Do underlying allergic respiratory diseases such as asthma and rhinitis predispose to a severe coronavirus (COVID-19) infection? We conducted this systematic review to map out and synthesize evidence of published literature.p = 0.08). The mortality rate significantly decreased in COVID-19-infected patients with asthma than patients without asthma .We searched five bibliographic databases for articles published between 1 January and 15 November 2020 using keywords: “COVID” AND “Allergic disease,” “Prognosis and COVID-19,” “SARS-CoV-2,” “Asthma,” “Allergic rhinitis.” We synthesized 32 eligible articles from a total of 11,376 articles retrieved from the search process. The profile of allergic respiratory conditions was identified, and only seven studies reported on the treatment administered. No significant difference was observed concerning the prevalence of COVID-19 in individuals with allergic asthma and those with non-allergic asthma (RR = 0.61, There is little evidence available on the role of asthma medications and risk factors influencing the prognostic outcomes for COVID-19 individuals with respiratory allergies, which invites further research. Respiratory allergy, which infers that IgE-mediated allergic reaction is the major underlying pathophysiology in the upper and lower airways, includes allergic rhinitis and asthma –3. In alThe chronic allergic disease is linked to the tissue remodeling process, and persistent inflammation with characteristic CD4 T helper 2 (Th2) polarization can impair the efficient antiviral immune response . In thatHowever, it is still unclear whether respiratory allergies such as asthma and rhinitis predispose one to rapid infection with COVID-19, or whether COVID-19 raises the risk of distressing respiratory allergies . In addiLikewise, there is limited published evidence on the prognostic outcomes for COVID-19 in individuals with respiratory allergies . One of Does underlying respiratory allergic disease increase risk of COVID-19 infection?What are the prognostic outcomes of COVID-19 infection in individuals with respiratory allergic diseases? Does Allergy medication affect the prognostics?To determine risk factors for COVID-19 and the prognostic outcome in patients with respiratory allergic conditions.This systematic review and meta-analysis were conducted and reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses  and MetaWe carried out a comprehensive search on PubMed/MEDLINE, Web of Science, Google Scholar, and EBSCO using a search strategy that was developed by two of our reviewers (AAES and BA). The search strategy contained medical subject headings (MeSH) and keywords that include “COVID” AND “Allergic disease,” “Prognosis and COVID-19,” “2019-nCoV,” “coronavirus,” “SARS-CoV-2,” “Asthma,” “Allergy,” “Allergic rhinitis,” and “COPD”. The time frame for the search process was between 1 January 2019 and 15 November 2020.The database retrieved from the search process was reviewed for the removal of duplicates by AAES. The initial search process was conducted in June 2020 and thereafter, another search was conducted 15 November 2020. Two other authors (AS and AH) independently carried out the title and abstract screening of the articles in the first database while AAES and RA independently screened the newly retrieved database. To ensure that the methodological rigor is maintained during the screening process, NBHD independently reviewed the database after the title and abstract screening has been carried out. Lastly, full text of identified eligible studies from the title and abstract screening process were evaluated to determine articles were finally selected for data synthesis.The titles and abstracts were screened and evaluated for selection into the study using our eligibility criteria which included the population , exposure , comparison , and outcomes (risk factors for COVID-19 and prognostic outcomes) (PECO) framework. To suit the context of our study, we replaced I (Intervention) in the usual PICO with E (exposures). In addition to the PECO inclusion criteria, only peer-reviewed published articles irrespective of language were included. Study designs of articles selected for further review and synthesis included case reports, case series, case-control, cross-sectional, cohort studies, and randomized control trials. Primary articles deemed eligible were also identified from the results section of systematic reviews in the database and selected for further review in our study. Articles were excluded if they involved other types of allergies  and articles .Two reviewers independently evaluated the quality of the eligible articles using the appropriate quality assessment tools for each study design of these articles. The NIH Quality Assessment Tool for observational studies  was usedThe data extraction process was done according to the list of items detailed in the design in a data extraction rubric. The data extracted include author, year of publication, geographical setting, study objectives, study design, study population such as respiratory allergic patients, sample size, treatment for COVID-19 and respiratory allergy, and treatment outcomes/useful statistical findings in the study. There were no scenarios of missing information or difficulty with the retrieval of full text for eligible articles. The PRISMA flow diagram . To further quantitatively determine the prognosis of COVID-19 in patients with respiratory diseases, we carried out a meta-analysis to report point estimates and the confidence interval. The meta-analysis was performed using a random effects model because of heterogeneity in the eligible studies that were synthesized. Heterogeneity of individual studies was evaluated using the The literature search retrieved 11,376 articles and 4541 duplicate studies were removed. After screening of titles and abstracts of the total 6835 articles after duplicates have been removed, we excluded 6487 studies that were not relevant to our inclusion criteria. We further conducted a full-text screening of the remaining 348 articles and, this resulted in the identification of 32 studies as eligible for inclusion in our systematic review , and this pooled result was homogenous  as illustrated in Fig. P < 0.136) as displayed in Fig. The prevalence of asthma in COVID-19 patients more than 11 years old was reported in 21 studies with 40,422 COVID-19 patients, under random effect model, the overall prevalence of asthma was 9.5% of COVID-19 patients with 95%, CI = 0.063, 0.128, P < 0.001), under the random effect model. the pooled result was heterogeneous  , under the random effect model. the pooled result was heterogeneous  . There is no significant difference in associated between COVID-19 with allergic asthma and non-allergic asthma . These pooled results were homogenous   studies with 7880 COVID-19 patients reported that the mean duration of hospitalization time in COVID-19 patients was . The pooled results for mortality rate and hospitalization time for COVID-19 infection in asthmatic patients were homogenous as presented in Fig. The pooled effect estimate showed that hospitalization time significantly increased with asthmatic patients more than non-asthmatic patient . Third, there is no detailed information on asthma severity, systemic antihistamines, leukotriene antagonists, and allergen immunotherapy displayed in the identified studies which keep us from further conclusions about their role in COVID-19 prognosis. Fourth, the pooled results of the prevalence of allergic rhinitis and asthma between COVID-19 patients were heterogenous. This might be related to methodological discrepancies in the sampling criteria and study design across the studies included in this part of the analysis.p = 0.04). Our study findings are similar to results from a previously published meta-analysis which reported the risk of mortality in patients with COVID-19 with asthma was  [I2 = 0%; p = 0.79). Among the four included studies in the current analysis, Desir et al. weighted 45.4%, noted that the prevalence of asthma as a comorbidity in severe COVID-19 seems to be parallel to that of coexistent conditions such as hypertension, diabetes, and hyperlipidemia.Regarding the outcome of COVID-19 infection in asthmatics patients, the pooled effect estimate showed that mortality rate was significantly reduced by 30% in COVID-19 patients with asthma than in patients without asthma  . Their r = 0.24)  . Our finding could be clarified by the fact that the symptoms of asthma are exacerbated by respiratory viral infections and the management of asthma becomes more complicated during the COVID-19 pandemic [The hospitalization time significantly increased with asthmatic patients more than non-asthmatic patient  . There wBased on current findings, there was little evidence on therapeutic management of respiratory allergic patients infected with COVID-19 and the impact on prognostic outcomes. Consequently, it is critical that asthmatic patients should continue to administer medications prescribed to maintain asthma control regularly, in particular, ICS, long-acting bronchodilators, antileukotrienes drugs to avoid complications as increased hospitalization time. Further investigation is needed to determine the role of asthma medications and immunotherapy in the outcome of COVID-19 infection in asthmatic patients. In addition, the association of severe COVID-19 with other risk factors in asthmatic patients should be the topic of future studies.


Biomaterials intentionally designed to support the expansion, differentiation, and three-dimensional (3D) culture of induced-pluripotent stem cells (iPSCs) may pave the way to cell-based therapies for chronic respiratory diseases. These conditions are endured by millions of people worldwide and represent a significant cause of morbidity and mortality. Currently, there are no effective treatments for the majority of advanced lung diseases and lung transplantation remains the only hope for many chronically ill patients. Key opinion leaders speculate that the novel coronavirus, COVID-19, may lead to long-term lung damage, further exacerbating the need for regenerative therapies. New strategies for regenerative cell-based therapies harness the differentiation capability of human iPSCs for studying pulmonary disease pathogenesis and treatment. Excitingly, biomaterials are a cell culture platform that can be precisely designed to direct stem cell differentiation. Here, we present a closer look at the state-of-the-art of iPSC differentiation for pulmonary engineering, offer evidence supporting the power of biomaterials to improve stem cell differentiation, and discuss our perspective on the potential for tissue-informed biomaterials to transform pulmonary regenerative medicine. DespiteRespiratory diseases present with significant heterogeneity among patients, creating considerable variability in disease onset, severity, and progression . PatientAnimal models are widely used to study lung development and disease pathology. Murine models, for example, have been fundamental in examining physiological processes such as branching morphogenesis, which develops lung architecture and tubular structures . Neverthin vitro alternative to animal models due to their ability to replicate in vivo cell morphology, physiology, and functionality  in the 2D condition and were a closer match to primary MSC than the 3D differentiated cells. The cells differentiated in 3D had a notable upregulation of genes related to the cardiovascular system and neurogenesis . The combination that produced the highest barrier function as measured by trans-epithelial electrical resistance (TEER) was dECM supplemented with laminin . In anotogenesis . These rCurrently, iPSC differentiation protocols rely extensively on natural, xenogenic materials such as Geltrex and Matrigel, which are basement membrane extracts rich in laminin-111, collagen IV, entactin, and perlecan . These eTissue-informed engineering strategies are a bottom-up approach to engineering materials meant to elicit specific cellular responses . First, 10RGDS (replicating fibronectin-binding sites) enhanced viability of iPSCs and allowed for differentiation into neural progenitor cells (NPCs) when cultured in 3D over 1 week  cells, a progenitor cell capable of differentiation into alveolar epithelial type I (ATI) cells, the cells lining the gas exchange surfaces of the lung. This research demonstrated that incorporation of two short peptide sequences that bind β1-class integrins (0.2 mM YIGSR and 0.1 mM RGDS) supported production of surfactant protein c, that is, maintained the functionality of ATII cells within PLCS for up to 21 days, in contrast to unembedded controls that only survive ~7 days in culture  to fibrotic ranges (E = 13.4 ± 0.82 kPa). These stiffened hydrogels induced a significant increase in the expression of myofibroblast transgenes within primary murine fibroblasts (Tuning the intrinsic and extrinsic properties of biomaterials using a tissue-informed approach has the potential to pave the way for a transformation in pulmonary regenerative medicine. Although there are currently fewer examples, engineered biomaterials have been incorporated into pulmonary medical research platforms for tissue regeneration and disease modeling. Bailey et al. systematically evaluated PEG-based hydrogels for supporting extended  culture . In a reroblasts . Likewisroblasts . These 3in vitro models of patient-specific disease and treatment (It is exciting to imagine a future where tissue-informed biomaterials can incorporate and release biomolecules to sequentially guide stem cell differentiation pathways such as integrin-binding peptides, cytokines, or small molecules , 83. Thireatment , 86. CurThe number of persons affected by chronic respiratory disease worldwide has grown significantly in the last three decades. The COVID-19 pandemic has provided clinical data showing pulmonary fibrosis in those that survive the infection , 87. It The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author/s.DC, CS, AR, and CM worked together to conceptualize the content of this perspective. CS and AR wrote the current strategies for modeling human lung development and regeneration section. DC and CM wrote the Opportunities for Tissue-Informed Biomaterials to Advance Pulmonary Regenerative Medicine section, and conceptualized and designed 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.


In patients with advanced non–small-cell lung cancer (aNSCLC), tumor mutational burden (TMB) may vary by genomic ancestry; however, its impact on treatment outcomes is unclear. This retrospective, observational study describes treatment patterns of patients with aNSCLC by genomic ancestry and electronic health record (EHR)-reported race and/or ethnicity and evaluates differences in TMB, cancer immunotherapy (CIT) access, and treatment outcomes across racial and ancestral groups.Patients diagnosed with aNSCLC after January 1, 2011, were selected from a real-world deidentified clinicogenomics database and EHR-derived database; continuously enrolled patients were evaluated. Race and/or ethnicity was recorded using variables from the EHR database; genomic ancestry was classified by single-nucleotide polymorphisms on a next-generation sequencing panel. A threshold of 16 mutations per megabase was used to categorize TMB status.P < .001); patients of African ancestry had the highest median TMB . In patients who had received CIT, high TMB was associated with improved overall survival compared with low TMB  across genomic ancestral groups.Of 59,559 patients in the EHR-derived database and 7,548 patients in the clinicogenomics database, 35,016 (58.8%) and 4,392 (58.2%) were continuously enrolled, respectively. CIT use was similar across EHR-reported race groups, ranging from 34.4% to 37.3% for non-Hispanic Asian and non-Hispanic Black patients, respectively. TMB levels varied significantly across ancestry groups (These results suggest that equitable access to next-generation sequencing may improve aNSCLC outcome disparities in racially and ancestrally diverse populations. However, we found differences in TMB on the basis of genomic ancestry, with patients of African ancestry having significantly higher median TMB scores (8.75 mutations/megabase) than patients of other ancestries. Across all ancestral groups, high TMB was predictive of improved overall survival in patients who received CIT.RelevanceInequitable access to next-generation sequencing testing has been reported previously; our results suggest that ensuring equal access to testing and CIT across racially and ancestrally diverse populations may improve outcome disparities in patients with advanced non–small-cell lung cancer.6 Generally, African American patients have disproportionately higher NSCLC incidence rates and worse outcomes compared with White patients.9 Multiple factors contribute to racial disparities in the incidence and survival of patients with NSCLC.11 Frequently, these differences are attributed to social determinants, such as differing smoking habits and access to and quality of care.12 Retrospective cohort studies have reported that lower socioeconomic status is an independent prognostic factor for poor survival in patients with early or advanced NSCLC (aNSCLC).14The overall prognosis for NSCLC remains poor, and prognostic factors associated with shorter survival include sex, race, and smoking status.16 Variations in biologic drivers may also contribute to outcomes; recent studies have reported that the genomic profile of several cancers, including NCSLC, vary by race and ethnicity. This supports the need for greater understanding of the intersection between social determinants of health and biologic drivers in treatment disparities in NSCLC.Although studies have shown that African American patients are overall less likely to receive treatment, when treatment is controlled for, survival outcomes are similar across racial and ethnic groups.17 High TMB was predictive of better outcomes in patients with aNSCLC treated with CIT, compared with those who had high TMB but did not receive CIT.20 As with other genetic biomarkers and targetable mutations, racial differences in TMB have been reported.22 Although differences in TMB levels have been described in NSCLC, the impact on treatment outcomes by ancestral composition has not been evaluated.The prognosis for patients with NSCLC has improved because of emerging therapies, including cancer immunotherapy (CIT), and increased understanding of disease drivers. Tumor mutational burden (TMB) is a biomarker that may predict response to CIT.The objectives of this study were to describe the characteristics and treatment patterns of patients with aNSCLC by genomic ancestry and electronic health record (EHR)-reported race and/or ethnicity and to explore potential differences in TMB and disparities in the access to CIT and treatment outcomes across genomic ancestral groups. We also sought to assess the degree of concordance between genomic ancestry and EHR-reported race and/or ethnicity.This retrospective, observational study used secondary data evaluating outcomes of patients diagnosed with aNSCLC between January 1, 2011, and March 31, 2020, who were selected from the nationwide (US-based) deidentified Flatiron Health (FH)-Foundation Medicine Inc (FMI)-linked clinicogenomics database (CGDB) and FH EHR-derived database. Patients included in the FH-FMI aNSCLC CGDB had undergone comprehensive genomic profiling (CGP) by FMI at any point. The deidentified data originated from approximately 280 US cancer clinics (≈800 sites of care). Retrospective longitudinal clinical data were derived from EHR data, comprising patient-level structured and unstructured data, curated via technology-enabled abstraction, and linked to genomic data derived from FMI CGP tests in the FH-FMI CGDB by deidentified, deterministic matching.25 To date, more than 400,000 samples have been sequenced from patients across the United States. The majority of patients in the database were from community oncology settings, but relative community or academic proportions may vary depending on study cohort.Genomic alterations were identified via CGP of > 300 cancer-related genes on FMI's next-generation sequencing (NGS)-based FoundationOne panel.Patients who met specific criteria in the aNSCLC FH database and FMI-linked CGDB were included in cohort 1 and cohort 2, respectively. Cohort 3 and cohort 4 comprised patients from cohorts 1 and 2, respectively, who were continuously enrolled in the FH network, defined as no visit gap of > 90 days from date of aNSCLC diagnosis to death or last visit. Cohorts 3 and 4 were used for the main analyses as this allowed for appropriate classification of a patient's line of therapy . Detailed inclusion criteria for the four analytic cohorts are described in the Data Supplement.24 Briefly, approximately 40,000 single-nucleotide polymorphisms (SNPs) across multiple baitsets (exact number of SNPs may vary by baitset) were used to classify patients into ancestral groups using a principal component analysis with the publicly available 1000 Genomes data as the reference genome. TMB status was categorized as high or low using a threshold of 16 mutations per megabase (mut/Mb). A single, fixed TMB threshold has not yet been defined, and different TMB thresholds have been used in previous studies.28 Patients with missing ancestry and/or TMB results were excluded from analysis.Patients from the FH database (cohort 1) were categorized into the following groups using the race and ethnicity variables provided: non-Hispanic White, non-Hispanic Black, non-Hispanic Asian, Hispanic or Latino, other non-Hispanic (ethnicity not recorded as Hispanic or Latino and race recorded as Other), or unknown (both race and ethnicity were recorded as null). For the CGDB cohort (cohort 2), a single race and/or ethnicity variable was provided by FH . These variables were used for EHR-reported race comparisons. Derivation of genomic ancestry  has been described previously by FMI.The primary outcome was overall survival (OS). OS was defined as the time from the date of advanced diagnosis until death; however, patients did not enter the risk set until their FMI report date to account for the immortal time bias that exists in the database. As month and year of death were provided, the date of death was imputed to the 15th of the month for all patients with a death date recorded.2 analysis for categorical variables were used to summarize the demographic and clinical characteristics for the different cohorts.Analysis of variance for continuous variables and χFor analysis of CIT use, the first LOT that included any CIT  was considered the index CIT. The duration of CIT was calculated using time-to-event analysis (Kaplan-Meier method). Two calculations were used: overall CIT duration and CIT duration of a given LOT. Overall CIT duration was determined using the time to last administration regardless of changes in other treatments as long as CIT was given continuously, to allow for treatment with CIT through multiple lines. CIT duration of a given LOT was determined using the date of first administration of CIT after a given start date, until there was a treatment switch, gap in treatment, or death, whichever occurred first.Event-free survival estimates were generated for cohorts 2 and 4. The association between TMB and OS was estimated using a series of univariate and multivariate Cox proportional hazards models using the advanced diagnosis date as the index date with delayed entry into the cohort at the FMI report date to account for the left-truncated nature of the data set. The assumption of proportional hazards was tested using the Schoenfeld residuals. Multivariate models used in this study are described in the Data Supplement. Analyses were further stratified by genomic ancestry and use of CIT at any point after advanced diagnosis date. Additional subgroup analysis included CIT-treated patients only.A total of 59,559 patients with aNSCLC were selected from the FH EHR-derived database (cohort 1); 67.2%  identified as non-Hispanic White, 8.4%  as non-Hispanic Black, 2.6%  as non-Hispanic Asian, 3.3%  as Hispanic, 8.2%  as non-Hispanic other, and 10.5%  as unknown. Smoking was less prevalent in non-Hispanic Asian patients (50.2%) compared with > 80% in non-Hispanic White, non-Hispanic Black, and non-Hispanic other populations. The prevalence of stage IV aNSCLC at diagnosis was highest in non-Hispanic Asian patients (70.5%) followed by 69.0%-60.9% in all other ethnic groups. Median duration of follow-up was longest in non-Hispanic Asian patients (431 days) versus 205-313 days in other ethnic groups.A total of 7,548 patients were included from the FH-FMI–linked CGDB (cohort 2). The CGDB provides EHR-reported race information; ethnicity was unavailable. Genomic ancestry distribution was 71.4%  European, 6.6% (n = 501) African, 4.3% (n = 326) American, 3.7% (n = 282) Asian, and 13.9%  unknown. A high degree of concordance was seen between EHR-reported race and genomic ancestry , 35,016 (58.8%) were continuously enrolled until death or end of study (cohort 3), and from the CGDB (cohort 2), 4,392 (58.2%) were continuously enrolled (cohort 4). The continuous enrollment criteria led to the exclusion of 5,990 and 1,881 patients who received CIT in the EHR-derived database and CGDB, respectively. Continuously enrolled patients in the CGDB (cohort 4) were more likely to be White, male, and stage IV at diagnosis compared with patients who were not continuously enrolled , there was no difference in the prevalence of CIT use on the basis of EHR-reported race. CIT use ranged from 34.4% in non-Hispanic Asian patients to 37.3% in non-Hispanic Black, Hispanic, and non-Hispanic other patients Table . The oveP < .001, Data Supplement).In continuously enrolled patients with aNSCLC in the CGDB (cohort 4), 13.8% (n = 605) of patients' samples were classified as high TMB and 71.1%  as low TMB on the basis of the 16-mut/Mb threshold. TMB data were unavailable or missing for 15.2% (n = 666) of patients in cohort 4. TMB status was not associated with any patient characteristics except smoking. The high-TMB group was composed of an increased proportion of patients who smoked (Data Supplement). In addition, there was no difference in the time from advanced diagnosis to FMI test on the basis of TMB status. Across all genomic ancestries, patients with a history of smoking had significantly higher TMB scores when compared with patients with no smoking history (P < .001), and among patients with a history of smoking, those of African ancestry had significantly higher TMB scores (Data Supplement).Patients of African ancestry had the highest median TMB level , and patients of Asian ancestry had the lowest median TMB level  Fig . High TMv 5.13 months; 95% CI, 4.47 to 6.47 for no CIT) and low-TMB  groups.In patients who had ever received CIT, high TMB was associated with improved median OS  compared with low TMB . Across all genomic ancestral groups, patients with a history of smoking had significantly higher TMB scores than those who had never smoked. Previous studies have also demonstrated that smoking is generally associated with higher TMB levels, although the underlying cause is unknown.32 In this study, median TMB scores across all genomic ancestral groups were lower than the 16-mut/Mb threshold for high TMB. Although a single, fixed TMB threshold has not yet been defined, a TMB threshold of ≥ 10 mut/Mb has been used for patients with NSCLC and established as an indicator for enhanced response to CIT.28 These results were consistent when a 10-mut/Mb threshold was used; however, because of the reduced response to CIT, the observed differences in OS between high- and low-TMB groups were less pronounced (Data Supplement).Differences in TMB on the basis of genomic ancestry were observed; patients of African ancestry had significantly higher TMB scores , whereas lower TMB scores were observed in patients of Asian ancestry . These results are consistent with a previous study in prostate cancer that demonstrated elevated TMB in patients of African ancestry.EGFR mutations in this ancestral group, which renders them suitable candidates for first-line treatment with tyrosine kinase inhibitors rather than CIT.33 Treatment with CIT improved OS regardless of TMB status. For patients treated with CIT, TMB status was predictive of improved OS across all genomic ancestral groups with a longer OS observed for high-TMB versus low-TMB groups. However, for patients who did not receive CIT, OS was similar between TMB groups. Additionally, OS was shorter in non–CIT-treated patients than has been previously reported, which may suggest that FMI-tested patients had a poorer prognosis compared with the broader NSCLC population.36 The median time from advanced diagnosis to FMI NGS testing for continuously enrolled patients in the CGDB ranged from 29 to 122 days, suggesting that some patients may undergo NGS testing later in the course of treatment. Patients who had undergone NGS testing may have more complex or advanced cancer, which may be reflected by the shorter OS observed in this study. It is likely that this discrepancy in OS will change over time as NGS testing becomes more widely incorporated into routine clinical care in the first-line setting.37CIT use was not found to vary significantly by EHR-reported race or genomic ancestry, with similar results observed across patient cohorts. However, CIT use was numerically lower for patients of Asian ancestry, who tended to receive CIT in later lines of therapy. This may be attributed to the higher prevalence of A limitation of this study is the lack of racial and ancestral diversity in the study population. Approximately 70% of patients identified as non-Hispanic White (cohort 1) or were of European ancestry (cohort 2). In addition, EHR-reported race was highly correlated with genomic ancestry (as defined by FMI). However, capture of EHR-reported race (self or physician reported) was limited to a few predefined categories, whereas genomic ancestry was on the basis of a small number of SNPs; neither method accounts for the influence of genetic admixture. The limited race and ethnicity designations in this real-world database may have increased the potential for missing data. Similarly, the requirement of NGS/TMB testing in the CGDB may introduce selection bias for those with access to, and under the care of, physicians with distinct practice patterns; thus, patients may not be fully representative of the overall aNSCLC population. Engagement with physicians in the FH network may indicate a generally high level of health care access and interaction with the health care network, which may affect the interpretation of any racial disparities. Since all participants had access to NGS/TMB testing and CIT, any observed differences in health outcomes would likely be attributable to biologic factors rather than inequitable access to care. Additionally, because of the current lack of available data, other broader social determinants were not assessed in this analysis.39 Menthol cigarettes have been shown to produce positive sensory effects, and evidence suggests that their use is associated with an increased risk of nicotine addiction and long-term daily cigarette use.40Overall, no obvious disparities in the use of emerging treatments (CIT) on the basis of EHR-reported race or genomic ancestry were observed. However, there were statistical differences in the prevalence of emerging biomarkers (TMB) by genomic ancestry, with higher TMB in patients of African ancestry despite a similar prevalence of patients with a history of smoking. Although race is a sociocultural categorization, the racial differences in TMB remain poorly understood. Racial differences in TMB status may be influenced by different patterns of tobacco consumption, including the type of tobacco consumed. For example, more than 80% of non-Hispanic Black cigarette smokers in the United States use menthol cigarettes compared with approximately 25% of non-Hispanic White smokers.41 the results presented here suggest that equal access to testing and CIT results in improved outcomes in patients with aNSCLC, regardless of ancestral background. These results further underscore the need to ensure equitable access to NGS testing and CIT across racially and ancestrally diverse populations to address and improve disparities in NSCLC outcomes.Since clinical and demographic characteristics, except smoking, were not associated with TMB status, it appears that high TMB is not associated with more severe disease characteristics. High TMB was predictive of improved OS in patients from different ancestral groups  who were treated with CIT. Given that previous studies using real-world data have reported racial disparities in access to NGS/TMB testing,


Catheter ablation for atrial fibrillation (AF) is a common treatment strategy in patients with drug-resistant, symptomatic AF. In patients with paroxysmal and short-standing persistent AF, pulmonary vein isolation (PVI) is often enough to prevent recurrence of atrial tachyarrhythmia (ATA). Point-by-point encircling of the PVs with radiofrequency (RF) applications, together with cryoballoon ablation, have been the mainstay strategies for the last 10 to 20 years. Each of these strategies, however, suffers from the delicate balance between preventing PV reconnection, on the one hand (toward more energy), and preventing  complications (toward less energy), on the other. The CLOSE protocol was developed as an RF ablation strategy that would result in the safe creation of durable isolation leading to improved outcomes. Basically, the aim of the protocol is to enclose the pulmonary veins with stable, contiguous  and optimized lesions . In this review, we describe the background of the CLOSE protocol and the studies from the St Jan Bruges research group on procedural performance, efficacy, and safety of the CLOSE protocol in (a) single-center prospective PILOT study (CLOSE-PILOT), (b) a single-center prospective study with continuous rhythm monitoring (CLOSE to CURE), (c) a database of systematic esophageal endoscopic studies, (d) a multicenter prospective study (VISTAX), and (e) the CLOSE database (comprising > 400 patients). We also discuss the results of the randomized POWER-AF study comparing conventional CLOSE to high power CLOSE (up to 50 W). Finally, we discuss the performance, safety, and efficacy of the CLOSE protocol in light of the emerging changes in the field of catheter ablation being ultra-short high-power ablation and electroporation. Atrial fibrillation (AF) is the most common arrhythmia worldwide. AF is a complex arrhythmia and may be classified into paroxysmal, persistent, long-standing persistent, or permanent AF, depending on its duration and mode of termination . ManagemSince Haïssaguerre et al. stipulated the importance of pulmonary vein (PV) triggers and drivers in the pathogenesis of AF in the late 1990s, PV isolation (PVI) has become the cornerstone of the treatment for patients with paroxysmal and persistent AF . PVI aimThe first steps toward the CLOSE protocol were published in 2017 when El Haddad et al. presented our work on the “weakest link” in CF-guided RF circles . The autAfter the study by El Haddad et al., AI and ITD became the key criteria in the CLOSE protocol, together with the use of the Thermocool Smarttouch™ catheter , the “peanut”-shaped roadmap before ablation , stabilip < 0.0001 and 18 ± 4 min versus 28 ± 7.5 min, p < 0.0001, respectively). Results further showed a higher incidence of adenosine-proof isolation in the CLOSE group . No complications were observed in the CLOSE group. At 12 months, single-procedure freedom from ATA was higher in the CLOSE vs. CONV-CF group . The first prospective trial on the clinical applicability of the CLOSE protocol was the CLOSE-PILOT study . In thisThese initial studies were still limited by the nature of intermittent monitoring and the single-center design. Therefore, we designed the CLOSE to CURE study and the VISTAX trial.p < 0.001). Single-procedure freedom from any ATA was 87% after the first year and 78% at year 2. Patients’ QOL improved significantly across all scores. Adverse events occurred in 5 out of 105 (4.8%) patients. These results have led to conclude that CLOSE-guided catheter ablation has become an effective procedure in paroxysmal AF with a major and maintained impact on ICM-detected ATA burden. While conventional survival analysis suggests a progressive decline in efficacy, the authors observed that burden reduction is preserved at longer follow-up. These data imply that ATA burden is a more optimal endpoint for assessing ablation efficacy [In the prospective, patient-controlled CLOSE to CURE study, patients undergoing CLOSE-PVI were implanted with an insertable cardiac monitor (ICM). In total, 105 patients with paroxysmal AF were implanted with an ICM 65 days prior to catheter ablation. The primary endpoint of the study was the reduction in ICM-detected ATA burden; secondary endpoints were single-procedure freedom from ATA, quality of life (QOL), and adverse events. After PVI (1.13 ± 0.39 procedure per patient), ATA burden decreased from 2.68 (0.09–15.02)% at baseline to 0 (0–0)% during the first year and 0 (0–0)% during the second 2-year (highly significant reduction in ATA burden of 100 (100–100)%, The VISTAX study was a prospective study aiming to evaluate CLOSE-PVI in a multicenter setting in patients with paroxysmal AF. The study began in early 2017 and was performed in 17 European centers. A total of 340 patients were enrolled in this trial. The trial aimed at the evaluation of the reproducibility and effectiveness of the CLOSE protocol across centers . ProceduIn the overall Bruges’ studies database comprising more than 800 patients, we reported 1 transient ischemic attack (CLOSE-PILOT study), 1 symptomatic PV stenosis (CLOSE to CURE), and no evidence for atrial–esophageal fistula. The rate of vascular complications (0.6%) and tamponade (0.6%) (both attributable to inadvertent puncture) reported throughout our studies was always comparable to previous ablation studies. At repeat ablations, performed throughout the last 8 years, there was no evidence for overt narrowing of the PVs. As esophageal injury remains the Achilles heel in PVI, we performed an endoscopic evaluation of the esophagus in patients with per-procedural esophageal temperature rise. Proton-pump inhibitors were prescribed for all patients post procedure. Wolf et al. reported on 85 patients undergoing echo-endoscopy 9 ± 4 days after CLOSE-PVI .The low incidence of esophageal ulceration in the CLOSE protocol is most likely attributable to the safety precautions at the posterior wall (including use of temperature monitoring), the short duration of applications, and/or the lack of dislocations and touch-ups. p = 0.453). In contrast, they were characterized by a higher incidence of low voltage areas in the left atrium . Patients with four isolated veins showed a lower 12-month freedom from AF after repeat ablation  [De Pooter et al. studied the prevalence of patients presenting with four isolated veins after CLOSE-guided PVI in patients undergoing repeat ablation. In total, 326 patients undergoing CLOSE-guided PVI for paroxysmal AF were included. Of those patients, 45 underwent repeat ablation for AF recurrence (11 ± 7 months after first PVI). In 62% of patients, all veins were still isolated. Compared to patients with PVR, these 28 patients showed similar clinical characteristics and similar time from first PVI to AF recurrence  seems notably higher, compared to prior prospective, multicenter studies with stringent monitoring and independent core laboratory analysis . If confirmed in a randomized controlled trial, the VISTAX study suggests an absolute improvement of 15% with CLOSE, implying a number-needed-to-treat of six individuals for the observed clinical benefit 0% seems ,14,15. The observed difference in clinical efficacy is paralleled by an increase in the durability of isolation. The reported durability rate of 62% after CLOSE-guided PVI implies a threefold increase in durability when compared to the 20% likelihood of finding four isolated veins, as reported in the FIRE and ICE trail. Additionally, prior studies reporting on cryoablation or conventional RF uncovered durability percentages ranging from 0% to 33% .Left atrial (LA) linear lesion formation is a technique that electrophysiologists use for the ablation of persistent AF and LA macro re-entrant tachycardia. Nonetheless, performing linear ablation is challenging. During CLOSE-guided PVI, it was shown that PVR resulted from an insufficient AI and/or from a too long ILD. As these criteria on minimal AI and maximal ILD had not yet been evaluated for linear lesions, RF linear ablation at the roof and mitral isthmus (MI) using point-by-point contiguous and optimized RF lesions was evaluated in the ALINE study. A total of 41 patients with symptomatic persistent AF underwent stepwise CF-guided catheter ablation during ongoing AF. The operators delivered a single linear set of RF lesions at the roof and posterior MI according to the Atrial Linear (ALINE) criteria. The ALINE criteria imply point-by-point RF delivery (up to 35 W) respecting strict criteria of contiguity and indirect lesion depth assessment, with an ILD ≤ 6 mm and AI ≥ 550, respectively. Wolf et al. assessed the incidence of a bidirectional block across the roof and posterior MI only after the restoration of sinus rhythm. The authors observed a first-pass block across roof lines in 93% of patients and in 23% of patients at the MI. Additional endo- and epicardial RF applications led to the final bidirectional MI block in the majority of patients (80%). Overall, 12 patients underwent repeat procedures during a median follow-up of 396 days. Reconnection was observed in 4 out of 12 and in 5 out of 10 previously blocked roof and MI lines, respectively. Wolf et al. did not observe any complications during their study. The authors concluded that anatomical linear ablation, when using strict criteria for contiguity and lesion depth, resulted in a high rate of the first-pass block at the roof but not at the MI. It was further concluded that the MI frequently required additional endo- and epicardial RF lesions in order to achieve bidirectional block as a consequence of the MI’s complex 3D architecture .In recent years, higher power (HP) RF delivery was proposed as a strategy to shorten PVI procedure time with the potential of improving safety/effectiveness by optimizing lesion quality. However, because higher power comes along with a narrower therapeutic margin, it was necessary to perform studies evaluating whether higher power CLOSE (up to 45 or 50 W) shortens procedure time without compromising safety/effectiveness. Nakagawa et al. showed that at these power ranges, lesion formation can still be predicted using the ablation index .p < 0.001), shorter RF time  with similar effectiveness in both groups. In the HP group, however, there was one esophageal perforation due to overshoot in AI (480) [We evaluated the performance, safety, and effectiveness of HP CLOSE in the randomized POWER AF study. In the control arm, patients received conventional CLOSE , whereas, in the active arm, the patient received higher power CLOSE . AI and ITD targets were identical in both arms. The study revealed that higher power results in a shorter procedure time  . This obTo deliver higher power, and to overcome the limitations seen with the Surround flow (SF) catheter (steam pop), Biosense Webster Inc. developed the QDOT MICRO catheter, together with temperature and flow-controlled ablation (TFCA). The catheter tip is embedded with six superficial thermocouples allowing reintegration of real-time temperature monitoring during ablation . AlmoradIn light of the above findings, it is now standard to perform CLOSE with higher power anterior (45–50 W) and conventional power posterior (35 W) using dedicated catheters. In this setting, RF applications last for only 10–20 s. CLOSE-guided PVI has become the key treatment approach for the ablation of patients with paroxysmal atrial fibrillation, as it is now associated with procedure times of approximately 80 min and an unprecedented high first-pass isolation rate, targeting 98%. Nonetheless, the EP-world stands at the door of a new era with new technologies such as ultra HPSD and electroporation. The QDOT MICRO catheter, together with temperature-controlled ablation (TCA), has introduced the ability to encircle the veins with ultra-short, 4 s, 90 W applications . AlthougTo evaluate whether 90 W PVI shortens procedure time without compromising the excellent safety/effectiveness balance in CLOSE, we are currently conducting the POWER-PLUS study  in six European centers (Bruges (Belgium), Luzern (Switzerland), Aarhus (Denmark), Graz (Austria), Linz (Austria), Leiden (The Netherlands) . In the Finally, it remains to be seen how pulsed-field ablation (PFA) will compare to CLOSE or vice versa (depending on what is or will be the gold standard). Until today, there are no studies comparing PFA to CLOSE-guided PVI. Single-arm studies using PFA have shown promising results. The IMPULSE, PEFCAT, and PEFCAT-II study evaluated the PFA system of Farapulse . PVI was achieved in all patients (100%) using PFA alone. One-year arrhythmia freedom was found in 78.5 ± 3.8% of patients and was found to be safe. Finally, the likelihood of finding four veins isolated at repeat was reported to be 100%. Whether this is superior to CLOSE-guided PVI or any other PVI strategy using thermal energy will require a randomized study. A late update of the Farapulse studies revealed an 84.8% durability rate at repeat. Moreover, one should keep in mind that repeat procedures in volunteers (protocol-mandated) are more likely to provide higher durability rates compared to the durability rates observed in patients suffering from arrhythmia recurrence .If the promise that electroporation results in tissue-selectivity and durability of isolation holds true, it seems obvious that that PFA will replace point-by-point RF ablation. However, building up the necessary clinical evidence will require time. In the meantime, CLOSE-PVI should stay in RF-guided PVI and, in our opinion, the preferred strategy in the respective control arms in PFA studies.


Chronic kidney disease (CKD) has been recognized as a highly prevalent risk factor for both the severity of coronavirus disease 2019 (COVID-19) and COVID-19 associated adverse outcomes. In this multicenter observational cohort study, we aim to determine mortality and readmission rates of patients hospitalized for COVID-19 across varying CKD stages. We performed a multicenter cohort study among COVID-19 patients included in the Dutch COVIDPredict cohort. The cohort consists of hospitalized patients from March 2020 until July 2021 with PCR-confirmed SARS-CoV-2 infection or a highly suspected CT scan-based infection with a CORADS score ≥ 4. A total of 4151 hospitalized COVID-19 patients were included of who 389 had a history of CKD before admission. After adjusting for all confounding covariables, in patients with CKD stage 3a, stage 3b, stage 4 and patients with KTX (kidney transplantation), odds ratios of death and readmission compared to patients without CKD ranged from 1.96 to 8.94. We demonstrate an evident increased 12-week mortality and readmission rate in patients with chronic kidney disease. Besides justified concerns for kidney transplant patients, clinicians should also be aware of more severe COVID-19 outcomes and increased vulnerability in CKD patients. Mortality rates of COVID-19 attributed to CKD may vary between 1.3% and 21.3%4. Whether disease severity and mortality rates depend on the CKD stage or are explained either by a higher prevalence of comorbid conditions in COVID-19 or by kidney-specific factors, such as uremic or immunological factors, is incompletely known. In January 2021, the European Renal Association and European Dialysis and Transplantation Association (ERA-EDTA) called for action to include all CKD stages in COVID-19 related clinical research5. So far, most reports about COVID-19 severity and outcomes do not include all CKD stages and direct comparisons with non-CKD patients are limited4. Also, a complete characterization of CKD patients hospitalized for COVID-19, including clinical and laboratory data at hospital admission, is infrequently reported. In this multicenter observational cohort study, we aim to determine mortality and readmission rates of patients hospitalized for COVID-19 across varying CKD stages.Chronic kidney disease (CKD) has been recognized as a highly prevalent risk factor for both the severity of coronavirus disease 2019 (COVID-19) and COVID-19 associated adverse outcomes8. The COVIDPredict is a consortium of eleven hospitals in the Netherlands that aim to understand better and predict which COVID-19 patients should receive which treatments and which type of care. All methods were carried out in accordance with relevant guidelines and regulations. The study protocol was reviewed by the medical ethics committees of the Amsterdam University Medical Centers . The need for informed consent was waived by the Institutional Review Board of Amsterdam University Medical Centres. An opt-out procedure was communicated by press release according to national guidelines and the European privacy law.We performed a multicenter cohort study among COVID-19 patients included in the Dutch COVIDPredict cohort9. Patients that were transferred from another hospital with an initial admission date > 48 h, readmission records and CKD patients with an undefined CKD stage pre-admission were excluded. Seven groups of CKD were defined based on the previously reported medical history of CKD. The pre-admission kidney condition was calculated with CKD-EPI formula10 and the eGFR was used to categorized CKD-stages according to the Kidney Disease Improving Outcomes stages of CKD stages11. Patients without CKD were used as controls (“no-CKD”).The cohort consists of hospitalized patients from March 2020 until July 2021 with PCR-confirmed SARS-CoV-2 infection or a highly suspected CT scan-based infection with a CORADS score ≥ 412. Overall, < 2% observations were missing, which were entirely considered at random and listwise omitted from the adjusted analyses. A P ≤ 0.05 was considered significant. Data analyses were performed with R (v3.6.1)13.We compared comorbid risk factors, baseline vitals and laboratory values, and disease severity across groups. Parametric variables were presented as mean and standard deviation (SD); for non-parametric data, the median and interquartile range (IQR) was used. Dichotomous data were presented with frequencies (n) and percentages (%). To compare differences for continuous data, we used a one-way ANOVA or Kruskal–Wallis (KW) test, depending on the type of distribution. If the overall group was deemed significant, posthoc pairwise t-tests (after one-way ANOVA) or Wilcoxon rank tests (after KW) were performed (Benjamini-Hochberg (BH), adjusted) to compare no CKD to the CKD group. For categorical data, we used the Fisher exact test to compare group differences, with pairwise posthoc tests (BH adjusted) with the no CKD group if overall significant. The primary outcome was a composite endpoint of all-cause mortality, readmission or palliative hospital discharge in a 12-week follow-up period. Logistic regression was used to adjust the association between CKD groups and primary outcome in a stepwise procedure for the following confounders: age, sex, ethnicity, number of comorbidities, and designated COVID-19 treatment wave, reflective of the introduction of dexamethasone as a standard treatment regimenOf the 5153 hospitalized COVID-19 patients enrolled, 755 were excluded because the admission was a readmission of COVID-19, it concerned a transfer from another hospital or were lossed to follow-up. A total of 247 patients with CKD were excluded due to missing pre-admission creatinine values and incomplete CKD stage information  died or were readmitted after 12 weeks of follow-up. In the unadjusted model, all CKD stages, except CKD stage 5, were associated with significantly higher mortality and readmission rate compared to no-CKD patients  and significant differences in hemoglobin and albumin—the latter being presumably directly related to CKD stage rather than COVID-19. The lack of an apparent factor that explains worse 12-week outcomes underscores that CKD as such is a COVID-19 risk factor.4. However, in contrast to KTX patients from our cohort, dialysis patients  do not appear to have significantly higher mortality and readmission rates after adjusting for known covariates. The significantly higher mortality after correction demonstrates that mortality and readmission rates in the KTX group are not dependent on known COVID-19 risk factors such as older age, male sex and ethnicity15. This is in contrast with our findings in dialysis patients in whom the worse 12-week outcomes to some extent seem to be explained by higher age and more prevalent comorbidities associated with worse COVID-19 outcomes in non-renal patients.However, some distinctions can be made, as we also analyzed mortality and readmission rates among CKD patients with dialysis and KTX. Our findings are in concordance with the ERACODA collaborative study, where a higher mortality rate was found among KTX and dialysis patients than data from the general population16. Various studies have also shown a limited yield of SARS-CoV-2 vaccines in patients with a solid transplantation18. This study again emphasizes the present-day increased risk of mortality in patients with KTX. Besides KTX patients, usage of immune suppressive medication in other CKD groups was not significantly different from the no-CKD group in our cohort.It has been suggested that COVID-19 associated mortality in patients with KTX is due to the immunosuppressive condition of patients, which leads to an inability to clear the SARS-CoV-2 infectionThere are some potential drawbacks associated with our study. First, although we can draw conclusions on the influence of CKD on COVID-19 outcomes, the influence of CKD severity was studied based on eGFR staging only. We were not able to include albuminuria stage, which could affect CKD severity and its association with outcomes. Furthermore, due to requiring pre-admission creatinine values, we have excluded 247 CKD patients. However, we believe this selection provides a more accurate representation of mortality within CKD groups. We also did not study the impact of the primary diagnosis causing CKD on the course of COVID-19 because these data were not completely available. At last, there are differences in baseline characteristics and in designated COVID-19 treatment wave, which might have resulted in different treatment regimens among groups. Although we adjusted for potential confounders, there remains a possibility of an overestimation or underestimation of results. However, we do believe this only makes our results more applicable to general clinical conditions in hospitals..Our study demonstrates a clinically significant increased mortality and readmission rate in patients with a history of CKD. While previous studies mainly highlighted increased mortality among dialysis and KTX patients, we also demonstrate a clear increased 12-week mortality and readmission rate of SARS-CoV-2 infected patients in nearly all CKD groups. Besides justified concerns for KTX patients, clinicians should also be aware of more severe COVID-19 outcomes and increased vulnerability in CKD patientsSupplementary Information.


The therapeutic role of immune checkpoint inhibitors (ICIs) has represented the cutting edge of clinical research in upper gastrointestinal (GI) malignancies, with these agents now included in the armamentarium of treatment options for advanced gastric and esophageal cancers.We performed a systematic literature review and pooled analysis to map out the currently available robust clinical evidence for the use of ICIs in upper GI cancers. Immunotherapy (IO), either as monotherapy or in combination with chemotherapy, and its role in first-line, maintenance, and second-line settings, as well as in specific clinical and biological subgroups, were critically appraised. All statistical tests were 2-sided.P < .001; based on 4 studies) and esophageal squamous cell carcinoma , albeit with heterogeneous efficacy according to biomarker expression. Patients with esophageal squamous cell carcinoma, and in particular high programmed cell death ligand-1 expression, derive survival benefit when treated with IO in the second-line setting . Clinical trials interrogating the combination of IO with chemotherapy in second-line treatment should be seriously considered in upper GI adenocarcinomas. The role of maintenance IO after initial disease control is still unclear and cannot be recommended. Impressive response rates and survival benefit from IO have been reported in patients with microsatellite instability-high tumors , and this warrants further prospective biomarker-driven studies.ICIs, in combination with chemotherapy, have provided statistically significant overall survival benefit in the first-line setting in gastric and gastro-esophageal adenocarcinomas (hazard ratio [HR] = 0.83, 95% confidence interval [CI] = 0.76 to 0.90, IO is changing the treatment landscape in upper GI malignancies. The rapidly developing evidence in the field needs to be critically appraised while further validation of the existing information from ongoing trials is awaited. Upper gastrointestinal (GI) tract malignancies include cancers of the esophagus, gastro-esophageal junction (GEJ), and stomach. Gastric and GEJ cancers are the fifth and esophageal cancer the sixth leading causes of cancer-related deaths globally . ChemothImproving the survival outcomes of patients with upper GI malignancies therefore remains an unmet need. Recently, immunotherapy (IO), in particular immune checkpoint inhibitors (ICIs), has been shown to confer statistically significant survival advantage for the treatment of a variety of tumor types. The use of ICIs in upper GI malignancies is a rapidly evolving and cutting-edge field of clinical research. Evidence from randomized controlled clinical trials of their clinical application has grown notably over the last few years and is expected to develop rapidly in the near future. For instance, treatment with ICI anti-PD1, nivolumab, has proven its superiority over placebo in third-line treatment in gastric and GEJ cancers, reducing the risk of death by 37% . AlthougWe performed an extensive and systematic literature search including both published (full articles) and unpublished  material to identify randomized clinical trials reporting data on the use of IO in the first-line, second-line, and maintenance treatment for advanced or metastatic upper GI malignancies. Clinical trials on third-line treatment and beyond were excluded. For further details of our search methodology, please see the step-wise approach description and CONSORT diagram summarized in P < .1), the random effects model was reported; otherwise the fixed effects model was adopted to estimate the pooled ratios. I2 statistic was also calculated to assess overall heterogeneity.Summary data methodology meta-analysis of available trials was used for the analyses. The Inverse-Variance and the Mantel-Haenszel statistical methods were applied for calculation of pooled hazard ratios (HRs) and odds ratios (ORs), respectively. Between-studies heterogeneity was evaluated with Cochran’s Q test; in case of statistically significant heterogeneity  were used for the analysis. For studies that reported CIs other than 95%, the 95% CIs were calculated and used in the pooled analysis. Statistical significance was set at the 2-sided .05 level. RevMan software V5.4 was used for the completion of the pooled data analysis.In total, we identified 6 first-line , 8 seconSix studies compared ICIs  in combination with chemotherapy vs chemotherapy alone . Three oIn KEYNOTE-062, patients with G or GEJ adenocarcinoma and PD-L1 expression were randomly assigned between treatment with pembrolizumab or chemotherapy. A high PD-L1 expression, based on a combined positive score (CPS) of 10 or greater, predicted a statistically significant median overall survival (mOS) benefit of almost 7 months for those treated with pembrolizumab compared with chemotherapy   has displayed clinically significant improvement in OS both in patients with G or GEJ adenocarcinoma and ESCC. In CheckMate-649, more than 1500 patients with G or GEJ adenocarcinoma were randomly assigned to receive either treatment with nivolumab plus chemotherapy or oxaliplatin, fluoropurimidine. There was improved survival with chemo-IO combination both in the overall population  and in the PD-L1–expressing tumors with CPS of at least 1  . NeverthIn ATTRACTION-4, 724 patients received treatment with either chemotherapy alone or nivolumab and chemotherapy. The trial, in which PD-L1 expression was not used for patient selection, did not identify any OS difference between the 2 study arms  , althougP = .0006) with the use of the chemo-pembrolizumab combination, which was even more pronounced in the group with high CPS ≥ 10;  (P < .0001) (KEYNOTE-590 was the first study to present results on patients with ESCC. The majority (73%) of the enrolled population in this trial (n = 749) had a diagnosis of esophageal squamous cancer. In this particular subgroup, there was a statistically significant OS gain of almost 3 months  . Patient= .0001) ,15  over chemotherapy alone and showed a 2-month survival improvement in the overall population and 4 months in the biomarker-selected population (CPS ≥ 1) for patients with ESCC . AlthougP < .001) and for any PD-L1 CPS subgroups considered (P < .001)   and any PD-L1 CPS expression may benefit and are good candidates for combination chemo-IO in first-line treatment. Similarly, PFS was also higher for chemo-IO irrespective of histology or PD-L1 expression   comparedPatients with gastric adenocarcinoma seemed to obtain survival benefit similarly to GEJ tumors in the first-line setting ,12. NeveAlthough we acknowledge that the final results from the 5 first-line studies described above are yet to be published in full, the statistical significance from our pooled analysis is promising, and chemo-IO is expected to have a prominent role in the care for advanced upper GI adenocarcinoma. Indeed, the U.S. Food and Drug Administration has recently approved pembrolizumab in combination with chemotherapy for esophageal and GEJ malignancy regardless of PD-L1 status based on the results from KEYNOTE-590 , and theThe role of maintenance therapy in upper GI cancer remains controversial. We identified 3 clinical trials that randomly assigned patients with Her-2 negative G or GEJ adenocarcinomas with disease control following completion of first-line chemotherapy . In the The comparison results of surveillance vs durvalumab after platinum-based induction chemotherapy in patients with esophagogastric adenocarcinoma were recently presented from the PLATFORM trial, a prospective, open-label, multicenter, adaptive phase II study. The study did not meet its primary endpoint, and durvalumab did not improve PFS compared with surveillance after first-line induction treatment with platinum-based chemotherapy  despite Understandably, the lack of benefit was confirmed in the pooled analysis from the 3 studies  without improvement in PFS or ORR (P < .001). Patients with ESCC and CPS greater than or equal to 1 had statistically significant survival benefit from IO , similar to those with CPS greater than or equal to 10 . This was not actually the effect of the high CPS, because patients with a score less than 5 still gained statistically significant survival benefit  (P = .07), and further randomized evaluation in this groups will be needed with the appropriate statistical design. Besides the OS benefit, CPS greater than or equal to 10 predicted for statistically significantly higher PFS  and response rate  and CPS greater than or equal to 1 predicted for higher PFS , as was initially reported in the ESCORT trial  , based pThe pooled analysis confirmed that IO was not superior to chemotherapy in patients with esophageal or G or GEJ adenocarcinoma  ,21. PatiThe presence of a deficient mismatch repair mechanism in cancer cells has been linked to development of a high mutational burden, with an improved response to and survival benefit from ICIs. This led to the accelerated approval of pembrolizumab in MSI-H malignancies . The proP < .001) as well as IO alone in first line of treatment . In the first-line setting, fitness did not predict for better response . Indeed,In the majority of studies analyzed, patients of Asian origin had better survival outcomes compared with non-Asian population ,17,19,25Despite the strengths of this review, certain limitations need to be considered. Most of the trials were designed to show superiority of the investigational agent. However, KEYNOTE-062 was a noninferiority study  that couPatients with upper GI adenocarcinoma did not benefit from IO alone in the second-line setting, but the combination of chemo-IO seemed to be effective as first-line treatment in this histological subtype. Indeed, when we performed pooled analysis for the treatment of upper GI adenocarcinoma in the second-line setting, there was a trend for better PFS and response rate in the chemotherapy arm 10, D. ThSo far, the reported studies included patients with Her-2–negative tumors. The combination of IO with anti-Her-2 monoclonal antibodies has provided promising results without raising safety issues ,51, and In early-stage disease, the recently presented CheckMate-577 study reported that nivolumab as adjuvant treatment after chemoradiotherapy and surgery for esophageal or GEJ cancer doubled disease-free survival compared with placebo . This trThis study is the first systematic review, to our knowledge, to interrogate the use of IO in early treatment lines for advanced or metastatic disease in upper GI malignancies to provide an evidence-based state of the art practice. Multiple pooled analyses were provided to better summarize and present the cumulative evidence when variable information for the same outcome measures, across different trials, was available.In anticipation of the final results, the initial signal for the combination of IO with chemotherapy seems very promising in the first-line treatment for advanced upper GI adenocarcinomas and ESCC, especially with high PD-L1 expression (CPS ≥ 1%). MSI testing should also be considered at baseline to guide management of the MSI-H subgroup, in whom tumors have been shown to be very sensitive to IO.IO is highly effective in the second-line treatment for ESCC in patients with high PD-L1 (CPS ≥10) expression, offering OS and PFS benefit as well as statistically significantly higher response rates, and this was confirmed in our pooled analysis. Similarly, statistically significant survival benefit has been observed in patients with ESCC and CPS greater than or equal to 1, although it is still unclear if they respond better. The role if IO in the CPS less than 1 group, needs to be further investigated to ascertain the benefit in this group as well. Nevertheless, the efficacy of IO has not been proven in second-line upper GI adenocarcinoma or in maintenance treatment after disease control with first-line chemotherapy. Thoughtfully designed trials with the appropriate biomarker selection will be necessary to navigate the future management of patients with advanced upper GI malignancies with the availability of IO, chemotherapy, and targeted therapies in the repertoire of treatment options available.None.Role of the funder: Not applicable.Disclosures: All authors disclose any conflict of interest.Author contributions: Conceptualization: KK, DM; Investigation: AA, DM, GZ, IG, KK, TG, MN, MT; Data Curation: DM, KK, PN; Formal analysis: DM, KD, PN; Writing-original draft: KK, DM, MT; Writing-review and editing: AA, GZ, IG, KD, MN, PN, TGThe data underlying this article are available in the article and in its online pkab088_Supplementary_DataClick here for additional data file.


The dynamics of acute respiratory syndrome coronavirus 2 (SARS-CoV-2) transmission and severity of disease among children and young people (CYP) across different settings are of considerable clinical, public health and societal interest. Severe COVID-19 cases, requiring hospitalisations, and deaths have been reported in some CYP suggesting a need to extend vaccinations to these age groups. As part of the ongoing Early Pandemic Evaluation and Enhanced Surveillance of COVID-19 (EAVE II) study, we aim to investigate the uptake, effectiveness and safety of COVID-19 vaccines in children and young people (CYP) aged 0 to 17 years in Scotland. Specifically, we will estimate: (i) uptake of vaccines against COVID-19, (ii) vaccine effectiveness (VE) against the outcomes of symptomatic SARS-CoV-2 infection, hospitalisation, intensive care unit (ICU) admissions, and death; (iii) VE for first/second dose timing among different age groups and risk groups; and (iv) the safety of vaccines.We will conduct an open prospective cohort study classifying exposure as time-varying. We will compare outcomes amongst first dose vaccinated and second dose vaccinated CYP to those not yet vaccinated. A Test Negative Design (TND) case control study will be nested within this national cohort to investigate VE against symptomatic infection. The primary outcomes will be (i) uptake of vaccines against COVID-19, (ii) time to COVID-19 infection, hospitalisation, ICU admissions or death, and (iii) adverse events related to vaccines. Vaccination status  will be defined as a time-varying exposure. Data from multiple sources will be linked using a unique identifier. We will conduct descriptive analyses to explore trends in vaccine uptake, and association between different exposure variables and vaccine uptake will be determined using multivariable logistic regression models. VE will be assessed from time-dependent Cox models or Poisson regression models, adjusted for relevant confounders, including age, sex, socioeconomic status, and comorbidities. We will employ self-controlled study designs to determine the risk of adverse events following COVID-19 vaccination.Ethics approval was obtained from the National Research Ethics Committee, South East Scotland 02. We will present findings of this study at international conferences, in peer-reviewed journals and to policy-makers. Weekly rates of acute respiratory syndrome coronavirus 2 (SARS-CoV-2) positive cases among children and young people (CYP) are increasing in many countries ,2. With Although research has found that SARS-CoV-2 is less likely to cause serious illness in CYP in comparison to older age groups, there is a need for further studies in CYP to understand who among them is at greatest risk of serious COVID-19 outcomes and why. Delahoy et al . The safIn the United States, weekly COVID-19-associated hospitalisation rate increased by about five-fold between June and mid-August 2021, with hospitalisation rates 10 times higher among unvaccinated compared to fully vaccinated groups . While iSwann et al.  estimateTaking into consideration the latest available data among CYP in the United Kingdom, the Joint Committee on Vaccination and Immunisation (JCVI), on 19 July 2021, advised the UK Government on COVID-19 vaccination among CYP [The proposed study on the uptake, effectiveness and safety of COVID-19 vaccines in children and young people (CYP) in Scotland is part of the ongoing Early Pandemic Evaluation and Enhanced Surveillance of COVID-19 (EAVE II) study . EAVE IIThis EAVE II sub-cohort of CYP will build on methods that have previously been described in detail ,29 to inWe aim to investigate the association between receiving one and two  doses of the Pfizer-BioNTech (and any other vaccines licensed for this age group in the future) and COVID-19 infection, hospitalisation, ICU admissions and death in children and young people aged 0 to 17 years in Scotland.We seek to estimate:Uptake of vaccine against COVID-19;VE against the outcomes of COVID-19 infection, hospitalisation, ICU admissions or death;VE for first/second dose timing amongst different age groups and risk groups; andSafety of COVID-19 vaccines.First, we will conduct an open prospective cohort study to determine uptake of vaccine and compare the risk of outcomes  amongst first dose vaccinated and second dose vaccinated to people who have not yet been vaccinated. In addition, a Test Negative Design (TND) case control study for infection nested within this national cohort will compare outcomes of interest between COVID-19 vaccine doses in CYP and unvaccinated controls.Children and young people aged 0-17 years who are resident in Scotland. We will exclude the following:persons aged 18 or more at the study start date;deceased prior to the study start date.Data from multiple sources will be linked using the Community Health Index (CHI), a unique identifier used for all health contacts in Scotland. These include:Primary care data: Collected from General Practices (n=940) with information on demographics, other co-existing infections (if data available) and vaccination data.Vaccination centre data: This includes vaccines administered in national vaccination centres and data available via the Turas Vaccination Management Tool (TVMT).Secondary care data: This includes hospital admissions through the Scottish Morbidity Record (SMR), Rapid Preliminary Inpatient Data (RAPID), and Paediatric Intensive Care Audit Network (PICANet).Laboratory test data: RT-PCR laboratory confirmed SARS-CoV-2 infection and data available via the Electronic Communication of Surveillance in Scotland (ECOSS) database.Sequencing data: This will be sourced from the Centre of Genomics (COG).This will be derived from the date of receiving Pfizer-BioNTech vaccine. Exposure categories are described as follows:0-13 days after dose 1 or no vaccine record;≥14 days after dose 1 and before dose 2;0-13 days after dose 2; and≥14 days after dose 2.To increase statistical power in secondary analyses, we will conduct analyses of whole population data for 0-17 year olds. We expect part of the effects of the vaccination programme to arise from behavioural responses .The primary outcome will be (i) uptake of vaccines against SARS-CoV-2, (ii) time to COVID-19 infection, hospitalisation, ICU admissions or death, and (iii) adverse events related to vaccines. Confirmed symptomatic SARS-Co-V-2 infection will be defined as any of COVID-19 symptoms in children with the virus confirmed by RT-PCR. Hospitalisation will be defined as any hospital admissions within 14 days of a positive RT-PCR test for SARS-CoV-2 infection, or tested positive within first 2 days of admission, or with International Classification of Diseases (ICD)-10 code for COVID-19 (in any diagnostic position). COVID-19 deaths will be defined as COVID-19 as the main ICD-10 cause of death recorded on the death certificate, or death from any cause within 28 days of a positive RT-PCR test for SARS-CoV-2 infection.Secondary outcomes will be the single outcomes of:positive SARS-CoV-2;COVID-19 hospitalisation; andCOVID-19 deaths.We anticipate the RT-PCR confirmed SARS-CoV-2 infection results to be more susceptible to bias arising from differential ascertainment and therefore anticipate treating these results as exploratory. Moreover, going by current evidence, we expect challenges in differentiating between admissions with incidental or asymptomatic SARS-CoV-2 and admissions due to COVID-19. Swann and colleagues  reportedPotential confounders will include:age, sex, socio-economic status (SES) measured by quintiles of the Scottish Index of Multiple Deprivation (SIMD) (1 refers to most deprived and 5 refers to least deprived),residential settlement measured by the urban/rural 6-fold classification ,household size,number and types of comorbidities commonly associated with COVID-19 illness , andHealth Board.We will also include care home status  as a potential confounder where data are available. In addition, stratification into different population groups by age group , sex, time intervals and vaccine exposures and a study of possible additive interactions will be performed.We will commence analysis by conducting descriptive analyses to visually inspect trends in vaccination uptake (objective 1). This will include inspecting the number of CYP who have received no doses, one dose and two doses and the length of time between the receipt of one dose and two doses. Differences in vaccine uptake will be measured in relation to demographic, socioeconomic and clinical population characteristics. We will employ univariable and multivariable logistic regression to determine associations between different exposure variables and vaccine uptake.For the cohort study, we will employ a time-varying exposure approach (objectives 2 and 3). Exposure time will be classified into unvaccinated, 0-13 days post-first dose, ≥14 days post-first dose, 0-13 days post-second dose and ≥14 days post-second dose. Follow-up will end on the first of: experiencing the outcome of interest, death (from any cause) or end of follow up period. The proportion of SARS-CoV-2 infection, hospitalisation and deaths will be estimated between vaccinated and unvaccinated cases. VE and 95% CIs will be calculated using the formula, VE = (1 − risk ratio) × 100 for adjusted VE estimates. A time-dependent Cox model or the equivalent Poisson regression models (taking into account the time at risk and the possibility of multiple events (not for death)) will provide the RRs and 95% CIs of VE for prevention of COVID-19, hospitalisations and deaths. Models will be adjusted for relevant confounders, including age, sex, SEP, geography, time-period and comorbidities.A TND case control study for infection, nested within the national cohort that compares outcomes of interest between COVID-19 vaccine doses in CYP and unvaccinated controls, will be carried out. The time-period of this study will begin on the first date of vaccine administration in CYP in Scotland and until the end of follow-up, in line with the TND protocol that has been defined and applied within the EAVE-II collaboration .As described in previous protocols ,31, we wTo monitor the safety of vaccines in children and young people as closely as possible, we will regularly review the literature and follow the reports on possible side-effects and adverse events following vaccination in this age group. To strengthen any results, we will try to include previous known allergies or a history of autoimmune conditions, cardiovascular and respiratory comorbidity, metabolic disorders and other comorbid conditions. We will then expand the list of our monitored adverse events accordingly, including myocarditis, pericarditis, thrombosis and other possibly interesting side-effects: pain at injection site, fatigue, headache, fever ≥38°C, mild rash, diarrhoea, sore throat, neck pain, difficulty sleeping, low blood sugars, vomiting, armpit swelling, blisters around the mouth, chest pain and shortness of breath, and others.Subgroup analyses by vaccine type (if appropriate), age group and sex will be performed. We will consider exploring the use of different time intervals following administration of the vaccine to define exposure. For sensitivity analyses, we will consider conducting falsification analyses (including positive and negative controls) for alternative time periods  to check the comparability of our exposure groups.Missing data will be reported as percentages of total or raw numbers where possible. Previous analyses have demonstrated that little missing data exist for our key variables of interest. For covariates that may have a higher proportion of missing data (such as BMI), we will either use records with no item missingness or use a missing category.Although there is not yet any study on VE among CYP in Scotland, sample size estimations will be based on the Scottish testing and vaccination data. From the first EAVE-II paper on VE against COVID-19 hospitalisation , VE at 2The established EAVE II Public Advisory Group (PAG), which includes diverse adult representation and has a foundational understanding of the wider EAVE II context, is contributing to this project.PPI contribution for this project will focus on the interpretation and dissemination of findings. This will be particularly in relation to missing data and proxy variables, and behavioural factors that may influence RT-PCR testing and vaccination uptake in CYP. All publication outputs will be supplemented by summaries in plain English that have been reviewed by the PAG.In order to involve appropriate lived experience in the interpretation of findings, we intend to convene a virtual panel of children and young people from suitable demographics who will be invited to discuss any results and relevant interpretations that arise from the analysis.P-values will be quoted to two decimal places, unless they are less than 0.001  or between <0.005 and >0.001, in which case they will be stated to three decimal places. Measures of association will be reported with 95% confidence intervals (CIs). Some analyses will be mainly descriptive due to the potentially small number of cases and outcomes.Results will be reported according to the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE)  and REpoManuscripts from this study will be submitted to a peer-reviewed journal. We will also seek to provide near real-time reports on vaccine safety, effectiveness and uptake for the various vaccines to the funders and the government’s COVID-19 advisory bodies as appropriate. All code will be made publicly available via the EAVE II GitHub repository. Meta-data will be made available via the HDR Gateway.