comparator-specific characteristics , and period (quintile: Q) of data collection . Given that the first case of COVID-19 in the USA was reported in January 2020, we expect very few, if any, studies with data collected prior to March 2020; if such studies are identified, they will be included in Q1.Two reviewers will extract data from each study independently using Covidence as an online data extraction platform. Data will be extracted from the original reports into specially designed and pilot-tested data extraction forms designed to serve the investigation of the primary and secondary outcomes described above. Conflicts will be resolved by a third reviewer and potentially discussion among all investigators. Given the time-sensitive nature of this rapid review, original data from the study investigators will not be sought for confirmation. Reviewers will enter data in electronic extraction forms. The following data will be extracted: first author, year of publicationThe risk of bias/quality assessment of primary studies will be evaluated using the Newcastle-Ottawa Scale (NOS) for observational  studies . Using tWe will perform narrative synthesis using evidence tables and evidence maps to describe the PICOTS elements, including study characteristics , population characteristics , outcome operationalization , covariates for which statistical models are adjusted, and findings. We will also assess whether covariates in adjusted models overlap sufficiently so that the reported conditional effects are estimates of the same estimand. Based on these elements, we will assess clinical and methodological heterogeneity and whether studies are statistically exchangeable to be meta-analyzed. The decision to meta-analyze is based on assumptions that are not testable with observed data as acknowledged by the Cochrane Collaboration . Hence, I2 statistic: the percentage of variance among studies that is attributable to genuine underlying differences in study properties rather than measurement error. We will explore potential sources of heterogeneity  using random effects meta-regression. These parameters are selected as they can influence outcomes through host factors  or different practices (including available treatments) in the management of COVID-19 . We will assess the presence of small-study effects visually with funnel plots and statistically using Egger’s regression; both methods provide evidence for whether smaller vs larger studies give systematically different results, which may be due to publication bias as well as other meta-biases [If the assumptions of study exchangeability are reasonably met, we will perform random-effects meta-analysis with the Sidik-Jonkman estimator and the Hartung-Knapp adjustment for confidence intervals to estimate a summary measure of association between history of transplant and each outcome. We are interested in binary outcomes for which we expect that studies report the measures of odds ratio, risk ratio, risk difference, or hazard ratio. To quantify statistical heterogeneity, we will use the a-biases .Although both adjusted and unadjusted estimates of association will be extracted, we will synthesize separately those for which primary studies have performed some adjustment for confounders, e.g., through regression, matching, or other approach.The Newcastle-Ottawa Scale (NOS) will be used to evaluate study quality as it is validated, adaptable, and useful as a potential moderator in systematic reviews and meta-analyses.Given the changing temporal and geographic landscape of the COVID-19 pandemic through the study inclusion period, we will perform subgroup analyses accounting for period of data collection, country and continent of study, and transplant center volume. We will also perform subgroup analyses for type of transplanted organ. To assess the role of methodological quality, we will perform subgroup analyses according to study quality determined by the NOS. We expect that studies will already report associations adjusted for covariates, which we will identify according to the publications. We will not adjust for confounders that are not included in the primary studies. If there is substantial variability in the covariates, we will consider potential categorizations  and perform analyses according to the relevant subgroup, if feasible. Finally, we will perform random-effects meta-regression to explore factors that may drive statistical heterogeneity.To assess the trustworthiness of the body of evidence and our confidence in the synthesized findings, we will use six quantitative criteria previously proposed  includinAll analyses will be conducted in Stata version 17  and R .Although descriptive reviews of SARS-CoV-2 infection in transplant recipients have been published , 4, 15, At the rapid review level, population and reporting differences between studies may limit the generalizability of our results. Variation in patient demographic reporting, outcome reporting , and matching parameters may render it difficult to form cohesive inferences. Furthermore, the COVID-19 pandemic has propagated in waves across time and geography. Since this review will include studies published over an extended period without geographic restriction, each study cohort may have experienced a vastly different infection rate, which could have resulted in variable outcomes. To address study-level limitations, we will conduct temporal and geographic sub-analyses accounting for period of data collection, country and continent of study, and transplant center volume.Any amendments made to this protocol when conducting the review will be outlined in OSF and reported in the final manuscript.Results will be disseminated through conference presentations and publication in a peer-reviewed journal. Through these routes, we expect this rapid review comparing outcomes of COVID-19 between OTr and non-transplant patients to inform best practice among clinicians, hospitals, researchers, and policymakers as they address the needs of the OTr population during the ongoing and future pandemics.Additional file 1. PRISMA-P  2015 checklist: recommended items to address in a systematic review protocol*Additional file 2. Search Strategy


Background: Ischemic stroke after coronary artery bypass (CABG) has been often linked to aortic manipulation during surgery.Objectives: The objective of the study was to estimate the rate of postoperative ischemic stroke within 30 days from CABG by surgical risk factors alone or in combination.Methods: The multinomial propensity score for multiple treatments was used to create six models with a total of 16,255 consecutive patients undergoing isolated CABG. For each model, a different classification variable was used to stratify patients.Results: Balance achieved in all models was substantial, enabling unbiased estimation of the treatment estimand. Both off-pump techniques with  or without proximal anastomoses , and surgery performed on the beating heart using cardiopulmonary bypass with  or without proximal anastomoses  showed a mean stroke estimate significantly lower than the other techniques. Off-pump surgery and on-pump surgery without an aortic cross-clamp yielded nearly equal incidences of stroke . Using an aortic cross-clamp significantly increased the stroke estimate , whereas using a side-biting clamp did not . The number of aortic touches  and the number of proximal anastomoses  did not significantly increase the incidence of stroke.Conclusions: Aortic cross-clamping was found to be the primary cause of post-CABG ischemic stroke. Instead, additional aortic manipulation from a side-biting clamp, on-pump surgery, multiple aortic touches, number of proximal anastomoses, and aortic cannulation were found not to increase the estimate of stroke significantly. Further research on this topic is warranted. Factors increasing post CABG incidence of ischemic stroke (red) and those which were not significant at the multi-model multifactorial analysis that analyzed all technical factors alone or in different combinations (green). Ischemic stroke following coronary artery bypass grafting (CABG) has been related to aortic manipulation, which may trigger the embolization of debris . SeveralHowever, despite the abundance of studies, most published data are the result of one-to-one comparisons of only a few of all the available techniques , 11, rulUsing a large patient population undergoing CABG, this study explored whether different surgical procedures encompassing vary degrees of aortic manipulation may have affected the incidence of ischemic stroke.The approval for this retrospective study was according to National Laws regulating observational retrospective studies.The study population included 16,255 consecutive patients undergoing isolated CABG between 1997 and 2017 at our Institutions.Patients were classified as follows by creating six propensity score models .Model 1—Patients stratified by surgical technique: (1) Off-pump technique (OPCAB) without proximal anastomoses on the aorta (NPA-Off); (2) OPCAB with proximal anastomoses on the aorta performed with the use of a side-biting clamp (SBCL-Off); (3) surgery performed on the beating heart but with the use of cardiopulmonary bypass without an aortic clamp, cardioplegic arrest, and proximal anastomoses (NPA-BHON); (4) surgery performed on the beating heart but on-pump with proximal anastomoses on the aorta made with the use of a side-biting clamp (SBCL-BHON); (5) on-pump technique without proximal anastomoses on the aorta, obtained using one or two internal thoracic arteries (ITAs) and/or Y graft anastomosed to ITAs (NPA-TAC-ON); (6) on-pump technique with proximal anastomoses performed without releasing the aortic clamp on cardiopulmonary bypass and without the use of a second side-biting clamp ; (7) on-pump technique with proximal anastomoses performed with the use of a side-biting clamp after releasing the aortic clamp (TAC-SBCL-ON).Model 2—Patients stratified by the number of touches on the aorta: (1) No-touch; (2) one-touch (side-biting clamp or aortic cannula); (3) two touches (side-biting clamp plus aortic cannula); (4) three touches ; (5) four touches ; (6) three or more touches without proximal anastomosis, with a single total aortic clamp, and with a full aortic clamp and side-biting clamp.Model 3—Patients stratified by the use of cardiopulmonary bypass (CPB): (1) Off-pump; (2) on-pump, with or without the use of a total aortic clamp.Model 4—Patients stratified by the use of a total aortic clamp: (1) No TAC; (2) TAC, with or without the use of a second side-biting clamp.Model 5—Patients stratified by the use of a side-biting clamp: (1) No SBCL, without proximal anastomoses or without using the single clamp technique; (2) SBCL with or without TAC.Model 6—Patients stratified by the creation and number of proximal anastomoses: (1) No proximal anastomoses; (2) proximal anastomosis; (3) one proximal anastomosis; (4) two proximal anastomoses; (5) three or more proximal anastomoses.Conventional full median sternotomy CABG was performed in a standard fashion. When surgery was carried out on-pump, middle hypothermic 30–32°C), CPB was instituted by cannulating the ascending aorta and the right atrium. In some patients, a cross-clamp was released at the end of the distal anastomoses, and an SBCL was applied once or twice to make proximal anastomoses. For the patients in the single TAC-on group, the aortic cross-clamp remained in place for both distal and proximal coronary anastomoses. When the intervention was performed off-pump, stabilization of the target arteries was accomplished with the Medtronic Octopus System . Regarding the beating heart on-pump technique, surgery was performed on the beating heart specifically on normothermic (32°C) CPB established by standard ascending aorta cannulation and the insertion of a two-stage venous cannula with no additional venting of the left ventricle. In the non-touch technique, no proximal anastomosis was performed either because it was unnecessary or because of the use of one or two internal thoracic arteries (ITAs) and/or Y graft anastomosed to ITAs. Data obtained preoperatively, surgically, and postoperatively in the unweighted population are shown in the 0–32°C, CThe objective of the present study was to estimate how frequently postoperative ischemic stroke may occur within 30 days of the procedure. Following the American Heart Association/American Stroke Association, ischemic stroke was defined as an acute episode of neurological dysfunction caused by focal cerebral, spinal, or retinal infarction with a diagnosis based on symptoms persisting 24 or more hours or until death on pathological imaging, or other objective evidence of ischemic injury in a defined vascular distribution, and excluding other pathologies  .Propensity score (PS) inverse-probability of treatment weighting estimation for multiple treatments was used, and six independent models were created. The balance was tested either graphically or utilizing balance tables. Graphical estimation used standardized effect plots and quantile-quantile plots, which provide an immediate visual evaluation of balance quality. In each model, absolute standardized mean differences (ASMD) were calculated using a cutoff of <0.20 for bias statistics. The average treatment effect (ATE) was chosen as the causal effect estimand of stroke. It was defined as the ratio of the incidence of stroke in the entire population undergoing one treatment over the impact of stroke of the whole population under another treatment.R software v. 3.6.1 and specific packages were used for analysis. More details can be found in the Balance plots and the explanation of how to interpret them are presented in the Model 1. Stratification by surgical techniqueStroke estimate was significantly lower in NPA-off, SBCL-off, NPA-BH-on, and SBCL-BH-on than in all the other methods without significant differences between these procedures . Also, iModel 2. Stratification by number of aortic touchesThere was no difference between the no-touch technique and procedures involving one or two aortic touches. In contrast, the ischemic stroke estimate was significantly higher in the case of three or four touches, with no significant difference between three and four touches . When aoModel 3 Stratification by cardiopulmonary bypassThe incidence of stroke was significantly higher in CABG on-pump compared with the off-pump technique . NonetheModel 4. Stratification by total aortic clampingThe use of full clamping significantly increased the estimate of stroke . BesidesModel 5. Stratification with a side-clamp for proximal anastomosesThe use of a side-biting clamp for proximal anastomoses did not influence the estimate of ischemic stroke rate . FurtherModel 6. Stratification by number of proximal anastomosesThe performance of one or more anastomoses slightly increased the ischemic stroke estimate without reaching statistical significance . HoweverComplete estimand tables and two-by-two comparisons are shown in the Several techniques have been proposed to minimize the risk of ischemic stroke –7. NonetThe main findings of the paper can be summarized as follows:1. The total aortic cross-clamp (TAC) turned out to be the main cause of postoperative stroke, whereas using a partial side-biting clamp did not affect its incidence. Model 1 shows that the estimate of stroke becomes significantly higher each time TAC is employed. Indeed, once the aortic clamp is added, a higher number of touches Model 2) or proximal anastomoses (Model 6), as well as the use of the side-biting clamp (Model 6), does not add any significant risk. Barbut et al.  in 1994  or proxi2. One of the main hypotheses rejected by our paper is that the off-pump technique may reduce the incidence of stroke. Different theories have been proposed to explain the potential beneficial effect of off-pump surgery , includiIndeed, in our experience, although the estimate of stroke was higher on the whole for on-pump patients, a more detailed analysis showed that this difference disappears when the TAC is considered (Model 3). Moreover, Model 1 shows comparable shock estimates between the off-pump technique and surgery performed on the beating heart. This finding demonstrates that the use of CPB itself does not add any risk of stroke.3. Neither the aortic clamping strategy for constructing proximal anastomoses in CABG nor the number of anastomoses affected the incidence of postoperative ischemic stroke.More specifically, Model 5 failed to find any difference in the estimate of stroke employing a side-biting clamp, either off-pump or on the beating heart, on CPB. This finding is in accordance with Emmert et al., who reported no change in stroke rate when comparing on-pump CABG vs. applying partial aortic cross-clamping in OPCAB  and withMoreover, Model 6 found no difference in stroke estimate whether proximal anastomoses were performed or not. This finding is in line with the lack of influence of SBCL on stroke. In addition, in Model 2, we found that one or two aortic touches did not influence the incidence of stroke. Nonetheless, three or four touches always included the use of the aortic cross-clamp. Hence the risk of stroke is independent of the number of touches and increases when TAC is used, independently of the technique employed.4. Our findings do not support the hypothesis that the incidence of post-CABG embolic stroke decreases by eliminating the second, partially occluding aortic clamp. Model 4 indicated clearly that the estimate of stroke did not increase with the application of the conventional second clamp for performing proximal anastomosis on an arrested heart. This result conforms with large studies showing similar rates of stroke with single or double cross-clamp techniques –30.5. Finally, our data do not confirm the hypothesis that cannulation of the aorta increases the risk of stroke. Model 1 indicated that, by adding aortic cannulation, with or without proximal anastomoses, the ischemic stroke estimate did not increase, and this was also confirmed by Model 3, showing comparable results between off-pump and on-pump without a cross-clamp. This finding is in agreement with the increasing evidence coming from other cardiac interventions that aortic cannulation involves low stroke risk In the real clinical world, the non-touch technique is seldom applicable. Furthermore, the use of double ITAs, radial artery, and Y or T anastomosis is not always possible, and these procedures are not unanimously accepted by the cardiac surgery community . Thus, tIf a patient should require a CABG technique entailing the use of CPB, our findings suggest that there is no difference between performing proximal anastomoses with a side-biting clamp after releasing the total aortic cross-clamp or creating an anastomosis on full CPB with the aorta cross-clamped. Hence, our data recommend caution in choosing the single clamp technique and suggest carefully evaluating every individual patient for the potential advantages of the double-clamp technique, including better myocardial protection , compareFinally, our data provide insufficient evidence to justify either the attempt to perform as many anastomoses as possible with a single partial clamp or to reduce the number of proximal anastomoses on the aorta.The current research is retrospective and, therefore, susceptible to all the inherent weaknesses of such studies. Second, no systematic assessment of the ascending aorta with epi-aortic ultrasound and transesophageal echocardiography was carried out. Third, the number of patients with facilitating devices or anastomotic connectors could not be included because the group was too small. Fourth, ischemic stroke was analyzed only from a surgical point of view, without taking into account other factors . Fifth, despite our aims, it was not possible to distinguish damages from TAC from potential injuries caused by the aortic needle since these two tools were always used together. Sixth, the majority of head computed tomography scans were performed early after surgery, so they may not have revealed some strokes detected by MRI afterward. Seventh, due to the number of patients between groups, we cannot exclude a Type 2 error. This should be taken into account when reading our results.The aortic cross-clamp is the leading cause of post-CABG ischemic stroke. In contrast, additional aortic manipulation from a side-biting clamp, on-pump surgery, multiple aortic touches, the number of proximal anastomoses, and aortic cannulation do not increase the risk of stroke. Further research on this topic is warranted.Competency in Medical Knowledge: The total aortic cross-clamp is the leading cause of postoperative stroke. The off-pump technique does not reduce the incidence of stroke.Competency in Patient Care: The use of the “no-touch” technique “at any cost” is not justified. Performing proximal anastomoses using a side-biting clamp off-pump or working on the beating heart on normothermic CPB guarantee comparable safety in terms of stroke compared to the fully “no-touch” technique.Translational Outlook 1: The mechanism by which the total aortic cross-clamp causes more ischemic stroke requires further investigation. New clamp designs, as well as a cross-clamp imaging-guided treatment, need to be evaluated.Translational Outlook 2: Additional research is needed in order to understand the interaction of technical factors and clinical risk factors  to lower the incidence of stroke after CABG that is still high.The original contributions presented in the study are included in the article/Ethical approval was not provided for this study on human participants because the Italian National Laws regulating observational retrospective studies . Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.SG: conceptualization, methodology, validation, formal analysis, investigation, resources, writing—original draft, writing—review and editing, visualization, project administration, and supervision. CT: investigation, resources, data curation, writing—original draft, and validation. FM: software, validation, data curation, writing—original draft, validation, and visualization. SP: validation, investigation, resources, data curation, writing—review and editing, and visualization. OP: software, validation, investigation, resources, and data curation. EP: validation, formal analysis, investigation, resources, data curation, review and editing, and visualization. AD: resources, data curation, conceptualization, methodology, validation, and review and editing. GP and LM: resources, data curation, review and editing, and visualization. ML: conceptualization, validation, data curation, review and editing, visualization, project administration, and supervision. MB: conceptualization, methodology, validation, formal analysis, investigation, writing—review and editing, visualization, project administration, and supervision. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


ABSTRACT IMPACT: I hope that our work will improve surveillance endoscopy experiences, by engaging both patients and providers. OBJECTIVES/GOALS: A large proportion of colonoscopies are performed for post-polypectomy surveillance. Data show that there is overuse of surveillance for low-risk adenomas (LRAs), which can be attributed to patient and provider factors. The objective is to understand patient and provider perspectives for decision-making for LRA surveillance colonoscopy. METHODS/STUDY POPULATION: Semi-structured, one-on-one virtual interviews of patients and providers are currently being conducted at Richard L. Roudebush VA Medical Center and Eskenazi Health. Using a criterion sampling approach, we identified patients 50-75 years of age who had a screening colonoscopy with finding of LRAs, and providers in primary care and gastroenterology, at each site. We plan to recruit at least 8 patients and 8 providers from each site until thematic saturation. Domains that will be covered include: perceived involvement with surveillance decision-making; experiences with, and preferences for, communication about test results; and barriers and facilitators to undergoing colonoscopy. A 3-phase approach, comprising immersion, reduction, and interpretation, is being used to collect and analyze data. RESULTS/ANTICIPATED RESULTS: This study is currently in the recruitment phase and results will be forthcoming. DISCUSSION/SIGNIFICANCE OF FINDINGS: Understanding decision-making for LRA surveillance colonoscopy will inform future interventions to improve endoscopic resource use and efficiency while improving patient and provider experiences with endoscopic care coordination.


During aging, the cardiovascular system is especially prone to a decline in function and to life-expectancy limiting diseases. Cardiovascular aging is associated with increased arterial stiffness and vasoconstriction as well as left ventricular hypertrophy and reduced diastolic function. Pathological changes include endothelial dysfunction, atherosclerosis, fibrosis, hypertrophy, inflammation, and changes in micromilieu with increased production of reactive oxygen and nitrogen species. The renin-angiotensin-aldosterone-system is an important mediator of electrolyte and blood pressure homeostasis and a key contributor to pathological remodeling processes of the cardiovascular system. Its effects are partially conveyed by the mineralocorticoid receptor (MR), a ligand-dependent transcription factor, whose activity increases during aging and cardiovascular diseases without correlating changes of its ligand aldosterone. There is growing evidence that the MR can be enzymatically and non-enzymatically modified and that these modifications contribute to ligand-independent modulation of MR activity. Modifications reported so far include phosphorylation, acetylation, ubiquitination, sumoylation and changes induced by nitrosative and oxidative stress. This review focuses on the different posttranslational modifications of the MR, their impact on MR function and degradation and the possible implications for cardiovascular aging and diseases. The MR is a ligand-dependent transcription factor with aldosterone as an endogenous ligand in humans. Cloning of the MR occurred relatively late compared to the other steroid receptors . The humThe N-terminal A/B domain is highly evolutionarily conserved but possesses less than 15% homology with the other steroid receptors. It contains an autonomous activation functional domain (AF-1) consisting of two parts, AF-1a and AF-1b, separated by an inhibitory domain (ID) . AF-1 isThe MR and its closest relative the glucocorticoid receptor (GR) evolved from a common corticoid receptor. Evolutionwise, a separation into MR and GR was first found in cartilaginous fish. However, these fish do not possess distinct ligands for the two receptors, so that 11-desoxycorticosterone, glucocorticoids but also progesterone act as natural ligands for both receptors . In lungIn the absence of ligand, the MR is primarily located in the cytosol , or it iin vitro independently of DNA or ligand , and angiotensin II stimulates aldosterone secretion. Classical epithelial MR effects occur in kidney, colon and sweat glands and include sodium and water reabsorption as well as proton and potassium secretion. MR effects in the kidney regulate overall volume and electrolyte homeostasis and thereby control systemic blood pressure. The MR is also expressed in various non-epithelial tissues. For example, in the vascular wall, the MR was detected in vascular smooth muscle cells (VSMCs), in endothelial cells but also fibroblasts and immune cells.MR antagonists have proven beneficial for different cardiovascular diseases going clearly beyond a lowering of blood pressure and optimization of water-electrolyte-homeostasis. Several large clinical trials indicate that MR antagonists effectively treat heart failure with reduced ejection fraction, a typical cardiovascular disease of the elderly . OverallDuring aging, plasma renin activity and aldosterone levels decrease, so it is not clear at first glance why RAAS should contribute to cardiovascular changes during aging . Howeverin vivo, MR activation can lead to both vasodilation or vasoconstriction depending on the experimental setup  signaling . MR exprHealthy endothelial cells play an important anti-inflammatory and antithrombotic role in the vasculature and convey vasorelaxation. Under physiological conditions, the role of the MR seems to be vasoprotective, but it is not as well characterized as in models with cardiovascular risk factors . In thesPosttranslational modification of steroid receptors allows fine-tuning of receptors stability, ligand-binding, transformation, co-regulator binding, DNA-binding and transactivation . Early s−/HCO3− exchangers, which prevented a lumen-negative potential from forming. Consequently, adjacent principal cells promoted an increase in sodium and water reabsorption but no K+ secretion. Hyperkalemia, on the other hand, increased phosphorylation of MR-S843 and thereby inactivated aldosterone effects in intercalated cells so that a lumen-negative potential with resulting K+ secretion occurred in the renal collecting duct. This mechanism serves as a switch allowing aldosterone to exert distinct effects in different physiological contexts  found under basal conditions. Subsequently, removal of a monoubiquitin, followed by polyubiquitination and degradation of the MR took place . Since aAdditionally, there are some indications that different PKC isoforms can affect MR signaling through direct phosphorylation of the receptor. Aldosterone triggered both an early nongenomic and a late genomic increase in sodium transport in rat cortical collecting duct cells dependent on PKCα. The early aldosterone-induced increase in short-circuit current involved rapid phosphorylation of MR on serine and threonine residues, which could be abolished by a PKCα inhibitor. In contrast, the late aldosterone-induced increase in ion transport and gene expression required protein synthesis but could also be inhibited by blocking the PKCα pathway so that a crosstalk between rapid and prolonged MR effects was suggested . In contAnother potential kinase for MR phosphorylation is the ubiquitously expressed serine/threonine kinase CK2. Inhibition of CK2 reduced the shift in gel band size of MR caused by aldosterone and inhibited MR transcriptional activity under control conditions . PeptideIn neuronal cells, MR has an impact on neuronal viability, synaptic plasticity and emotional changes. There, CDK5 interacted with the LBD of the MR and aldosterone-dependently phosphorylated the MR-NTD residues S128, S250, and Th159, identified by mass spectrometry analysis and mutation experiments. Phosphorylation of MR reduced its transcriptional activity in an MMTV-reporter assay but did not affect nuclear accumulation. On the other hand, aldosterone and CDK5 increased the expression of brain-derived neurotrophic factor in rat cortical neuronal cells . This suin vitro so that PKA seems to act indirectly, probably by relieving the effect of an MR repressor . Activation of cAMP-PKA signaling stimulated GRE-containing promoters in a ligand-independent manner and also synergistically after aldosterone activation. Protein kinase-inhibiting peptide (PKI) prevented both cAMP and aldosterone induction, which indicates that a functional cAMP pathway is required for MR transactivation activity. Binding of the MR to a GRE-containing oligonucleotide in a gel shift assay was enhanced by PKA and required the NTD of the MR. However, purified MR NTD protein was not directly phosphorylated by PKA epressor . Conversepressor . It is lepressor . In vivoignaling . HoweverAcetylation is a general epigenetic modification responsible for controlling the activity of various cytosolic and nuclear proteins involved in gene expression like histones, nuclear receptors and chaperones . It is a+ absorption and increased SGK1 activity and abundance. HDAC inhibition by trichostatin A could inhibit aldosterone/MR dependent regulation of SGK1/ENAC signaling leading to sodium reabsorption. Insulin-dependent activation of SGK/ENAC signaling was not modified. Consequently, the SGK1-ENAC pathway was not affected by pan HDAC inhibition, but the control of MR over this pathway was perturbed, which again supports that MR acetylation inhibits MR activity  increased MR acetylation and decreased MR transcriptional activity in reporter gene experiments. This corresponded to reduced MR target gene expression as well as reduced pol II recruitment to the respective promoters. Pathophysiological relevance of MR acetylation was also demonstrated with HDAC inhibitors. In mCCD cells, aldosterone augmented ENaC-induced Naactivity . Furtherteronism . Althougteronism . These rteronism . An inditeronism .in vivo DNA occupancy time, indicating that ubiquitination is involved in regulating GR stability , which possess four isoforms SUMO1-4 in humans. SUMOs are preferentially attached to lysine in the consensus sequence ΨKD/E and share a similar structure with ubiquitin. As with ubiquitination, attachment requires three enzymes E1-E3. The MR contains five consensus SUMO-1 binding sites, four in the AF1 domain of the NTD and one in the LBD. PIAS1 and some of its family members can function as E3 ligases and are able to interact with the MR. They can directly sumoylate the MR as demonstrated by multiple shifted bands in Western blot analyses, which are missing after mutating respective amino acids. Overexpression of PIAS-1, which led to increased MR sumoylation, had no effect on MR expression or subcellular localization but reduced its transcriptional activity upon ligand binding. The inhibition was equally strong after deleting the first 453 amino acids of the NTD but was not present for GR and dexamethasone . Mutatio2O2 was enhanced by iron and inhibited by sulfhydryl reducing reagents, suggesting that disulfide bonds of cysteines are responsible (in vitro and in vivo in adrenalectomized rats inhibited both steroid-binding capacity and aldosterone-dependent sodium-retaining properties (in vivo glutathione depletion (3H]aldosterone. Agonist-bound MR was resistant to cysteine modifying agents while free hMR and antagonist-bound hMR was sensitive. Therefore, sulfhydryl groups are involved in binding of ligands to the MR, and their accessibility varies depending on the ligand-status of the MR and the receptor conformation (During aging, oxidized proteins accumulate in tissues because of increased ROS generation and a reduced antioxidative capacity . Overallponsible . Treatmeoperties . As a meepletion . Furtherormation . Anotherormation . Associaormation . Overallormation .In vivo in two rat pulmonary arterial hypertension models, MR antagonists prevented or reversed pulmonary vascular remodeling. There elevated endothelin-1 levels were associated with elevated aldosterone levels in plasma and decreased lung NO metabolites (Not only oxidative stress but also nitrosative stress occurs during aging and affects MR signaling. For the GR it has been shown that NO can react with SH groups to form S-nitrosothiols, which inhibit binding of GR to ligand without affecting MR-HSP90 interaction . For theabolites .in vivo relevance of posttranslational modifications for MR function needs further exploration for understanding the mechanisms of cardiovascular diseases and healthy aging.Besides exerting classical epithelial effects on volume-and electrolyte homeostasis, the MR has a large impact on cardiovascular pathophysiology with cell-type-specific and context-dependent functions. While ensuring homeostasis in young and healthy tissues, the MR tends to aggravate pathological changes in aged or pre-injured tissues exposed to cardiovascular risk factors. It is unclear what causes the switch from physiological to pathological functions, but one possibility is posttranslational modification induced by a pathological micro-milieu. Signaling of the MR resembles that of its steroid receptor relatives and involves cytosolic association to chaperones, binding of ligand, nuclear translocation and function as a transcription factor. For the MR, many variants are known and have contributed to the understanding of MR structure and function. Loss of function mutations, which in the extreme cause pseudohypoaldosteronism type 1, and gain-of function-mutations, which give rise to inherited forms of hypertension, usually lead to structural alterations of the MR that affect its fundamental functions like binding of ligand or DNA . Over 38


Obesity has been reported to be a risk factor for breast cancer, but how obesity affects breast cancer (BC) remains unclear. Although body mass index (BMI) is the most commonly used reference for obesity, it is insufficient to evaluate the obesity-related pathophysiological changes in breast tissue. The purpose of this study is to establish a DNA-methylation-based biomarker for BMI (DM-BMI) and explore the connection between obesity and BC. Using DNA methylation data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO), we developed DM-BMI to evaluate the degree of obesity in breast tissues. In tissues from non-BC and BC population, the DM-BMI model exhibited high accuracy in BMI prediction. In BC tissues, DM-BMI correlated with increased adipose tissue content and BC tissues with increased DM-BMI exhibited higher expression of pro-inflammatory adipokines. Next, we identified the gene expression profile relating to DM-BMI. Using Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) database, we observed that the DM-BMI-related genes were mostly involved in the process of cancer immunity. DM-BMI is positively correlated with T cell infiltration in BC tissues. Furthermore, we observed that DM-BMI was positively correlated with immune checkpoint inhibitors (ICI) response markers in BC. Collectively, we developed a new biomarker for obesity and discovered that BC tissues from obese individuals exhibit an increased degree of immune cell infiltration, indicating that obese BC patients might be the potential beneficiaries for ICI treatment. Breast cancer (BC) is the most commonly diagnosed cancer and the second leading cause of cancer death for women in the world . It was Body mass index (BMI), defined as a person’s weight in kilograms divided by the square of height in meters, is the most commonly used method for obesity evaluation. However, it is more like a surrogate measure for body fatness for obesity should be calculated using the excess accumulation of adipose tissues rather than body mass . As therIt is well known that obesity is affected by multiple factors  . Recentlhttps://portal.gdc.cancer.gov/). Clinical features of BC patients in TCGA-BRCA are listed in The training set includes genome-wide methylation data of 221 normal breast tissues in GEO (GSE88883 and GSE101961) while the validation sets includes data of 44 normal breast tissues . Data of 70 tumor-adjacent breast tissues  in GEO (GSE67919 and GSE74214) were used to develop the DM-BMI score. BMI data of the above cases are listed in β value ranging from 0 (no DNA methylation) to 1 (complete DNA methylation) was used to define the methylation level of each probe. Probes with missing value in over 50% samples were removed while the probes with missing value in less than 50% of samples were imputed with the k-nearest neighbors (knn) imputation method. Probes located on the sex chromosome and probes containing known single nucleotide polymorphisms (SNPs) were removed. Eventually, 301,998 probes were included in this study. BMIQ normalization for type I and II probe correction was performed. Data from multiple studies was integrated and the Combat algorithm was performed to remove the batch effects. The above processes were carried out using the R package ChAMP  before further analysis, which is shown as follows:The parameter healthy.BMI was set to 25, referring to the upper limit of BMI in healthy population.A lasso regression was used to regress the DM-BMI in the form of F(BMI) based on the BMI data and DNA methylation data with 301,998 probes; 42 probes were selected in the lasso regression model as BMI predictors according to the lambda.min value . The coeAdipose tissue accounts for a large proportion of breast tissue composition. Based on DNA methylation, we used a deconvolution algorithm to calculate the proportion of adipose tissue in breast and BC tissues. Forty-two probes were selected in the lasso regression model as BMI predictors. The distribution of 42 probes on chromosome, CpG island, and TSS regions was assessed using the R package ChAMP. BMI predictors, differentially methylated between BC tissues and tumor-adjacent breast tissues in the TCGA database, were identified using the R package Champ. The survival correlation of BMI predictors was assessed using TCGA BRCA data. Correlation between the methylation level of BMI predictors and DM-BMI was assessed.DM-BMI of TCGA-BC tissues were calculated using DNA methylation data. Spearman correlation coefficient was used to assess the correlation of DM-BMI and clinical characteristics  in BC. Gene expression profile related to DM-BMI was identified; functional analysis of the related genes was process by GO and KEGG analysis. Besides, we performed gene set variation analysis (GSVA) to identify DM-BMI related gene signature using gene expression data in TCGA . The aboTumor mutation burden (TMB) was defined as the number of non-synonymous mutations/Mb of genome. As previously reported , TMB of http://cibersort.stanford.edu/)  . Correlahttp://tide.dfci.harvard.edu). The relevant data are listed in Biomarkers used to predict the immunotherapy response includes: IFN-γ signature (IFNG) , IFNG hat-test to assess the predictive accuracy of the DM-BMI model. DM-BMI showed a significant correlation with BMI . Using a deconvolution algorithm, we evaluated the breast tissue composition and observed that the increased DM-BMI was significantly correlated with higher proportion of adipose tissue  were selected as the training cohort to develop the DNA-methylation-based BMI (DM-BMI) prediction model . The medwith BMI  while pae tissue . These rt-test revealed that there was no significant difference between DM-BMI and BMI . Moreover, DM-BMI is significantly correlated with adipose tissue proportion in both normal and tumor-adjacent breast tissues  and 70 tumor-adjacent breast tissues  were enrolled for external validation . The med tissues . The aboFurthermore, we assessed the DM-BMI of paired tumor and tumor-adjacent breast tissues in TCGA database. The tumor tissues exhibited a higher level of DM-BMI compared with its paired tumor-adjacent tissues . In BC tAs DM-BMI was significantly correlated with obesity status, which has been suggested to regard as a risk factor for BC, we further assessed the relevance between BMI predictors and BC. As hyper-methylation of CpG island at gene promoter regions often causes gene silencing, we first evaluated the distribution of BMI predictors. Among 22 pairs of chromosomes (Chr), Chr1 and 16 are the most common region for BMI predictor distribution; 45.2% of BMI predictors were located at the gene body regions while only 23.8% of them were located at the promoter regions (TS1500 and TS200). Furthermore, we observed that only a few parts of BMI predictors were located at CpG islands .Next, we assessed the methylation variation of BMI predictors between tumor and tumor-adjacent breast tissues. Twenty-six differentially methylated probes (DMP) were identified: 22 BMI predictors were hyper-methylated in tumor tissues compared with the tumor-adjacent breast tissues; 4 were hypo-methylated in tumor . Three oLater we explored the biological significance of DM-BMI in breast cancer tissues. The survival correlation of DM-BMI was evaluated in BCs and the subgroup of BCs with cancer therapy . DM-BMI was consistently correlated with higher mortality risk in the whole cohort of BC patients and subgroups of patients with chemotherapy, endocrine-therapy or radiation-therapy, respectively . TissuesPrevious studies showed that adipokines produced by obese adipose tissues leads to obesity-mediated inflammation and BC progression. In BC tissues, sections of adipose tissue were positively correlated with DM-BMI. Expression of six pro-inflammatory adipokines was positively correlated with DM-BMI while the expression of two anti-inflammatory adipokines was negatively correlated with DM-BMI . These rFurthermore, we assessed the DM-BMI (obesity)-related gene expression profile and mRNA expression of 10,032 genes significantly correlated with DM-BMI. To evaluate the biological effect of obesity on BC, we performed a GSEA analysis of DM-BMI-related genes using KEGG and GO database. GO analysis showed that gens positively correlated with DM-BMI were significantly involved in antigen process and presentation, immune cell activation, MHC protein binding, and immune receptor activity in BC . KEGG coWe evaluated the correlation between obesity and immune response to BC. Gene mutation which changes the protein-coding sequence and leads to the expression of abnormal proteins was suggested to be the driving factor for cancer development. Also, the abnormal protein derived from tumor mutation might rouse immune response. In BC tissues, we observed a positive correlation between DM-BMI and TMB . Using tBased on the DNA methylation pattern, we developed an obesity evaluation model (DM-BMI) in the study. We then further identified the obesity-related gene expression profile based on the DM-BMI model. Although obesity has been shown to be a BC risk factor for many years, most studies have been focusing on the correlation between obesity and clinical prognosis while studies about the biological and genomic impact of obesity on breast cancer were limited. The adipose tissue, as the major agent mediating obesity-related biological effects, is an important starting point for the study of the obesity impact. In both breast and BC tissue, we observed a positive correlation between the proportion adipose tissue content and the DM-BMI. Previous studies reported that the expansion of adipose tissue, accompanied by the dysregulation of the endocrine function (adipokine secretion) of the adipose cells, was driven by an increase in size of adipose or by a formation of a new adipose cell . As the In addition to the expansion of adipose tissue, we also observed a promoting effect of obesity on immune response in BC tissue. For those obese individuals, adipose tissue expands with the increasing demand of oxygen, which induces the development of the hypoxia environment . The act2 to reduce toxicity when calculating the dose of chemotherapy  . AlthougThe identification of BMI predictors naturally causes the assumption that these CpGs are critical regulators of obesity. In our study, only 11 of 42 BMI predictors were significantly correlated with DM-BMI while the others exhibited negligible correlation with DM-BMI. Although DNA methylation level was negatively correlated with gene expression in over half of BMI predictors, 45.2% of BMI predictors were located at the body region of gene sequence. How the CpGs located at the body region regulate gene expression remains unclear. As a previous study reported, the variations of DNA methylation pattern are the consequence, rather than cause, of adiposity . WhetherCollectively, we established a new biomarker for obesity evaluation and discovered that BC tissues of obese individuals exhibit an increased degree of immune cell infiltration, indicating that obese BC patients might be the potential beneficiaries for ICI treatment.


Aims: Thromboembolic events, including stroke, are typical complications of COVID-19. Whether arrhythmias, frequently described in severe COVID-19, are disease-specific and thus promote strokes is unclear. We investigated the occurrence of arrhythmias and stroke during rhythm monitoring in critically ill patients with COVID-19, compared with severe pneumonia of other origins.Methods and Results: This retrospective study included 120 critically ill patients requiring mechanical ventilation in three European tertiary hospitals, including n =60 COVID-19, matched according to risk factors for the occurrence of arrhythmias in n = 60 patients from a retrospective consecutive cohort of severe pneumonia of other origins. Arrhythmias, mainly atrial fibrillation (AF), were frequent in COVID-19. However, when compared with non-COVID-19, no difference was observed with respect to ventricular tachycardias (VT) and relevant bradyarrhythmias  with consequent similar rates of cardiopulmonary resuscitation . AF was even more common in non-COVID-19 , which resulted in a higher need for electrical cardioversion . Despite these findings and comparable rates of therapeutic anticoagulation (TAC), the incidence of stroke was higher in COVID-19 . These events also happened in the absence of AF (50%) and with TAC (50%).Conclusions: Arrhythmias were common in severe COVID-19, consisting mainly of AF, yet less frequent than in matched pneumonia of other origins. A contrasting higher incidence of stroke independent of arrhythmias also observed with TAC, seems to be an arrhythmia-unrelated disease-specific feature of COVID-19. The novel coronavirus disease COVID-19 caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a worldwide healthcare crisis with an overstrain of hospital resources –5. AlthoThe present retrospective study was conducted in three European tertiary centers in Germany and Austria . The study was conducted in accordance with the Declaration of Helsinki and the standards of good clinical practice. All three local ethic committees approved the present study .via a tightly fitted face mask or helmet, as opposed to invasive ventilation necessitating endotracheal intubation. All patients included in the study had some form of mechanical ventilation (patients who merely needed oxygen insufflations were not included) between March and May 2020. Patients were treated according to recent recommendations . The COVID-19 cohort consisted of 60 consecutive patients with available ICU rhythm monitoring who suffered severe pneumonia. Severe pneumonia was defined as pneumonia-associated respiratory failure requiring mechanical ventilation [noninvasive ventilation (NIV) or invasive ventilation]; the term NIV in this study refers to mechanical ventilation involving end-expiratory and inspiratory positive air pressure support The control group was recruited from a consecutive collective of 1,222 patients suffering severe pneumonia of non-COVID-19 origin. All patients in the control group were treated between January 2014 and Mach 2020 at the ICU according to current intensive care guidelines . PatientIn all eligible patients, data were retrospectively collected from electronic medical records. Data obtained comprises demographics, medical history, laboratory examinations, comorbidities, complications, specific treatment measures, and outcomes, and also 12-lead ECGs at ICU admission and complete rhythm monitoring during ICU stay (continuous standard three-lead ECG during complete ICU stay). Laboratory samples were collected within the first hours after ICU admittance, and follow-up was conducted on a daily routine according to the need for clinical assessment. With regards to rhythm monitoring, baseline rhythm was evaluated and documented every hour during the entire ICU stay. Analyses of ECGs, classification of arrhythmias, and quantification of the duration of arrhythmias in the rhythm monitoring were analyzed and documented by a trained team of ICU nurses and physicians in one of the recruiting centers. Cardiac arrhythmias during ICU rhythm monitoring were classified according to current guidelines –6. AF waDiagnosis of thromboembolic/thrombotic events including pulmonary embolism, thromboembolic stroke, and transient ischemic attack was established in agreement with current guidelines , 8. The http://www.R-project.org/) using the packages “MatchIt,” “optmatch” and “RItools,” “stddiff,” and also SPSS , and was carried out blindly by our statistical analytic team. Descriptive statistics were obtained for all study variables. All categorical variables were compared by using the Fisher exact test. Ordinal data are presented as median (interquartile range [IQR]). Median values were compared using the Mann–Whitney-U test. Normal distribution of continuous variables was tested using the Kolmogorov–Smirnov test. According to results, continuous variables were compared using the independent student t-test or the Mann-Whitney U test, as appropriate. Continuous data are expressed as mean and standard deviation (SD) or median (interquartile range [IQR]) values. A p < 0.05 was regarded as statistically significant. Covariate imbalance was assessed by calculating standardized differences for the covariates age, gender, coronary artery disease, valvular heart disease, arterial hypertension, diabetes mellitus, atrial fibrillation, atrial flutter, stroke, and heart failure, and also by calculating an omnibus test and significant differences between the two investigated groups using Wilcoxon rank-sum test and χ2 test.”Statistical analysis was conducted using R , R Foundation for Statistical Computing, Vienna, Austria; Patients or the public were not involved in the design, or conduct, or reporting, or dissemination of our research.p = 0.556) revealed no statistically significant differences between the two investigated groups   .The baseline characteristics of both patient cohorts are presented in The analyses of the continuous rhythm monitoring during the ICU stay are presented in Table 4) in non-COVID-19. Consequently, while mortality was high in both groups, a significantly higher rate in the non-COVID-19 group was observed  levels. This was further accompanied by increased lactate levels and decreased pH (observed , indicat2DS2-Vasc scores, a significantly higher incidence of thrombotic strokes/TIA was revealed (In contrast to these observations and in line with previous reports , we obserevealed . Of noterevealed , indicatThe typical finding in severe COVID-19 disease is pneumonia accompanied by acute lung injury . In thisTo account for underlying medical conditions predisposing to cardiac arrhythmias, the study cohorts were matched for preexisting AF as well as age, gender, coronary artery disease, valvular heart disease, arterial hypertension, diabetes mellitus, atrial fibrillation, atrial flutter, stroke, and heart failure. Reliability of the matching process was further confirmed by analyzing covariate imbalance between the two investigated, showing no significant differences.In contrast to former studies conducted on arrhythmias in COVID-19, the present project included monitoring data on arrhythmias for the entire ICU-stay in addition to standard 12-lead ECGs, thus allowing for a more precise analysis of the arrhythmic burden. To avoid potential interference of novel treatment options, such as dexamethasone, with our findings, patients were recruited during the first wave of the pandemic before publication of the “RECOVERY Trial in July 2020.” The impact of COVID-19 disease on myocardial arrhythmias might be better reflected through this approach, since outcomes are not influenced by this treatment regime, which is now routinely applied in the involved study centers. Accordingly, COVID-19 specific therapy is low in the present patient collective as it was mostly experimental during this investigated period.In the COVID-19 group, AF was the most frequent arrhythmia and was observed in 18.3% of all patients . It is iSince inflammatory processes are known to increase the vulnerability for arrhythmias , 18, theWhile no significant increase of arrhythmias in the COVID-19 cohort was evident, thromboembolic events showed a significant increase compared with non-COVID-19 patients. This is reflected by a higher incidence of pulmonary embolism and stroke/TIA in our COVID-19 cohort . AccordiThe present study has by design its limitations, while contributing novel clinical findings. Our sample size may be too small to detect differences in arrhythmias with low incidence, such as ventricular tachyarrhythmias and bradyarrhythmias. The heterogeneity of our comparison group, which consists of patients suffering from pneumonia of diverse origin might in part differ with regards to the pathogenetic mechanisms compared with COVID-19 pneumonia. Thus, the findings of the present study have to be considered as hypothesis generating. The passionate use of untested treatments in a number of COVID-19 patients (such as tocilizumab or hydroxychloroquine, In summary, AF is common in severe COVID-19, but we found it to be less frequent than in severe pneumonia of non-COVID-19 origin. Arrhythmia might be mainly attributed to a high inflammatory activity and disease severity, instead of a COVID-19 specific mechanism. The contrasting higher incidence of stroke, despite the lower rate of AF, seems to be a disease-specific feature of critical COVID-19, consistent with high rates of pulmonary embolisms. Further research will hopefully clarify the potential role of TAC to prevent thromboembolic events, which are independent of AF.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by University Hospital Münster: Nr. 2020-306-f-S, Maria Hilf Hospital Mönchengladbach: Nr. 143/2020, and University Hospital Salzburg: Nr. 1071/2020. Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Chronic respiratory diseases (CRDs) are common and disabling conditions that can result in social isolation and economic hardship for patients and their families. Pulmonary rehabilitation (PR) improves functional exercise capacity and health-related quality of life (HRQoL) but practical barriers to attending centre-based sessions or the need for infection control limits accessibility. Home-PR offers a potential solution that may improve access. We aim to systematically review the clinical effectiveness, completion rates and components of Home-PR for people with CRDs compared with Centre-PR or Usual care.We will search PubMed, CINAHL, Cochrane, EMBASE, PeDRO and PsycInfo from January 1990 to date using a PICOS search strategy . The strategy is to search for ‘Chronic Respiratory Disease’ AND ‘Pulmonary Rehabilitation’ AND ‘Home-PR’, and identify relevant randomised controlled trials and controlled clinical trials. Six reviewers working in pairs will independently screen articles for eligibility and extract data from those fulfilling the inclusion criteria. We will use the Cochrane risk-of-bias tool and Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach to rate the quality of evidence. We will perform meta-analysis or narrative synthesis as appropriate to answer our three research questions: (1) what is the effectiveness of Home-PR compared with Centre-PR or Usual care? (2) what components are used in effective Home-PR studies? and (3) what is the completion rate of Home-PR compared with Centre-PR?Research ethics approval is not required since the study will review only published data. The findings will be disseminated through publication in a peer-reviewed journal and presentation in conferences.CRD42020220137. A systematic review of the effectiveness, completion rates and components of Home-pulmonary rehabilitation (Home-PR) for chronic respiratory diseases (CRDs) is needed to inform patients and providers especially when healthcare accessibility is restricted by geography, demography or during pandemics.The review methods are in accordance with Cochrane methodology and Preferred Reporting Items for Systematic Reviews and Meta-Analyses publishing guidelines.Issues like heterogeneity, poor reporting of published trials may affect confidence in results although we expect to provide robust evidence supporting the successful implementation of Home-PR services for people with CRDs.The multi-disciplinary, multinational research team will enable a nuanced interpretation of the findings.Chronic respiratory diseases (CRDs) including chronic obstructive pulmonary disease (COPD), remodelled asthma, pulmonary impairment after tuberculosis (PIAT), interstitial lung disease (ILD), bronchiectasis and cystic fibrosis (CF), among others, affect an estimated 545 million people globally.5 6Pulmonary rehabilitation (PR) is an essential component of CRD care12 13Despite proven effectiveness,24 25et al,et alet al in a scoping review also included people recovering from COVID-19.35Typically, PR is provided in hospital centres (Centre-PR),A recently published Cochrane review assessed the effectiveness and safety of telerehabilitation for people with CRDs when compared with Centre-PR or no rehabilitationAn additional distinction is that we defined Home-PR as comprising both exercise and at least one non-exercise component for a duration of not less than 4 weeks. This contrasts with other reviewsIn people with CRDs, we will:Assess the clinical effectiveness of Home-PR .Compare the completion rate (defined as participating in at least 70% of PR sessions) of Home-PR with Centre-PR.We will follow Cochrane methodology,We will develop a search strategy, including disease-specific search terms, and identify records through searching the following databases: PubMed, CINAHL, Cochrane, EMBASE, PeDRO and PsycInfo . The str10.1136/bmjopen-2021-050362.supp1Supplementary dataWe will select studies that compare Home-PR for people with CRDs with Centre-PR and/or Usual care  criteria in Our primary outcomes will be HRQoL and functional exercise capacity. We are interested in preassessment and postassessment or if an immediate post is not provided, the nearest figure to that. See We will develop a customised data extraction form based on Cochrane Effective Practice and Organisation of Care (EPOC) guidance.Methodological quality of all included randomised controlled trials (RCTs) will be assessed independently by reviewers  using the ‘Cochrane Risk of Bias’ tool.We will assess and investigate reasons for any heterogeneity using the I² statisticWe plan to undertake meta-analysis for the primary outcomes and some secondary outcomes , comparing Home-PR first with Usual care and then with Centre-PR. Heterogeneous outcomes for which a meta-analysis is inappropriate will be synthesised narratively. For homogenous data from RCTs, we will perform a pooled quantitative synthesis using an inverse variance method and a random-effects model in the meta-analysis. We will consider pooled mean differences if the same outcome measurement tool is used in the included RCTs. However, if (as expected) outcome measurement tool varies among trials, we will consider standardised mean differences (SMDs). Our hypothesis is that Home-PR is non-inferior to Centre-PR, but a clinically meaningful non-inferiority margin cannot be inferred using SMDs. If sufficient studies use the same measure for functional exercise capacity or health-related quality of life, we will define the non-inferiority margin as the minimum clinically important difference. We will use Review Manager software  to perform meta-analysis.The components of Home-PR will be described and a matrix compiled to identify any associations with successful interventions.We will use a narrative approach to synthesise completion in Home-PR and Centre-PR groups. If sufficient studies report completion rates, we will consider a sub-group analysis based on the threshold of 70% completion.Depending on the papers included, we will perform subgroup analyses. Subgroups may include high/LMICs, CRD diagnosis , severity as defined in internationally recognised guidelines,We will use the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approachPatients who are involved in the RESPIRE programme of work on PR have endorsed the importance of Home-PR for improving accessibility to rehabilitation. They will be involved in interpreting the findings and the implications for intervention development and the overall programme of workHome-PR has particular resonance at the time of developing this protocol because of the COVID-19 pandemic which has resulted in Centre-PR services being halted. More generally, there is an interest in offering Home-PR as a strategy to overcome the practical barriers of time and distance and increase the accessibility of PR services especially in LMICs. There are, however, concerns that the relative lack of supervision and the loss of peer group support may reduce effectiveness. Hence a review on the effectiveness of Home-PR and its components is timely to inform patients, professionals and healthcare service providers considering Home-PR options.This systematic review protocol will use publicly available data without direct involvement of human participants. Therefore, approval from an ethics committee is not essential. We will present our review findings at national and international scientific meetings and conferences, and publish in a peer-reviewed journal. In addition, we will use innovative dissemination strategies including virtual seminars and social media.