Hepatocellular carcinoma causes intrahepatic metastasis via the trans-portal vein. Thus, appropriate mapping of portal segments is necessary for laparoscopic anatomical liver resection. However, because of the difficulty in identifying tactile sensations and the limited surgical view of laparoscopy, augmented reality (AR) has recently been utilized in laparoscopic liver surgery to identify the tumor, vessels, and portal segments. Moreover, artificial intelligence (AI) has been employed to identify landmarks in two-dimensional (2D) images because of concerns regarding the accuracy of superimposing a three-dimensional (3D) model onto a 2D laparoscopic image. In this study, we report an AR-based projection mapping method of portal segments superimposing preoperative 3D models assisted by AI in laparoscopic surgery. The liver silhouette in laparoscopic images should be detected to superimpose 3D models. Labeled liver silhouettes were obtained from 380 images in surgical videos as learning images to implement AI-based silhouette detection. To implement this technique, we used Detectron2, a PyTorch-based object detection library by Facebook AI Research . In the videos, the liver edges were displayed as green outlines according to AI. Additionally, 3D liver models with segmental mapping were generated using the open-source software 3D Slicer from computed tomography images. For AR display, we utilized the model target function of Vuforia SDK , an industrial AR library with silhouette-based AR display. Lastly, we merged the AI output video with a 3D model in Unity  to establish the projection mapping of the portal segment on 2D surgical images. The accuracy was assessed by measuring the maximum error between the liver edges of laparoscopic images and 3D liver silhouettes in five surgical videos. The maximum error between liver edges and 3D model silhouettes ranged from 4 mm to 22 mm in the AI-based approach and 12 mm to 55 mm in the non-AI-based approach. Meanwhile, the mean error was 14.5 and 31.2 mm in the AI-based and non-AI-based approaches, respectively. Despite camera movement, 3D AR displays were maintained. Thus, our AI-assisted projection mapping of the portal segment could offer a new approach for laparoscopic anatomical liver resection. Hepatocellular carcinoma causes intrahepatic metastasis via the trans-portal vein; thus, appropriate liver mapping of portal segments is crucial in laparoscopic anatomical liver resection (LALR) in order to systematically excise the tumor-bearing portal territory . RecentlAugmented reality (AR) is a digital technology that superimposes 3D models from preoperative images onto surgical fields, thereby enhancing the recognition of vascular structures and liver portal segments by projecting transparent models. Deng et al. reported a case of laparoscopic right anterior sectionectomy utilizing a 3D-model-based AR navigation system integrated with ICG technology . RecentlWith the ongoing advancements in AR technology, artificial intelligence (AI) has been increasingly incorporated into the medical field to aid in the identification of anatomical landmarks during surgical procedures. In recent years, a growing number of institutions have synergistically integrated AR navigation and AI, facilitating more precise visualization of anatomical structures ,8.In the present research, we introduced an AR-driven methodology for delineating portal segments because of the critical role of segmental mapping of the liver’s portal territory in LALR. This method involves overlaying preoperative 3D models and was further enhanced through AI assistance within the context of laparoscopic surgery.Parts of this work were presented at the Frontiers of Computer-Aided Surgery Symposium in Tokyo, Japan on November 2, 2022. Further aspects of this research were discussed at the 123rd annual congress of the Japan Surgical Society in Tokyo, Japan on April 28, 2023, and some findings were shared at the 35th meeting of the Japanese Society of Hepato-Biliary-Pancreatic Surgery on July 1, 2023. More of this work was presented at the 78th General Meeting of the Japanese Society of Gastroenterological Surgery on July 13, 2023. This technical report provides a comprehensive compilation of our research and findings that have not been published in their entirety before.This study was approved by the Medical Ethics Committee of Meiwa Hospital . All patients provided written informed consent. Figure AI implementationInitially, AI  was utilized for identifying liver silhouettes in images captured during laparoscopic liver resection. These silhouettes were annotated by experienced hepatobiliary surgeons using LabelMe , an open-source graphical image annotation tool  . Utilizi3D model reconstruction and model target generation3D Slicer, an open-source software, was employed to generate a 3D liver model with portal segmental mapping, derived from computed tomography images with a slice thickness of 2 mm . We inteWe utilized a 3D liver model and generated a model target using Vuforia’s Model Target Generator. This feature within the platform supports the rigid transformation of a 3D model with a single camera based on pre-registered models. The engine can identify and track natural silhouettes within an image, provided they remain at least partially visible to the camera. Considering potential obstructions from organs including the kidney, gallbladder, and colon, our registered 3D models comprised only the frontal surface. Models of the right and left lateral liver lobes were used distinctly for individual segmentation. The primary function of the AI system was to delineate liver boundaries, as illustrated by the green lines in Figure We presented 3D liver models with portal segmental mapping utilizing AI-enhanced video and compared their accuracy to that of the original video. We identified the maximum error in the starting position, measured in millimeters, to assess the system’s precision. We converted pixel values into millimeters by referencing the dimensions of the 3D liver model. This conversion allowed us to evaluate the error in tangible units of measurement, providing a more insightful understanding of the system’s level of accuracy.ResultsOur AR system was tested using a dataset comprising five surgical scenes, each lasting 20 seconds. In the first case, the original surgical video is displayed in the upper-left quadrant, and the AI-processed video is situated in the lower-left quadrant, showcasing the AI’s detection of liver edges in Video Similar to the first case, the AI-based method proficiently identifies the liver silhouette, whereas the non-AI-based method encounters difficulties in Video In the third case, the non-AI-based method inaccurately detects the liver silhouette; however, despite some registration errors, the AI-based method still outperforms the non-AI-based method in Video In the fourth case, although the non-AI-based approach seems to register correctly, the AI-based method exhibits superior accuracy, particularly when the liver silhouette undergoes changes in Video Finally, in the fifth case, the non-AI-based method exhibits inconsistencies in performance, whereas the AI-based method maintains consistent and accurate liver registration in Video The registration error results are summarized in Table The precision of image-to-patient registration is vital for the efficacy of AR navigation systems. Many studies have reported enhanced results with AR systems that incorporate additional equipment, such as stereo cameras or specialized positional tracers -15. HoweIn the context of a monocular camera environment, silhouettes or anatomical landmarks of the liver, including ligaments, are frequently utilized for registration purposes. In 2017, Koo et al. reported a system that employs 3D to two-dimensional (2D) silhouette-based registration for laparoscopic liver surgery . This sySimilarly, Labrunie et al. reported a U-net-based deep-learning registration method that initiated registration with tumor target registration errors ranging from 7.2 mm to 22.4 mm ,17. The While AI technology eliminates the need for specialized sensors and tracers, its accuracy needs to be further improved . NonetheIn laparoscopic liver surgery, the impact of pneumoperitoneum on the liver silhouette is notably significant. Various strategies have been advanced to counter liver deformation in order to mitigate this effect, including locally rigid registration , biomechOur proposed method, which was executed within the Unity and Vuforia SDK environments, is relatively straightforward to establish, owing to its low-code structure that eliminates the need for extensive programming. This simplicity is advantageous, facilitating easy deployment in standard operating rooms. Although Vuforia SDK is user-friendly and easy to implement, it provides only rigid registration. This limitation may be significant, especially considering the dynamic deformation of the liver, which can lead to registration errors. Our approach takes cues from the locally rigid registration paradigm proposed by Song et al., which posits that local rigid registration within a small region of interest is sufficient for image guidance without deformable modeling . For insFinally, aside from the limitations that were mentioned previously, our method possesses additional constraints. It is applicable solely prior to the dissection phase as significant alterations to the liver’s shape during dissection render object tracking ineffective. Moreover, interference may arise because of the use of surgical instruments  and echo sonography. Consequently, future iterations of AI and AR systems must be sufficiently robust to navigate and mitigate such challenges effectively.The application of AI has proved beneficial for the projection mapping of liver portal segments in laparoscopic liver surgery, which is achieved via AR superimposition. This approach can serve as a valuable supplementary technique, particularly for patients wherein ICG segmental mapping is challenging.For the successful integration of our proposed method into clinical practice, physiological organ deformation should be considered, and potential obstacles  should be accounted for. These considerations are crucial to improve the technique and ensure its robustness in the dynamic surgical environment.


While the amount of studies involving single-cell or single-nucleus RNA-sequencing technologies grows exponentially within the biomedical research area, the kidney field requires reference transcriptomic signatures to allocate each cluster its matching cell type. The present meta-analysis of 39 previously published datasets, from 7 independent studies, involving healthy human adult kidney samples, offers a set of 24 distinct consensus kidney cell type signatures. The use of these signatures may help to assure the reliability of cell type identification in future studies involving single-cell and single-nucleus transcriptomics while improving the reproducibility in cell type allocation. Nephron sub-structures are organized following the urine flow: blood arrives to the glomerulus and filtered through fenestrated capillaries and the slit-diaphragm (n.b. this active fenestration process is controlled by podocytes), then primary urine passes first through the Bowman capsule lined by parietal epithelial cells (PEC) and then through the tubule per se, including the proximal tubule , the loop of Henle , the distal tubule consisting in the distal convoluted tubule (DCT) and the connecting tubule , and finally flows into the collecting ducts in the cortex (CCD) and medulla  until its storage in the bladder3.The kidney is a vital and highly complex organ responsible for blood filtration, elimination of metabolites and waste products, and body homeostasis . These critical functions are enabled through its functional subunit, the nephron, an intricate interplay between the nephron sub-structures and some mesenchymal cells, involving the coordinated action of more than 20 cell types  from the entry of the blood in glomerular capillaries to the urine compartment6, such approach is not suitable for investigating renal cell type-specific features at a single cell scale. More recently, advances in high-throughput single-cell (scRNA-seq) and single-nucleus (snRNA-seq) transcriptomics allowed to evaluate cell populations and biological processes of different tissues at the single-cell/nucleus level9. Except for liquid samples , scRNA-seq involves tissue dissociation, single-cell emulsion and encapsulation, passage in the microfluidics one cell at a time, creation of a library through high-throughput sequencing, and finally data analysis. As it may be performed on frozen tissue, snRNA-seq may overcome some issues observed with scRNA-seq, such as dissociation-induced stress response leading to the expression of specific set of genes, poor viability and loss of rare and fragile cell types11. Although the heterogeneity between individuals and cell states have been demonstrated13, studies are often performed on a reduced number of samples due to the limited availability of human tissue and the cost of scRNA-seq and snRNA-seq experiments. Other critical confounding factors in both experimental and analytical settings may affect scRNA-seq and snRNA-seq data, including low sequencing depth, context-dependent cell states, clustering settings, or markers checked for cell type identification.Although bulk transcriptomics have critically promoted the understanding of kidney development, physiology and diseases14. To date, scRNA-seq or snRNA-seq studies of human kidneys have involved different technologies and different data preprocessing and analysis workflows. Cell type labelling in particular suffers from the lack of a universal definition of known nephron segments and cell types, as well as standard lists of RNA markers depicting each kidney cell types, which may therefore lower the comparison reliability between studies. Chen et al. already reported this issue and proposed a nomenclature for kidney epithelial cells to better compare studies15. However, no consensus list of human kidney cell type transcriptomic markers has been published so far. Thus, the establishment of consensus transcriptomic kidney cell type signatures might be of utmost importance considering significant batch effects within scRNA-seq and snRNA-seq datasets18. Here we present a meta-analysis of publicly available scRNA-seq and snRNA-seq datasets from 39 healthy adult kidneys, consisting in 68,028 single cells and 33,412 single nuclei. As data were taken from different sources, data were normalized following the SCTransform analysis pipeline in Seurat v4 and batch effects were mitigated by integration of scRNA-seq and snRNA-seq samples, respectively. Cell types were attributed to clusters using broad cell type markers, consensus cell type signatures were computed, and labelled scRNA-seq and snRNA-seq samples were integrated together to map cell types depending on the method used (sc/snRNA-seq). Finally, single-cell and single-nucleus consensus signatures were benchmarked by enrichment in previously published and annotated datasets.Still, scRNA-seq and snRNA-seq are very powerful techniques increasingly used within the biomedical field in general, and in the kidney field in particular32, encompassing a total of 101,431 cells and 35,764 nuclei, from 32 and 7 healthy adult kidneys, respectively  plot, before and after integration using both Harmony and Seurat v4 correction Fig. . The corans Fig. .Fig. 2InUnsupervised clustering  resulted in 54 distinct clusters Fig. . Despite54 , it is clear that sample GSM3135714 from batch GSE114156 is not well integrated to the dataset  consisted mainly in nuclei from sample GSM3135714   resulted in 53 distinct clusters Fig. . As expe 54 Fig. .Fig. 7UnThe computation of HVG for every cell type has been performed, and these gene lists correspond to the consensus transcriptomic cell type signatures of kidney nuclei from healthy adult individuals  and Lake et al.57 (snRNA-seq). Sample expression matrices were processed and integrated as previously. Then CelliD v1.058 was used to perform enrichment analysis for scRNA-seq or snRNA-seq consensus signatures in every single cell or nucleus respectively, and the results were compared to the original labelling of the authors. To better evaluate automatic cell type annotation on test datasets, original labels were adapted to match consensus signatures nomenclature 55 , scRNA-seq dataset from Kuppe )55 Fig. . Enrichmels Fig. . Some diels Fig. . Overallion Fig. .Fig. 11Set al.57 snRNA-seq dataset was processed as previously described to remove poor quality nuclei, and finally consisted in 17,375 nuclei from 43 samples that belonged to 16 individuals, including 14 tumor-free regions of nephrectomies and 2 deceased donor kidneys9 . Mapping reads to different versions of the reference genome, as well as the pre-processing of the data are also critical factors participating in batch effects between studies. This results in limited reproducibility and reliability between the different studies involving human kidney scRNA-seq and snRNA-seq. In this meta-analysis, we performed integration of 32 scRNA-seq and 7 snRNA-seq samples, from 3 and 4 different studies respectivelyOur present study tried to standardize cell type nomenclature by the way of meta-analysis. Even though proximal nephron is functionally and anatomically divided in three segments (S1 to S3), our study could not discriminate these segments and all proximal tubule data is lumped into one proximal category. Same is true for the three descending thin limbs segments and distal convoluted tubule that is not resolved into DCT1 and DCT2. One plausible explanation is that these subpopulations are part of the unattributed population, i.e. PTC.na and LoH.na. There is also a possibility that we did not find these subpopulations because of the sparsity of the data, especially with such heterogeneity in the data sources. The datasets used in this study are the first published in the field, they were pre-processed with different tools and suffer from strong batch effects that prevent to detect many markers. However, the signatures that we proposed still allow to identify their cell types in the validation step we did.i.e. read count) in every single cell, or every single nucleus, within a suspension of cells. The advantages of sn- over scRNA-seq have been studied in healthy and fibrotic mouse kidney tissue, and include the following: less dissociation bias, less stressed or dead cells, and the possibility to use frozen tissue pieces which may allow to process more and better quality biological samples11. Furthermore, scRNA-seq and snRNA-seq samples may present too different transcriptomes in certain cell populations to allow a good detection of every cell type in both kind of experiment. This is not striking since the set of RNA expressed in the nucleus differs from the set of RNA expressed in an entire cell. In other words, scRNA-seq samples contain nuclear, mitochondrial and cytosolic RNA, while snRNA-seq samples only contain nuclear and cytosolic RNA. Therefore, cell type assignment depending on the expression of canonical marker genes, which is the standard in single cell/nucleus transcriptomics analyses, may differ between scRNA-seq and snRNA-seq. Our analysis confirmed these assumptions and as a consequence provides two sets of cell type signatures, obtained by scRNA-seq or snRNA-seq strategies. Besides, we were not able to find immune cells within snRNA-seq datasets except few T cells, which is consistent with previous reports attesting that snRNA-seq in the kidneys failed to detect immune cells in general59. Interestingly, we detected a population of parietal epithelial cells in both scRNA-seq and snRNA-seq datasets that express pluripotent cell, tubular epithelium and podocyte markers  and may actually correspond to previously described parietal epithelial stem cells60. These cells look very different from the other clusters, express self-renewal markers  and match with the PAX2+ CD24+ population previoulsy observed in the glomerulus60. By contrast, we failed to detect any CD133+ mesenchymal stem cell-like population.Single cell and single nucleus transcriptomics allow to study the expression of every detected gene (e.g. CelliD58).To introduce biological heterogeneity and mitigate technical variability, we encourage authors who would use previously published healthy kidney datasets as control datasets for their purpose, to integrate several samples from different studies instead of using the samples from a single study. For those who would add new healthy human kidney samples to their single-cell or single-nucleus studies, we would advice to compare the cell type signatures from control cells with the consensus signatures we provide, and to assign cell types in their dataset using enrichment of consensus signatures  than for the one of DCT cells  in the scRNA-seq dataset, for instance. In the future, these signatures may benefit from being updated by integrating newly published healthy human kidney single cell datasets that may increase the biological variability and the number of cells for every population while mitigating the batch effects even better. In addition, the very low sequencing depth of these experiments implies that the results should be interpreted with caution. To solve this issue in cell type identification while specifically working with kidney tissue and validate the identified cell type-specific signatures, a bulk transcriptomic analysis of micro-dissected healthy human nephron segments would be really helpful, as it has been performed in rodents6. Nevertheless, cell type allocation by enrichment of consensus signatures may depend on the size of the signatures – i.e. the size of the gene lists, spanning between 27  and 311  genes in the present meta-analysis. Thus, we recommand to perform such enrichment with both the complete signatures, and truncated signatures that are close in size.However this approach is biaised in the sense that cell type enrichment depends on the tested cell types, and if a cell type is not tested it could not be attributed to cells/nuclei, even if it should. Thus, one of the main limitation of this method is that every cell or nucleus will be attributed a cell type from the tested list: the enriched cell type with the lowest p-value will be attributed, which can be misleading . This further means the consensus signatures we provide only define the cell types identified in the current meta-analysis. Therefore, depending on the settings, it could make sense to use only certain consensus signatures, for instance if the studied cells or nuclei populations have been purified by FACS prior to the transcriptomics. For the same reason, such cell type enrichment may be used as a decision helper instead of a decision maker in cell type attribution to cells/nuclei. However, a more unbiased approach is possible for original studies, based on unsupervised clustering followed by extraction of the cell-specific signatures using CelliD, and finally enrichment of functional terms or pathways of these signatures. A more general limitation of such single cell studies is the statistical power for the computation of HVG (Wilcoxon Rank Sum test), that depends on the number of cells allocated for every single cell type. Indeed, the statistical power is higher for the computation of PTC signature  and a diversity in the references used for cell type recognition. In this meta-analysis, 32 scRNA-seq samples from 3 studies, and 7 snRNA-seq samples from 4 studies, were integrated and analysed. This resulted in the computation of 30 consensus cell type signatures for kidney cell types. Future studies in the field may benefit from the use of these signatures to automatically allocate cell types to cells/nuclei.https://www.ncbi.nlm.nih.gov/geo/) as count matrices32. The collection consists of 7 snRNA-seq samples from 4 independent studies  and 32 scRNA-seq samples from 3 independent studies 32. The clinical and technical informations regarding the samples gathered from these studies are provided in Tables 23. Data downloaded from GEO were already pre-processed for each dataset, in different ways across the different studies involved 56 scRNA-seq dataset was obtained from zenodo repository (https://zenodo.org/), and Lake et al. snRNA-seq dataset was downloaded from GEO under accession number GSE12186257. These datasets consisted in 19 chronic kidney disease samples and 43 healthy samples, respectively.To test whether the computed consensus signatures may be useful to automatically allocate cell types to clusters, we also downloaded available annotated datasets. Thus, Kuppe https://www.r-project.org/) and Seurat v4.0.5 package61  to perform the analysis. As observed in previous studies, human kidney scRNA-seq datasets generally present with high mitochondrial gene counts, which may be attributed to the processing time of human kidney samples as well as the processing itself. Moreover kidney tissue notoriously contains a lot of mitochondria, consistent with the high levels of energy needed for a proper filtration process. Therefore the standard filtering out of cells with >5% mitochondrial gene expressed was not suitable for the processing of these scRNA-seq data. Cells with <200 or >3500 (cell debris and doublets) expressed genes, and >30% mitochondrial gene expressed, were filtered out, whereas nuclei with <200 or >3500 expressed genes, and >5% mitochondrial gene expressed, were filtered out. In total, 68,028 high quality cells and 33,412 high quality nuclei were obtained after applying these thresholds. Table i.e. number of cells/nuclei, mean number of reads per cell/nucleus, mean number of features expressed per cell/nucleus, % mitochondrial genes, % ribosomal genes), prior to and after filtering. Data were normalized and scaled , and highly variable genes computed using the SCTransform function35 (Seurat v4) for every scRNA-seq and snRNA-seq sample. Identified HVG were then used to compute PCA for every sample. SCTransform is a newly implemented statistical method in Seurat v4, pooled from the sctransform R package , that aims to better resolve the technical variability and sequencing depth differencies between cells/nuclei across datasets35. It is particularly interesting when working with datasets obtained from different sources, which induce important variability.We used R software v4.1.0 . Because further computations depend on this process, the quality of the integration deserves to be evaluated. Thus, two integration approaches were considered: the Seurat v4 method that outputs a corrected expression matrix for a list of genes to consider, and the Harmony v0.1.0 method that directly corrects the residues of the PCA for each sample.Single-cell and single-nucleus samples always depend on confounding variables and may thus present differences that are called batch effects. To allow any comparison between samples, batch effects need to be mitigated as much as possible, which is done by the integration process  of integrated scRNA-seq and snRNA-seq datasets. Harmony ran as well and UMAP was computed on the 30 first corrected PCs of both dataset. The distribution of the cells or nuclei from the different samples was compared between the two methods. Of note, Seurat and Harmony are among the best batch effect correction methods to dateet al. and Lake BB, et al. were changed . Distribution of samples across clusters was studied thanks to the pheatmap v1.0.12 R package. The cells were then labelled according to the expression of specific markers (Table ed Table .


Background: Kidney transplant recipients (KTRs) who have a highly impaired immune response are in need of intensified and safe vaccination strategies to achieve seroconversion and prevent severe disease. Methods: We searched the Web of Science Core Collection, the Cochrane COVID-19 Study Register and the WHO COVID-19 global literature on coronavirus disease from January 2020 to 22 July 2022 for prospective studies that assessed immunogenicity and efficacy after three or more SARS-CoV-2 vaccine doses. Results: In 37 studies on 3429 patients, de novo seroconversion after three and four vaccine doses ranged from 32 to 60% and 25 to 37%. Variant-specific neutralization was 59 to 70% for Delta and 12 to 52% for Omicron. Severe disease after infection was rarely reported but all concerned KTRs lacked immune responses after vaccination. Studies investigating the clinical course of COVID-19 found remarkably higher rates of severe disease than in the general population. Serious adverse events and acute graft rejections were very rare. Substantial heterogeneity between the studies limited their comparability and summary. Conclusion: Additional SARS-CoV-2 vaccine doses are potent and safe in general terms as well as regarding transplant-specific outcomes whilst the Omicron wave remains a significant threat to KTRs without adequate immune responses. Vaccination remains the most effective tool to prevent severe disease after infection with SARS-CoV-2. The currently dominating variant of concern (VOC), Omicron B.1.1.529), and its sublineages have shown to be less dangerous than the Delta strain for the general population with regard to severe disease .1.529, a,4. For eKidney transplant recipients (KTRs) compose the largest group of people receiving an organ transplant  and beloWhilst pooled evidence exists for humoral and cellular responses to additional SARS-CoV-2 vaccine doses in solid organ transplant recipients, these results are not transferable to KTRs, who tend to be more immunocompromised than, for example, liver transplant recipients . Varioushttps://osf.io/nsyq4/ (accessed on 15 April 2023)”. The reporting of this systematic review follows the PRISMA checklist [This study was registered with PROSPERO (CRD42022315409) and is accessible at Open Science Framework under “We searched the Web of Science Core Collection, the Cochrane COVID-19 Study Register and the WHO COVID-19 global literature on coronavirus disease up to 22 July 2022. The search strategies can be found in the mRNA vaccines: BNT162b2 by BioNTech/ Pfizer  mRNA-1273 by Moderna ;Non-replicating viral vector vaccines: ChAdOx1 by Oxford/AstraZeneca , Ad26.COV2.S by Johnson & Johnson ;Inactivated viral vaccines: Sinovac by Sinovac Biotech , BBIBP-CorV by Sinopharm , BBV152 by Bharat Biotech ;Protein subunit viral vaccines: NVX-CoV2373 by Novavax ;The non-replicating viral vector vaccine rAd5 by Gamaleya  despite its pending approval due to its wide distribution.We included randomized controlled studies or prospective observational studies reporting on at least 20 adult KTRs receiving a minimum of 3 SARS-CoV-2 vaccine doses with either vaccines authorized for use by the European Medicines Agency (EMA) or vaccines granted Emergency Use Listing by the World Health Organization (WHO). As of 22 February 2022 those were :mRNA vacStudies were considered eligible for inclusion if they reported one or more of the following predefined main outcomes: SARS-CoV-2- infection, the composite endpoint hospitalization or death, seroconversion, antibody titers and/or t-cell responses. Whenever available, we extracted the following predefined additional outcomes: Serious adverse events (SAE) and the development of de novo donor-specific antibodies (DSAs) as markers of alloimmunization, as well as the incidence of acute graft rejection after COVID-19 vaccination. Furthermore, we assessed variant-specific neutralization capacity against the delta and omicron VOC.Five authors selected the studies on a web-based online platform (Rayyan ); each sStudy and population characteristics, as well as intervention-related information, were extracted by two authors independently. We did not extract data on healthy controls; they were scarce and not matched to our cohort of KTRs regarding age or clinical condition.The risk of bias in each study was independently assessed on the outcome level by two review authors and discussed until a consensus was reached. For observational studies without a comparison, a tool for overall prognosis studies currently under development was used (RoB-OPS ). The toThere was substantial clinical heterogeneity; some studies reported immunologic outcomes only for participants with negative serostatus, co-interventions or relevant discrepancies in immunosuppressive therapy. Methodological diversity existed in terms of variances in study design, outcome definition and measurement. Thus, we did not pool the outcome rates into a meta-analysis but we present the data descriptively in forest plots without a combined effect estimate, or in table format. To explore the risk of bias visually, we excluded all studies with high risk of bias as predefined in our study protocol . For theFor our prioritized outcomes, we assessed the certainty in the evidence using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach , startinThe literature search resulted in 1318 records after deduplication. After title and abstract screening, we assessed 235 full texts for eligibility and included 37 published studies into the review. At the time of our update search, 23 studies were ongoing or completed without published data .From the included studies, 26 were from Europe, 6 from the USA, 3 from Israel and Canada and 1 from Thailand and Uruguay, each. We identified 2 RCTs, 8 non-randomized studies comparing interventions and 27 prognostic studies without a control arm. Twenty-six studies investigated a study population containing seropositive KTRs after their previous vaccination series ,44,45,46®, Spikevax®, Vaxzevria®, COVID-19 Vaccine Janssen® and Coronavac®). Twenty-two studies reported on mRNA vaccines. One examined triple vaccination with viral vector vaccines [The included studies investigated five different vaccines  and one used an activation-induced marker assay (AIM) . ELISpotWe identified 14 studies reporting on breakthrough infections after three or four vaccine doses and sorted the studies according to the study period to show vaccine efficacy for the individual SARS-CoV-2-waves c. In 659Four hospital admissions (three ICU admissions) or deaths occurred in 564 patients. Remarkably, none of these patients had seroconverted after vaccination.We found two studies reporting exclusively on the clinical course of COVID-19 in KTRs during the Omicron wave. Malahe, 2022, reported on 45 infected KTRs (38 triple vaccinated) with 9 (6 triple vaccinated) patients in need of hospital admission of whom five were seronegative. In Wong, 2022, 7 out of 41 KTRs (23 had 3 vaccine doses) were admitted to ICU, 16 needed ward-based care and 1 patient died (triple vaccinated). These findings suggest that due to short follow-up in most studies reporting breakthrough infections, the rate of severe disease might not have been captured adequately.Nine studies reported on SAE in 996 patients; eight studies reported no SAE. All five events that were possibly treatment-related were reported in BOOST-Tx 2021, without any difference according to vaccine type (homologous mRNA vs. heterologous). Seija, 2022, found recurrence of IgA-nephritis in one KTR after the 4th vaccine dose.There were no reports of a decline in renal function after vaccination in general. However, KTRs have frequent assessments of creatinine levels in their routine visits, so even if data on renal function are not published, it can be assumed that a vaccination-associated decline in kidney function would have been presented. De novo DSAs were reported in 3 of 157 patients with an event rate from 0 to 0.5% d. In oneFour trials reported on seroconversion rate and safety investigating the reduction or hold of mycophenolic acid (MPA) and one study investigated changes to MPA-free regimens . Two of Three studies reported only on KTRs with three vaccine doses treated with Belatacept. De novo seroconversion rates were severely impaired at 12 to 20% .Patients who did not seroconvert had a lower median transplant age than those who seroconverted .There was not enough information on immunosuppression, age, graft type, diabetic status and transplantation number to compare outcomes between subgroups.Regarding immunogenicity outcomes, a risk of bias occurred due to missing data or in outcome measurement. In total, 4 out of 14 and 5 out of 15 studies reporting de novo and total seroconversion after three vaccine doses were at a high risk of bias. From studies of four vaccine doses, two out of four and one out of four studies were at a high risk of bias, respectively. One of four studies investigating variant-specific neutralization after three vaccine doses was at a high risk of bias and none after four vaccine doses. One of six studies investigating t-cell responses was at a high risk of bias.From the 14 studies investigating COVID-19 disease after vaccination, 9 studies failed to adequately define the outcome or did not report how infection was assessed. None of these 14 studies performed routine SARS-CoV-2 testing and, thus, the risk of overseen infections is high.Five out of nine studies failed to assess SAE systematically or reported the occurrence of SAE only narratively, without a definition or details on the outcome measurement.Acute graft rejection was examined by nine studies. Four of these nine studies did not report on outcome measurement and were therefore rated as at a high risk of bias in this domain. None of the three studies reporting on the development of donor-specific antibodies was at a high risk of bias.The risk of bias of each study is depicted in detail in This systematic review aimed to gather evidence on the immunogenicity, efficacy and safety of additional SARS-CoV-2 vaccine doses in KTRs. Our findings on seroconversion rates show that the probability of seroconversion decreases with the number of applied vaccine doses. However, up to 60 and 30% of previously negative KTRs seroconvert after the third and fourth vaccine doses and up to 80% of all vaccinated KTRs reach seroconversion after three and four vaccine doses in general.®, for which lower immune responses have previously been reported [This may not hold true for KTRs with a primary vaccine series with Coronavacreported ,59. Morereported .Nevertheless, the prevalence of neutralizing antibodies against the Omicron VOC after three vaccine doses was remarkably lower than in the general population, where 97% were able to neutralize the virus after three vaccine doses . It follCo-interventions such as the reduction of MPA peri-vaccination were insufficiently comparable to allow a conclusion. Larger, well-designed trials, for example CPAT-ISR, currently investigate this promising strategy to increase vaccine efficacy .The rate of hospital admission and death in the studies that reported breakthrough infections in this review is low, which is explainable by the very short follow-up periods in most studies that reported primarily on immunogenicity outcomes. Two studies in our review reporting on the clinical course of Omicron infections in KTRs found alarming hospital admission rates between 16 and 50%. Further studies in KTRs ,69 and oThe safety profile observed in clinical trials investigating three or more vaccine doses in the general population is consistent with our observations in KTRs ,76,77,78Considering the development of de novo DSAs, our evidence is limited by the scarcity of information. Two events occurred, unrelated to the reduction of immunosuppression, in a study with 150 patients, but only two acute graft rejections were observed in a study with nearly one thousand patients . This evA meta-analysis comparing rejections in SOTRs after SARS-CoV-2 vaccination vs. infection found six events post-vaccination and thirty events post-infection . This unSince new Omicron-specific vaccines contain the same mRNA platform with a few nucleotides exchanged , their sOur study aimed to give a broad outline of important aspects of COVID-19 vaccination in KTRs rather than reporting on immunogenicity alone and is, to our knowledge, unique in this respect. However, it has several limitations. Firstly, the predefined outcomes relevant for inclusion in our systematic review focused on immunogenicity and breakthrough infections, which lowered the reporting on other outcomes, especially for the development of de novo DSAs. Furthermore, our confidence in the evidence of several outcomes is limited due to heterogeneity in study design and the lack of standardized assays used for outcome measurement. This relates particularly to the t-cell responses after vaccination, for which we cannot draw consistent conclusions due to the large number of different tests.The investigation of predefined subgroups was not adequately possible, since information on immunosuppression regimens in context with positive or negative seroresponse hardly existed.Our systematic review provides an evidence-based framework to guide clinical decision making, health care policies and future research in organ transplantation. Continued research is needed for alternative approaches to ensure the establishment of an effective immune response in KTRs, for example by the reduction of immunosuppression during vaccination or examination of the efficiency of the variant-adapted vaccines. Preexposure prophylaxis with monoclonal antibodies should still be considered an alternative worth investigating for seronegative KTRs.Overall, our systematic review highlights the importance and effectiveness of three and four SARS-CoV-2 vaccine doses for the induction of humoral responses and prevention of severe disease. Nevertheless, protection against infection was impaired during the Omicron VOC. In KTRs vaccinated thrice, Omicron-specific neutralization was low and, thus, more vaccine doses are required to induce protective levels. The benevolent safety profile, which also applies to transplant-specific outcomes, permits this strategy.


Can a large language model (LLM)-based chatbot outperform surgeons in generating readable, accurate, and complete procedure-specific risks, benefits, and alternatives (RBAs) for use in informed consent?This cross-sectional study of 36 RBAs for 6 commonly performed surgical procedures found that the LLM-based chatbot generated more readable, complete, and accurate consent documentation than the surgeons.These findings indicate that LLM-based chatbots are a promising tool for generating informed consent forms, easing the documentation burden on physicians while providing salient information to patients. Informed consent is a critical component of patient care before invasive procedures, yet it is frequently inadequate. Electronic consent forms have the potential to facilitate patient comprehension if they provide information that is readable, accurate, and complete; it is not known if large language model (LLM)-based chatbots may improve informed consent documentation by generating accurate and complete information that is easily understood by patients.To compare the readability, accuracy, and completeness of LLM-based chatbot- vs surgeon-generated information on the risks, benefits, and alternatives (RBAs) of common surgical procedures.This cross-sectional study compared randomly selected surgeon-generated RBAs used in signed electronic consent forms at an academic referral center in San Francisco with LLM-based chatbot-generated  RBAs for 6 surgical procedures .Readability was measured using previously validated scales . Scores range from 0 to greater than 20 to indicate the years of education required to understand a text. Accuracy and completeness were assessed using a rubric developed with recommendations from LeapFrog, the Joint Commission, and the American College of Surgeons. Both composite and RBA subgroup scores were compared.P = .10). The mean (SD) composite completeness and accuracy score was lower for surgeons’ RBAs at 1.6 (0.5) than for LLM-based chatbot RBAs at 2.2 (0.4) (P < .001). The LLM-based chatbot scores were higher than the surgeon-generated scores for descriptions of the benefits of surgery  and alternatives to surgery . There was no significant difference in chatbot vs surgeon RBA scores for risks of surgery .The total sample consisted of 36 RBAs, with 1 RBA generated by the LLM-based chatbot and 5 RBAs generated by a surgeon for each of the 6 surgical procedures. The mean (SD) readability score for the LLM-based chatbot RBAs was 12.9 (2.0) vs 15.7 (4.0) for surgeon-generated RBAs (The findings of this cross-sectional study suggest that despite not being perfect, LLM-based chatbots have the potential to enhance informed consent documentation. If an LLM were embedded in electronic health records in a manner compliant with the Health Insurance Portability and Accountability Act, it could be used to provide personalized risk information while easing documentation burden for physicians. This cross-sectional study compares large language model−based chatbot- vs surgeon-generated information on the risks, benefits, and alternatives of surgical procedures. This study sought to evaluate RBAs generated by an LLM-based chatbot vs those by surgeons to compare their readability, accuracy, and completeness.For an electronic consent form to be useful and equitable, the information it provides needs to be readable, accurate, and complete.STROBE) reporting guideline for observational studies.This cross-sectional study compared RBAs generated in May 2023 by an LLM-based chatbot  with RBAs produced by surgeons for a range of common surgical procedures. The study protocol was deemed exempt by the University of California San Francisco Institutional Review Board and informed consent was waived due to minimal risk to patients. This study was conducted in May 2023 and followed the Strengthening the Reporting of Observational Studies in Epidemiology  database. Each consent form was generated by a different surgeon, with 5 unique surgeons per procedure. All surgeons were members of the UCSF Health medical staff (not trainees).29 These measures consider sentence length, word length, and overall text complexity, and provide a US academic grade level for an average student.31 We calculated readability scores for each scale using an online tool.32We evaluated readability using multiple scales, including the previously validated Flesh-Kincaid grade level, Gunning Fog index, the Simple Measure of Gobbledygook score, and the Coleman-Liau index .29 These33 , the Joint Commission, the American College of Surgeons, and relevant available literature33 . ComponeA multidisciplinary group of surgeons, including acute care surgery, surgical critical care, vascular surgery, orthopedic surgery, and surgical oncology, reviewed the LLM-based chatbot- and surgeon-generated procedure-specific RBAs for accuracy and completeness using the process described. Reviewers were blinded to the source of the RBA; each response was scored by at least 2 individual reviewers.We reported average readability scores for LLM-based chatbot vs surgeon-generated RBAs, both along the individual scales and an average of all scores . We also reported the proportion of RBAs that adhered to important benchmarks . We reported average accuracy and completeness scores for surgeon-generated and LLM-based chatbot-generated RBAs, as well as the proportion of responses that met key benchmarks . We compared mean readability, accuracy, and completeness scores of surgeon-generated vs LLM-based chatbot-generated RBAs using Wilcoxon rank-sum tests.P < .05. We performed all data analysis in Stata, version 16 (StataCorp).Our primary analyses were comparing the average readability scores for LLM-based chatbot vs surgeon-generated RBAs  and comparing the average accuracy and completeness scores and subscores for LLM-based chatbot vs surgeon-generated RBAs . All other analyses were secondary analyses (including comparisons between procedures) and should be considered exploratory. All hypothesis tests were 2-sided, with an a priori threshold of significance set to We included 1 LLM-based chatbot- and 5 surgeon-generated RBAs for each of the 6 surgical procedures. Together these yielded 36 responses.P = .10). The least complex LLM-based chatbot RBA was 10.3 for spine fusion (10th grade) and its most complex was 15.8 for colectomy (college level) (The mean readability score for the RBAs generated by ChatGPT was 12.9 (college level) vs 15.7 (college level) for those written by surgeons . The LLMe level) . The leaP < .001) (P < .001), alternatives to surgery , and overall impressions . There was no significant difference between the LLM-based chatbot- vs surgeon-generated scores for description of the risks of surgery .The mean (SD) composite completeness and accuracy score for all surgeon-generated RBAs was 1.6 (0.5), whereas for LLM-based chatbot-generated, it was 2.2 (0.4) ( < .001) . When coWhen considering scores by surgery type, the composite LLM-based chatbot score was higher than the surgeon score for each of the 6 surgical procedures . No LLM-36 However, few studies to date have provided data on reliability, completeness, and accuracy of output of LLMs in surgical contexts, especially those related to operative consents. In this study comparing LLM-based chatbot- vs surgeon-generated informed consents for common surgical procedures, we found that the chatbot RBAs were more readable, complete, and accurate than those produced by surgeons.Much has been written about the potential of artificial intelligence and LLMs to alter the practice of medicine.21 However, the chatbot-generated RBAs did trend toward being less complex compared with surgeons’ RBAs for all 6 included surgical procedures. Given its interactivity, users have the ability to ask the LLM-based chatbot to make its response even more simple which may yield responses at the target reading level.37 However, the tool did not reliably generate RBAs for common procedures at the sixth-grade reading level even when prompted to do so.In terms of readability, every surgeon and chatbot-generated RBA was more complex than the recommended sixth-grade reading level. This finding is consistent with many other studies reporting that informed consent documentation is too complex.28 Given this dynamic, at least for the time being, physicians should have to review and edit informed consent documentation generated by LLM-based chatbots. However, this approach still may be simpler, less time-consuming, and more accurate than generating informed consent de novo each time. Future studies should compare informed consent documentation generated by LLM-based chatbots and reviewed by physicians vs those generated by surgeons alone.When compared with surgeon-generated RBAs, LLM-based chatbot-generated RBAs had better scores for completeness and accuracy for every surgical procedure specified per our established study rubric. This difference was primarily driven by the LLM-based chatbot descriptions of the benefits and alternatives to surgery, given that there were no significant differences in the descriptions of surgical risks between the 2 sources. The reviewers infrequently assessed the consents as being inaccurate and the only consents with inaccurate elements in the study sample were generated by surgeons. However, caution should still be used when incorporating LLM-based chatbot responses into informed consent documents, in which reliability is critical, given that these models have been shown to generate plausible but incorrect responses.38 Furthermore, documenting that a conversation occurred, rather than describing the information relayed in the conversation, may not provide appropriate protection in the event of litigation.Some surgeon-generated RBAs described a conversation with the patient detailing the risks, benefits, and alternatives to surgery rather than documenting them explicitly. Although a thorough conversation between surgeon and patient is essential for informed consent to occur, failing to also document the salient risks, benefits, and alternatives in the consent form deprives the patient of additional time to review the information at home, with family, caregivers, or other resources available. This opportunity for review is critical considering that prior research has shown that patients immediately forget 40% to 80% of medical information provided by clinicians and almost half of the information that is remembered is incorrect.39 Together, this would allow for the adoption of more transparent sharing of complication risks with patients as part of the informed consent process. Finally, we expect that LLMs will allow for additional training examples of consent language (as opposed to zero-shot training used in this study) for continuously improved results that are better optimized for automated generation of more personalized informed consent language.Additional studies should incorporate patient perspectives and opinions on the adequacy of LLM-based chatbot-generated informed consent documentation to build on this work. Ultimately, if an LLM is embedded in the EHR in a manner compliant with the Health Insurance Portability and Accountability Act, we anticipate it could be used to provide personalized risk language based on disease severity and underlying conditions.28 we anticipate that the gaps we demonstrated will widen as LLMs continue to evolve and improve. Second, our study rubric incorporated the documentation of expectations . Some surgeons may not have known to include this information in their documentation of risks. However, setting patient expectations has been shown to be an essential part of patient-physician trust and relationships.40 There were no significant differences in ChatGPT- vs surgeon-generated RBAs along these specific metrics, suggesting that the rubric was not unfairly penalizing to surgeons. Third, our study evaluated the LLM-based chatbot -generated RBAs without physician alteration. This is unlikely to occur in practice. Further study should be undertaken to evaluate consent documents created by LLM-based chatbots and surgeons working together, which is a more realistic application of LLMs in the health care settings. We conducted this study at a single quaternary care center  where the practice of surgeons documenting information in the EHR may differ from that of other institutions. In general, surgical informed consent discussions and documentation have not been actively taught as part of surgical training and are far from standardized. The introduction of artificial intelligence in this area may be an opportunity to recognize the importance of this gap and develop new training paradigms for surgeons.This study had certain limitations. First, we chose use version 3.5 of the chatbot because it is accessible without a paid subscription. Given that model 4.0 has already been shown to outperform model 3.5 on various professional and academic benchmarks,This cross-sectional study found that that RBAs generated by an LLM-based chatbot were more readable, accurate, and complete than RBAs generated by surgeons for 6 common surgical procedures. Large language model−based chatbots are a promising tool that could ease the documentation burden on physicians while providing salient information preoperatively to patients in language that they can understand.


Are concerning computed tomography findings among patients seen in the emergency department with acute, low-risk pulmonary embolism (PE)  associated with differences in treatment and/or clinical outcomes?In this cohort study of 817 patients, concerning computed tomography findings were associated with increased hospitalization and resource utilization but not short-term adverse clinical outcomes.These findings suggest that concerning computed tomography imaging findings may be a significant barrier to outpatient treatment among patients with otherwise low-risk acute PE. This cohort study evaluates the association of concerning computed tomography (CT) findings with outcomes and treatment of patients in the emergency department with acute, low-risk pulmonary embolism (PE). Most patients presenting to US emergency departments (EDs) with acute pulmonary embolism (PE) are hospitalized, despite evidence from multiple society-based guidelines recommending consideration of outpatient treatment for those with low risk stratification scores. One barrier to outpatient treatment may be clinician concern regarding findings on PE-protocol computed tomography (CTPE), which are perceived as high risk but not incorporated into commonly used risk stratification tools.To evaluate the association of concerning CTPE findings with outcomes and treatment of patients in the ED with acute, low-risk PE.This cohort study used a registry of all acute PEs diagnosed in the adult ED of an academic medical center from October 10, 2016, to December 31, 2019. Acute PE cases were divided into high- and low-risk groups based on PE Severity Index (PESI) class alone or using a combination of PESI class and biomarker results. The low-risk group was further divided based on the presence of concerning CTPE findings: (1) bilateral central embolus, (2) right ventricle–to–left ventricle ratio greater than 1.0, (3) right ventricle enlargement, (4) septal abnormality, or (5) pulmonary infarction. Data analysis was conducted from June to October 2022.The primary outcome was all-cause mortality at 7 and 30 days. Secondary outcomes included hospitalization, length of stay, need for intensive care, use of echocardiography and/or bedside ultrasonography, and activation of the PE response team (PERT) .P < .001). Low-risk patients with concerning CTPE findings were less frequently discharged from the ED than those without concerning CTPE findings  and had more frequent echocardiography  and PERT activation for consideration of advanced therapies .Of 817 patients  female patients; 129 [15.8%] Black and 645 [78.9%] White patients) with acute PEs, 331 (40.5%) were low risk and 486 (59.5%) were high risk by PESI score. Clinical outcomes were similar for all low-risk patients, with no 30-day deaths in the low-risk group with concerning CTPE findings (0 of 151 patients) vs 4 of 180 (2.2%) in the low-risk group without concerning CTPE findings and 88 (18.1%) in the high-risk group (In this single-center study, CTPE findings widely believed to confer high risk were associated with increased hospitalization and resource utilization in patients with low-risk PE but not short-term adverse clinical outcomes. Indeed, of the major strategies for identification of low-risk patients—the PE Severity Index (PESI) score,10 the simplified PESI (sPESI) score,11 the Hestia criteria,12 and the European Society of Cardiology (ESC) guidelines7—only the ESC guidelines include imaging findings, and these are limited to signs of RV enlargement or RV dysfunction (RVD).Of the approximately 250 000 patients diagnosed with acute pulmonary embolism (PE) in US emergency departments (EDs) each year, most are hospitalized, despite evidence from multiple studies and society-backed guidelines recommending consideration of discharge for the 25% to 50% with low risk stratification scores.14 Later studies, which directly examined the prognostic value of CTPE findings, focused on their potential to predict decompensation in hemodynamically stable patients, rather than those with low risk stratification scores.16 Most recently, 2 meta-analyses18 produced conflicting results, with one finding higher rates of early adverse outcome in patients with low-risk PE and RV dysfunction on echocardiography or CTPE and the other finding no association between abnormal findings on CTPE and in-hospital or 30-day mortality.In reality, little evidence is available regarding the prognostic value of CTPE imaging in patients with acute PE and low risk stratification scores. Early studies focused on echocardiographic markers, rather than CTPE findings, and were performed prior to the validation and widespread use of risk stratification tools.These results aside, there remains concern among many emergency medicine (EM) clinicians that certain CTPE findings confer higher risk of adverse outcome, irrespective of risk stratification score. These include bilateral and centrally located emboli, extensive clot burden, pulmonary infarction, and radiographic evidence of RV strain . In this study, we sought to understand the association of these so-called concerning CTPE findings with hospitalization, resource utilization, and patient outcomes, taking advantage of a large and well-curated registry of patients with acute PE diagnosed in the ED.19 including use of a standardized data abstraction form (STROBE) guidelines.20This study was granted exemption from review and the requirement for informed consent by the institutional review board of the University of Michigan (UM). Construction of the UM registry of acute PEs diagnosed in the ED  is described in detail in eMethods in ion form , which wRace and ethnicity were self-reported with the following categories: American Indian and Alaska Native, Asian, Black or African American, Native Hawaiian or other Pacific Islander, White, unknown, other, and patient refused. Race and ethnicity were included in our analysis to help describe the diversity of the population studied so that future studies can compare and assess how population differences may impact their resultsAbstractors recorded any PESI score or class documented in the patient medical record and also calculated the PESI score using abstracted variables and peak vital signs during the ED stay. Interrater reliability was determined for the calculated PESI class, and in the event of disagreement, an adjudicating review was performed.Troponin I and high-sensitivity troponin T  were included in the registry when measured as part of the ED evaluation. For the subset of acute ED-PEs for which biomarkers were available, we performed a parallel analysis in which patients with abnormal troponin levels were classified as high-risk irrespective of PESI class.CTPE findings were abstracted from the radiology reading, including laterality , largest vessel involved , RV-to–left ventricle (LV) ratio, and presence of RV enlargement, septal abnormality , or pulmonary infarct. Missing data were obtained by fresh review of CTPE images by 2 board-certified radiologists (A.L.L. and M.S.K.). Patients were classified as having concerning CT imaging findings if 1 or more were present: (1) bilateral embolus described as saddle or main pulmonary arteries, (2) RV-LV ratio greater than 1, (3) RV enlargement, (4) septal abnormality consistent with RV pressure overload , or (5) pulmonary infarction.Bivariate linear and logistic regression analyses were used to test hypotheses about risk-group differences in continuous and categorical outcomes, respectively. For continuous outcomes, effect sizes were calculated as unstandardized between-group differences. For categorical outcomes, effect sizes were calculated as unstandardized marginal effects . An α level of .05 was used for all analyses, and all hypothesis tests were 2-sided. Analyses were conducted with the Stata statistical software package version 15 (StataCorp). Statistical analysis was performed in June to October 2022.Construction of the acute ED-PE registry is shown in flow sheet form in eFigure 1 in P = .36). However, more high-risk cases were saddle PEs or involved the main pulmonary arteries vs low-risk cases . Likewise, high-risk cases had statistically higher mean (IQR) RV-LV ratios . There was no statistically significant difference between groups for RV enlargement or septal abnormalities, but more patients in the high-risk group vs the low-risk group had these findings . Pulmonary infarction was less common in the high-risk group vs the low-risk group .We next examined the frequency of various CTPE findings in low- and high-risk groups . There wP < .001). Even low-risk acute ED-PEs with the most concerning appearing CTPEs, eg, 41 cases with 3 concerning findings of bilateral, central emboli with an RV-LV ratio greater than 1 and septal abnormalities, had no deaths at 30 days.As shown in P = .86). Both low-risk groups were significantly different from the high-risk group, in which 80 patients (16.5%) were admitted from ED directly to ICU . The pattern remained unchanged when considering requirement for ICU-level care at any time during hospitalization: 4 (2.6%) and 5 (2.8%) for low-risk groups with and without concerning CTPE findings, respectively  and 103 (21.1%) for the high-risk group . Even multiple concerning CTPE findings for an individual patient did not have a significant association with ICU utilization in low-risk patients, with only 2 of 55 patients (3.6%) with 2 or more concerning CTPE findings requiring ICU-level care.Very few patients treated in the ED from either low-risk group required admission to the intensive care unit (ICU) , with no significant difference between the low-risk group with concerning CTPE findings and the high-risk group . The pattern was reversed for hospital LOS, which was a mean (SD) of 2.3 (1.9) and 2.6 (3.5) days for the low-risk groups with and without concerning CTPE findings, respectively , and 5.8 (5.9) days for the high-risk group .P < .001) and 87 (57.6%) vs 49 (27.2%) for TTE . Similarly, the multidisciplinary PE response team (PERT), which advises ED clinicians in cases in which they believe advanced therapies  might be beneficial, was activated in 34 (22.5%) low-risk cases with concerning CTPE findings vs 11 (6.1%) without . The frequency of POCUS (130 [26.8%]), TTE (262 [53.9%]), and activation of the PERT (138 [28.4%]) in the high-risk group were not statistically different compared with the low-risk group with concerning CTPE findings (Both cardiac point-of-care ultrasonography (POCUS) and formal transthoracic echocardiography (TTE) were performed more frequently in low-risk cases with than without concerning CTPE findings: 35 (23.2%) vs 15 (8.3%) for POCUS  had at least 1 troponin level measured as part of the ED evaluation. We performed a parallel analysis  had no obvious association with short-term mortality or need for intensive care in otherwise low-risk patients.18 published in the past several years that concluded that RVD is associated with short-term mortality in low-risk PE. Both reports, however, pooled data from studies using different measures of RVD, and their primary conclusions were based on combinations of CTPE, echocardiography, and biomarker testing. In the one case in which imaging modalities and biomarkers could be separated—due to an individual patient-data meta-analysis (IPDMA) method—RVD assessed via CTPE was not found to be associated with in-hospital or 30-day mortality. Of note, this pooled IPDMA population also matched our cohort fairly well in terms of the age, comorbidities, rate of concerning CTPE findings, and overall 30-day mortality among low-risk patients.18At first glance, our results seem to conflict with recent reports in the field. Specifically, there have been 2 meta-analyses23 A number of implementation studies have been conducted, focusing on creation of tools for electronic clinical decision support and protocols to facilitate identification, appropriate management, and timely follow-up of low-risk patients.24 These studies, however, have either explicitly excluded patients with concerning CTPE findings or simply not addressed the potential association between perceived risk and physician decision-making. Our findings suggest not only that outpatient management may be considered for these patients, but that concerning CTPE findings represent an important barrier to discharge. Compelling evidence, including the results of the current study, will likely need to be paired with effective implementation strategies to overcome their perceived risk. Indeed, as clinicians and health systems become more comfortable and facile with other aspects of home treatment, we expect a widening of the gap in discharge of low-risk patients with and without concerning CTPE findings.While our findings require confirmation, it is worth considering their potential impact on EM practice. Over the past 2 decades, a strong evidence base has been established to support safe outpatient management of PE, but adoption by EM clinicians has been slow and remains limited in most settings.Beyond clinical implications, our study has interesting aspects from the stand point of PE research and quality improvement. In particular, construction of the acute ED-PE registry required a multimodal approach, combining manual medical record abstraction (by the MEDIC collaborative), query of the EMR, and a substantial amount of physician medical record review to identify and exclude inappropriate cases. Nonacute and nonsignificant PEs were often difficult to distinguish from acute ED-PEs without physician review of the documented medical decision-making. For example, patients who presented to our facility for second opinion after recent diagnosis and treatment at another hospital were treated quite differently by EM clinicians, as evidenced by the greater than 10-fold higher rate of discharge, but typically had acute-appearing emboli on imaging and final clinical impressions of acute PE. Similarly, identification and separation of insignificant subsegmental PEs, radiographic mimics , and chronic PEs are likely to remain a major challenge for automated EMR queries or non–medically trained abstractors. Our approach with repeated physician reviews resulted in a high-fidelity registry with essentially no missing data and high confidence in the accuracy and acuity of each PE diagnosis. At the same time, the experience raises concerns about the accuracy of PE data acquired from national databases or unfiltered EMR queries. These observations may be particularly important as health systems and researchers create interventions to evaluate and increase outpatient PE treatment.Our study does have some limitations. The primary outcome was uncommon, so our study may be underpowered to detect modest differences between groups. The study was also retrospective and limited to a single center. These limitations are mitigated, to some extent, by the relatively large number of cases in the registry and the numerous steps taken to minimize issues typically associated with retrospective medical review, eg, repeated physician review of each medical record, radiology overread of CTPE scans with missing measurements, and so on. These measures aside, retrospective design limits the ability to discern what factors influenced physician behavior at the time of patient care and introduces the possibility of confounding variables that may not have been accounted for, eg, social and economic factors requiring admission. Similarly, our practice setting—an academic, tertiary health care center with a large population of patients with advanced cancer and cardiopulmonary disease—does not reflect all hospitals, and our cohort had limited racial and ethnic diversity. To be truly generalizable, our findings will need to be reproduced in prospective, multicenter studies encompassing the full spectrum of EM practice. Our study is also somewhat limited in its focus on concerning CTPE findings as opposed to ultrasonographic findings. While many patients in our registry underwent formal TTE, it was infrequently completed during ED evaluation, and POCUS was limited by inconsistency in the training of operators and quality of documentation. Our analysis was also limited to short-term clinical outcomes, and it is possible that CTPE findings could be associated with other clinically significant endpoints, eg, post-PE syndrome, recurrent venous thromboembolism, or chronic thromboembolic pulmonary hypertension. Furthermore, our study does not address risk of bleeding, although other studies have consistently shown low rates of major bleeding in low-risk patients with acute ED-PE.In summary, ED patients with acute, low-risk PE had similar short-term outcomes irrespective of CTPE results. Nonetheless, specific CTPE findings were associated with increased resource utilization and hospitalization of these patients. Future implementation studies aimed at maximizing guideline-recommended outpatient management of acute low-risk PE should account for and address EM clinician concerns regarding CTPE imaging.


Human papillomavirus (HPV) is a common sexually transmitted infection, causing multiple cancers, including cervical, penile, and anal. Infection and subsequent health risks caused by HPV can be diminished by HPV vaccination. Unfortunately, vaccination rates among Hmong Americans are substantially lower than those among other racial and ethnic groups, despite having higher cervical cancer rates than non-Hispanic White women. Such disparities and sparse literature highlight the need for innovative and culturally appropriate educational interventions to improve HPV vaccine rates in Hmong Americans.Hmong Promoting Vaccines website (HmongHPV website), for Hmong-American parents and adolescents to improve their knowledge, self-efficacy, and decision-making capacities to obtain HPV vaccinations.We aimed to develop and evaluate the effectiveness and usability of an innovative web-based eHealth educational website, the t tests (2-tailed) to measure the change in knowledge, self-efficacy, and decision-making processes, and used template analysis to identify a priori themes for website usability.Through social cognitive theory and community-based participatory action research process, we created a theory-driven and culturally and linguistically appropriate website for Hmong parents and adolescents. We conducted a pre-post intervention pilot study to assess the website’s effectiveness and usability. Overall, 30 Hmong-American parent and adolescent dyads responded to questions about HPV and HPV vaccine knowledge, self-efficacy, and decision-making at preintervention, 1 week after intervention, and at the 5-week follow-up. Participants responded to survey questions about website content and processes at 1 and 5 weeks, and a subset of 20 dyad participants participated in telephone interviews 6 weeks later. We used paired P=.01; vaccine knowledge, P=.01) and children , which were sustained at the 5-week follow-up. Parents’ average self-efficacy score increased from 21.6 at baseline to 23.9 (P=.007) at post intervention and 23.5 (P=.054) at follow-up. Similar improvements were observed in the teenagers’ self-efficacy scores . Collaborative decision-making between parents and adolescents improved immediately after using the website (P=.002) and at follow-up (P=.02). The interview data also revealed that the website’s content was informative and engaging; in particular, participants enjoyed the web-based quizzes and vaccine reminders.Participants’ HPV and HPV vaccine knowledge improved significantly from pre- to postintervention stage and follow-up. Knowledge scores increased from preintervention to 1 week after intervention for both parents . Nearly 80 million men and women in the United States are infected by the human papillomavirus (HPV), making it the most common sexually transmitted infection . HPV is Uptake of HPV vaccines can reduce the occurrence of such cancers. However, HPV vaccination rates are alarmingly low in all adolescents. Numerous studies have shown that Asian-American populations have even lower HPV vaccination rates -10. AccoOne potential reason for the limited uptake of the HPV vaccine in Hmong Americans may be the low parental and adolescent awareness and knowledge of HPV effects and HPV vaccine benefits. In a conveniently sampled survey of Hmong Americans, only 38% of boys had heard of the HPV vaccine . In anotBarriers to HPV knowledge and vaccination within the Hmong-American community exist at multiple levels . Similar. Over 90% of adults in the United States have internet access, 96% have some type of cell phone, and these trends continue to increase [eHealth uses digital platforms such as dynamic websites, apps, or mobile and wireless devices to deliver health information and engage users to improve health literacy, behaviors, and outcomes . eHealthincrease . Accordiincrease . The proincrease ,31. eHeaHmong Promoting Vaccines (HmongHPV website) to improve their knowledge, self-efficacy, and decision-making capacities to obtain HPV vaccinations among Hmong-American parents and adolescents.Health behavior change, such as initiating HPV vaccinations, is a complex process influenced by many factors. Using a relevant theory for behavior change, such as Social Cognitive Theory (SCT), can guide the creation of an effective intervention targeted at multiple factors  . EngaginWe used the CBPAR approach to develop and evaluate an innovative, web-based eHealth educational website. CBPAR is a research approach in which community members, academicians, and providers form an egalitarian partnership to conduct the study, including the formulation of research questions, intervention design, recruitment, implementation, data analysis, and dissemination of research findings ,34. The SCT guided the development of the web-based educational HmongHPV website ,35. SCT Findings from focus groups with Hmong-American parents and adolescents shaped our educational intervention’s content and communication strategies . ParentsThe HmongHPV educational modules were designed by our academic community research team, CAB members, and a Hmong-based media organization. HmongHPV is an internet-based website with (1) a 5-module educational program tailored to Hmong-American parents or teens; (2) links to HPV-related resources; (3) a GPS locator feature for nearby health care clinics to obtain an HPV vaccination; including potential financial support; and (4) automated text reminders to complete educational components and schedule clinic visits for recommended HPV vaccinations. In addition, a bilingual Hmong-American health navigator was available to support the users with additional questions. The 5 educational modules included didactic learning with written text, visual pictures, videos, and web-based quizzes based on SCT. The 5 topic areas were (1) HPV infection and diseases; (2) HPV vaccine; (3) communication between clinics, parents, and teens; (4) concerns about HPV vaccines; and (5) clinics to get HPV vaccines. Parents’ and adolescents’ intervention contents were similar, but the message strategy followed either the gain or loss frame. In addition, the parents’ messages were available in Hmong and English, whereas the adolescents’ messages were in English only. The modules ranged in length from 7 to 10 minutes to complete and were intended to be viewed 1 per day; however, our CAB recommended allowing users to view the modules based on their learning style or convenience within a 1-week time frame. Over 8 months, the research team members worked with website developers  to draft and finalize the website, which underwent alpha and beta testing to optimize the website’s usability and acceptability with community members and the CAB.Hmong HPV website, we used a quasi-experimental, pre-post study design consisting of surveys and interviews. We recruited Hmong parents and adolescents to evaluate the HmongHPV website at Hmong schools, Hmong community events, and Hmong markets via in-person discussions and culturally and linguistically appropriate flyers on social media such as Facebook, listserves, and emails; at a local community clinic through calling Hmong patients between the ages of 12 and 16 years who had and had not had their HPV vaccines; and by word of mouth. With slow enrollment, we increased the study incentives from US $50 to US $150 per person.To evaluate the effectiveness and usability of the After providing informed consent, participants completed the preintervention questions, reviewed the website’s 5 modules, and then completed postintervention questions 1 week later and follow-up questions 5 weeks later. A subset of adolescents and parents also completed telephone-based interviews to assess the website's usability. The University of Minnesota gave institutional review board approval for the implementation of the study. Participants were provided with US $150 gift cards to compensate for their time. The study data were anonymized and deidentified for confidentiality. All the procedures performed in this study were in accordance with the ethical standards of the University of Minnesota Institutional Review Board on Social and Behavioral Research (#1612S01841).Composite scores assessing HPV disease and HPV vaccine knowledge were calculated as the number of correct responses to the 14 and 12 questions, respectively. “Not sure” answers were treated as incorrect responses for analysis. Adolescents answered 5 self-efficacy questions, with responses ranging from 0 (least confident) to 100 (most confident), which were rescaled from 0 to 10. Parents’ self-efficacy scores were the sum of seven 0-4 Likert responses. Other continuous measures such as decision-making regarding HPV vaccination and HmongHPV usability and acceptability were answered on a 0-5 Likert scale. The remaining outcomes were categorical with “Yes,” “No,” and “Not Sure” responses.t tests (2-tailed) and summarized with means and 95% CIs. Changes from baseline for binary endpoints were analyzed using McNemar test if there were >25 discordant pairs or analyzed using the exact binomial test if there were <25 discordant pairs. Only univariate analyses were conducted because of the small sample size of the pilot study.All analyses were performed using R  . Our anaTemplate analysis was used to analyze the interview data . The resA total of 30 parent-adolescent dyads were enrolled in the study, and 29 pairs completed the pre-post questions. Of the 20 dyads invited to participate in the qualitative interviews, 19 dyads and 1 parent completed the telephone interviews (1 child declined to participate). P=.001; HPV vaccine knowledge P<.001) and adolescents  and were sustained at the 5-week follow-up. The median correct responses to the 14 HPV knowledge questions increased from 6 to 11 for parents and from 4 to 10 for children. Of the 12 HPV vaccine knowledge questions, the median number of correct responses increased from 8 to 11 for parents and from 6 to 10 for children. Many of these improvements are attributable to initial “Not sure” responses shifting to correct answers. At baseline, parents and adolescents demonstrated that they understood the value of vaccines in general but not the specifics of the HPV vaccine. Composite scores of HPV knowledge and HPV vaccine knowledge  increaseP=.02) and genital warts (P=.02) from preintervention to 1 week post intervention (P=.02) and a significant increase in boys’ concerns about penile cancer (P=.02) 1 week post intervention, but similar to their parents, these concerns attenuated at follow-up.rvention . HoweverP<.001). However, fear of vaccination increased at follow-up and was not significantly different from the baseline (P=.13).Parents’ modest concerns, fears, and tensions about the vaccine did not change significantly throughout the study . In contP=.03) and their feelings of support for getting the HPV vaccination (P=.02) significantly increased. In addition, there was a substantial increase in parents’ agreeing that providers thought that HPV vaccination was important (P=.002), they had enough information to make a decision about the HPV vaccination (P=.002), and they knew where to receive the HPV vaccination (P=.008).P<.001), read printed materials (P<.001), read web-based information (P<.001), communicated with their providers (P=.008), and searched on the web for a clinic to receive HPV vaccination (P=.007). Overall, teenagers did not show substantial changes in communication about HPV or the vaccine throughout the study period. However, there were substantial improvements in information-seeking from baseline to 1 week post intervention in reading printed materials (P=.005) and web-based information  and follow-up (P=.002). Approximately 40% (11/29) of adolescents agreed or strongly agreed that their parents decided that they would receive an HPV vaccination. However, like their parents, teenagers increasingly agreed that they jointly decided to receive an HPV shot, with P=.03 at 1 week post intervention and P=.02 at follow-up. Less than a quarter of parents and adolescents agreed that environmental and religious factors influenced their decision-making, although there was a substantial increase from baseline to follow-up on the influence of friends for parents (P=.02).Parents’ and adolescents’ agreement with decision-making statements regarding HPV vaccination are shown in P=.007) and follow-up (P=.05). The improvements were driven by an increased intention to talk with their child about getting the HPV vaccine, talking with their child’s physician or nurse, and initiating conversations with their child’s provider. Similar improvements occurred in the teenagers’ composite self-efficacy score, increasing at 1 week post intervention (P=.009) and follow-up (P=.007). The largest increase in adolescents’ self-efficacy from baseline to follow-up was knowing what to expect when receiving the HPV vaccination, although increases were seen across all 5 self-efficacy measures.Overall, parents had strong intentions to receive HPV vaccination for their children at baseline , which iP=.29). At follow-up, 59% (17/29) of adolescents also reported having received at least one HPV shot; unfortunately, adolescents were not asked this question preintervention. Many responses changed from “Not sure” to “Yes,” suggesting that the intervention increased parents’ knowledge of their child’s actual vaccination status.Although this pilot did not track receipt of the HPV vaccine, parents reported an increase in their children having had at least 1 HPV vaccine from 41% (12/29) at preintervention to 59% (17/29) at follow-up  allow users more control and flexibility when going through the educational modules , (2) make messages and videos more concise, and (3) make the website more accessible .The pilot feasibility study showed that the HmongHPV website substantially improved and sustained parents’ and adolescents’ knowledge regarding HPV and the HPV vaccine and self-efficacy about obtaining the HPV vaccine over the 5-week study duration. In addition, parents’ and adolescents’ concerns about HPV-causing cancers increased, whereas concerns about the HPV vaccine causing harm decreased modestly. Parents’ health-seeking and communication behaviors increased, whereas parents’ and adolescents’ collaborative decision-making about receiving the HPV vaccination improved. In addition, the HmongHPV website was well received.definitely vaccinate their child, indicating that improvement in knowledge may translate to HPV vaccine uptake. Although intention does not directly correlate with actual behavior, previous studies [Theory-based eHealth studies on HPV adherence and uptake in Asian Americans are sparse. To our knowledge, this is the first study to create and evaluate a theory-based and CBPAR-informed Hmong-specific eHealth HPV vaccination educational intervention. Our SCT-informed intervention posits that personal , behavioral , and environmental  factors and their interactions influence an individual’s awareness and knowledge. With regard to personal factors, baseline knowledge of HPV and the HPV vaccine among participants was low, similar to other studies with Asian Americans whose baseline knowledge ranged from 19% to 65% ,18,43,44Importantly, at the end of the study, parents  and adolescents  reported increased collective decision-making, significantly supporting their self-efficacy in obtaining vaccination. Zhu et al  found thParents and adolescents positively evaluated the website for usability, information quality, and interface quality while making recommendations for improvement. We attribute this reception to CBPAR practices, whereby Hmong-American community members on the research team and CAB served as equal partners during the intervention design, implementation, analyses, and interpretation. Parents rated the website more favorably than adolescents. Website expectations may be higher for adolescents than parents, as they are often more frequent internet users. As demonstrated in a disease prevention eHealth application with Vietnamese participants aged 15 to 24, older users perceived eHealth apps as more helpful and usable than younger participants .The most relevant question is whether educational eHealth programs, such as HmongHPV, can improve HPV vaccination rates. However, this was not assessed in the pilot study. Although there was a slight increase in parents’ reporting that their children had an HPV shot during the study period, we could not attribute this to an actual increase in shots or improved knowledge of their child’s vaccination status throughout the study. In an eHealth study that used culturally tailored text messages for Korean-American women to obtain HPV vaccines, 30% of the participants initiated the HPV vaccine series within 3 months of the intervention and the intent to receive the vaccine within 1 year increased from 63% to 97% from pre- to post intervention . OverallAs a small pilot study with a nonprobability sample, the findings from this study may not be generalizable to the greater Hmong population and may contain self-report bias. Despite various recruitment approaches, enrolling participants was challenging and required a large incentive that may have led to additional self-report bias. In addition, the small sample size and short study duration limited the ability to examine potential predictors of increased HPV vaccine intentions or outcomes. A future randomized controlled study could be conducted to test the outcomes of HPV vaccination .Recent systematic reviews and studies on eHealth interventions to increase HPV vaccination adherence and uptake are promising, although none have addressed the US-based Asian communities, much less Hmong-American adolescents and their parents ,46,47. MHmong Promoting Vaccines website was also well received by adolescents and adults, suggesting the potential for broader application beyond this study group. With the current COVID-19 pandemic, the use of eHealth applications can ensure that safety precautions are adhered to and may become the preferred method of implementation of health education materials and interventions in the future. Further research is needed to determine whether the current eHealth web-based education is indeed useful in the uptake and completion of the HPV vaccine series, the key factors contributing to vaccine acceptance, and how best to disseminate and implement such eHealth interventions sustainably. Future studies should continue to offer interventions informed by the CBPAR principles to address communities’ specific issues in receiving preventive health care services.This study’s findings show that within the Hmong-American population, an eHealth HPV intervention created in partnership with community members can improve knowledge, self-efficacy, decision-making, and information-seeking behaviors regarding HPV and the HPV vaccine. The


Breakthrough hemolysis (BTH) is the return of hemolytic disease resulting in an overall increase in complement activation in a patient being treated for paroxysmal nocturnal hemoglobinuria (PNH) with complement inhibitors (CI). BTH after COVID-19 vaccination has only been reported in PNH patients treated with the traditional C5 CI eculizumab and ravulizumab. We report on a new association of BTH in a newly COVID-19 vaccinated, previously stable PNH patient treated with pegcetacoplan, a C3 CI.The patient is a 29-year-old female diagnosed with PNH in 2017 and was started on eculizumab but was switched to pegcetacoplan in 2021 after continuing to exhibit symptomatic hemolysis. Subsequently, the patient returned to PNH remission serologically and symptomatically until her first COVID-19 vaccination. Since then, her lactate dehydrogenase (LDH) and hemoglobin counts have not fully returned to previous baseline levels, with significant exacerbations after her second COVID-19 vaccine and de novo COVID-19 infection. As of May 2022, the patient requires packed red blood cell transfusions every two to three months and has undergone a bone marrow transplant evaluation.This case study suggests that the administration of the upstream C3 CI, pegcetacoplan, is associated with active extravascular hemolysis in the setting of COVID-19 vaccinations and active COVID-19 infection. The pathophysiology of this hemolysis is unclear as hemolysis could be related to the underlying complement factor deficiency or amplification of complement factors causing extravascular hemolysis. There are conflicting reports in the literature regarding the mechanism by which COVID-19 vaccination and infection cause BTH in PNH patients, regardless of the choice of CI treatment. Bringing awareness to this case of BTH secondary to COVID-19 in a PNH patient treated with pegcetacoplan can further warrant the investigation of the role of COVID-19 in complement disruption and its role in BTH. Paroxysmal nocturnal hemoglobinuria (PNH) can be a life-threatening hematopoietic stem cell disease and is caused by an acquired defect in the synthesis of the glycosylphosphatidylinositol (GPI) associated proteins CD55 and CD59 . DeficieEculizumab is a monoclonal antibody that inhibits complement component 5 (C5) in forming the terminal complement system. Until the advent and clinical use of eculizumab in 2007, the median survival for newly diagnosed PNH patients was 15 to 20 years . ComplemThis case report discusses the presentation and management of a 29-year-old female with a history of PNH in remission, who was treated with pegcetacoplan, who developed a series of acute hemolytic episodes that were temporally associated with receiving two COVID-19 vaccinations and then a de novo COVID-19 infection. Reports of PNH relapse secondary to COVID-19 vaccination have only been reported in patients receiving eculizumab and ravulizumab. Our search yielded no results for a similar situation in post-COVID-19 vaccinated PNH patients maintained on pegcetacoplan.This patient is a 29-year-old female who was referred to the hematology clinic in 2013 while pregnant at age 20. At that time, she was noted to have a platelet count of 23,000 and was diagnosed with immune thrombocytopenic purpura (ITP). In the subsequent years, the patient was unresponsive to steroid and intravenous immunoglobin (IVIG) therapy. Her diagnosis was modified to PNH in 2017. Eculizumab therapy was initiated in 2017, resulting in complete hematologic remission. In February of 2021, maintenance of eculizumab was no longer effective as the patient developed symptomatic disease activity characterized by severe, worsening fatigue, brain fog, chest pain, and active hemolysis. Under an expanded access protocol, authorization to treat with pegcetacoplan was approved. Treatment commenced in February 2021, resulting in complete clinical and serologic remission  783 U/L and a drop in hemoglobin to 7.6 gm/dL).Subsequent to her receiving the second Pfizer SARS-CoV-2 vaccine, the symptoms outlined above slowly improved but nevertheless persisted, accompanied by continued low-grade hemolysis. She tested seropositive for COVID-19 in January 2022. At that point, she was short of breath (SOB), experiencing exertional chest pain, bleeding from her gums upon brushing her teeth, and easy bruising. Her LDH was 1056 U/L, and her hemoglobin was 6.1 g/d. Platelet and RBC transfusions were administered over two weeks.Her LDH and hemoglobin have yet to fully stabilize to previous baseline levels since the completion of her Pfizer SARS-CoV-2 vaccination schedule. As of May 2022, the patient requires packed RBC transfusions every two to three months and has undergone a bone marrow transplant evaluation. The patient did not retest following initial seropositivity testing for COVID-19; however, any symptoms directly related to COVID-19 infection have resolved.This report describes a case of acute hemolysis temporally associated with COVID-19 vaccinations and COVID-19 infection in a patient with previously remitted PNH maintained on pegcetacoplan. Current literature supports a correlation between COVID-19 vaccination and hemolytic episodes in PNH patients treated with older therapies (eculizumab and ravulizumab). However, this is the first report of acute hemolysis associated with COVID-19 vaccinations and acute COVID-19 infection in a patient maintained on pegcetacoplan. Yu et al. report that the spike protein of SARS-CoV-2 competes with complement factor H for heparan sulfate binding and amplifies the alternative complement pathway on the cell surface . HoweverBoth conclusions may play a role in the cases of BTH reported in the current literature; however, the literature is evident in that both eculizumab and ravulizumab are not protective of these episodes ,8. SimilOur case study suggests that the traditional C5 CI  and the upstream C3 CI (pegcetacoplan) may leave PNH patients vulnerable to BTH after COVID-19 vaccination and infection. However, conflicting reports exist regarding the mechanism by which both COVID-19 vaccination and infection may cause BTH in PNH patients, regardless of the choice of treatment. Thus, the role of COVID-19 in complement disruption and its effects on CI deserves further investigation. This data provides a basis for additional investigation to clarify the mechanism of interaction between the COVID-19 vaccine, the COVID-19 virus, and current PNH CI therapies.