Objective: The aim of this study was to explore the respective use of angiotensin-converting-enzyme inhibitors (ACEis) or angiotensin receptor blockers (ARBs) on the outcomes of patients who could be weaned from dialysis-requiring acute kidney injury (AKI-D).Methods: This case–control study enrolled 41,731 patients who were weaned from AKI-D for at least 7 days from Taiwan’s National Health Insurance Administration. We further grouped AKI-D patients according to ACEi and ARB use to evaluate subsequent risks of all-cause mortality and re-dialysis. The outcomes included the all-cause mortality and new-onset of end-stage kidney disease  following withdraw from AKI-D.Results: A total of 17,141 (41.1%) patients surviving AKI-D could be weaned from dialysis for at least 7 days. The overall events of mortality were 366 (48.9%) in ACEi users, 659 (52.1%) in ARB users, and 6,261 (41.3%) in ACEi/ARB nonusers, during a mean follow-up period of 1.01 years after weaning from AKI-D. In regard to all-cause of mortality, pre-dialysis ARB users had lower incidence than ACEi users . Compared with ACEi/ARB nonusers, continuing ARB users had a significantly low risk of long-term all-cause mortality  after propensity score matching. However, new users of ACEi at the acute kidney disease (AKD) period had a higher risk of re-dialysis after weaning than ACEi/ARB nonusers , whereas neither ACEi nor ARB users confronted significantly increased risks of hyperkalemia after weaning.Conclusions: Compared with patients without ACEi/ARB, those continuing to use ARB before the event and after weaning had low all-cause mortality, while new users of ACEi at AKD had increased risk of re-dialysis. AKI-D patients continuing to use ACEi or ARB did not have higher risk of hyperkalemia. Future prospective randomized trials are expected to confirm these findings. Angiotensin-converting-enzyme inhibitors (ACEis) and angiotensin receptor blockers (ARBs) are both frequently prescribed in treating patients with hypertension, congestive heart failure, or chronic kidney disease. However, due to the concern of their possible worsening effect on acute kidney function impairment, it has been suggested that ACEi/ARB should be withheld prior to or during some clinical scenarios . The KidPrevious studies explored the impacts of the use of ACEi/ARB on post-AKI patients provided conflicting data . ACEi anIn a study of 14,117 patients with pre-dialysis stage 5 chronic kidney disease (CKD), ACEi users were associated with higher mortality rates than ARB users, particularly in a subgroup of diabetic patients . CurrentThe study enrolled all patients between 18 and 80 years of age who were diagnosed with AKI and underwent dialysis treatment from May 2015 to December 2017 in Taiwan, with the final patient follow-up on 31 December 2018 . Our study used a longitudinal database through the Applied Health Research Data Integration Service from Taiwan’s National Health Insurance Administration (NHIA). The longitudinal database contains comprehensive healthcare information, including but not limited to data regarding individual demographic background, acute inpatient hospitals, outpatient primary care and subspecialty office visits, outpatient pharmacies, diagnoses, prescriptions, long-term care facilities, and medical events. To detect possible fraud in the NHI, the NHIA has been routinely auditing data and records submitted by healthcare institutions and providers . The NHIThe study protocol was approved by the Research Ethics Committee of the National Taiwan University Hospital (201807119RIND) and that of National Health Research Institutes (EC1060402-E), and the need for informed consent was waived because of its retrospective nature and no identifiable patient data could be accessible.n = 133), and the others were classified into following three groups before dialysis: AKI-D patients who were administered ACEi (ACEi users), who were administered ARB (ARB users), and who were administered neither ACEi nor ARB (ACEi/ARB nonusers). The baseline demographic data, comorbidities, and the prescribed medications of these patients were collected . We further inspected the respective effects of RASi during the AKD period. The patients who were not administered RAS inhibitors during AKD were divided into following three groups: prior ACEi user (prior ACEi usage only), prior ARB user (prior ARB usage only), and ACEi/ARB nonusers (neither ACEI nor ARB usage), while the patients who kept on usage of RASi were divided into continuing ARB and continuing ACEi users. The new user of RAS inhibitors during the AKD periods were defined as new users.th Revision, Clinical Modification (ICD-9-CM), and ICD-10 administrative data  following withdrawal from AKI-D. Additional outcome measures included hospitalization with a major adverse cardiovascular event (MACE) as the major diagnosis and MACE-related death, which was defined as death with hospitalization for MACE during the 90 days prior to the death.Finally, to assess whether observed associations between the respective ACEi or ARB administration and the outcomes of interest were attributable to different health statuses, we further compared the risk of gastrointestinal bleeding, an outcome believed not to be affected by the choice of RASi treatments, as a negative control test.post hoc analysis consisting of t-tests with the Bonferroni correction for continuous variables and the χ2 test for categorical variables. We compared the risks for AKI and mortality among these aforementioned groups using the COX proportional hazard model, adjusting for age, gender, medication, comorbidities, and eGFR  (The baseline variables were shown as means ± standard deviations (SDs) for continuous variables and percentages for categorical variables in the three groups. Differences between these groups were compared using the and eGFR . The sigrd (sHR) .Given the differences in baseline characteristics and risk of outcomes of interest between the ACEi/ARB users and nonusers, we matched the three groups using a greedy matching algorithm with a caliper width of 0.2 SDs of the log of the odds of the estimated propensity score with a 1:1:1 ratio. The predictive variables of prescriptions or RASi with logistic regression analysis by applying a propensity score are shown in A forest plot was constructed for the hazard ratio of ACEi vs. ARB users on subsequent mortality according to prior comorbidities and clinical conditions.p-value < 0.05 was considered to be statistically significant.All analyses were performed using SAS 9.2 (SAS Institute Inc.) and Stata/MP version 16  for data analysis and figure plotting. A two-sided  survival patients could be weaned off from dialysis for at least 7 days during the AKD period. Among them, there were 748 (4.36%) patients with prior ACEi use and 1,263 (7.37%) patients with prior ARB use . There wn = 1711, 85.1%), followed by diabetes , and prior cerebrovascular accident . The ACEi or ARB users before AKI-D had a higher Charlson comorbidity score  than nonusers. The levels of baseline eGFR were significantly lower in prior ACEi or ARB users  than those of the patients without prior ACEi or ARB.The clinical characteristics of enrolled patients before index admission are shown in During index hospitalization , comparen = 650), ARB users (n= 650), and non-RASi users  after propensity score matching (The enrollees were divided into three groups: ACEi users (matching .p = 0.038) than non-RASi users by Cox proportional hazard analysis.After a mean follow-up period of 1.01 ± 0.94 years , it was p = 0.013)  or continuing (both before and at the AKD period) RASi use to identify the effect of respective RASi. In a further analysis, compared with non-RASi users, patients who received continuing ARB after AKI-D had a significantly low risk for post-weaning all-cause mortality  ; Table 3p = 0.145). The data did not present a statistically significant protective effect for ARB regarding MACE-related death, either .Regarding hospitalization for MACE, we did not identify a statistically significant protective effect for ARB relative to ACEi .In the other compatible groups, those patients who had only prior/continuing ARB usage or only prior ACEi usage did not have increased risk for re-dialysis following weaning from AKI-D in this matched COX proportional hazard model, taking mortality as a competing risk. However, the new users of ACEi at the AKD period had increased risk of re-dialysis (adjusted sub-distribution hazard ratio (sHR) 2.22; 95% CI: 1.55–3.18, p = 0.017). To compare differences between ACEi and ARB, we identified respective findings in the subgroup analysis  and ACEi (p = 0.219) did not increase the risk of hyperkalemia after weaning from AKI-D. For each patient, we also collected data on eGFR in the 1 year following withdrawal of dialysis and calculated the mean level. The mean eGFR values for ARB user, ACEi users, and nonusers are 32.7, 28.7, and 30.6, respectively. No statistically significant difference was detected (p = 0.103).We further analyzed the episodes of hyperkalemia, defined by serum potassium greater than 5.3 mmol/L , and found that continued use of both ARB (p = 0.198) or ARB usage (p = 0.157) had similar risks of gastrointestinal bleeding after weaning from AKI-D.To attribute the possible health indication biases or unobserved confounders, we further identified the risk of new onset of gastrointestinal bleeding after ACEi or ARB usage. The patients with continued ACEi usage . However, our current study provided the first evidence that their effects on reducing the risk of all-cause mortality after weaning from AKI-D may be different at the AKI to CKD transition.We found that AKD patients who had continuing ARB usage had lower risk of all-cause mortality, whereas there was no increased risk of re-dialysis after AKI-D/AKD. However, the mortality rate in continuing ACEi users was not remarkably lower than that in the non-RASi users. Since the transition from AKI to AKD and to CKD is an interconnected syndrome, our study provides a novel insight into the feasibility of various pharmacological therapies influencing the post-AKI care and even the prognosis of these patients .In some clinical scenarios, ARB could provide better protection than ACEi does. For example, in the REACH cohort, a real-world practice, ARB was superior to ACEi in reducing cardiovascular events among high-risk patients ; moreovede novo RAS inhibitors when they were weaned-off from AKI-D.According to a secondary analysis of the RENAL study in critically ill patients with AKI, ACEi administration during the follow-up period was infrequent and was not associated with the statistically significant impact upon patient survival . A previIn patients administered with ARB or ACEi, plasma angiotensin II levels were augmented in the ARB group but no similar findings were noticed in the ACEi group ; thus, AACE2 expression is abundant in the kidney and is thought to provide protection against kidney injury . PreclinHyperkalemia is a possible caveat of the RASi prescription. However, we found that patients given either ARB or ACEi did not have increasing risk of hyperkalemia following the AKI-D.It is the first large-scale study to investigate the individual impact of ACEi versus ARB in patients after weaning from AKI-D via utilization of a well-maintained high-quality population cohort, in which the selection bias could be reasonably minimized. Additionally, we had a longer follow-up period than that was usually reported in clinical trials and thus enabled the evaluation of longer-term risks and benefits of RASi therapy in the real-world practice.Our study also has some limitations. First, our study was an observational study; therefore, the associations were not prospective, and strong causality cannot be inferred. Some important covariates, such as blood pressure, urine output, and body mass index after discharge were not available in our cohort. The observational nature of this study was an intrinsic and unavoidable limitation because the lack of randomization precluded a definite investigation of treatment advantages. Second, obviously, the treating physicians at the time of prescribing the medication had already made a risk assessment and decided that the benefits of ACEi or ARB outweighed the potential nephrotoxicity. Some patients could present AKI related to RAS inhibitors. However, we found that patients continuing use of ACEis or ARBs among AKD patients did not have increasing risk of re-dialysis. Although eGFR dip has strong association with subsequent progression to end-stage kidney disease , the curHowever, it is very challenging to perform a randomized controlled trial because ACEi and ARB are standard therapeutic agents and widely used in treating hypertension, diabetic kidney disease, and congestive heart failure. Moreover, using the validated outcome of gastrointestinal bleeding that was not interfered by ACEi/ARB, we could confirm that the selection bias was minimal, if any, from our study design. Additionally, the disease severity score after propensity score matching is similar between the study groups. Actually, regarding kidney function at baseline and the AKD period after weaning, ARB users in this study had the lowest eGFR than others before matching. Even though the ratios of comorbidities  were more severe in ARB users in our cohort, we still noticed the significant survival benefit of ARB usage.Given the better outcome efficacy but fewer adverse events with ARB , risk-toIn the future, prospective head-to-head comparison trials are the only ironclad way to compare the efficacy and safety of ARB objectively and to test whether the ARB outcome “paradox” really holds true ironclad.In conclusion, our present study revealed that prior and continuing ARB usage was associated with lower risk of mortality after AKI-D patients weaned off dialysis, while the use of ACEi did not have survival benefit. New users of ACEi among these AKD patients had a higher risk of re-dialysis after mortality was controlled as a competing risk. The use of ACEi or ARB at the AKD period did not increase the risk of hyperkalemia. Further prospective randomized studies are needed to verify our findings.


Since March 2020, SARS-CoV-2 has plagued the world with COVID-19 and individuals of all ages have experienced varying symptoms of disease. Older adults were experiencing more severe disease compared to children and were prioritized by vaccination efforts. While biologic therapies and vaccinations were implemented, there were changes in public health restrictions with subsequent surges resulting in more infected children. During these surges there was a rise of different SARS-CoV-2 variants with the dominant variant initially alpha (B.1.1.7 and other Pango lineages) and epsilon (B.1.427/B.1.429) in early 2021 and a dramatic shift to delta (B.1.617.2 and other Pango lineages) by mid-summer 2021. In this study we aimed to characterize the clinical severity and host factors associated with disease by SARS-CoV-2 variant and evaluate if there are differences in disease severity by circulating variant. We retrospectively included all individuals 0–25 years of age who presented to our center and had a positive SARS-CoV-2 RT-PCR, SARS-CoV-2 variant mutation testing, and documented clinical notes from 1 January 2021 through 31 December 2021. We identified 745 individuals who met inclusion criteria and found the delta variant was associated with severe/critical disease compared to the other variants studied. The results of the model showed that underlying respiratory disease and diabetes were risk factors for progression to severe disease. These insights are important when evaluating public health measures and treatment options for children as more variants arise. The novel coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been associated with less severe outcomes in children in comparison to adults. Over the course of the COVID-19 pandemic, adult patients filled hospitals to capacity across the United States with children's hospitals experiencing severe cases to a lesser extent .With implementation of vaccinations alongside other SARS-CoV-2 therapeutics, there has been a rise in variants of concern for SARS-CoV-2 . SARS-CoAs of November 2021, the World Health Organization (WHO) had designated five SARS-CoV-2 variants as VOCs: alpha , beta , gamma , delta , and omicron  . In MarcThroughout 2021 in the United States there was a notable change in the dominant SARS-CoV-2 variant in circulation with a shift from alpha (B.1.1.7 and other Pango lineages) to delta (B.1.617.2 and other Pango lineages) by mid-year  and variant genotyping was performed at the Stanford Clinical Virology Laboratory. Initial respiratory SARS-CoV-2 NAAT was conducted on a variety of platforms according to manufacturer and emergency authorization instructions as previously described .E gene  cycle threshold (Ct) <35, or transcription-mediated amplification relative light units (RLU) > 1,100 were subject to different multiplex allele-specific genotyping RT-qPCR reactions targeting spike mutations associated with known variants of concern. Due to the evolving variant landscape, individual samples may have been genotyped by one, two, or all three of the following previously-described RT-qPCR reactions: Reaction 1 targeting mutations in N501Y, E484K, L452R with internal control of wildtype N501 , ReactioE gene . ReactioE gene .We utilized the Stanford University research data repository (STARR) for the EPIC electronic medical record at both hospitals to identify individuals. A pediatric infectious physician team member also manually reviewed each chart to collect relevant clinical information. The study was approved by the Stanford University Institutional Review Board (IRB protocol 60259). Individuals were classified by the NIH/CDC criteria for acute COVID-19 disease into five categories: asymptomatic/pre-symptomatic infection, mild illness, moderate illness, severe illness, and critical illness . AsymptoU test was used to compare non-normally distributed continuous variables, and independent sample t-test to compare normally distributed continuous variables. The Chi-Square test statistic was also used to compare independence between disease severity and variant subtype, and between disease severity and other covariates in the study. When assumptions of the Chi -square statistic used in our analysis were violated, the non-parametric equivalent Fisher's exact test was used. Univariate and multivariate proportional odds models were then used to evaluate the influence of various SARS-CoV-2 variants on disease severity. We conducted proportional odds model analysis examining factors impacting disease severity  among our study participants. Given the low number of patients with severe and critical disease we combined these categories as all individuals in this category required oxygen support. Overall unadjusted and adjusted models did not meet the proportional odds assumption and so, we report the average effect of our models. All statistical tests were 2-sided, and p-values < 0.05 were considered statistically significant. Informed consent for retrospective data collection was waived as approved by the institutional review board.SAS (r) Proprietary Software 9.4, Copyright (c) 2016 by SAS Institute Inc., Cary, NC, USA was used to perform the statistical analysis of the study data. To assess the normality of distribution of continuous variables in our dataset, the Shapiro Wilk  test was used. Descriptive statistics for continuous variables that were normally distributed included mean ± standard deviation and median (min-max) for non-normally distributed variables. Mann Whitney-Initially 2,137 SARS-CoV-2 RT-PCR positive individuals aged 0–25 years old were identified by testing through Stanford Children's Health and Stanford Healthcare at Stanford University from 1 January 2021 to 31 December 2021. Of those 1,504 had variant data and the remaining 633 without were excluded. In review of the variant data, 591 were identified to be the omicron VOC at the end of December 2021 and were excluded from this study. In review of the charts, 165 did not have any relevant clinical data and were excluded. Three individuals were identified to have multisystem inflammatory syndrome in children (MIS-C) and excluded. After meeting all the inclusion/exclusion criteria for our study, a total of 745 individuals were included for analysis as shown in p-value =< 0.0001). Individuals infected with SARS-CoV-2 variants other than the delta VOC were on average less likely to have severe disease as seen in both the unadjusted and adjusted models. Age was evaluated as a continuous variable and an increase in age by one unit was also likely to increase the risk of severe disease among our study participants. Unadjusted, Individuals with diabetes had a 2.8 times higher likelihood of having severe disease compared to individuals without diabetes which was statistically significant . However, upon controlling for other independent variables in our model, there was only a 2.2 higher likelihood of severe disease among those with diabetes compared to those without diabetes .The overall unadjusted and adjusted results of the proportional odds models examining disease severity following exposure to different SARS-CoV-2 variants were significant  with a 2.2-fold increase in the odds of more severe disease among individuals with underlying respiratory disease (other than COVID-19) when compared to individuals with no underlying respiratory disease . The results from our unadjusted and adjusted proportional odds models are shown in Our study however did find that the unadjusted model met the proportional odds assumption  given there was a rise in cases at the end of December 2021 with majority of cases falling outside the window for this study, resulting in an incomplete characterization for this variant.An additional limitation is in the methodology of multiplex RT-qPCR genotyping as a way to identify and differentiate between variants of concern. While theoretically inferior in accuracy when compared to whole genome sequencing, our RT-qPCR approach allowed for genotyping of a much larger number of samples, including samples with lower viral loads that could not be successfully sequenced. Furthermore, sensitivity and specificity of these RT-qPCR reactions when compared with whole genome sequencing was >99% in the literature –15. All This study highlights that the delta variant was associated more with severe disease than prior variants in children at our center and that certain vulnerable groups (with respiratory disease and diabetes) are at risk for more severe disease. Further studies can investigate the differences with newer variants as they arise.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by Stanford University Institutional Review Board. Written informed consent for participation was not provided by the participants' legal guardians/next of kin because: This was a retrospective chart review and did not directly affect any of the study participants. The standard of care was achieved for all individuals for treatment in the hospital setting independent of this study. This study in no way changed patient care or require anything further of the study participants.AK worked on conceptualization, chart review, analysis, writing, and editing. CI worked on analysis, writing, and editing. HW worked on conceptualization, data collection, writing, and editing. MKS, CH, DS, and FY worked on data collection/generation. SN worked on analysis and editing. BB worked on data generation. BP worked on conceptualization, data collection/generation, and editing. AL worked on conceptualization, analysis, and editing. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.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.


P < 0.05). This study showed satisfactory physician adherence to contemporary treatment for HFrEF. Optimal adherence to HF medication significantly correlated with better PROs.This Korean nationwide, multicenter, noninterventional, prospective cohort study aimed to analyze physician adherence to guideline-recommended therapy for heart failure (HF) with reduced ejection fraction (HFrEF) and its effect on patient-reported outcomes (PROs). Patients diagnosed with or hospitalized for HFrEF within the previous year were enrolled. Treatment adherence was considered optimal when all 3 categories of guideline-recommended medications  were prescribed and suboptimal when ≤ 2 categories were prescribed. The 36-Item Short Form Survey (SF-36) scores were compared at baseline and 6 months between the 2 groups. Overall, 854 patients from 30 hospitals were included. At baseline, the optimal adherence group comprised 527 patients (61.7%), whereas during follow-up, the optimal and suboptimal adherence groups comprised 462 (54.1%) and 281 (32.9%) patients, respectively. Patients in the suboptimal adherence group were older, with a lower body mass index, and increased comorbidities, including renal dysfunction. SF-36 scores were significantly higher in the optimal adherence group for most domains ( Recent HF guidelines recommend evidence-based medications to reduce mortality in patients with HF with reduced ejection fraction (HFrEF)4. These medications include angiotensin-converting enzyme inhibitors (ACEis)/angiotensin receptor blockers (ARBs), beta-blockers (BBs), and mineralocorticoid receptor antagonists (MRAs)5. Based on the results of landmark randomized controlled trials, angiotensin receptor-neprilysin inhibitors (ARNIs) were included as a class I indication in the recently updated HF guidelines. Subsequently, recent trials have investigated the potential of ARNIs in increasing the survival and quality of life of patients with HF9. However, to date, large-scale performance-measure trials in HF have not included patients treated with ARNIs, a drug class that can improve patient outcomes and treatment cost-effectiveness10. The changing clinical profiles of patients with HFrEF necessitate a reassessment of patient quality of life and physician adherence to the latest HF guidelines, which now include 5 different classes of recommended medications (class I indication).Heart failure (HF) is a major threat globally, owing to its association with increased morbidity, mortality, and deterioration in the quality of life of patients. It also imposes a substantial economic burden on the society11. Furthermore, compelling data from a previous study show that many patients with HF do not take their medications as prescribed by their healthcare providers. According to these data, the overall compliance among patients with HF was 72%, and noncompliance contributed to worsening of HF symptoms, thereby leading to hospitalization12. Therefore, further studies on contemporary medical treatment patterns, including use of ARNIs, in patients with HFrEF are necessary to gain insights into improved treatment strategies in these patients.Moreover, a gap exists between the recommended guidelines and the current practice of HF treatment with respect to physician adherence. An observational nationwide study using the Korean National Health Insurance Claims database showed that 28.6% of elderly patients with HF did not receive optimal evidence-based treatment13. Patient-reported outcome (PRO) measures are used to evaluate patient-reported information in terms of subjective health, including health-related quality of life, symptoms of anxiety and depression, and symptom burden. Evaluation of PROs in patients with HFrEF is important because HF is a common chronic illness that is accompanied by frequent acute exacerbations, often requiring hospitalization, and a significant symptom burden14. PROs enable physicians to deliver more patient-centered care, thereby improving patients’ quality of life. A recent study showed that nonadherence to medication also correlated with poor PROs15. Real-world nationwide data on adherence to guideline-recommended treatment and PROs in Asian patients with HF are lacking with respect to ARNIs. Therefore, this study aimed to analyze the treatment patterns of patients with HFrEF in the era of ARNIs and to evaluate PROs according to physician adherence to guideline-recommended treatments.Poor quality of life resulting from uncontrolled symptoms is a major concern and an important target for treatment in patients with HF. Notably, patients with HF with uncontrolled symptoms had low scores in all domains of the 36-Item Short Form Survey (SF-36), a tool designed to evaluate quality-of-life parameters such as physical health and mental statusThis was a Korean nationwide, multicenter, noninterventional, prospective cohort study. Patients with HFrEF who were diagnosed with HF or hospitalized for HF within the previous year were enrolled on an outpatient basis. Data were collected at enrollment (baseline) and after 6 months by review of medical records and patient paper surveys. Only patients who completed the 6-month follow-up were included in the final analysis. Adult patients aged ≥ 19 years with a documented diagnosis of HF using the International Classification of Diseases 10th Revision (ICD-10) codes I50, I50.0, I50.1, I50.9, I11.0, I13.0, I13.2, I25.5, I42, or I42.x on the main or first subdiagnosis; patients with HFrEF with a left ventricular ejection fraction (LVEF) < 40% and New York Heart Association class II-IV; patients diagnosed with HF or hospitalized for HF within the previous year; and patients with an outpatient status at the enrollment date were included in the analysis. Patients who had participated in an interventional clinical trial 1 year before enrollment and patients with an inpatient status at the enrollment date were excluded. The study design is summarized in Fig. The study was performed in accordance with the principles outlined in the Declaration of Helsinki and was approved by the institutional review board of Wonju Severance Christian Hospital (IRB number CR317108) and each participating center . All patients provided written informed consent before enrollment in the study.Adherence to guideline-directed medical therapy for HFrEF  was evaluated using the prescription information at baseline and after a follow-up of 6 months. Adherence to treatment was considered optimal when all 3 categories of medications were prescribed and suboptimal when ≤ 2 categories of medications were prescribed.The primary objective of the study was to evaluate the treatment patterns of patients with HFrEF according to physician adherence in the era of ARNIs. Patient characteristics and treatment patterns were obtained from hospital medical records.16, which provides scores for physical health as well as mental status. SF-36 consists of the following 10 domains: physical functioning (PF), role physical (RP), bodily pain (BP), general health (GH), vitality (VT), social functioning (SF), role emotional (RE), mental health (MH), physical component summary (PCS), and mental component summary (MCS). The scores for each domain range from 0 to 100, with higher scores indicating better quality of life.Quality of life was measured using SF-36SF-36 scores were compared between the optimal adherence and suboptimal adherence groups at baseline and at 6 months. In addition, the time to HF hospitalization, defined as the duration from study enrollment to hospitalization for HF during the 6-month follow-up, was compared between the 2 groups.t-test was used to compare the variables at baseline and at the 6-month follow-up within each group. Comparisons of continuous variables between the optimal adherence group and suboptimal adherence group were made using the Student’s independent 2-sample t-test. For categorical variables, the chi-square test was used to compare the data between the 2 adherence groups. The log-rank test was used to compare time to hospitalization due to HF between the 2 groups. A 2-tailed P value of < 0.05 was considered statistically significant. Statistical analyses were performed using IBM SPSS Statistics, version 21 .All data were analyzed without adjustments for outliers or imputation for missing values. Categorical variables are presented as numbers and frequencies, whereas continuous variables are presented as means ± standard deviations. A paired A total of 975 patients from 30 hospitals were enrolled, of whom 854 completed the 6-month follow-up and were included in the analysis. Patients were enrolled from July 2018 to April 2019, and data were collected from July 2018 to November 2019, with a mean ± standard deviation follow-up duration of 183.4 ± 28.7 days . Of the 854 patients, 527 (61.7%) were in the optimal adherence group and 327 (38.3%) were in the suboptimal adherence group based on the prescription data collected at enrollment , BBs, and MRAs, respectively . At the 6-month follow-up, SF-36 scores for all domains were significantly higher in the optimal adherence group than in the suboptimal adherence group . A significant increase in scores during the follow-up period was also noted in the optimal adherence group, whereas the increase in scores was less prominent in the suboptimal adherence group. SF-36 scores are presented in Table SF-36 scores for PROs at baseline and at the 6-month follow-up were significantly better in the optimal adherence group for most domains. The optimal adherence group had significantly higher scores at baseline for all domains, except VT, MH, and MCS, than the suboptimal adherence group .A total of 49 patients (9.3%) in the optimal adherence group and 34 patients (10.4%) in the suboptimal adherence group were hospitalized for HF during the 6-month follow-up. The log-rank test showed no significant difference between the 2 groups  physician adherence to guideline-directed medical therapy was satisfactory ; (2) patients in the suboptimal adherence group tended to be older and had a lower body mass index and increased comorbidities, including renal dysfunction; and (3) patients in the optimal adherence group had better PROs at baseline and a more prominent improvement in PROs at the 6-month follow-up compared with those in the suboptimal adherence group.21. Data on physician adherence from previous HF registries or trials were focused only on the 3 categories of guideline-recommended HF medications—ACEis/ARBs/ARNIs, BBs, and MRAs. Data from these HF registries21 revealed a lower prescription rate for all 3 categories of medications. However, recent prospective HFrEF trials showed a higher prescription rate for these medications15. In the present study, the use of renin-angiotensin system blockers was 91.5%, which included ARNIs (32.4%). The use of BBs and MRAs was also high, accounting for 89.8% and 72.3%, respectively. Compared with previous registry data in the country, the current data show a substantial improvement in physician adherence to HF therapy guidelines, particularly with respect to the use of BBs (49.9% in the The Korean Acute Heart Failure (KorAHF); Fig. 17. Compared with previous studies, this study showed a satisfactory prescription rate, which could be attributed to the effect of indirect intervention that may have enhanced physician awareness, and the fact that most patients in this study were enrolled at tertiary university hospitals with dedicated HF specialists. Moreover, the emergence of ARNI, a new treatment option for HFrEF, and its large diffusion could have also influenced adherence to HF therapy guidelines.Data regarding treatment patterns obtained from the current Korean nationwide prospective cohort study are more robust compared with the data obtained from previous international or national registriesARNIs 32.%. The us22. Physician adherence is also important in the management of patients with HF27. PRO measures indicative of feelings or functions related to the patient’s health and treatments are considered important indicators of HF, owing to the significant symptom burden of the disease14. Among the various PRO measures, SF-36 provides information on a wide range of parameters indicative of health status. SF-36 has been validated for measuring health-related quality of life in patients with chronic illnesses in several countries31, but data on the Asian population are still lacking. The results of this study showed that optimal adherence was associated with higher SF-36 scores at baseline, and a noticeable improvement was observed at the 6-month follow-up. However, considerable improvements were also observed in several SF-36 domains in the suboptimal adherence group as patients in this group received at least some degree of guideline-directed pharmacological treatment, and nonpharmacological treatment was administered regardless of the medication status during the study period. SF-36 scores observed in this study were higher than those reported in the previous registry data from Western countries32; this may be attributable to the prospective nature of the current study, which might have had an indirect effect on physician adherence, resulting in higher PRO scores.Patient adherence to guideline-directed HF medications is crucial to reduce mortality and morbidity33. The interventions implemented in the current study to improve patient adherence, such as training/education sessions, patient reminder systems, self-care support, physician factors, and organizational changes, were effective in decreasing mortality and rehospitalization.Various measures have been developed and applied to increase patient-level adherence or compliance for better outcomes34. This result indicates the difficulty in maintaining optimal compliance with an increase in the number of medications. Physicians need to pay continuous attention during their everyday practice to maintain an optimal level of treatment in patients with HF.In the previous study, patients’ noncompliance to therapy was significantly associated with an increase in the number of medicines35. These factors also correlated with poor outcome and further increased the risk of poor physician adherence to optimal management36. In this study, we observed that older age, female sex, low body mass index, more diverse comorbidities, elevated NT-proBNP, decreased renal function, and a relatively preserved left ventricular systolic function were consistently associated with suboptimal adherence at baseline and at the 6-month follow-up. Worsening renal function and combined comorbidities associated with polypharmacy may interfere with optimal HFrEF medication in these patients. Significantly higher NT-proBNP level also reflect the high-risk features of suboptimal adherence group. However, patients with comorbidities who are at higher risk of adverse outcomes require more intensive optimal medical therapy. Patients with relatively preserved left ventricular systolic function (LVEF > 35% to < 40%) are not frequently prescribed all 3 categories of medications as the current guidelines do not recommend routine use of MRAs for LVEF > 35% and partly because of physician inertia in patients with a relatively higher LVEF. Improving physician adherence is crucial, particularly in the context of such high-risk patients. As the aging population increases worldwide, particularly in Asia (including Korea), the issue of adherence trend linked to underlying patient factors needs to be addressed.According to a previous study, the factors associated with underuse of guideline-directed therapy in HF were female sex, older age, renal dysfunction, liver dysfunction, bradycardia, and hypotensionTo the best of our knowledge, this is the first prospective cohort study to evaluate the effect of physician adherence on PROs in the era of ARNIs. Current HF guidelines recommend the use of ARNIs over ACEis/ARBs to improve outcomes. Considerable use of ARNIs (> 32%) is reflective of the current real-world treatment pattern for HF.Despite the above-mentioned strengths, this study has several potential limitations. First, adherence to guidelines was evaluated by medication categories without considering the target dose. However, because of the diversity in the up-titration and dose-adjustment process, calculation of the absolute value of the medication dose during a specific period is difficult. Furthermore, a substantial number of patients cannot reach the target doses even in prospective trials, and a lower dose of medication has proven to be effective in those trials. Second, unlike the previous studies on physician adherence, this study showed no difference in clinical events . This could be due to the short follow-up period and the relatively lower incidence of adverse events observed in the present study. The nonblinded nature of the study might have had an impact on physician and patient awareness, resulting in better HF education and self-management in the entire study population, thereby weakening the early effect of optimal physician adherence. Third, the patients included in this study were relatively younger than those in the previous HF registry study. The trend toward a younger study population has also been seen in previous PRO studies that required patients to have preserved cognitive function to answer the survey questions. Extended observation might elucidate the effect of physicians’ optimal adherence on clinical outcomes.Data from the Korean nationwide, prospective registry showed favorable physician adherence to contemporary medical therapy for HFrEF. Optimal physician adherence to HF medications was associated with better PROs. Further studies are required to elucidate the effect of optimal physician adherence on clinical outcomes.Supplementary Figure 1.Supplementary Information.


The neoadjuvant use of immune checkpoint inhibitors (ICI) in resectable non-small cell lung cancer (NSCLC) is being increasingly adopted, but questions about the most appropriate applications remain. Although patients with resectable NSCLC are often treated with surgery and adjuvant chemotherapy or targeted therapies +/− radiotherapy, they still have a high risk of recurrence and death. In recent years, immune checkpoint inhibitors (ICI) (anti-PD-1/PD-L1 and anti-CTLA-4) have provided a new and effective therapeutic strategy for the treatment of advanced NSCLC. Therefore, it is possible that ICIs for early-stage NSCLC may follow the pattern established in metastatic disease. Currently, there are several ongoing trials to determine the efficacy in the neoadjuvant setting for patients with local or regional disease. To date, only nivolumab in combination with chemotherapy has been approved by the U.S. FDA in the preoperative setting, but data continue to evolve rapidly, and treatment guidelines need to be determined. In this article, we review the current preclinical and clinical evidence on neoadjuvant ICIs alone and combination in the treatment of early-stage NSCLC. Lung cancer is the leading cause of cancer mortality in the U.S. each year, representing nearly one-quarter of all cancer-related deaths . SurgeryIn recent years, the advent of immunotherapy has greatly changed the landscape of thoracic oncology care. The use of immune checkpoint inhibitors (ICIs), compared with conventional therapeutic modalities, has been found to be safe and effective in patients with advanced NSCLC ,7,8,9. WThe process of cancer detection by the immune system features several key steps, known as the cancer-immunity cycle . The firOne of the early requirements for a cancer cell’s survival and propagation is the task of avoiding host immune detection and destruction, described in the cancer-immunity cycle, and cancer cells possess many different mechanisms to accomplish this immune evasion . One of A second, incompletely understood, mechanism for blocking T-cell activation occurs through programmed cell death protein 1/programmed cell death ligand 1 (PD-1/PD-L1) binding . PD-1 onIn 1996, it was discovered that the anti-CTLA-4 antibody (Ab) demonstrated potent antitumor effects with its administration in tumor-transplanted mice, leading to the rejection of the tumor, even when anti-CTLA4 was given a week after initial transplantation of the tumor . Later, In recent years, preclinical investigations, vital for application in the clinical setting, have focused more on further understanding in depth the dynamic immune response mechanism of ICIs across organ systems and on exploring strategies to apply this understanding to maximize antitumor benefit . SpecifiA unique feature of preclinical immune checkpoint investigations in the neoadjuvant setting is the ability to study the in vivo effects of ICIs on the peripheral blood and tumor microenvironment, which is valuable in studying the details of the mechanisms of the antitumor effects seen with ICIs. A recent study in an orthotopic mouse model of early-stage KRAS-driven NSCLC found changes to the tumor microenvironment with treatments using anti-PD-1, which, with further investigation, may serve as useful predictive markers for disease response to treatment . Prior tMoreover, studies have demonstrated profound changes in monocyte and macrophage subsets following anti-PD1/CTLA4 treatment, including elevated inducible nitric oxide synthase and decreased CD206 expression. Tumor-associated macrophages can respond actively to microenvironmental changes caused by checkpoint blockade, suggesting they should be considered when designing combinatorial strategies. Moreover, current data show that PD-L1 treatment can remodel the macrophage compartment, resulting in a more proinflammatory phenotype in both monocytes and macrophages. As a result of anti-PD-L1 treatment, macrophage polarization contributes significantly to enhancing T-cell responses, and that manipulation of macrophages in the tumor microenvironment can be used to augment the activity of anti-PD-L1 .Characterizing the tumor microenvironment continues to be an exciting area of future study, about which relatively little is known. A more thorough understanding of the tumor microenvironment and its changes with treatment, such as neoadjuvant ICI, is expected to be valuable for the potential identification of biomarkers that could be used to inform more individualized treatment decisions in the clinic . In the p = 0.007), and a 13% reduction in the relative risk of death , which only represented a modest improvement of 5% in absolute survival at 5 years [n = 21), two preoperative doses of the PD-1 inhibitor nivolumab were administered in adults with untreated, surgically resectable, early-stage  NSCLC, demonstrating no delays in surgery. An MPR occurred in 9 of 20 resected tumors , with 15% of all patients achieving a pathological complete response (pCR). The neoadjuvant nivolumab was associated with few side effects. Treatment-related adverse events of any grade occurred in 5 of 22 patients , and only one event was of grade 3 or higher. Furthermore, at the time of resection, tumors with an MPR had a higher frequency of T-cell clones that were shared between intratumoral and peripheral compartments, and a higher clonality of the T-cell population, as compared with tumors without an MPR. In early-stage lung cancer patients, achieving an MPR was highly associated with an increased tumor-mutational burden (TMB), similar to responses to PD-1 blockade in advanced NSCLC patients. These findings indicate that the TMB may be a primary determinant of the depth of pathological response to PD-1 blockade. Moreover, nivolumab also increased tumor infiltration of CD8+/PD-1-positive immune cells [After immunotherapy showed survival benefits in metastatic NSCLC, investigations on its use in the neoadjuvant setting followed ,34. Prio 5 years  reportedne cells . ICIs weVarious clinical trials, including Keynote-223 (MK3475-223) , LCMC3 , and NEOn = 30), without an MPR observed. However, the lack of response was attributed to the short delay between treatment with ICI and surgery, which occurred within 3–4 weeks after immunotherapy [Results of the phase-1 study Keynote-223 (MK3475-223)  demonstrotherapy .n = 29; 95% CI, 14–28%) and a pCR rate of 6% . Pathological response was significantly correlated with baseline PD-L1 tumor proportion score (TPS) , with an MPR being achieved more frequently in patients with a tumor showing a TPS of ≥50. Similarly, an MPR in patients with TMB ≥ 16 mutations per Mb was 33% (5 of 15). Neither a radiographical response nor an MPR was observed in tumors with EGFR or ALK mutations. The safety profile was consistent with that observed in advanced disease. The most common treatment-related adverse events of grade ≥3 were pneumonitis  and pneumonia  [The phase-2 LCMC3  is the lp = 0.057), non-effector tissue-resident memory T cells (p = 0.041), and effector tissue-resident memory T cells (p = 0.034) in samples treated with both nivolumab and ipilimumab vs. nivolumab monotherapy. These results suggest that the combination of immunotherapy led to higher levels of tumor-infiltration of both cytotoxic and memory cells, which may explain the higher levels of MPRs and pCRs seen in this study [With the growing body of evidence of a tolerable and safe profile and possible benefits in MPR and pCR, the phase-2 NEOSTAR trial  sought tis study .Similarly, Reuss et al.  conducten = 26) and in combination with the anti-NKG2A antibody monalizumab (n = 20), the anti-CD-73 antibody oleclumab (n = 21), and the anti-STAT3 antisense oligonucleotide danvatirsen (n = 16) in the neoadjuvant setting to treat patients with stage-I—IIIA resectable NSCLC. These novel immunotherapy combinations resulted in higher MPR and pCR rates. The safety profile in the durvalumab monotherapy arm (treatment-related adverse events in 34.6% of patients) was similar to previously published data for anti–PD-1/anti–PD-L1 antibodies. No new safety signals were identified with any of the combination regimens [Nonetheless, the positive initial clinical studies on the neoadjuvant use of ICIs in resectable NSCLC have sparked further investigations into its use as single agent, as well as combined with other ICIs or novel agents . The pharegimens . Based op = 0.0052)). Among those treated with nivolumab plus chemotherapy, the pCR rate was 24%, and it was 2.2%  in those treated with chemotherapy alone. In the nivolumab-plus-chemotherapy group, 33.5% of patients experienced grade-3 or -4 adverse events, compared with 36.9% of those who received chemotherapy alone. There was a delay in surgery in 3.4% of patients receiving nivolumab plus chemotherapy, and in 5.1% of those receiving chemotherapy alone, leading to surgery cancellation in 1.1% and 0.6%, respectively. Moreover, in patients treated with nivolumab plus chemotherapy, the percentage of patients with ctDNA clearance was higher  than in the group of patients receiving chemotherapy alone . Patients with ctDNA clearance showed higher EFS and pCR rates than those without it, in both treatment groups [The concept of combining chemotherapy with immunotherapy was validated in metastatic NSCLC . The addition of chemotherapy was hypothesized to lead to faster and deeper responses, with the release of more tumor antigens, thus augmenting the immune response and ICI activity. Efficacy in the neoadjuvant setting was evaluated in CHECKMATE-816 , a randot groups . On Marct groups .p = 0.0071). The combination of an immuno-chemotherapy regimen also improved MPR rates vs. chemotherapy alone (52% vs. 14%). Definitive surgery occurred for 91% of patients treated with adjuvant immunotherapy, and for 69% in the chemotherapy arm. According to data presented at the 2022 World Conference on Lung Cancer [p = 0.025). The OS rates at 12 and 24 months were 98.2% and 84.7%, respectively, in the nivolumab-plus-chemotherapy group, compared with 82.1% and 63.5% in the chemotherapy group. Median OS was not reached in either arm . Those results seem to reinforce the superiority of nivolumab in combination with chemotherapy vs. chemotherapy alone, significantly improving PFS, MPR and pCR rates in patients with stage-IIIA/B NSCLC.Additionally, the phase-2, two-arm NADIM II trial  enrolledg Cancer , patientWith the U.S. FDA approval of the use of nivolumab in conjunction with chemotherapy as a neoadjuvant treatment and of atezolizumab as an adjuvant treatment of resected NSCLC, clinicians are faced with the clinical dilemma of how best to incorporate immunotherapy in the multimodality treatment of early-stage NSCLC. Several clinical trials have investigated the role of neoadjuvant and adjuvant immunotherapy, specifically trying to determine whether sequential neoadjuvant chemoimmunotherapy and adjuvant immunotherapy improve clinical outcomes. The TOP1501 trial (NCT02818920)  enrolledThe SAKK 16/00 trial   administA major challenge in identifying patients who would most benefit from neoadjuvant ICI therapy is a lack of surrogate endpoints of clinical efficacy in many trials. While MPR has been shown to be a useful surrogate marker following neoadjuvant chemotherapy, its role following ICIs is less clear, with a significant number of patients with NSCLC found to be unresponsive to ICIs . It is tThe predictive role of PD-L1 expression has yet to be defined, constrained by heterogeneity among clinical trials utilizing different ICI agents in mono- and combination regimens, varying lengths of neoadjuvant therapies, and limited tissue availability in some cases. There are studies suggesting a positive correlation between high PD-L1 expression and an MPR ,52, whilIn the NADIM trial, TMB- and PD-L1-staining failed to show a correlation, but pretreatment circulating tumor DNA (ctDNA) was associated with survival . ctDNAs Other biomarkers under investigation include the composition of the gut microbiome and further analysis of the tumor-immune microenvironment, such as the intensity of CD8+ cell-infiltration and other immune-cell subsets . Recent As the treatment paradigm shifts now towards the novel inclusion of ICIs in the neoadjuvant phase, new considerations emerge for the avoidance of potential pitfalls. First, it is imperative to ensure appropriate patient selection. Currently, the data available do not support attempts at “downstaging” patients with marginally resectable tumors via reliance on neoadjuvant ICIs +/− cytotoxic- and radiotherapy. The first step in clinical decision-making is the early involvement of thoracic surgery teams through multidisciplinary discussions to ensure that patients are appropriate surgical candidates with resectable disease .Furthermore, there are insufficient data at present to determine the optimal ICI agent choice and duration. It is a thoughtful balance between administrations of a sufficient length of therapy to allow response while avoiding delays in curative surgical resections. This is further complicated by whether ICIs are administered alone, as a monotherapy, or in combination, and whether they are combined with chemotherapy and/or radiotherapy .Concern arises about potential immune-related adverse events that can occur during neoadjuvant therapy and lead to delays in surgical treatment, albeit most were found to be manageable and did not prevent patients from undergoing surgery . A recenWhile the phenomena of pseudo- and hyper-progression with ICIs have been noted in the metastatic setting, and radiographic response to assessment can be inaccurate, it is overall felt that progression on neoadjuvant immunotherapy is much more commonly a typical disease progression and should be managed as such . The thoFrom a surgical standpoint, it is uncertain whether utilizing ICIs in the neoadjuvant setting can lead to intraoperative difficulties, such as perihilar fibrosis, which may be related to duration between systemic neoadjuvant therapy and timing of surgery . It is aAs the field moves into this new direction of combined ICI and cytotoxic- and radiotherapy in the neoadjuvant setting and survival outcomes mature, a focus on accurate pathologic evaluation and close assessment of treatment-related complications is essential to clearly understand therapeutic efficacy and develop a toxicity profile to help clarify future clinical guidelines.


COVID-19 affects healthcare resource allocation, which could lead to treatment delay and poor outcomes in patients with acute myocardial infarction (AMI). We assessed the impact of the COVID-19 pandemic on AMI outcomes.We compared outcomes of patients admitted for acute ST-elevation MI (STEMI) and non-STEMI (NSTEMI) during a non-COVID-19 pandemic period  and a COVID-19 pandemic period .p < 0.05). Primary percutaneous intervention was performed significantly more often in Group 1 patients than in Group 2 patients, whereas thrombolytic therapy was used significantly more often in Group 2 patients than in Group 1 patients . However, the rates of and all-cause 30-day mortality and major adverse cardiac event (MACE) were not significantly different in the two periods . For NSTEMI patients, Group 2 patients had a higher rate of conservative therapy, a lower rate of reperfusion therapy, and longer FMC times . All-cause 30-day mortality and MACE were only higher in NSTEMI patients during the COVID-19 pandemic period (p < 0.001).For STEMI patients, the median of first medical contact (FMC) time, door-to-balloon time, and total myocardial ischemia time were significantly longer in Group 2 patients (all COVID-19 pandemic causes treatment delay in AMI patients and potentially leads to poor clinical outcome in NSTEMI patients. Thrombolytic therapy should be initiated without delay for STEMI when coronary intervention is not readily available; for NSTEMI patients, outcomes of invasive reperfusion were better than medical treatment. COVID-19 pandemic causes treatment delay for AMI and leads to poor clinical outcome.Thrombolytic therapy should be initiated without delay for STEMI when coronary intervention is not readily available.For NSTEMI patients, outcomes of invasive reperfusion were better than medical treatment.All hospitals must accommodate expeditious and appropriate care for AMI during COVID-19 pandemic.On March 11, 2020, the World Health Organization announced that the new coronavirus disease 2019 (COVID-19) had become a global pandemic. How to balance the care of cardiovascular emergency patients and the control of COVID-19 has become a global challenge during the pandemic. For patients with acute myocardial infarction (AMI) who also have COVID-19, a safe and effective medical environment is required in parallel with effective reperfusion therapy. Based on the experience of AMI management during the COVID-19 pandemic, Peking Union Medical College Hospital has made medical recommendations for China  and shouAccordingly, our hospital initiated response measures in January 2020 to combat the COVID-19 epidemic and revised the reperfusion treatment guidelines for AMI patients. However, at the same time, appropriate but important restrictions have been imposed on routine medical care to comply with the regulations on physical alienation in the public health guidelines and to help conserve or redirect limited resources. During this time, most invasive cardiovascular procedures and diagnostic tests have been postponed, and the North American Cardiovascular Society advocates the classification of patients and the management of patients on waiting lists . UnfortuAccordingly, our hospital launched emergency response measures in January 2020 to combat the COVID-19 outbreak, and it revised guidelines for reperfusion therapy in AMI patients. However, concurrently, appropriate but significant restrictions have been made on routine medical care to comply with public health guidance on physical distancing and to help preserve or redirect limited resources. During this time, most invasive cardiovascular procedures and diagnostic tests have been deferred, with North American cardiovascular societies advocating for intensified triage and management of patients on waiting lists . UnfortuThe study protocol was approved by the Ethics Committee of our Hospital (No. 2018KY-010-01), and all study steps were conducted under the supervision of this committee. All the patients were provided with written and oral explanations on the study course and goals. Participants then gave written informed consent before enrollment. Moreover, this study was conducted in accordance with the Declaration of Helsinki. This cross-sectional, single-center study enrolled patients with AMI diagnosed according to the Fourth Universal Definition of Myocardial Infarction  and the According to the COVID-19 trend and current best guidelines for AMI treatment , 16, ourPrior to receiving any cardiovascular procedure or test, patients received routine screening to help ensure the safety of health care workers. The testing included nasopharyngeal swab nucleic acid test according to the manufacturer’s instructions.U test, or the independent samples Kruskal–Wallis test, whereas the Chi-square or Fisher's exact tests were used for comparison of categorical values, depending on the distribution of data. The Kaplan–Meier method was used to compare the MACE-free survival time and all-cause death-free survival time for patients with non-COVID-19 and COVID-19, and curves were compared using the log-rank test. All statistical assessments were two-tailed, were considered significant at a p-value < 0.05, and were performed with IBM SPSS statistical software version 25 for Windows .The Kolmogorov–Smirnov test was used to verify the normality of all continuous variables. Continuous variables were reported as mean ± standard deviation (SD) or median and interquartile range (IQR), as appropriate. Categorical values were presented as absolute values or percentages. Comparison of continuous variables was performed with one-way ANOVA, the Mann–Whitney p > 0.05), although the heart rate was significantly higher in group 2 patients than in group 1 patients (p < 0.015).Patients’ baseline characteristics are presented in Table p < 0.05). The median time to first medical contact was about twice as long in Group 2 patients as in Group 1 patients, and the median door-to-balloon (DTB) time also was longer in the Group 2 patients. Total myocardial ischemia time was about twice longer in Group 2 patients than in Group 1 patients .Clinical treatment of STEMI patients during the non-COVID-19 pandemic period (Group 1) and the COVID-19 pandemic period Group 2) is presented in Table  is presep < 0.05). As with STEMI patients, though, median FMC times were significantly longer in Group 2 NSTEMI patients than in Group 1 NSTEMI patients (p < 0.05).Comparison of clinical treatment during the non-COVID-19 pandemic period (Group 1) and the COVID-19 pandemic period (Group 2) NSTEMI patients is presented in Table p > 0.05). In contrast with STEMI patients, NSTEMI patients in the COVID-19 pandemic period (Group 2) had significantly higher rates of all-cause mortality, MACE, and MACE-associated all-cause mortality than did patients in the non-COVID-19 pandemic period .Thirty-day outcomes of STEMI and NSTEMI patients in the non-COVID-19 pandemic period and the COVID-19 pandemic period are presented in Table p < 0.05).In Kaplan–Meier plot analysis Fig. , STEMI pThis study analyzed the management of patients with acute coronary artery disease during a two-month period of the COVID-19 pandemic compared with management during a similar two-month period a year earlier. Substantial differences—some with important effects on patient outcomes—were identified: For NSTEMI patients, reperfusion therapy was used significantly less often in the pandemic period, whereas conservative treatment was used significantly more often, and first medical contact times were longer. Correspondingly, NSTEMI patients had significantly higher probability of MACE, MACE-associated death, and all-cause death in the COVID-19 pandemic period than in the non-COVID-19 pandemic period. These findings imply that delays in initiating cardiac care imposed by COVID-19 resulted in poorer outcomes for NSTEMI. In contrast with NSTEMI patients, rates of reperfusion therapy and conservative therapy for STEMI patients were not significantly different between the non-pandemic and pandemic periods; also, although FMC and total myocardial ischemia times for STEMI patients were much longer in the pandemic period than in the non-pandemic period, the probabilities of MACE, MACE-associated death, and all-cause death were not significantly different in the two periods. Ours is the only study we know of that related conservative therapy, FMC time, and prognosis in NSTEMI patients during the COVID-19 pandemic and non-COVID-19 periods. We also know of no study that has correlated the high risk of all-cause mortality and MACE with the increased FMC time and conservative therapy of NSTEMI patients during these two periods.The COVID-19 pandemic has led to marked global morbidity and mortality –19. GuidPrompt diagnosis and treatment can reduce mortality, improve prognosis, and reduce the duration of hospital stay in patients with STEMI . ReperfuTimely implementation of reperfusion therapy is key in the management of STEMI, since the greatest benefit gained from reperfusion therapy occurs within the first two–three hours of symptom onset , 30. ShoThis was a single center experience with limited patient number, and it is a retrospective, chart review study, with all the potential for bias in that format.COVID-19 pandemic causes treatment delay in AMI patients and potentially leads to poor clinical outcome in NSTEMI patients. Thrombolytic therapy should be initiated without delay for STEMI when coronary intervention is not readily available; for NSTEMI patients, outcomes of invasive reperfusion were better than medical treatment. All hospitals not only must prepare to treat immediate COVID-19 cases but also provide expeditious and appropriate care for patients with acute coronary artery disease.


Thyroid hormones widely affect the cardiovascular system, but the effects of mild thyroid dysfunction on the clinical prognosis of patients with acute ST segment elevation myocardial infarction (STEMI) remains unclear. Our aims were to analyze the relations between mild thyroid dysfunction at admission and clinical outcomes in Chinese patients with STEMI.A total of 1,176 STEMI patients with the available data of thyroid function and follow-up were analyzed, including 348 patients with mild thyroid dysfunction  and 828 patients with euthyroid function. During a median 4.4-year follow-up, in-hospital mortality, cardiac and all-cause mortalities were subsequently compared among the four groups.Compared with the euthyroid group, STEMI patients in the SHyper and LT3S groups faced obviously increased risks of in-hospital death  and all-cause mortality HR: 1.647, 95% CI: 1.072–2.531, p = 0.023] than those with euthyroid at baseline, whereas no significantly increased mortality was found for STEMI patients with SCH and SHyper at baseline.STEMI patients with SHyper at admission had increased risk of in-hospital mortality, and STEMI patients with LT3S at baseline had worse prognosis and higher incidences of in-hospital mortality and cardiovascular and all-cause deaths compared with euthyroid patients. Acute myocardial infarction (AMI) is caused by a variety of factors and remains at a high rate of mortality, even though great progresses are made in pharmacotherapy and myocardial reperfusion , 2. In tFurthermore, the studies regarding the influences of mild thyroid dysfunction on the poor prognosis in Chinese patients suffering from AMI are also extremely limited. One of our aims was to compare and assess the effects of mild thyroid dysfunction on cardiac function and in-hospital mortality in Chinese patients with acute ST segment elevation myocardial infarction (STEMI). Moreover, we also explored and evaluated the impacts of mild thyroid dysfunctional states at baseline on the cardiovascular and all-cause mortality rates during a median follow-up period of 4.4 years.A total of 1,847 Chinese AMI patients who were admitted to the Department of Cardiology in Shanghai Jiao Tong University Affiliated Sixth People’s Hospital during the period from September 2007 to September 2014 were enrolled in the present study. Among them, 671 candidates were successively eliminated due to the following reasons: (1) patients with non-ST-elevation AMI (NSTEMI) (n=95); (2) known or clinically thyroid disorders (n=76); (3) current or previous treatment with thyroid hormone supplementation, antithyroid medications, corticosteroids, dopamine, dobutamine, amiodarone or lithium (n=52); (4) thyroid indicators were obtained after coronary angiography or CTA (n=239); (5) unable to complete coronary examination due to end-stage diseases (n=83);and (6) a lack of clinical data or loss of follow-up (n=126). Ultimately, 1,176 participants took part in this analysis and then they were divided into four groups including euthyroidism, SCH, SHyper, and LT3S according to their thyroid hormone values. During a median 4.4-year follow-up, we subsequently made comparisons on in-hospital mortality, cardiac and all-cause mortalities among the four groups. Our study was approved by the ethics committee of the Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, and all participants signed written informed consent forms.−1.154 × (age)−0.203 (× 0.742 if woman)  were recorded and detailed information on the history of diabetes, hypertension, alcohol use, and smoking habits was collected through a standard interview when the patients entered into the Department of Cardiology. Body mass index (BMI) was obtained as weight divided by the square of height. Thyroid profile including free triiodothyronine (FT3), free thyroxine (FT4), thyroid-stimulating hormone (TSH), and other blood indicators such as white blood cell (WBC), hemoglobin, C-reactive protein (CRP), serum creatinine (SCr), serum albumin, total cholesterol (TC), total triglyceride (TTG), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), fasting plasma glucose (FPG), N-terminal pro-B-type natriuretic peptide (NT-proBNP), and troponin I (TnI) were obtained from blood samplings after an overnight fast within 24 h after admission and prior to coronary angiography or CTA. The thyroid function profile was gathered using a chemiluminescence technique . The estimated glomerular filtration rate (eGFR) was obtained by the simplified MDRD formula: eGFR = 186.3 × (serum creatinine)f woman) .via an Acuson Sequoia 512 scanner with a probe of 5-13-MHz following a standard protocol. The data regarding Killip class, revascularization (percutaneous coronary intervention or coronary artery bypass graft), medications at discharge, and in-hospital deaths were obtained from their discharge summaries. After the discharge from hospital, a regular clinical follow-up was conducted through telephone or office visits annually.All patients underwent coronary angiography or CTA to make a definitive diagnosis, and the culprit vessels were treated by oral medications, percutaneous coronary intervention, or coronary artery bypass graft , 12. TheAMI was diagnosed when chest pain for more than 30 min with dynamic 12-lead electrocardiogram (ECG) changes or elevated troponin enzymes and STEMI were defined as AMI accompanied by ST segment elevation in ≥2 contiguous ECG leads according to the ACC/AHA guidelines . The refAccidental death was excluded, and all deaths were caused by any natural factor. Cardiovascular death was defined as the mortality attributable to myocardial infarction, cardiogenic shock, significant arrhythmia, progressive heart failure, or pulmonary embolism without a precipitating factor. Sudden unexpected death outside the hospital was regarded as a cardiac death, and no autopsy was performed. In-hospital deaths were not included into all-cause mortality and cardiovascular death. All events were identified and sorted by two cardiologists. We calculated the survival times from the date of the STEMI to the date of death.Data were analyzed by SPSS 19.0 software. Firstly, normality was checked for continuous variables by Q-Q plots. Normally distributed variables were expressed as mean ± standard deviation and were compared using one-way ANOVA with LSD, whereas unevenly distributed variables were represented as median with interquartile range (IQR) and were compared by the Kruskal–Wallis test. Secondly, categorical variables were expressed as absolute numbers (percentages) and were compared by the χ2 test. Thirdly, three binary logistic regression models were used to assess the association of mild thyroid dysfunction and in-hospital mortality: a non-adjusted model; an age- and sex-adjusted model; and a multivariable model that included all variables with p-value < 0.05 from the univariate analyses through the forward stepwise procedure. The results were expressed as odds ratios (ORs) with associated 95% confidence intervals (CIs). Fourthly, the univariate, age-, and sex-adjusted and multivariate Cox regression analyses were performed to analyze the effects of mild thyroid dysfunction states on cardiovascular and all-cause mortality. All baseline variables with p-value <0.05 in univariate analyses were entered into the multivariate Cox regression analysis and analyzed by forward stepwise regression. Results were reported as hazard ratios (HRs) with associated 95% CIs. The cumulative survival rates were described by Kaplan–Meier curves and were compared between groups by the log rank test based on the euthyroid group as the reference group. P < 0.05 was considered as statistically significant.Of the 1,176 participants analyzed, 828 patients (70.4%) were euthyroid, 81 patients (6.9%) had SCH, 51 patients (4.3%) had SHyper, and 216 patients (18.4%) had LT3S. The baseline demographic and clinical characteristics of these four groups are displayed in A comparison of myocardial injury and cardiac dysfunction among the four groups is shown in The comparison of mortality rate among the four groups is displayed in via binary logistic regression analyses. The SCH group exhibited a remarkably higher risk of in-hospital death than the euthyroid group in the non-adjusted model, but the significant association disappeared after adding other confounders. Additionally, given the euthyroid group as a reference, the SHyper group and LT3S group showed an obviously increased risk for in-hospital death  even after adjusting for various confounding factors.In this prospective, single-center observational study, the impacts of mild thyroid dysfunction on in-hospital mortality, long-term cardiovascular and all-cause mortality were assessed in Chinese STEMI patients. Our results demonstrated that the STEMI patients with SHyper and LT3S faced a remarkably increased risk of in-hospital mortality in relation to euthyroid patients. During a long (median 4.4-year) follow-up, we found that LT3S at baseline was still associated with worse cardiovascular and all-cause mortality while SCH or SHyper at baseline did not affect the long-term prognosis of STEMI patients.For AMI patients with SCH, the research on the associations of SCH and worse clinical outcomes was quite limited, although several observational studies suggested that elevated TSH beyond the normal range was a reliable marker for adverse outcome in AMI patients. For example, Zhu et al.  reportedDifferent from us, a retrospective observational study by Izkhakov et al.  in STEMIWith respect to the relations of SHyper with cardiovascular and total mortality, many studies have been made but with conflicting conclusions. For example, seven meta-analyses were found to discuss this issue so far. The third of them demonstrated that patients with SHyper faced a rising risk of total mortality and CHD mortality, particularly for those with suppressed TSH levels < 0.10 mIU/L , 8, 24, Recently, a systematic review and meta-analysis discovered that the prevalence of LT3S in heart failure (24.5%), myocardial infarction (18.9%), and acute coronary syndrome (17.1%) is quite high . SimilarSeveral limitations should be mentioned. Firstly, the objects who took part in our study were STEMI and from a single center of Chinese Han population, which may confine the generalizability of our results to patients with NSTEMI and other ethnic groups. Secondly, a thyroid function test was performed only before coronary angiography or CTA without tracking follow-up, but all samples were collected in the morning to avoid a circadian variation of thyroid hormones . ThirdlyOur results suggested that SHyper may be a risk factor for in-hospital deaths in STEMI patients. Furthermore, LT3S may be considered as a prognostic indicator for poor short- and long-term mortality. The current findings indicate that a routine testing of thyroid function prior to coronary angiography or CTA should be recommended and is highly valued to help identify and administer AMI patients at high risk of adverse events and deaths. Further studies are needed to evaluate the additional role of mild thyroid dysfunction in a prognostic algorithm of AMI severity and whether thyroid replacement therapy lowers mortality in AMI patients.The original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding authors.The studies involving human participants were reviewed and approved by Shanghai Jiao Tong University Affiliated Sixth People’s Hospital. The patients/participants provided their written informed consent to participate in this study.Q-MF and J-BL designed the study, revised and reviewed the manuscript. M-FL, Z-TW and SL collected clinical data and follow-up. M-FL and Z-TW worked together, performed statistical analysis and wrote the manuscript. All authors edited the manuscript and approved the final manuscript.The authors declare that this study received fundings from the National Natural Science Foundation of China (grant numbers 81502316), the Translational Medicine National Key Science and Technology Infrastructure Open Project (grant number TMSK-2021-116), and the Exploratory Clinical Research Project of Shanghai Jiao Tong University Affiliated Sixth People’s Hospital (grant number ynts202105). The funders were not involved in the study design, collection, analysis, interpretation of data, the writing of this article or the decision to submit 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 marked a health and economic crisis of massive proportions. In its early months, literature was centered on adult medical and critical care. As time progressed, international reports of COVID-19 infection in children steadily grew; however, data on disease features in the United Arab Emirates' pediatric population was noticeably lagging.  The presented research was conducted at Latifa Women and Children Hospital Emergency Department to ascertain an association between a child's presenting features and basic investigations to a subsequent positive COVID-19 test result. Data was collected via electronic medical records and statistical analysis performed with SPSS version 22.0. p < 0.05) between testing positive for COVID-19 infection and history of exposure to COVID-19-positive individuals; the presence of runny nose, cough, poor feeding, and abdominal pain with reassuring physical examination findings; and predominantly normal reports of basic blood investigations and chest X-ray images.  A total of four hundred and five (405) patients were analyzed, with 32 (8%) being COVID-19 positive on initial testing in emergency department. There is a statistically significant correlation ( This research demonstrates that a minority of children tested for COVID-19 in the initial wave of the pandemic tested positive. A significant proportion of COVID-19-positive pediatric patients exhibit history of exposure to COVID-19-positive individuals; the presence of runny nose, cough, poor feeding, and abdominal pain; normal physical examination; normal basic blood investigations and chest X-ray findings. December 2019 marked the start of a global medical emergency, one which proved itself unique as no assured foresight could be made about the nature of COVID-19 infection in humans. The adult and elderly age groups were the hardest hit initially, and children seemed to be a more ambiguous group of the population.Studies were swiftly issuing worldwide to navigate adult patient care; however, data on children lagged significantly and at most was in the form of case reports. A vague clinical spectrum of pediatric infections presented itself, and so the indications to test a child for COVID-19 infection were obscure.SARS-CoV-2 infection was first brought to attention in December 2019 after clusters of pneumonia cases erupted in the Chinese city of Wuhan . The numSARS-CoV-2 virus is believed to have originated from an animal source, with subsequent disease transmission primarily via airborne particles and contact with contaminated surfaces [Clinical characteristics of COVID-19 are diverse and involve multiple organ systems at varying degrees . DiseaseChildhood infection with SARS-CoV-2 may range from an asymptomatic individual to upper respiratory tract infection, skin rashes, pneumonia, gastrointestinal upset, acute respiratory distress syndrome, nervous system involvement, rhabdomyolysis, and the newly recognized Kawasaki disease like presentation of Multisystem Inflammatory Syndrome in Children –13.A general pattern has been reported from multiple countries, revealing the fact that children have a much milder disease severity than adults, and scant reports are available on pediatric mortality secondary to COVID-19 . SeveralThe value of screening children from COVID-19 is being increasingly recognized, as asymptomatic or mild presentations may lead to neglected isolation precautions and subsequent dissemination of infection. Studies have also demonstrated prolonged fecal shedding of SARS-CoV-2 virus in children who have apparently recovered from COVID-19, raising the possibility of children acting as major sources of disease spread among communities . MoreoveThe presented research is aimed at shedding light on the clinical features of children tested for COVID-19 infection and their subsequent test outcome, with an underlying target of guiding testing in children. If a significant relation can be made between a child's complaint and eventual COVID-19 result, pediatricians can be alerted to these trends and be better able to judge which child needs a COVID-19 test. Judicious testing enables superior hospital resource utilization as unnecessary testing would be reduced, and key disease features can be sought out to avoid missing the opportunity to diagnose a child who is COVID-19 positive. Moreover, international data on pediatric disease features may not be a true reflection of the patterns displayed by children in the United Arab Emirates; hence, the importance of a local study cannot be overstated.The study was conducted in the setting of Latifa Hospital Pediatrics Emergency Department in Dubai, UAE, as this hospital was one of the largest pediatrics tertiary care facilities of Dubai Health Authority. This study is designed as a noninterventional, retrospective cross-sectional study.The underlying rationale of this research is to establish a comprehensive picture of the local pediatric population in the context of testing for COVID-19. This will help pediatricians navigate the testing process in children and hold a certain amount of confidence when judging which child is at a higher likelihood of eventually testing positive for COVID-19 infection. The research is justified in the light of ascertaining a relationship between the variables studied and a subsequent COVID-19 result.There is a statistically significant association between certain features of presenting history, physical examination, initial laboratory investigations, and chest X-ray findings to the COVID-19 test outcome.The target population is all pediatric patients who attended Latifa Hospital Emergency Department and underwent testing for COVID-19 infection via RT-PCR nasopharyngeal swab from January 1st to August 31st, 2020. The inclusion and exclusion criteria are elaborated as below:All children from birth (zero years) to thirteen years oldBoth males and females includedSymptomatic children of any severity who underwent testing for COVID-19Children who were diagnosed with surgical conditions however held a mixed etiology (may have infectious origin): acute appendicitis and skin abscessesAsymptomatic children who were brought for testing after close contact with a known COVID-19-positive individual or recent return from high-risk country Testing method via reverse transcriptase polymerase chain reaction (RT-PCR) nasopharyngeal swab or secretion aspirate for SARS-CoV-2 virusThe following are the inclusion criteria:Children beyond the age of thirteen years were not included in the study as this age group was not considered to be within the pediatric population in the hospital of studyChildren presented with exclusively surgical conditions : strangulated/incarcerated inguinal hernias; ovarian/testicular torsions; and intestinal malrotation/obstruction due to underling gut anomalies Children attended with traumatic or environmental injuries: thermal/chemical burns, drowning/near-drowning, nonaccidental child abuse, bone fractures, skin lacerations, and animal/human bitesPatients were electively screened for COVID-19 infection in the emergency department prior to elective preplanned admission for a nonemergency procedure: elective surgery, enzyme replacement therapy, and endoscopy/colonoscopySecond and subsequent swab results of children were tested multiple times for COVID-19 infection after hospital admission. Only the initial COVID-19 swab result from emergency department visit was included in the study, and the remainder of the tests once the child was admitted to the hospital were disregarded and excluded from the studyChildren who brought reports of COVID-19 result from an external non-Dubai Health Authority facility were not included as the reliability of the test results was doubtful and in repeated for confirmation before management decisions made in real timePatients presenting beyond the specified age, study time frame, and location were excluded as wellThe following are the exclusion criteria:After obtaining ethical approval, patient data was obtained from the hospital's electronic medical record system  with absolute confidentiality and sensitivity to patient rights. A total of six hundred and twenty-nine (629) patients' records were obtained. Two hundred and twenty-three (223) patients were excluded based upon the exclusion criteria as aforementioned. All the remaining four hundred and five (405) patients successfully met the study's inclusion criteria and hence were fully retained for further data analysis and not randomly sampled out. The principal investigator handled patient data.Data was obtained from the hospital electronic medical records system management team , who provided a list of patients who attended Latifa Hospital Emergency Department from January 1st to August 31st, 2020, and had the relevant International Classification of Disease (ICD) coding documented in their medical file  and ICD-10: Z11.59 ). The “Salama” team had extracted these patients from their data base and provided the list in an excel sheet. The total number of patients obtained was six hundred and twenty-nine (629) as aforementioned and were narrowed down to four hundred and five (405) for statistical analysis and interpretation.(i)Demographic data: patient age in years, gender, and nationality(ii)Presence of a known COVID-19 exposure(iii)Presenting symptoms Physical examination findings ; dehydration; lymphadenopathy; chest crackles/wheezes on auscultation; abdominal tenderness; skin rash; and joint or local tissue swelling)Basic blood investigation results (white cell count (WBC); hemoglobin (Hb); absolute neutrophil count (ANC); absolute lymphocyte count (ALC); platelet count; c-reactive protein (CRP); procalcitonin; presence of hyponatremia and low serum bicarbonate)Chest X-ray features ; and finally, COVID-19 RT-PCR swab result (negative or positive)Presence of a preexisting medical/surgical comorbidityVariables studied in this research are as follows:Frequency tables, graphs, and descriptive statistics were performedNormal distribution of the continuous variables was assessed using the Kolmogorov-Smirnov test. Median and interquartile range (IQR) was used for the data that do not follow the normal distributionCategorical variables were presented as numbers and percent and were compared using the chi-square test. Fisher's exact test and Monte-Carlo exact test were used in case of small frequencyUnivariate logistic regression was used to investigate factors associated with positive COVID-19 test. The dependent variable is COVID-19 test , and independent variables are demographic characteristics, morbidity, and history of contact, presenting symptoms, physical examination findings, chest X-ray results, and laboratory parameters. The results were presented by odds ratio (OR) and 95% confidence interval , 19Stepwise multiple logistic regression was carried out to delineate the predictors of positive COVID-19 test, where the significant factors from the univariate logistic analysis were entered the modelStatistical analysis was carried out using Excel software program and Statistical Package for the Social Sciences (SPSS) version 24.0. The following statistical analyses were carried out:p values of <0.05 was the cut off level of significance.The The presented study was conducted on a total of four hundred and five (405) patients who attended Latifa Hospital Emergency Department from January 1st to August 31st, 2020.p value of 0.000).Among the overall studied patient population: gender wise, females were of higher percentage than males (54.3% versus 45.7%). Non-UAE locals were more than UAE locals (64.0% versus 36.0%). The predominant age group was from 1 to <5 years (31.9%). Underlying comorbidities  were absent in 54.3%, and 19.5% have a known previous exposure to COVID-19 infection. Of the 405 patients studied, 32 (8%) tested positive and 373 (92%) tested negative for COVID-19 infection. Patient characteristics were compared according to COVID-19 swab test results with a highly statistically significant difference demonstrated between known exposure to COVID-19 infection and positive swab result (The commonest presenting symptoms included fever (41.7%), vomiting/diarrhea (31.9%), and cough (21.5%). Each individual presenting symptom was subsequently studied according to COVID-19 swab test results. Patients with positive COVID-19 test results presented with the symptoms of fever (59.4%), runny nose (34.4%), cough (37.5%), poor feeding (3.1%), and abdominal pain (3.1%) as compared to those with a negative result , and the differences were statistically significantA diverse range of physical examination features was observed, the commonest being congested ear/nose/throat (15.3%), dehydration (13.1%), and tenderness on palpation of the abdomen (11.4%). Each individual physical examination finding was subsequently studied in relation to COVID-19 swab outcomes; there is no statistically significant difference in all the examination findings between patients with negative or positive COVID-19 testp < 0.05).The basic laboratory parameters collected near universally for ill children presenting to the emergency department were analyzed. Certain advanced tests such as procalcitonin, D-dimer, ferritin, and fibrinogen were not included in the current study given the scarce utilization of such higher tier investigations in the primary wave of the pandemic. As Radiologic imaging findings were broadly grouped into three categories upon basis of commonality in the studied population: normal, nonspecific infiltrates, and lobar consolidation. It was found that the highest percent of the patients demonstrated nonspecific infiltrates (64.4%). Each individual chest X-ray finding was subsequently studied in relation to COVID-19 swab outcomes; patients with positive COVID-19 test showed a higher percent of nonspecific infiltrates than those of negative test (80% versus 63.3%). No statistically significant difference could be ascertained. Advanced imaging modalities such as computed tomography scans of the lungs were not in practice as per routine in suspected patients, hence not included in the studyp < 0.05). Patients with fever and cough had double the risk of having positive test relative to those with fever or runny nose (p < 0.05). Higher nonsignificant risk was observed among those with lymphadenopathy (OR = 4.08) (p > 0.05)  . Patient > 0.05) .  Table Published reports from different countries over 2020 have shown that pediatric patients represent a marginal proportion of COVID-19 cases  , 20. OurIncreasing reports seem to suggest that infants under the age of 1 year and those with underlying comorbidities may be at increased risk of severe illness from SARS-CoV-2 infection . Our stuThe main reported associated factors for the pediatric COVID-19 infections are close contact with a family member with an infection and/or a history of travel or residence in an endemic area . Our stup < 0.05).Among the commonly reported symptoms in children aged ≤9 years are fever (46%) and cough (37%) . Our stuPhysical examination findings of congested ear/nose/throat (15.3%), dehydration (13.1%), and tenderness on palpation of the abdomen (11.4%) were demonstrated in our overall study population; however, most COVID-19-positive cases had minimal examination features correlating with a mild upper respiratory tract infection. As in adults, children with severe COVID-19 may develop respiratory failure, myocarditis, shock, acute renal failure, coagulopathy, and multiorgan system failure , but forInvestigation-wise, nucleic acid detections using reverse transcriptase real-time polymerase chain reaction qualitative or quantitative are the commonest methods for diagnosis , as is uChest X-rays in pediatric COVID-19 infections are often reported as either normal or with nonspecific viral pneumonia-like changes . Our stuThe present study bears certain limitations as it is retrospectively conducted; hence, data is heavily reliant upon accuracy of physician assessment, documentation, and quality of obtaining COVID-19 nasal swab.In conclusion, our study has demonstrated that only a minority of the studied pediatric population (eight percent) has tested positive for COVID-19 infection in the first eight months of the pandemic. This research has shown that the COVID-19-positive pediatric population exhibits parallel findings to international reports regarding: exposure to COVID-19-positive individuals with high significant risk of about eighteen times, frequent presence of fever, and cough, with the associated of almost double the risk of getting positive, reassuring physical examination findings, and predominantly normal reports of basic blood investigations in addition to abnormal findings in chest X-ray images as nonspecific infiltrations and lobar consolidation.It is recommended to invest in continuation of similar pediatric research studies over the coming year of 2021 in order to understand the clinical evolution of subsequent COVID-19 infection waves and the potential impact of mass vaccination on the picture of COVID-19 infection in children.


So far, existing studies do not show superiority of either approach in treatment of esophageal cancer, and the largest published meta-analysis of 52 studies found no difference in 5-year overall survival.3Transhiatal esophagectomy (THE) and transthoracic esophagectomy (TTE) are valid surgical procedures for esophageal cancer. TTE allows for more extensive lymphadenectomy via thoracic dissection, while THE has been preferred in frail patients, as some studies have shown higher morbidity and short-term mortality after TTE. Both of these procedures can also be performed with minimally invasive techniques. However, available evidence of long-term oncological outcomes after THE compared with TTE4 We used Cox regression adjusted for confounders to investigate 5-year and 90-day survival, as well as explanatory subgroup analyses. The observed 5-year survival was 39.3% after THE and 45.0% after TTE, and 90-day observed survival was 89.5% versus 92.3%, respectively. However, no statistically significant differences were present in 5-year or 90-day observed survival comparing THE with TTE in any of the adjusted models, nor in the five subgroups examined.We conducted a population-based, nationwide cohort study including all 1338 patients with esophageal cancer undergoing curatively intended THE and TTE in Finland from 1987 to 2016.The present study suggests similar 5-year survival after THE and TTE. Despite higher counts of examined lymph nodes in the transthoracic approach, no difference in long-term survival was present. The cervical anastomosis inherent to the THE technique has been associated with higher leak rates; however, leaks after TTE can be more severe due to mediastinal manifestations. In the current study, complication rates were not studied; however, 90-day mortality rates were similar after THE and TTE. Although it seems from this evidence that the surgical approach can be chosen on the basis of surgeon preference, further studies are needed, especially on certain subgroups such as tumors with high T-stage, tumors located in the middle third of the esophagus, those with lymph node metastases in thoracic nodes, and operations performed with minimally invasive techniques.