BRAF, EGFR, KRAS, and NRAS common hotspot mutations that do not require specialized trained personnel. Moreover, the interpretation of results is fully automated, with rapid turnaround time. Though Idylla testing and NGS have been shown to have high concordance in identifying EGFR, BRAF, KRAS, and NRAS hotspot mutations, there is limited experience on optimal ways the Idylla system can be used in routine practice. We retrospectively evaluated all cases with EGFR, BRAF, KRAS, or NRAS mutations identified in clinical specimens sequenced on two different NGS panels at the University of Rochester Medical Center (URMC) molecular diagnostics laboratory between July 2020 and July 2021 and assessed if these mutations would be detected by the Idylla cartridges if used. We found that the Idylla system could accurately identify Tier 1 or 2 actionable genomic alterations in select associated disease pathologies if used. Yet, in a minority of cases, we would have been unable to detect NGS-identified pathogenic mutations due to their absence on the Idylla panels. We derived algorithmic practice guidelines for the use of the Idylla cartridges. Overall, Idylla molecular testing could be implemented either as a first-line standalone diagnostic tool in select indications or for orthogonal confirmation of uncertain results.Testing of tumors by next generation sequencing (NGS) is impacted by relatively long turnaround times and a need for highly trained personnel. Recently, Idylla oncology assays were introduced to test for  BRAF in cutaneous melanoma; KRAS, BRAF, and NRAS in colorectal cancer; and EGFR mutations and ALK and ROS1 gene rearrangements in lung adenocarcinomas [Development of personalized therapies for cancer patients in the last two decades has had a substantial impact on the treatment strategies of different tumor types . Testingrcinomas ,3,4.The gold standard for detecting different genomic alterations in tumors is using next generation sequencing (NGS)-based assays . InstituTM oncology assays  were launched to complement NGS testing. The Idylla system is an allele-specific qPCR-based assay platform in which all wet-bench steps are automated and confined to a single use cartridge. The assay starts after the insertion of sample-loaded gene(s) specific cartridges into the unit that are connected to a user interface console that displays result summaries. qPCR curve results generated from the assay are visualized through a secure web-based interface. The Idylla BRAF, EGFR, KRAS, and NRAS/BRAF mutation tests (cartridges) on the Idylla platform allow the detection of EGFR, BRAF, NRAS and KRAS hotspot mutations with rapid turnaround times (<3 h). Unlike NGS-based assays, the Idylla system can directly use formalin-fixed paraffin-embedded (FFPE) tissue sections without the need for DNA preparation and extraction, with interpretation of the results being fully automated. Several studies have demonstrated the validity and accuracy of the Idylla system in comparison to NGS in detecting EGFR, BRAF, KRAS, and NRAS hotspot mutations [Recently, Idyllautations ,10,11,12EGFR, BRAF, KRAS, or NRAS mutations detected in specimens that were sequenced on two different NGS panels at the University of Rochester Medical Center (URMC) molecular diagnostics laboratory and assessed if the mutations would be detected on the Idylla system cartridges. The EGFR, BRAF, KRAS, or NRAS NGS detected mutations were compared to mutations that could be identified by the Idylla cartridges if used. We classified gene mutations identified by the NGS panels according to their tier grouping and evaluated to what extent the Idylla platform would have detected these mutations if utilized. Furthermore, we selected NGS-diagnosed BRAF or NRAS mutation positive cutaneous melanomas, BRAF mutation positive hairy cell leukemia, KRAS or EGFR mutation positive lung adenocarcinomas, and BRAF, KRAS or NRAS mutation positive colorectal cancer cases to assess what proportion of the identified mutations would have been recognized on the Idylla platform. Lastly, we also uncovered a proportion of NGS-evaluated cases with mutations that would have been detected on the Idylla system but had additional, Idylla non-identifiable mutations.The overall objective of this study has been to start developing a formalized workflow on the optimal use of the Idylla system as a first-line diagnostic tool for the detection of different actionable genomic mutations in routine clinical practice. To this end, we retrospectively identified cases with TM Myeloid sequencing panel  for all studies with greater than 500 recorded point mutations. These data included the following studies: [BRAF, EGFR, KRAS, and NRAS. This created a list of 11,420 unique ‘study-sample’ concatenation records.Point mutation data was collected from the “cBioPortal for Cancer Genomics” website . We designed a Python programming language script to compare each of the Idylla-identifiable mutations against each entry in the ‘four-target-gene-only’ data aggregate from the selected cBioPortal studies. We included successful matches in a list of ‘study-sample’ string-concatenations. Lastly, we filtered these results for unique values to avoid over-counting specimens which may have had multiple Idylla-identifiable mutations. We then compared the portion of Idylla-identifiable point mutations to the total number of ‘four-target-genes-only’ mutations found in the prepared cBioPortal data.Data analysis and figures were created by using Microsoft Excel, GraphPad 8.3, and CorelDraw 2019 software programs.https://www.biocartis.com/en-US/meet-idylla/idylla-oncology-assays (accessed on 29 December 2021).In the Idylla system, all assay cartridges are ready-to-use and contain the necessary reagents to perform sample preparation and real-time PCR amplification and detection, starting from insertion of FFPE tissue sections into the cartridges. The detectable variants for each target gene by the Idylla BRAF, KRAS, EGFR, and NRAS/BRAF cartridges are listed in BRAF mutations, 133 with NRAS mutations, 303 with KRAS mutations, and 96 with EGFR mutations from the URMC NGS database from June 2020 to July 2021. We compared the NGS assay-detected nucleotide (protein) changes on these genes to the Idylla-detectable variants for these four genes  could likewise be identified by the Idylla system  followed by lung adenocarcinoma (19%) and malignant melanoma (17%) (For ould not A. We cata system B if usedma (17%) C.NRAS mutations, 89% (118 of 133) of the variants identified by NGS testing could be identified on the Idylla system as well (NRAS mutations (116 of 127) could be detected by the Idylla NRAS cartridge if used (NRAS mutations were from acute myeloid leukemia patients (approximately 38%), followed by malignant melanoma (21%) and lung adenocarcinoma (4%) (For the identified  as well D. 91% of if used E. Most soma (4%) F.KRAS mutation analysis revealed that 93% (283 of 303) of the NGS-detected mutations could be identified by the Idylla system  would be detected on the Idylla system if utilized  of the NGS-identified EGFR mutations could likewise be detected by the Idylla system if run . The data comprised a total of 11,420 unique samples with either EGFR, BRAF, KRAS, or NRAS gene mutation profiles, spread across 44 studies (see Methods). This data set contained 2483 samples with BRAF mutations and 2960 with EGFR mutations, of which 1346 (54%) BRAF mutations and 1122 (38%) EGFR mutations could be identified by the Idylla system if used  KRAS and 1423 (87%) NRAS mutations as positive if utilized  and small indel profiles identifiable by NGS testing at the URMC Molecular Diagnostics laboratory for  if used . Furtherutilized .EGFR mutations or cutaneous melanoma with NRAS or BRAF mutations) would demonstrate higher concordance with hotspot mutations recognized by the Idylla system and may also uncover additional clinically significant NGS-identified gene mutations not detected by Idylla. The comprehensive results are detailed in The utility of the Idylla system may vary from one tumor type to another. Thus, to determine the type and frequency of gene mutations that would be missed by the Idylla system, we next grouped gene alterations with their associated disease pathologies. We hypothesized that associating the NGS-identified gene mutations to their specific associated disease pathologies  could also be detected by the Idylla BRAF and BRAF/NRAS cartridges if run  could be also detected if run on the Idylla system  were classified as Tier 1  at diagnosis . Indeed,utilized . Three , of which 51 (96%) had NGS identified BRAF mutations that would be detected on the Idylla system if performed  could be identified on the Idylla system if run  of the identified genomic alterations could be identified on the Idylla system  could be identified using the Idylla EGFR cartridge  could be identified using the Idylla KRAS cartridge  or for orthogonal confirmation of uncertain or very low allele frequency mutation results.Taken together, our analyses have shown that the Idylla platform is able to identify the majority of common pathogenic mutations in the


The sum of the secreted compounds released into the extracellular space is called the secretome. Secretomics, the comprehensive study of molecules that are secreted by a cell, a tissue or an organism, has become a key methodological approach to unlock the secrets of plant-microbe interactions.Understanding the mechanisms underlying plant-fungal interactions is paramount to develop new disease control strategies. The association between plants and fungi is a two-way process, yielding alterations in both partners largely initiated and sustained Bradley et al. The microbial nutritional lifestyle is associated with the number and type of GHs secreted. Many secreted microbial GHs promote plant colonisation and as such, serve as virulence factors with a myriad of functions, including nutrient acquisition, detoxification and manipulation of plant microbiota. Interestingly, these enzyme effectors can either suppress plant immune responses by preventing activation of microbe recognition by plant pathogen receptors (PPRs), or conversely activate host immunity as microbe-associated molecular patterns (MAMPs) or by creating damage-associated molecular patterns (DAMPs) as a consequence of GHs’ enzymatic activity. This review draws a comprehensive picture of secreted GHs and their critical roles in plant infection by fungi and oomycetes. In addition to providing thorough insights into this layer of plant-pathogen interaction, current knowledge gaps that should be addressed by future research are identified.Fungal and oomycete microbial glycoside hydrolases (GHs) delivered to cell surfaces and surrounding extracellular environments during host colonisation were reviewed by Botrytis squamosa and Botrytis elliptica are necrotrophic fungal pathogens of onion and lily, respectively. Both fungi are closely related and assumed to share a considerable number of proteins to induce host PCD. This hypothesis was confirmed by Malvestiti et al. using genomics to disclose a high level of synteny between the two species, with a few balanced structural chromosomal arrangements. Post-genomics (secretomics and transcriptomics) analyses of culture filtrates inducing cell death responses upon leaf infiltration identified orthologous cell death-inducing proteins displaying similar expression patterns during infection of their respective host. Such comparative -omics studies are greatly needed to shed light on the mechanisms that make some pathogens more host-specific than others.Necrotrophs have evolved specialized proteins that actively induce plant cell death by co-opting the programmed cell death (PCD) machinery of the host, in order to access nutrients. Fusarium oxysporum causes vascular wilt diseases of economically important crops throughout the world and, as a result, is actively researched in breeding programs that target crop resilience. Based on their host specificity, F. oxysporum isolates are grouped into formae speciales. Because of the genetic heterogeneity and polyphyletic nature of F. oxysporum strains, their assignment to formae speciales using non-experimental procedures remains challenging. To address this, Brenes Guallar et al. have developed the Fusarium oxysporum Effector Clustering (FoEC) pipeline that processes genome assemblies to classify strains by forma specialis based on hierarchical clustering of the presence of predicted putative effector sequences. The updated FoEC2 pipeline was improved to be more user-friendly, customizable and to offer greater multithreading scalability. FoEC2 was applied to 537 F. oxysporum genomes to successfully classify isolates into formae speciales and identify their subtypes. The FoEC2 pipeline allows reducing the workload and number of experiments required to confirm host specificity and presents a valuable tool to minimise the time and maximise the resources needed to characterize newly assembled genomes.The root fungal pathogen F. oxysporum secretes numerous effectors into the extracellular space, including Foa3 that is internalised by plant cells and suppresses molecular pattern-triggered defense responses. Tintor et al. performed a functional characterisation of this effector. Foa3 suppresses defense responses irrespective of whether the protein carries a secretory signal peptide or not, suggesting that Foa3 harbours an internalisation signal. Foa3 localizes to mobile subcellular structures of unknown identity, among other subcellular localizations. Foa3 can deliver an orthotospovirus avirulence protein-derived peptide into the cytosol, activating the matching resistance protein. Foa3 can also cause a strong suppression of pattern-triggered immune responses even in absence of the pathogen. This paper is an important contribution to the mystery of how fungal effectors translocate into host plant cells, a very timely research field that is critical to understand the full picture of effector biology and molecular and cellular plant-microbe interactions.F. oxysporum strains, the genes for the effectors Six3 (Avr2) and Six5 form a gene pair on the pathogenicity chromosome. Whilst it was known that Avr2 suppresses plant defence responses and is required for full pathogenicity, Six5’s role warranted further investigation. Using transgenic Arabidopsis lines expressing SIX5, Blekemolen et al. report that the effectors Avr2 and Six5 function together to expand the size exclusion limit of plasmodesmata via un unknown mechanism to enable cell-to-cell movement of the effectors Avr2, Six6 and Six8. The unique combined functions of the Avr2/Six5 pair pave the way to explore novel fungal virulence processes, and it will be valuable to explore whether similar combined effector functions exist in other plant-infecting microbes.In tomato-infecting Louet et al. propose an innovative and efficient way to tackle literature covering seminal research on plant pathogen effectors. Their biometric pipeline, coined HIPEs , selected 249 highly cited articles from the last two decades covering a wide variety of pathosystems. Countries, organizations, and journals were considered, along with the evolution of research trends, model molecules, and model organisms. HIPEs classified this dynamic scientific area into seven main Research Topics and 20 subtopics, with contrasting publication trends over time. Notably, HIPEs revealed that research on effectors from biotrophic and hemibiotrophic fungi is on the rise. Such biometric tools should be widely adopted by scientists to expertly mine the literature, identify trends and plan future research projects.How can secretomics help unravel the secrets of plant-microbe interactions?) tackled in vitro secretomics, exosomes, proteases, effectors and bioinformatics tools, as well as crop breeding for microbial pathogen resistance. The second collection (Secretomics: More Secrets to Unravel on Plant-Fungus Interactions) highlighted the importance of extracellular vesicles as an alternative secretion pathway to facilitate the exchange of secreted components in a bidirectional flow between the host and its pathogen. This third volume unlocks more secrets and shows that gaining knowledge on the intricacies of plant-fungus associations demands efficient literature reviews, sophisticated experimental designs, cutting-edge technical platforms, powerful bioinformatics tools, as well as cross-disciplinary collaborations.The collection of articles published in the first instalment of this Research Topic (DV wrote the first draft of the editorial. All corresponding authors edited the manuscript and approved the final version.


Cerebrovascular events remain a serious complication in patients undergoing transcatheter aortic valve implantation with an incidence of 2–3% at 30 days. While expanding TAVI to younger low-risk patients, prevention of periprocedural strokes becomes even more important. Different cerebral embolic protection devices have been tested but a clear clinical benefit has not been demonstrated in randomized trials. Due to the multifactorial aetiology with different predisposing factors, stroke prevention should include procedural and periprocedural strategies. This article aims to summarize different approaches and discuss open questions. Despite continuous improvements in outcomes after transcatheter aortic valve implantation (TAVI), periprocedural strokes remain a devastating complication with severe implications on quality of life, morbidity, and mortality , 2. Largballoon postdilatation. Postprocedural aspects included antithrombotic medication or new-onset atrial fibrillation , 10–14 .According to several studies, 91.5–98.3% of cerebrovascular events were of ischemic origin and most strokes became apparent within the first days following TAVI –18. HoweWhile expanding TAVI to younger and lower risk patients, procedural safety—including the prevention of periprocedural strokes in particular—becomes even more important. One approach to reduce procedural cerebrovascular events is to capture or deflect embolic debris from the brain-supplying arteries during TAVI. Several devices for cerebral embolic protection (CEP) have been designed and a significant increase of CEP utilization has recently been described for the United States  . Three dThe SentinelTM  is a CE-marked, FDA-approved, and widely commercially available CEP. It consists of a 6-French compatible dual-filter (140 μm pore size) intra-luminal embolic protection device introduced via the right radial, ulnar, or brachial artery. A proximal filter is positioned in the brachiocephalic artery and a distal filter is deployed in the left carotid artery for the time of the TAVI procedure see , as prevSeveral studies demonstrated a reduction in the total volume of new cerebral lesions, however, no significant changes in the number of patients with new lesions or the total number of new lesions were observed –25. In aThe left vertebral artery arising from the left subclavian artery remains unprotected with the SentinelTM. This may leave a relevant number of patients only partially protected against embolic debris and illustrates a potential limitation of a dual filter CEP-device .To gain additional evidence on the reduction of clinically apparent strokes with CEP during TAVI, the large-scale PROTECTED TAVR (NCT04149535) and British Heart Foundation PROTECT-TAVI (ISRCTN16665769) trials are underway and first results are expected to be presented soon.The TriGUARD3  is the latest iteration of a 8-French compatible self-positioning deflection filter system (115 μm pore size) that is introduced through the common femoral artery and deployed in the aortic arch see . By coveAfter evaluation of the earlier TriGuard™ CEP in the DEFLECT III trial , the resThe ProtEmbo Cerebral Protection System  is currently under clinical investigation. It consists of a 6-French compatible implantable aortic filter (pore size 60 μm) designed to cover all three major cerebral arteries in the aortic arch and deflect embolic debris away from the cerebral circulation into the descending aorta during TAVI. It is delivered via the left radial arteria, deployed at the aortic arch roof and retrieved at the end of the procedure see . A firstDespite promising results in smaller single-center analyses for CEP devices, trials have failed to decrease stroke rates in randomized controlled trials until now. Due to an unclear clinical benefit and additional economic constraints, widespread clinical adoption remains limited at current.The observation that a relevant number of strokes occur early after TAVI but not necessarily during the procedure itself , 15–18 aIn the absence of specific recommendations for TAVI, non-vitamin K antagonist oral anticoagulants (NOAC) or Vitamin K antagonists (VKA) are frequently switched to low-molecular weight heparin during diagnostic workup in patients with an indication for oral anticoagulation  and resumed after the procedure. Several trials demonstrated that uninterrupted anticoagulation throughout cardiovascular procedures, e.g., catheter ablation for atrial fibrillation, was safe and associated with a lower risk for bleeding or stroke , 33. FirTAVI procedures are performed after anticoagulation with unfractionated heparin to achieve a target activated clotting time of >250 s. At the end of the procedure, protamine is frequently given for heparin reversal to avoid bleeding complications. A recent non-randomized, single center analysis of 873 TAVI procedures found a significant reduction of the primary endpoint , of 3.2% after heparin reversal with protamine compared to 8.7% in the control group, driven by less bleeding complications . ImportaFollowing the procedure, sufficient antithrombotic therapies or oral anticoagulation aim to prevent ischemic events early and late after TAVI. However, in this vulnerable patient population, ischemic risk must be weighed against bleeding risk, particularly in the early postprocedural phase. Recently, several trials explored different therapeutic regimen in patients with and without an indication for oral anticoagulation due to atrial fibrillation, the latter of whom are at particular risk for cerebrovascular events during follow-up after TAVI.In general, oral anticoagulation prevents embolism of fibrin-rich thrombi which mainly occur in areas of low shear stress  while antiplatelet therapy is thought to prevent platelet-rich thrombi developed in areas of high shear stress  . AccordiIn the POPular TAVI trial aspirin alone was associated with a lower incidence of bleeding  and the composite of bleeding or thromboembolic events  at 1 year compared to aspirin plus clopidogrel administered for 3 months . In patiThe ATLANTIS  and the These results led to a de-escalation of antithrombotic regimen after TAVI in most heart teams and a corresponding update in the recent European guidelines on the management of valvular heart disease . HoweverIn summary, cerebrovascular events in patients undergoing TAVI remain a multifactorial phenomenon  with difBoth authors listed have made a substantial, direct, and intellectual contribution to the work, and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


The COVID-19 pandemic has brought new challenges to almost every aspect of parents’ and their children’s lives, posing an acute threat to the families’ quality of life (FQOL). This study had two aims: (1) to identify changes in family coping-strategy profiles among parents pre- and during the first COVID-19 lockdown and (2) to analyze interactions between the clusters of coping strategies pre-COVID with FQOL during the first lockdown. A sample of 253 parents (58.5% mothers) of children (3 to 18 yr old) completed the Family Pandemic Oriented Personal Evaluation Scales and the FQOL Scale about their family life pre- and during the COVID-19 lockdown. Four family coping-strategy clusters were found. Differences were found between those clusters pre- and during the first COVID-19 lockdown, with a high percentage of families using the positive appraisal strategy more often. Significant interactions were found between the family coping-strategy clusters pre-COVID-19 and the FQOL factors before and during the pandemic. Most families maintained their FQOL levels during the first lockdown. Close and frequent interactions between family members had relationships with positive emotions and significant effects on well-being. Results showed that positive cognitive appraisal was a protective factor against a significant decrease in FQOL during the first COVID-19 lockdown. The COVID-19 pandemic has disrupted economic stability, increased stress levels, and changed families’ daily routines worldwide . It has The COVID-19 pandemic transformed the dynamics of family life worldwide, and many parents found the situation difficult , 5. Govecoping as cognitive and behavioral strategies to manage external or internal demands caused by stressors. The techniques to deal with stress have been defined as coping strategies ).coping styles are traits suggesting inherent personality characteristics (clusters before the pandemic), whereas coping processes exhibit the dynamic interplay of person—or in our case, family—and environment and might explain the changes in coping profiles during the pandemic.In the terminology of the resiliency model of family adjustment and adaptation , parentsOur factor analysis revealed four family-strategy clusters both before and during the COVID-19 crisis, but the clusters changed between the two periods. We looked deeply at the differences between the four clusters before and during the pandemic. Not all the families in the same cluster before the pandemic were characterized under the same cluster during COVID-19. Interestingly, however, regardless of their pre-pandemic cluster, a high percentage of the families added the appraisal strategy during the pandemic. Positive coping strategies are postulated to mitigate the effects of stress on parenting. In this study, appraisal represented positive coping strategies emphasizing strength to overcome obstacles, reappraising, and making stressors more manageable.appraisal. Appraisal theory examines the process by which an individual’s subjective interpretation or evaluation of important events or situations elicits emotions. Hence, it is a person’s evaluation of events to determine their safety relative to their place in the environment. Coping ensues after the individual appraises the acute event. An individual uses coping strategies in one of two ways. Problem-focused coping focuses on situation-specific goals and allows a sense of mastery and control in working toward attaining those goals. Alternatively, emotion-focused coping involves positive reappraisal—cognitively reframing difficult thoughts in a positive manner ).Positive emotions, such as comfort, happiness, joy, love, and gratitude, can help maintain and improve mental health. However, given the positive emotions often experienced in interpersonal relationships, the current situation—which requires social distancing and more home time with family members—might explain the positive emotions parents and their children experienced. It may have helped them maintain their well-being, specifically in parenting and family-relations aspects. Comparing coping abilities among families in Cluster 3 with families in the other three clusters again strengthens understanding of the importance of positive appraisal. As presented in the Results section, Cluster 3 describes families that did not view the pandemic positively or as a chance to grow and develop. In this study’s terminology, embracing the challenges and treating them as opportunities  translatThis study allowed us to investigate how parents cope in a unique situation. When Israel instituted its first lockdown, parents were forced to cope with a previously unknown stressor. Because lockdowns were a tool implemented worldwide to contain the spread of COVID-19, it seemed important to examine their possible effects on families.Despite this study’s uniqueness and interesting results, it has limitations. The study sample was relatively homogeneous in demographic variables. As with surveys of this type, our sample was restricted to parents with Internet access and willingness to participate. Thus, the results cannot automatically be generalized to other families in Israel. Another limitation of the current study is that parents’ reports of pre-pandemic coping strategies might be prone to recall bias. Thus, changes in coping since the onset of the crisis might be underestimated. Research has suggested insights into retrospective questions during COVID-19: Respondents tend to remember their past as more similar to their present  when their experience or feeling of interest changed between the time points of interest (past) and data collection (present) .Despite their limitations, this study’s results have important implications. First, emotion-focused coping emerged as a protective factor that affected FQOL positively. Considering their positive effects on well-being and FQOL, emotion-focused coping strategies, specifically positive appraisal, might be a good target for interventions to help parents use more adaptive coping strategies than they had been using. Other implications relate to interactions among family members, their relationships with positive emotions, and their significant effect on well-being. Our research found that being together at home and closely interacting promote family cohesion and strengthen the family’s ability to cope in difficult times. Thus, parents should create more opportunities for family time in day-to-day regular times. We recommend that future studies examine families’ coping profiles relative to other family crises and compare them to this study’s findings. Further, our results regarding the positive effects on FQOL highlight the need for more studies to assess family coping strategies and the potential for positive growth in crises.Assessments of coping are necessary because results might help therapists identify parents’ needs and design counseling or training programs for stress reduction and coping strategies. Such intervention programs might promote the parents’ ability to adapt their coping strategies and maintain or even enhance aspects of FQOL during crises.During the COVID-19 pandemic, it is imperative to understand how families have coped with such a major disaster. Our study captured positive and negative impacts and found coping-strategy differences between before and during the first lockdown. Alongside decreased material well-being, we found no differences—or improved—FQOL in parenting and family relations during the pandemic. The ability to use positive cognitive appraisal was a protective factor against a significant decrease in FQOL during the pandemic.S1 Table(DOCX)Click here for additional data file.S2 Table(DOCX)Click here for additional data file.S3 Table(DOCX)Click here for additional data file.


Heart failure remains a leading cause of mortality and a major driver of health care utilization. Despite numerous medical advances in heart failure, associated hospitalizations continue to increase, owing largely to suboptimal outpatient management. Remote patient monitoring (RPM) aims to further address this current need in heart failure care by providing data to clinical teams to act pre-emptively to address clinical decompensation. However, to date, RPM approaches using noninvasive home-based patient sensors have failed to demonstrate clinical efficacy.The Novel Data Collection and Analytics Tools for Remote Patient Monitoring in Heart Failure (Nov-RPM-HF) Trial aims to address current noninvasive RPM limitations. Nov-RPM-HF will evaluate a clinician co-designed RPM platform using emerging data collection and presentation tools for heart failure management. These tools include a ballistocardiograph to monitor nocturnal patient biometrics, clinical alerts for abnormal biometrics, and longitudinal data presentation for clinician review.Nov-RPM-HF is a 100-patient single-center prospective trial, evaluating patients over 6 months. The outcomes will include patient adherence to data collection, patient/clinician-perceived utility of the RPM platform, medication changes including the titration of guideline-directed medical therapy to target doses, heart failure symptoms/performance status, and unplanned heart failure hospitalizations or emergency department visits.This prospective trial began enrollment in March 2020 and anticipates enrollment completion by June 2022, with trial completion by December 2022.This trial protocol aims to provide a systematic framework for the evaluation of heart failure RPM strategies, which are currently heavily used but seldom robustly studied. The trial results will help to inform the role of noninvasive RPM as a viable clinical management strategy in heart failure care.DERR1-10.2196/32873 Heart failure (HF) remains a leading driver of morbidity and mortality in the United States, affecting 6.5 million Americans . DespiteEffective HF care requires vigilance for indications of clinical HF decompensation. Failure to detect and manage these indicators can result in unplanned emergency department (ED) visits and hospitalizations. Although patients and care teams attempt to detect signs of impending decompensation with conventional techniques such as daily weight measurements, these approaches have not demonstrated consistent clinical efficacy .Optimal HF care also relies on maximizing guideline-directed medical therapies (GDMTs). Several pharmacotherapies such as renin-angiotensin-aldosterone system inhibitors and beta-blockers have demonstrated mortality benefit in patients with HF with reduced ejection fraction (HFrEF) ,9. HowevRemote patient monitoring (RPM) aims to address these gaps in current HF care. RPM is a strategy that allows care teams to monitor and manage patients outside of traditional in-person health care encounters. The strategy could enhance current efforts for more rapid medication titration and avoidance of clinical decompensation and unplanned acute care visits. RPM has demonstrated a reduction in HF hospitalizations, but only by using an invasive hemodynamic patient sensor (CardioMEMS) . RPM strThe field of noninvasive RPM continues to evolve, with recent advances in data collection and monitoring now demonstrating improved predictive power for clinical decompensation . HoweverThe Novel Diagnostic Tools for Remote Patient Monitoring in Heart Failure (Nov-RPM-HF) Trial aims to address these limitations through the design and evaluation of a novel RPM platform for HF management that incorporates these emerging data collection tools. The trial will evaluate the perceived utility of the RPM platform, its impact on timely GDMT optimization and medication changes, and its impact on unplanned ED visits and hospitalizations.The Nov-RPM-HF trial is a single-center prospective study of an RPM platform and its adoption, clinical utility, and ability to optimize GDMTs and reduce unplanned acute care events among patients with HFrEF. Specifically, the trial will evaluate patient adherence with passive and active data collection, patient-perceived usability and utility of the RPM platform to monitor their health status, clinician-perceived usability and utility of the RPM platform for HF management, clinical utility of the RPM clinical alerts, impact of RPM on medication changes and titration of HF GDMT, and impact of HF RPM on clinical outcomes .Full inclusion and exclusion criteria are summarized in Inclusion criteriaAge≥18 yearsHF (heart failure) hospitalization or emergency department visit in last 12 monthsHF with reduced ejection fraction: most recent left ventricular ejection fraction (LVEF) of <50% and at least 1 recorded LVEF of <40%New York Heart Association Functional Class II-IVSleeps in same bed ≥4 days per weekAmbulatoryWillingness to complete the required surveys, measurements, and study activitiesExclusion criteriaAdvanced HF therapies: inotrope therapy, left ventricular assist device or cardiac transplantationWearable defibrillator or other worn device that may affect ballistocardiogram measurementsEnd-stage renal disease on chronic dialysisMalignancy undergoing active therapyWeight >385 lbs at time of enrollmentLiving in a skilled nursing facility or other chronic care facilityPlanned major surgeries or procedures requiring hospitalization in next 6 monthsHospice care or life expectancy <1 yearPatients were prospectively screened and recruited from the Advanced Heart Failure clinic at the Washington University School of Medicine’s Division of Cardiology. This clinic specifically treats patients with HF, with a focus on implementation of GDMTs and evaluation for advanced therapies including mechanical circulatory assist devices and cardiac transplantation when indicated. The trial was approved by the institutional review board at Washington University for either written or phone-based informed consent. The trial began recruitment in March 2020.The trial was approved by the ethics review board of the Washington University Office of Ethics and Integrity, with all information for patient informed consent reviewed. The trial was deemed to be in equipoise with current standard of care for heart failure management.The RPM platform for the trial was provided by a third-party vendor, Myia Health . The platform consists of patient biometric sensors, a digital “Home Hub” tablet to aggregate data from the sensors and transmit to the vendor for analysis, and a web-based clinical interface for clinicians to review data. The clinical interface was co-designed with the advanced HF clinicians to incorporate clinician priorities in its design. To ensure that the RPM platform was optimally designed for clinician and patient needs, Myia conducted clinician and patient interviews (n=51), and incorporated their input into the design of the RPM platform . These iThe RPM platform :Patient biometric sensors: Sensors include a weight scale, BP cuff, and a ballistocardiograph. The ballistocardiograph is a pressure-based sensor that is placed under a patient’s bed mattress. It measures ballistic forces related to heart and lung movement to derive heart rate (HR), respiratory rate (RR), and other associated physiologic parameters. Importantly, the ballistocardiograph is always “on” and only requires the patient to lie in bed to collect data, thus minimizing the data collection burden for patients.Home Hub tablet: An Android (Google) LTE-enabled tablet loaded with the Myia application serves as a data aggregation and transmission point for collected vital sign sensor data. It also includes a user interface to solicit, collect, and transmit patient-reported outcomes.Clinical interface: The clinician interface displays sensor data for all patients currently enrolled in the trial. The interface includes a data visualization workspace that juxtaposes longitudinal health data  with event data  to aid in clinical management. Patient data is prioritized for clinical review using alerts. Alerts are customized based on patient-specific thresholds , with deviations outside normal range triggering an alert. Additionally, among patients on submaximal GDMTs, medication-specific alerts are included to allow for rapid HF medication up-titration.Following enrollment, study participants have the Home Hub and sensors shipped to their homes. Once the kit is delivered, the technical support team will reach out to assist with home monitoring and sensor setup.As part of the study, patients will take measurements daily from all study sensors. The first 7 days for each patient will be a run-in period where patient data is collected. If sufficient data is collected and transmitted, study participants will transition to the active management phase. Sufficient data is defined as transmission from both BP cuff/weight scale and ballistocardiograph sensors in at least 4 of the 7 days. If minimum requirements are not met, patients are continued in the run-in period for an additional week (up to 3 weeks maximum). Technical support will contact patients to determine if lack of transmission represents a technical issue versus nonadherence. If patients were unable to meet minimum data requirements after 3 weeks, then they were disenrolled from the study.Following run-in period completion, study participants will enter the 6-month active management phase of the study. A designated research nurse is responsible for daily monitoring of the RPM clinical interface. This includes monitoring the RPM clinical interface daily for clinical alerts, contacting patients to assess clinical status in response to alerts, and escalating to the patient’s HF cardiologist if clinical status warrants management changes. This research nurse will also be responsible for contacting study participants for issues with data transmission or poor adherence to patient data collection.On a monthly basis, enrolled patients will have their clinical data reviewed by a multidisciplinary team including a triaging nurse and an HF cardiologist. The purpose of these reviews is to assess participant’s clinical status and adherence to data transmissions, and to identify opportunities for optimized medical management, including maximizing GDMT. RPM platform monitoring is outlined in Several clinical monitoring alerts will be used prospectively during the management phase of the study. Each alert has default thresholds that are customizable to individual study participants. Absolute threshold alerts will be turned on by default in all patients, while GDMT alerts can be opted-in by the clinical team for patients deemed to be on submaximal GDMT. Default values are shown in Absolute thresholds alertsHigh and low thresholds for weight, blood pressure (BP), and heart rate (HR). Thresholds include both default absolute values and patient-specific deviation from baseline values.Weight>3 lbs over 1 day>5 lbs over 3 daysBPSystolic blood pressure (SBP)>200 mmHgSBP>180 mmHg each day for 3 consecutive daysSBP<80 mmHgHRHR<35 bpm average in 1 nightHR>150 bpmGuideline-directed medical therapy (GDMT) alertsThese alerts are generated for patients on submaximal GDMT. They are designed to permit rapid up-titration of GDMT, customized based on drug class.Beta-blockerHR>80 bpm (nightly average) and SBP>100 mmHg for 3 consecutive daysAngiotensin-converting enzyme inhibitor, angiotensin receptor blocker, angiotensin receptor neprolysin inhibtor, and mineralcorticoid receptor antagonistSBP>110 for 3 consecutive daysTrial outcomes were designed to both directly evaluate the perceived utility of the RPM platform and to assess its impact on clinical outcomes.active  and passive  sensor.Patient data collection adherence will be measured for all home BP cuff, scale, and ballistocardiograph sensors as percentage of days with data transmission from each device over the 6-month trial duration. “Minimally-useful data profile” is defined as the percentage of weeks with at least 4 days of data transmission from both an Patients’ assessment of the RPM platform utility and usability will be assessed through a series of surveys /angiotensin receptor blocker (ARB)/angiotensin receptor-neprilysin inhibitors (ARNIs), magnetic resonance angiographies (MRAs), hydralazine, nitrates, and loop diuretics. The distance to target dose will also be assessed for GDMT medications, beta-blocker, ACE/ARB/ARNI, and MRA drug classes. Based on previously established methodology , baselinStudy participants’ symptoms and performance status will be evaluated using the Kansas City Cardiomyopathy Questionnaire (KCCQ-12) at 0, 3, and 6 months , with abThe study’s primary clinical end point is HF hospitalizations. Secondary clinical events include other unplanned hospitalizations and ED visits. Clinical events will be obtained through monthly electronic health record review by the research team and with monthly patient surveys. All hospitalizations will be adjudicated by the clinical team as either HF or other unplanned hospitalizations. Clinical end points will be compared to those of matched controls.Patient medication changes and clinical events will be compared to 100 matched historical controls. Controls will be patients with HFrEF matched on an HF hospitalization in the past year, age within 5 years, sex, race, and comorbidities .t tests, and categorical variables will be assessed via chi-square tests.Statistical analysis for clinical end points will be in comparison with matched controls. For survey data, including RPM platform utility and patient symptom assessments, these will be evaluated for change over the trial’s 6-month duration. Continuous variables will be assessed via sample P<.001) [This trial is powered at 99% to assess for 50% more medication changes in the study arm compared to historical controls. We will use a type I error of 0.05, assuming Poisson distribution . This meP<.001) .This trial is powered at 84% to assess for a 6-point increase (SD 20) in KCCQ scores for trial participants over the trial duration. We will use a type I error of 0.05. This improvement in KCCQ scores was based on the Minnesota Living with Heart Failure symptom assessments improvements observed in the CHAMPION trial .Regarding HF hospitalizations, Nov-HF-RPM is underpowered for this end point. Power calculation for clinical HF events was conducted using the baseline event rates observed in the CHAMPION trial given similar inclusion criteria . Effect This prospective trial began enrollment in March 2020 and anticipates enrollment completion by June 2022, with trial completion by December 2022.Optimal HF care requires the ability to effectively monitor and treat impending clinical decompensation so as to prevent ED visits and hospitalizations. RPM aims to address the current gaps in outpatient clinical care. To date, the only RPM strategy using an invasive hemodynamic sensor (CardioMEMS) has demonstrated the ability to reduce HF hospitalizations . RPM strSeveral limitations of noninvasive RPM strategies are thought to contribute to the lack of demonstrated efficacy in these prior studies. These include poor patient adherence to monitoring, a lack of clinically actionable patient data and alerts, and a lack of clinical buy-in. The design of the Nov-RPM-HF study seeks to overcome these limitations.passive sensors for patient data collection that do not require direct patient action. The trial will also directly compare data collection adherence between passive  and active sensors . The ballistocardiograph adds a novel component to the home sensor collection, with the potential to augment adherence and provide continuous nightly data for HR and RR. To date, several studies using ballistocardiograph data-derived algorithms have demonstrated the ability to effectively classify compensated versus decompensated disease states in HF [Poor patient data collection adherence was observed in the majority of noninvasive RPM clinical trials and is thought to have contributed to neutral outcomes . Both paes in HF ,22. HoweA lack of clinically actionable RPM alerts has been commonly observed in prior noninvasive RPM studies. A systematic review of noninvasive RPM trial clinical alerts revealed patients were contacted only 39% (range 29%-52%) for follow-up and management changes . FurtherAlthough seldom measured in RPM clinical trials, adoption and buy-in from the clinical team is essential for maximal and effective RPM use. Factors affecting clinical adoption include perceived utility of RPM-provided patient data and integration into existing clinical workflows . Nov-RPMNov-RPM-HF will provide an important contribution to the field of RPM for patients with HFrEF. Its design attempts to overcome prior limitations of prior RPM strategies and determine its impact on patient engagement and satisfaction, clinical satisfaction, and HF medical optimization. Insights from the study will inform the future role of noninvasive RPM as a viable HF clinical management strategy.


Immunotherapy is a rapidly evolving treatment paradigm that holds promise to provide long-lasting survival benefits for patients with cancer. This promise, however, remains unfulfilled for the majority of patients with gastrointestinal (GI) cancers, as significant limitations in efficacy exist with immune checkpoint inhibitors (ICIs) in this disease group. A plethora of novel combination treatment strategies are currently being investigated in various clinical trials to make them more efficacious as our understanding of molecular mechanisms mediating resistance to immunotherapy advances. In this article, we summarize the current status of immune checkpoint blockade in GI cancers and discuss the biological rationales that underlie the emerging treatment strategies being tested in ongoing clinical trials in combination with ICIs. We also highlight the promising early results from these strategies and provide future perspectives on enhancing response to immunotherapy for patients with GI cancers. Gastrointestinal (GI) cancers collectively represent the most common cancer worldwide and the second leading cause of global cancer deaths. In the UBeyond conventional therapies, immune checkpoint blockade has now emerged as a new treatment paradigm across multiple solid tumors that could potentially provide long-lasting survival benefits.,5 HoweveTo make immunotherapy more efficacious in GI cancers, sound biological understanding of the primary and secondary resistance mechanisms to immunotherapy in this disease group will be necessary. Critical too will be the development of predictive companion diagnostic biomarkers to select patients for immunotherapy. In this article, we review the current status of ICIs in GI cancers and discuss the key biological mechanisms impeding immunotherapy efficacy in GI cancers together with the emerging novel strategies being employed in ongoing clinical studies in combination with ICIs to overcome resistance.The most promising results with ICIs in GI cancers are observed in patients with MSI high tumors. A single-arm, Phase II trial evaluated pembrolizumab, a programmed death 1 (PD1) inhibitor, as a second- or third-line agent in 41 advanced cancer patients . The objen = 7) of the patients achieved complete response and 62% (n = 52) achieved PR.), median PFS , and ORR  were observed in the atezolizumab plus bevacizumab arm.[Encouragingly, recent data are emerging to support combining PD1/PD-L1 blockade with anti-angiogenesis agents for better efficacy in patients with advanced HCC. In a recent Phase 1b trial of multikinase inhibitor lenvatinib plus pembrolizumab in patients with unresectable HCC, four patients achieved complete response (6.0%), 26 PR (38.8%), and 25 SD (37.3%). However,umab arm. Based onMounting an immune response to tumors by host is a multistep process and theoretically, any deficiency in this process could lead to tumor immune escape. Based onOne of the major roadblocks to the efficacy of ICIs in MSS GI cancers is that they are poorly immunogenic with a low tumor mutation burden (TMB) (< 50/genome). It is knOne particular approach to address low tumor antigenicity is utilizing a personalized neoantigen vaccination approach to augment the existing antitumor T cell responses, either alone or in combination with other strategies. Inhibiting DNA repair may also lead to an increase in neoantigen generation and expression by tumor cells and enhance recognition by the immune system.,36 SuppoStrategies to bypass traditional T cell activation through recognition of MHC: Ag complexes are also currently being evaluated to improve CR. This includes bi-specific antibodies that simultaneously bind to surface tumor-associated antigens and CD3 on T cells, leading to their activation and proliferation. Clinical trials are currently evaluating carcinoembryonic antigen (CEA)–T cell bi-specific (TCB) antibody directed toward CEA, a protein that is often overexpressed on the surface of CRC tumor cells.,42 NotabThe second molecular roadblock to ICIs in GI cancers is the deficient cancer antigen presentation through MHC downregulation. ConstituTargeting oncogenic pathways using kinase inhibitors may also increase MHC expression and antigen presentation. To this end, there is strong preclinical data to support that targeting MAPK pathway using MEK inhibitors increased tumor neo-antigen expression, intratumoral effector T cell infiltration, and synergy with PD1 blockade in CRC models.,51 NonetThe tumor microenvironment (TME), consisting both of adaptive and innate effectors, plays a vital role in determining response to immunotherapy. For instance, MSI high CRC tumors had increased enrichment of cytotoxic CD8 + T-cells, natural killer (NK) cells, Th1 helper T-cells, and a greater degree of Th17 T-cell activation in comparison to MSS counterparts. MoreoverModulation of the immune TME in order to reduce immunosuppressive mediators and enhance cytotoxic activity has long been proposed as a viable strategy to combine with ICIs. Currently, there are several trials investigating this approach in GI cancers. Inhibiting CD73 and CD39 is of particular interest. CD73 has a dual role in T-regulatory self-reinforcing autocrine stimulation as well as paracrine suppression of effector T-cell activity within the TME. Considerin vivo studies using colon adenocarcinoma mouse models have demonstrated a synergistic antitumor effect of anti-angiogenesis and PD1 blockade,[Targeting tumor angiogenesis may also reverse immunosuppressive TME to enhance ICIs. Beyond the direct antitumor effect of anti-angiogenesis agents, studies have suggested a synergistic relationship between anti-angiogenesis agents and ICIs.,69 Anti-blockade, lending blockade, Indeed, blockade,in vivo studies have shown that knockdown of PI3K in colon cancer models can lead to reduced MDSCs and decreased tumor growth.[n = 7; ORR 29%) and gastric cancer  in a Phase Ib study.[Interestingly, EGFR inhibitors were shown to induce favorable immune activation through increase in intratumoral cytotoxic T-cell activity and suppression of T-regulatory and MDSC function in preclinical models. Other kir growth.,81 Furthr growth. SupportiIb study. Lastly, Ib study.,85 TargeIb study. In direcIb study.Tumor-reactive T cells are often exhausted as a consequence of chronic TCR stimulation in the absence of co-stimulation that is characterized by unresponsiveness. During this time, different co-receptors become upregulated that correlates with the degree of exhaustion, which may differ between distinct TMEs. Thus, identifying appropriate co-receptors expressed by tumor infiltrating lymphocytes may be necessary for overcoming T cell exhaustion in addition to PD1 to enhance cytotoxic antitumor immune responses. To this end, LAG3, TIM-3, and CD38 are emerging targets . Previouin vivo metastatic PC models has demonstrated increase in activated cytotoxic T-cell activity, suppression of MDSCs, and significantly improved tumor-free survival. Although the mechanisms by which HDAC inhibition can result in immunomodulation have yet to be fully elucidated, recent preclinical data suggest that combination with ICI may be a promising avenue for enhancement of antitumor immune response.[Epigenetic modifiers hold potential to reprogram tumor as well as immunosuppressive cells in TME for therapeutic advantage. For example, through modification of histone and nonhistone proteins, histone deacetylase inhibitor (HDACi) has a wide range of effects that include induction of apoptosis, cell cycle inhibition, vascular function, and immunomodulation. The roleresponse.,99Considering the current status of immune checkpoint blockade in GI cancers, progress must be made in order to augment ICI efficacy. Beyond MSI status, and PD-L1 positivity, few other predictors of CR currently exist. As such, most current clinical trials do not employ patient selection strategies beyond these markers. A significant proportion of MSI high patients still demonstrate a lack of response to ICIs alone and in combination with other regimens. Greater understanding of the biological basis behind responders and nonresponders within MSI high patient populations may aid in determining which tumor markers and components of the TME play a pivotal role in rendering tumors sensitive or insensitive to ICIs. While this would be beneficial for expanding the subset of MSI high patients who benefit from ICIs, it may also expose molecular mediators in the MSI stable microenvironment that underlie the lack of response to ICIS.Elucidating differences in specific neoantigen epitope expression and their qualities is an exciting proposition. However, attempts to do this thus far have demonstrated that there are thousands of different neoantigens that may be expressed, and that only exceedingly few of these are consistently observed between different tumors even within the same cancer type. This beiThe current literature consistently revealed key immune-suppressing mediators in TME of GI cancers. Among these are immature DCs, MDSCs, TAMs, regulatory T-cells, and CAFs. Two distinct strategies could potentially be used to address these roadblocks. First, recruitment of new immune-activating mediators to the tumor site may aid in shifting the microenvironment balance in favor of responsiveness. Multiple trials are already testing this hypothesis clinically. Second, reprogramming already-present immune suppressive cells within the TME into immune-activating mediators may shift the balance of stimulating versus constraining components in favor of a more robust immune response.Among the most exciting combination strategies are those utilizing ICIs with the addition of immunomodulators such as LAG3 inhibitors, TIM3 inhibitors, and CD73 antibodies. A preponderance of preclinical data suggests that these approaches may act synergistically with immune checkpoint blockade. Therapeutic cancer antigen vaccines may still have a role in combination with other agents due to their potential for more efficient immune priming. Lastly, epigenetic modifiers have the potential to reprogram immunosuppressive cells in the TME into therapeutic advantage. However, this remains speculative at this juncture, and increased understanding of the role of different epigenetic modulators, their targets, and precise effects of these drugs on the immune TME will be necessary before their true potential is fully realized.The current status of immunotherapy in GI cancers reveals that efficacy has been largely limited to patients with MSI high tumors and a small subset of patients with MSS tumors. Thus far, no ICIs have been approved for patients with MSS pancreatic and CRCs, the two most common causes of GI cancer-related deaths in the USA. Although there are emerging treatment strategies to make immunotherapy more effective in GI cancers, the apparent lack of patient selection strategies beyond using PD-L1 and MSI status hampers progress in this field. Further molecular insight into the heterogeneity of tumor intrinsic as well as extrinsic mechanisms mediating resistance to ICIs will be key in making significant advances in enhancing response to ICIs in GI cancers.


Pulmonary surgery is an innovative discipline with increasing demands for minimally invasive techniques in complicated anatomical resections, warranting adequate preoperative imaging of relevant surgical anatomy to ensure safe and radical resection of target lesions. Over the recent years, the emergence of imaging techniques enabling three-dimensional reconstruction has exerted promising influence on pulmonary surgery, facilitating optimal surgical planning and easier identification of the spatial relationship between bronchovascular structures in the individual patient and aiding the safe resection of target pulmonary lesions. The goal of this mini-review is to provide an overview of three-dimensional computed tomography imaging within pulmonary surgery.The authors performed a targeted qualitative review of the literature to identify current trends and to provide better understanding of three-dimensional reconstruction within the boundaries of pulmonary surgery.Three-dimensional reconstructive techniques can be used for resectability assessment, identification of surgically relevant interindividual anatomic variance and may improve perioperative outcomes.Three-dimensional reconstruction using computed tomography imaging improves surgical planning and there is evidence that it results in shorter operative times, less intraoperative blood loss and lower rates of surgical conversion, as it can be applied both pre- and intraoperatively. Over the last decades, the surge of minimally invasive techniques has impacted pulmonary surgery, accelerating the development of less invasive approaches for anatomical resections, primarily for early detected cancerous lesions –3. With With emerging evidence of the benefits of increasingly smaller resections through minimally invasive approaches, the added potential complexity of these procedures poses an important challenge. They require precise knowledge of the individual patient anatomy regarding bronchovascular structures, while taking the effects of pulmonary deflation during surgery into account. This is especially true for segmental resections because of the individual variability at segmental levels. Innovations in imaging techniques might prove valuable in overcoming these challenges, as technological improvements regarding imaging modalities have provided surgeons with additional ways to prepare for individual cases. Mainly computed tomography (CT) based technologies offer three-dimensional (3D) reconstruction that creates many options for pre- and intraoperative planning that were previously unavailable. Compared to conventional 2D-imaging, they offer the advantage of improved spatial orientation and identification of surgically relevant structures and their interindividual variance.In this mini-review, we provide an overview of the clinical application of these techniques in the context of pulmonary surgery. We will not focus on the specific techniques for 3D reconstruction, such as volume rendering and maximum intensity projection, but describe the added clinical value of such techniques in general.The authors  performed a targeted qualitative review of the literature within the PubMed database (date: 25th of October 2022) to identify current trends and to provide better understanding of 3D reconstruction within the boundaries of pulmonary surgery. Key search words included terms related to 3D reconstruction and different surgical approaches for pulmonary surgery, including VATS, pneumonectomy, lobectomy, segmentectomy, etc. . The seaEarly-stage lung cancer is an important indication for pulmonary resection. To achieve adequate resection of a cancerous lesion, it is crucial that sufficient resection margins are respected. Multiple studies demonstrated that both lobectomy and segmentectomy are able to provide adequate resection margins, although the chance of local recurrence is increased in cases of segmentectomy with a margin to tumor size ratio <1 cm or if tumor size exceeded 2 cm , 12, 13.To date, many surgeons use traditional 2D CT imaging to estimate the resectability of a lesion and decide on operative approach. However, 3D-imaging using CT-based simulation techniques, sometimes assisted by artificial intelligence , can be The clinical efficacy and safety of preoperative 3D reconstruction in assessing resectability prior to anatomical sublobar resection is demonstrated by a recent study conducted by Hamada et al.  They shoAdditionally, preoperative knowledge regarding the histologic origin of a specific tumor, if available, may also influence surgical decision-making. In most instances, preoperative histological specimens are required to tissue-type a tumor and decide on the most fitting surgical resection. In this regard, 3D-reconstructive techniques might also be of added value. A recent study used 3D reconstruction to identify hallmarks suggestive of malignancy, such as the presence of a solid component, lobulation, vascular convergence, or an air cavity density, as well as nodule size . These rPulmonary bronchovascular patterns are diverse and constitute complex spatial configuration. Surgeons must be familiar with both the general and patient-specific anatomy of pulmonary bronchovascular structures to conduct anatomical (sublobar) resections safely and adequately. Multiple studies showed that by using preoperative 3D reconstruction it was possible to accurately identify up to 98% of surgically relevant and potentially complicating pulmonary artery branches, including anomalous or uncommon variations in vascular branching patterns. Thereby, 3D reconstruction facilitates surgical resections by avoiding blind dissection of vessels and increases surgeons confidence in their knowledge of the spatial relationship between the lesion and adjacent anatomical structures in the individual patient , 28–43.Adequate resectability assessment and enhanced identification of potentially complicating anatomical variants suggest improved perioperative outcome when 3D-reconstructive techniques are used in the preoperative work-up. Results from multiple, primarily retrospective, comparative studies in patients operated on for a variety of pulmonary diseases, confirm this hypothesis, although the quality of evidence is debatable due to their retrospective nature . In thesWhen comparing 3D-imaging to more other reconstructive techniques, such as 3D-printing, there is evidence that the use of 3D-printing has additional benefits regarding reduction of operative time, perioperative blood loss and conversion rates when compared to both 3D-imaging and conventional 2D-imaging, especially in more complex cases , 48.Besides its role in preoperative assessment, the use of 3D-reconstructive techniques during surgery has also been reported. Examples include the use of a tablet during surgery to display preoperatively constructed 3D images, with specific focus on pulmonary bronchovascular anatomy related to the target lesion. Several authors report that the reconstructions displayed on the tablet helped to identify important anatomic structures and their spatial relationship, while being able to review and manipulate them during surgery. This significantly benefitted their intraoperative understanding of the relevant surgical anatomy and enhanced their ability to safely perform anatomical resections , 50.Another example includes binocular stereo-navigation using 3D polarized glasses which displayed 3D-reconstructed images during surgery, to be used as an intraoperative navigation tool during VATS. This enabled easier and accurate identification of relevant bronchovascular structures, while achieving sufficient resection margins .Chen et al.  used 3D-The high-quality 3D reconstructions rendered by modern CT-imaging techniques might also possess educational value in obtaining informed consent from patients regarding the surgical procedure they are subjected to. Also, evidence suggests it might improve surgical residency training , 52, 53.Pulmonary surgery is an innovative discipline with increasing demands for minimally invasive techniques in complicated anatomical resections. Proper, usually CT-based, imaging to assess surgical anatomy in the individual patient during preoperative assessment is an important step in the preoperative work-up towards surgery. Therefore, sophisticated 3D-reconstructive techniques might positively influence individual patient outcomes. The accumulating evidence in favor of using 3D reconstruction over conventional 2D-imaging is expanding, with recent studies providing evidence of shorter operating time, more extensive lymph node dissection, reduced perioperative blood loss and lower conversion rates when using advanced 3D-reconstructive techniques both pre- and intraoperatively.Furthermore, it has been suggested that these techniques might also aid in estimating the chance of malignancy by identifying certain hallmarks of a suspicious nodule by 3D reconstruction, thereby improving preoperative planning and potentially reducing intraoperative uncertainty regarding the specific origin of a nodule, which is now often solved by either time-consuming frozen section sampling or surgical resection, which might prove redundant when postoperative histological analysis shows a benign lesion.Despite the limited comparative evidence, the perceived added value of 3D reconstruction is subjectively highlighted by most authors. In their opinion, 3D reconstruction resulted in a better preoperative understanding of relevant individual surgical anatomy and variations, which enabled accurate surgical planning and improved the ability to identify segmental and subsegmental borders. Furthermore, it prevented accidental injury to bronchovascular structures, improved intraoperative navigation, patient counseling and surgical training, it reduced the unnecessary exploration of surrounding structures during surgery and enabled better prediction of patients at risk of surgical conversion , 48, 54.An often-mentioned limitation to the use of 3D reconstruction in surgical planning is the added time constraints regarding processing time for visualizing relevant structures. However, most studies report that with recent advances in reconstructive software, the processing times have been reduced to minutes, rendering this argument invalid , 55–58. An important limitation to this review is related to the retrospective nature of most comparative studies regarding 3D reconstruction vs. conventional 2D-imaging, which makes it difficult to draw definitive conclusions regarding patient outcome due to the inherently increased risk of bias in these studies. An encouraging finding is the confirmation of the beneficial outcomes related to the application of 3D-imaging and reconstructive techniques, such as 3D-printing in a single prospective study . NeverthRegarding future research, we propose the next step in the validation of 3D-imaging in pulmonary surgery would be the conductance of a prospective, randomized-controlled trial for direct comparison of conventional 2D-imaging vs. 3D-reconstructive techniques to further elucidate the clinical potential of 3D reconstruction in preoperative assessment and investigate its influence on patient outcomes. Another important finding requiring further investigation concerns the indication that 3D reconstruction of pulmonary nodules might be helpful in risk prediction of malignancy . This isIn conclusion, evidence suggests a benefit of 3D reconstruction in pulmonary surgery by reducing operating times, intraoperative blood loss and lowering the rate of surgical conversion. It enables adequate surgical planning surgical, assessment of resection margins in oncological surgery and might be of added value in both residency training and patient education. By visualizing the complex spatial relationship between surgically relevant bronchovascular structures, it enables surgeons to perform minimally invasive and complex anatomical resections safely and adequately. Future research should focus on confirming these results in prospective clinical trials.


Doege Potter syndrome is a rare condition causing non-islet cell paraneoplastic hypoglycaemia associated with fibrous tumours, which can be both benign and malignant. The vast majority are solitary and located within the chest. Non-islet cell tumour-induced hypoglycaemia, as in Doege Potter syndrome, is quite rare and occurs around 4 times less often than islet cell-associated paraneoplastic hypoglycaemia. We present a case of Doege Potter syndrome with severe hypoglycaemia in conjunction with multiple recurrent fibrous tumours of the lung and pleura. Doege Potter syndrome is a rare condition in which affected patients suffer from non-islet cell paraneoplastic hypoglycaemia in conjunction with fibrous tumours. Doege Potter syndrome is a rare condition in which affected patients suffer from non-islet cell paraneoplastic hypoglycaemia in conjunction with fibrous tumours. Most often, these patients present with a solitary fibrous tumour (SFT), usually in the chest. We present a case of Doege Potter syndrome presenting as severe hypoglycaemia in conjunction with multiple recurrent fibrous tumours of the lung and pleura .This patient is an 81-year-old male with a history of insulin-dependent diabetes mellitus type 2 and recurrent SFTs of the chest who presented to us with 6 months of symptomatic, progressive hypoglycaemia and was ultimately diagnosed with Doege Potter syndrome. In 1989 and 2009, he underwent resection of benign SFTs in the right chest, both of which were via right thoracotomy. Final pathology for both resections demonstrated benign SFT. Following resection, routine postoperative surveillance demonstrated recurrence of suspected fibrous tumours. Due to his age and lack of symptoms, the pleural masses were actively monitored with annual computed tomography (CT) scans. Ten years following his last surgery, he developed increasing episodes of symptomatic hypoglycaemia despite a history of type II diabetes. Because of his progressive hypoglycaemia, he was started on oral prednisone to maintain euglycaemia. Repeat CT scan revealed continued growth of a right apical lung mass and several smaller pleural masses . PreoperFollowing surgery, the patient’s hypoglycaemia resolved. He was discharged home on postoperative day 8 and is currently doing well. Surveillance imaging has demonstrated a 14-mm nodule on the right hemidiaphragm, which has been unchanged in size over the last year and he remains asymptomatic.Doege Potter syndrome is defined as non-islet cell paraneoplastic hypoglycaemia associated with fibrous tumours. These tumours are usually solitary; however, our patient presented with multiple recurrent fibrous tumours of the lung and pleura. Non-islet cell tumour-induced hypoglycaemia, as in Doege Potter syndrome, is quite rare and occurs around 4 times less often than islet cell-associated paraneoplastic hypoglycaemia , 3. Thesen bloc resection [Evidence suggests that neoplastic non-islet cell tumour hypoglycaemia can be cured by complete esection . FollowiConflict of interest: none declared.


Bladder cancer is the most common malignant tumor of the urinary system. Bladder cancer stem cells (BCSCs) play key roles in tumor initiation, metastasis, relapse and drug-resistance. Investigation of BCSCs is of great value. On the basis of a review of normal bladder stem cells and universal cancer stem cells (CSCs), we summarize the origin of BCSCs, isolation and identification of CSCs from bladder cancer, signaling pathway of BCSCs, BCSCs targeted therapy, and relationship of BCSCs with non-muscle invasiveness and muscle invasiveness. This review aims to provide better elucidation about BCSCs, and provide constructive data for classification, prognosis, treatment and early intervention of bladder cancer. Cancer stem cells (CSCs) play an important role in tumor survival, proliferation, metastasis and recurrence. CSCs maintain the vitality of tumor cell populations through self-renewal and unlimited proliferation; the movement and migration capabilities of CSCs make tumor cell metastasis possible. These functions are considered to give rise to formation of heterogeneous tissue and high recurrence rates of tumor . At the Bladder cancer is one of the major global problems that need imperative solutions. It has typical clinical features such as high recurrence rate, high metastasis rate and prominent heterogeneity. In academia, it is generally believed that bladder cancer CSCs are most likely to be the original causes of clinical features and other complex biological behaviors of bladder cancer. Therefore, it is important to further study and reveal the mechanisms of CSCs in tumor behaviors such as bladder cancer recurrence and metastasis. This poses practical significance by providing possible new research directions and therapeutic targets as measures against high recurrence rate and high metastasis rate of bladder cancer.Bladder epithelium stores urine and provides a protective barrier to bladder from urine. Bladder epithelium can be divided into three cell layers based on degree of differentiation: basal layer, middle layer and umbrella cell layer. Basal layer is located between urothelial cells and lamina propria, composed of undifferentiated small cubic cells; umbrella cell layer is a large, flat cell layer on the surface; middle layer is composed of cuboid cells with sizes between basal cells and umbrella cells. When bladder mucosa is damaged by pathogens , stem cells in urothelium which are initially at rest phase can resume proliferation and provide repair for the damaged epithelium .Epithelial integrity of organ is maintained by regulation of proliferation and differentiation of stem cells. Although epithelium of certain organs (such as intestine) maintain the ability to regenerate and proliferate continuously, mammalian bladder can be transformed from an almost static state to a highly proliferative state under induction of epithelial damage. The mechanism of damage-induced regenerative response remains unclear. Shin et al. revealed that Hedgehog/Wnt feedback loop enhanced bladder epithelial stem cells regeneration and proliferation. Proliferative response induced by infection or injury of bladder was regulated by the signal feedback between urothelial basal cells and stromal cells located in underneath layer . UrothelHowever, specific location of bladder stem cells remains controversial. It is conventionally believed that undifferentiated urothelial cells are precursor cells of two other bladder epithelial cells; umbrella cells are the most differentiated bladder epithelial cells; and basal cell layer provides a perfect survival environment for stem cells, protecting stem cells from damage by toxic substances. Therefore, most researchers tend to believe that bladder stem cells are located in basal cell layer . In 2008p53/Rb/PTEN gene inactivation . This subpopulation of cells were proven to have strong proliferation and self-renewal ability  BCSCs were isolated by using CD44 splice isoform (CD44v6). Another experiment successfully isolated 67LR + CEACAM- BCSCs using the 67L-kDa laminin receptor and carcinoembryonic antigen-associated cell adhesion factor 6 (CEACAM6). . . In the in vitro small sphere formation assay and serial tumor transplantation using ALDH1A1 negative group as control, positive group was demonstrated to possess greater colony-forming ability and tumorigenicity. After shRNA was used to functionally knock down the ALDH1A1 gene, clonality and tumorigenicity of bladder cancer CSCs were reduced. More interestingly, ALDH1A1+ cells were found to be a subtype of CD44+ cells, suggesting that such cells may be the more primitive bladder cancer CSCs , of which SHH has the highest expression . HedgehoNotch signaling affects multiple processes in normal cell morphogenesis, including differentiation of pluripotent progenitors, apoptosis and cell proliferation. This pathway includes four receptors (Notch1 to Notch4) and five ligands, and involves in expression regulation of multiple target genes . ThroughThe Wnt signaling pathway is a complex network of proteins that function most commonly in embryonic development and cancer. This pathway is closely related to maintenance of stemness regulation in CSCs . The WntFollowing activation of the Wnt signaling pathway, Wnt binds to cell surface receptors FZD and LRP5/6, thereby triggering intracellular signaling. First, cytosolic protein Dsh is activated and the activated Dsh then combines with Axin and Frat1. Under resting conditions, Axin forms a complex with GSK-3β and APC, Frat1 mediates detachment of GSK-3β from Axin and this inhibits phosphorylation of β -catenin. After the non-phosphorylated β-catenin accumulates to a certain extent in cells, it is transported to the nucleus to activate target genes. Target genes of β-catenin include protooncogene c-myc, matrix lyase, fibroblast growth factor, epithelial cell growth factor and cyclin D1. The expression products of these genes can promote tumor development. Therefore, when tumorigenic β-catenin mutations present, they may lead to dysregulation of Wnt pathway in CSCs and thereby induce tumorigenic proliferation .Gene mutations activate the JAK-STAT signaling pathway and induce tumorigenesis. Studies have shown that the tumorigenicity of various CSCs is closely related to the activation of STAT3. In addition, IL-6 plays an important role in maintaining stemness of stem cells, and can allow conversion of non-CSCs into CSCs by regulating CSCs-associated OCT2, CD44 and SOX2 genes. Other studies have shown that the IL6/JAK/STAT3 signaling pathway maintains not only the plasticity of CSCs, but also stemness by activating the mTORC1-STAT3 signaling pathway. . TumorigThe high proliferative, invasive and metastatic capacity of bladder cancer may be associated with BCSCs. Resistance of bladder cancer to chemotherapy and radiotherapy is also commonly thought to be due to BCSCs. On this basis, it is important to investigate drug resistance mechanisms of BCSCs . Drug reABC transporters in stem cells, especially verapamil-sensitive ABCG2 proteins, are capable of pumping intracellular metabolites, drugs, and toxic substances out of cells. This serves as the basis for CSCs isolation by SP sorting method described previously . InvestiAcetaldehyde dehydrogenase (ALDH) is highly expressed in BCSCs . In a trChemoradiation causes reactive oxygen species to accumulate in cells, damage DNA and kill cells. To protect DNA from endogenous or exogenous reactive oxygen species, epithelial stem cells have a strong free radical scavenging system . Urothelin vitro by activating the expression of anti-apoptotic genes. These apoptotic genes include cFLIP/FLAME-1 and Bcl-xL . Interleukins have been shown to promote the survival and growth of tumor cells d Bcl-xL . High led Bcl-xL . Among td Bcl-xL .In conclusion, bladder cancer CSCs express many cytokines which render CSCs better tolerance to drug therapy and mediate tumor recurrence. Therefore, investigation and validation of molecular mechanisms involved in CSCs drug resistance are of great significance to establish accurate and effective treatment options.+ CSCs have higher CD47 expression level compared to subset of CD44−tumor cells. CD47 interacts with plasma membrane protein SIRPa which is mainly expressed in bone marrow cells ; this results in reduced immune cell activities and thus inhibition of macrophage phagocytosis (In vitro, blocking CD47 using monoclonal antibodies could induce macrophage phagocytosis in muscle invasive bladder cancer cells (Monoclonal antibodies targeting tumor specific antigen is the most effective anticancer treatment. Analyses using immunofluorescence and fluorescence-activated cell technology confirmed that CD47 is widely expressed in most urothelial carcinoma cells, and CD44ocytosis . In vitrer cells . Treatmeer cells . Li et aer cells . BCSCs a+ cells present in basal cell layer of normal urothelial and urothelial carcinoma (+ cells. Subsequently, by using serial xenograft models, they identified a subpopulation of tumor cells with expression of CD44 from freshly isolated human bladder transitional cell carcinoma. These CD44+ cells were 10–200 times higher than those of CD44−cells. Later, the authors investigated heterogeneity of different CD44+ bladder transitional cell carcinoma subpopulations and they detected a variety of self-renewal proteins in active form, such as nuclear Bmi-1, Stat3, and p-catenin. They also found that GIi1 gene expression activity was higher in 85% of the CD44+ tumor cells, suggesting that the GIi1 gene may be a important molecular target (Yang et al. found that CD44arcinoma . Chan etr target .CD47 may be the potential targets for cancer therapy. As mentioned above, bladder cancer CSCs may have high level of drug resistance. During the use of drugs, ways to avoid or minimize drug resistance are aspects that should not be overlooked in order to achieve therapeutic effects. On this basis, enhancement of drug specificity using bladder cancer CSCs-specific markers can significantly prevent tumor resistance. Unlike conventional radiotherapy, we expect that chemoradiotherapy and stem cell pathway small molecule inhibitors targeting CSCs will destroy tumors more accurately.Cancer stem cell theory was first discovered in human hematological malignancies and subsequently applied to other solid tumors. At present, experimental subjects using cells extracted from patient tumor specimens and genetically engineered mice greatly enhance our understandings on stem cell theory. However, classic stem cell theory has yet to achieve clinical success. Solid CSCs are usually isolated as single cells. However, compared to hematological malignancies, their cell formation requires cell-cell and cell-matrix interactions. Further, they largely require involvement of endothelial cells, fibroblasts and inflammatory cells in formation of tumor microenvironment; such conditions remain difficult to simulate. Regarding origin and production mechanisms of CSCs and their existence in solid tumor, there are no consensus conclusions yet and many unknowns remain to be discovered.There are currently no effective treatment for a variety of malignant tumors including bladder tumor, and most tumor prognosis are unsatisfactory. Theory of BCSCs has been proposed in recent years. There are many questions with regard to the theory remain to be solved, and a large number of studies are required prior to clinical application. During studies of BCSCs, it is of utmost importance to identify specific CSCs markers of bladder cancer, and to isolate and identify BCSCs with self-renewal and differentiation abilities. Findings of such studies can provide better elucidation about BCSCs, and provide constructive data for classification, prognosis, treatment and early intervention of the disease. We believe that diagnosis and treatment of bladder cancer will make great progresses in the near future with more in-depth understandings of BCSCs.


A potential benefit of electronic health records (EHRs) is that they could potentially save clinician time and improve documentation by auto-generating the history of present illness (HPI) in partnership with patients prior to the clinic visit. We developed an online patient portal called AEGIS  that systematically collects patient GI symptom information and then transforms the data into a narrative HPI that is available for physicians to review in the EHR prior to seeing the patient.This study aimed to compare whether use of an online GI symptom history taker called AEGIS improves physician-centric outcomes vs usual care.We conducted a pragmatic controlled trial among adults aged ≥18 years scheduled for a new patient visit at 4 GI clinics at an academic medical center. Patients who completed AEGIS were matched with controls in the intervention period who did not complete AEGIS as well as controls who underwent usual care in the pre-intervention period. Of note, the pre-intervention control group was formed as it was not subject to contamination bias, unlike for post-intervention controls. We then compared the following outcomes among groups: (1) documentation of alarm symptoms, (2) documentation of family history of GI malignancy, (3) number of follow-up visits in a 6-month period, (4) number of tests ordered in a 6-month period, and (5) charting time (difference between appointment time and time the encounter was closed). Multivariable regression models were used to adjust for potential confounding.P>.05).Of the 774 patients who were invited to complete AEGIS, 116 (15.0%) finished it prior to their visit. The 116 AEGIS patients were then matched with 343 and 102 controls in the pre- and post-intervention periods, respectively. There were no statistically significant differences among the groups for documentation of alarm symptoms and GI cancer family history, number of follow-up visits and ordered tests, or charting time (all Use of a validated online HPI-generation portal did not improve physician documentation or reduce workload. Given universal adoption of EHRs, further research examining how to optimally leverage patient portals for improving outcomes are needed. To facilitate communication between patients and physicians in electronic health record (EHR)–integrated environments, we developed an online patient portal  that uses a computer algorithm called Automated Evaluation of Gastrointestinal (GI) Symptoms (AEGIS) to systematically collect patients’ symptom information before the clinic visit. Once collected, the data are transformed into a full narrative history of present illness (HPI) that clinicians can review prior to meeting the patient. While our prior studies noted that AEGIS creates higher quality HPIs and collects more alarm features vs physicians ,2, we foWe performed a pragmatic controlled study among adults aged ≥18 years scheduled for a new patient visit at an academic GI teaching practice and 3 community-based GI clinics at Cedars-Sinai Medical Center. This study was approved by the Cedars-Sinai Institutional Review Board, Los Angeles, CA (Pro45243).During the intervention period , patients were invited via email to complete AEGIS via the MyGiHealth app 1 week prior to their visit. We describe AEGIS elsewhere , but in Once recruitment ceased, 5 resident physicians reviewed patient charts and collected outcomes data using a REDCap data abstraction sheet [P<.05 was considered significant in all analyses. For bivariate analyses, we used analysis of variance and chi-squared tests to compare continuous and categorical data, respectively. We also conducted multivariable regression analyses on our outcomes and included group assignment, patient age, sex, race/ethnicity, and clinic site as covariates when appropriate. Specifically, logistic regression analyses were performed on the AEGIS completion and documentation of alarm symptoms and GI cancer family history outcomes. We used linear regression analysis to compare charting time between the intervention and control groups. Lastly, numbers of follow-up visits and tests ordered within 6 months of the initial visit were compared using zero-inflated negative binomial and negative binomial regression models, respectively.Statistical analyses were performed using Stata 13.1 . A two-tailed Of the 774 patients invited to complete AEGIS (Patients who completed AEGIS (n=116) were matched with 343 patients from the pre-intervention period and 102 from the intervention period who did not complete AEGIS. In We discovered that uptake of AEGIS was low, as only 15% of patients accessed the online portal. Surprisingly, this rate was lower than that seen in our prior AEGIS trial 37%) focused on patient-centric outcomes 7% focuse-8 and th. Alternatively, given our pragmatic design, clinicians may not have reviewed the AEGIS report or incorporated it into their note for some patients. We also noted that the app and its computer-generated HPIs did not impact health care utilization or charting time. In short, we did not find that leveraging an online HPI-generation portal measurably improved physician-centric outcomes in this study.While AEGIS was built to enhance patient-physician communication by systematically collecting salient components of the history, one-time use of the app did not increase documentation of alarm symptoms or family history of GI malignancy in the initial note. This suggests that physicians in our study may adequately screen for and document relevant red flags and family historyOf note, we previously found that AEGIS collected more alarm features when compared to physicians . The disA limitation of our study was that we could not fully assess whether and how closely physicians reviewed the AEGIS reports in the EHR. While 40.5% of physicians’ notes for the intervention patients contained a portion of the AEGIS report, we do not know how rigorously they reviewed the report after copying it into their notes. On the other hand, for the remaining patients, it is possible that clinicians thoroughly read the AEGIS report in the EHR but chose to not copy and paste it into their official consultant notes. Development of novel, effective methods for alerting and assessing how clinicians use newly uploaded, app-generated data in the EHR and that maximize its use at the point of care are urgently needed. Another limitation was that AEGIS was administered as a one-time intervention; longitudinal use of the app for tracking symptom severity could have impacted outcomes such as numbers of follow-up visits and ordered tests. Notably, longitudinal symptom monitoring via a portal decreased emergency room visits and improved survival among patients with metastatic cancer ,10.In summary, we found that uptake of AEGIS was low, as less than 1 in 6 patients completed it before their visit. Moreover, one-time use of a carefully developed and validated patient-provider portal did not improve documentation of key elements of the note nor reduce clinician work burden. This is disappointing as it is well known that the EHR has greatly increased physician charting time ,12; our


Therefore, we adopted asanguineous priming in our clinical routine. However, optimizations inthe traditional circuit, if on the one hand reduce the consumption of blood products, onthe other, require the use of vacuum-assisted venous drainage (VAVD). VAVD is essentialto reduce the length of the circuit, to place the oxygenating system and the venousreservoir at the child patient's height and to optimize venous return. We read with highinterest the article “Impact of Vacuum-Assisted Venous Drainage on Forward Flow inSimulated Pediatric Cardiopulmonary Bypass Circuits Utilizing a Centrifugal ArterialPump Head”, by Guimarães et al. . The authors analyze the impact of VAVD on arterial pump flow in asimulated pediatric CPB circuit utilizing a centrifugal pump (CP) with an externalarterial filter. The study concluded that the use of VAVD reduces arterial flow when aCP is used as the main arterial pump. The reduction in forward arterial flow increasesas the vacuum level increases. The loss of forward flow is further reduced when thearterial filter purge line is kept in the recommended open position. The use of aminimally invasive extracorporeal circulation (MiECC) system would allow, in thiscontext, to maximize the benefits already obtained with the optimized CPB, removing andeliminating the use of VAVD, roller pumps and blood-air interface (BAI). In a study byKadner et al. , a total of 38pediatric patients underwent surgical interventions for a variety of congenital heartdiseases with MiECC. In these patients, MiECC perfusion was successfully performed inall patients (100%). Median patient age was 9.5 months (range 0.2-176 months) with amedian weight of 8.1 kg (range 2.3-49 kg). For both MiECC types, no system-relatedtechnical complications were found. MiECT can be performed using standard techniques forclosed and open cardiac procedures for the correction of a variety of malformations inneonates and children with good results and uneventful postoperative course.Minimally invasive extracorporeal technologies (MiECT) are in great expansion in theliterature and have an impact in adult cardiac surgery, however, a future challenge willbe to expand MiECT to pediatric cardiac surgery. In the context of pediatric MiECT,there are not enough studies in the literature on this topic, which seems a paradoxbecause the optimizations in cardiopulmonary bypass (CPB) are the essence on literatureand practice in the pediatric approach during cardiac surgery. In pediatric cardiacsurgery, body weight-adjusted miniaturized CPB circuits within a comprehensiveblood-sparing approach can reduce transfusion requirements. Haemodilution resulting frommixing the patient's blood with a CPB crystalloid solution may be reduced to the extentthat asanguineous priming becomes possible