Early detection of atrial fibrillation (AF) is important. Japan has a universal screening system, and regular health screening (HS) is available to support AF detection without a hospital visit. However, health‐related outcomes and other characteristics of HS‐detected and conventionally diagnosed AF remain unknown.That the characteristics and health‐related outcomes of patients with HS‐detected AF may differ from those of patients whose AF was detected by other procedures.In total, 3318 consecutive newly referred AF cases were enrolled; demographic characteristics and health‐related and clinical outcomes were compared between two groups created based on the mode of AF detection (the HS and non‐HS groups). Health‐related outcomes were assessed using the AF Effect on QualiTy‐of‐life (AFEQT) questionnaire at baseline and after 1 year of follow‐up.2 scores , higher prevalence of persistent AF  and asymptomatic presentation , and better baseline QoL scores . Catheter ablation was more frequently performed in the HS group at follow‐up . At 1‐year follow‐up, the AFEQT scores of the HS group were significantly better in most subdomains.AF was detected by HS in 25.0% of patients; these patients had lower CHADSIn the Japanese registry, AF was detected via HS in 25% of patients referred to specialty centers for management. Notably, the overall health status of patients with HS‐detected AF improved after medical interventions, including catheter ablations. Dedicated study coordinators updated the status of major cardiovascular events, laboratory test results, procedures performed, and subsequent changes in medications. Data quality assurance was achieved via quantitative reporting of data completeness (%), thorough quarterly education, and training of dedicated clinical research coordinators. Supervision by the senior study coordinator (I. U.) and exclusive on‐site auditing by study investigators  ensured proper registration of each patient. The institutional review board approved the protocol of all institutions, and the study was conducted in accordance with the Declaration of Helsinki. All participants provided written informed consent.2.2http://www.afeqt.org) questionnaire.In addition to the traditional data collected by healthcare providers, the KiCS‐AF collected patient‐reported outcomes using the internationally validated atrial fibrillation effect on quality‐of‐life  days after registration. There were 2092 patients in the non‐HS group and 692 in the HS group. We compared patient background characteristics, AFEQT scores, and clinical outcomes between the two groups. This cohort underwent follow‐up after 1 year for the occurrence of hospital admission, heart failure, stroke, bleeding, acute coronary syndrome, and death.All data available until the 1‐year follow‐up examination of patients who were enrolled between September 12, 2012, and May 16, 2018, were included. At the time, 2742 (82.6%) of 3318 consecutive registered outpatients with AF had available 1‐year follow‐up data. At follow‐up, patients answered the AFEQT questionnaire at an average of 414 ± 72.0  and 95% confidence intervals (95% CIs) were subsequently calculated. Statistical significance was set at p < .05. All statistical analyses were performed using SPSS version 26.0 (IBM Corp.).The data are presented as mean ± standard deviation (SD), percentage, or number of cases. Asymptomatic AF was defined as AF without any symptoms such as palpitations, dyspnea, fatigue, dizziness, chest pain, and syncope. Differences in characteristics and QoL assessments between the two groups were compared using the student's 33.1n = 2268; age, 68 ± 12 years; CHADS2 score, 1.4 ± 1.2; CHA2DS2‐VASc score, 2.5 ± 1.7). Persistent AF was identified in 1450 (44.4%) patients. Among them, 3291 (99.2%) and 2768 (83.4%) had ECG data recorded at baseline and 1‐year follow‐up visit, respectively. AF‐related symptoms were reported in 3318 (100%) patients.The study population consisted of 3318 registered patients with AF  patients had AF detected via HS. The baseline characteristics of the HS and non‐HS groups are summarized in Table p Figure . A histo3.3p < .001). The incidence of admission (due to heart failure) and death was significantly higher in the non‐HS group, whereas the incidence of stroke, bleeding, and acute coronary syndrome did not differ between the two groups.A comparison of outcomes at 1‐year follow‐up is presented in Supporting Information: Table 3.4The QoL scores of 3299 (99.4%) and 2742 (82.6%) patients were obtained at baseline and after 1 year of follow‐up, respectively. The proportion of patients with asymptomatic AF was doubled while complaints of palpitations were reduced by almost half in the HS group compared with the non‐HS group. A comparison of QoL scores between the non‐HS and HS groups both at baseline and follow‐up is shown in Figure The HS group had significantly higher baseline AFEQT scores for all domains . At the 1‐year follow‐up visit, the AFEQT scores were significantly better in all domains except for the satisfaction domain in the two groups. A detailed comparison of each QoL questionnaire is provided in Supporting Information: Table 4In this multicenter Japanese registry, approximately one‐quarter of patients had their AF detected via HS. HS‐detected AF was characterized as asymptomatic, persistent, and more prevalent in the young population. More than half of patients in the HS group were asymptomatic, which might be because symptomatic patients would visit the hospital for diagnosis. More persistent AF was included in the HS group since paroxysmal AF was associated with a more symptomatic presentation. In addition, a single ECG examination in HS hardly detected infrequent paroxysmal AF. In the present study, patients in the HS group were younger than those in the non‐HS group, while patients with persistent AF were expected to be older than those with paroxysmal AF.We showed that medical interventions could improve the outcomes of patients in the HS group with relatively higher baseline QoL scores. In the present study, a considerable number of patients in the HS group started anticoagulation therapy and underwent catheter ablation. Consequently, the HS group had a higher rate of increase in sinus rhythm at the 1‐year follow‐up examination. Furthermore, among patients in the HS group who did not receive anticoagulants at baseline, concerns about the side effects of blood thinners did not significantly change between baseline and the 1‐year follow‐up visit  are considered ideal candidates for direct OACs since they (particularly East Asians) have a better safety profile.More than 80% of the selected patients in our registry received OACs, which was considerably higher than the numbers reported in previous AF studies.4.3Promoting an aggressive therapeutic strategy might be difficult in a population with a well‐preserved QoL. The RACE II trial showed that the stringency of heart rate control did not influence QoL.4.4The present study was conducted in a single medical network within the metropolitan Tokyo area. Thus, the results might not be reproducible in all populations. In other words, the generalizability of our findings to individuals of different ages, races, or ethnicities is uncertain. Additionally, this registration enrolled many patients referred for catheter ablation. Therefore, patients’ background might not be identical to that of the general Japanese population. Furthermore, the benefit of OACs in patients with AF was typically studied in symptomatic patients with standard ECG diagnosis, while the advantage in patients diagnosed through mass screening programs remains unclear. Moreover, HS may not be suitable for detecting asymptomatic paroxysmal AF in young patients with few comorbidities; this is a challenge that needs to be addressed in the future. Although the government mandates HS, employers may refuse to undergo ECG examinations or other screening programs. Hence, both methods of data collection have limitations.5In the Japanese registry, AF was detected via HF in 25% of the patients referred to specialized centers for treatment. Notably, the overall health of patients with HS‐detected AF improved following medical interventions such as catheter ablations.This study was funded by Bayer Yakuhin Ltd.Supporting information.Click here for additional data file.


Deficits in speech understanding constitute one of the most severe consequences of hearing loss. Here we investigate the clinical and genetic risk factors for symmetric deterioration of speech recognition thresholds (SRT) among cancer survivors treated with cisplatin.SRT was measured using spondaic words and calculating the mean of measurements for both ears with symmetric SRT values. For clinical associations, SRT‐based hearing disability (SHD) was defined as SRT≥15 dB hearing loss and clinical variables were derived from the study dataset. Genotyped blood samples were used for GWAS with rank‐based inverse normal transformed SRT values as the response variable. Age was used as a covariate in association analyses.p = 0.004). Current smoking (p = 0.002), years of smoking (p = 0.02), BMI (p < 0.001), and peripheral motor neuropathy (p = 0.003) were positively associated with SHD, while physical activity was inversely associated with SHD (p = 0.005). In contrast, cumulative cisplatin dose, peripheral sensory neuropathy, hypertension, and hypercholesterolemia were not associated with SHD. Although no genetic variants had an association p value < 5 × 10−8, 22 genetic variants were suggestively associated (p < 10−5) with SRT deterioration. Three of the top variants in 10 respective linkage disequilibrium regions were either positioned within the coding sequence or were eQTLs for genes involved in neuronal development .SHD was inversely associated with self‐reported health (Current results improve our understanding of risk factors for SRT deterioration in cancer survivors. Higher BMI, lower physical activity, and smoking are associated with SHD. Larger samples would allow for expansion of the current findings on the genetic architecture of SRT. We investigated the risk factors associated with decline in understanding speech as measured by speech recognition threshold among testicular cancer survivors. Associated factors were higher BMI, lower physical activity and smoking, and peripheral motor neuropathy alongside genetic variants with suggestive associations including those related to three genes involved in neuronal development. Chemotherapy consisted of cisplatin‐based regimens; survivors did not have prior chemotherapy for other cancers and completed chemotherapy more than a year prior to the enrollment. Enrolled survivors completed comprehensive health questionnaires, underwent brief physical examination and were audiometrically evaluated. The Platinum Study involves eight medical centers in the United States, Canada, and United Kingdom.2.2Hearing was evaluated by a licensed audiologist conducted in a clinical setting, inside a sound‐treated booth using calibrated equipment. Pure‐tone and speech audiometry was obtained for each ear following professional standards.Figure For each subject, SRT values for left and right ears were compared Figure  and subj2.32 with body surface area (m2). When not available, body surface area or chemotherapy cycle details were imputed to meet the expected standard cisplatin cycle dosage (100 mg/m2 per cycle).To obtain the dose of administered cisplatin, chemotherapy treatment regimens and/or individual chemotherapy cycles were abstracted from the subjects' medical records. Cumulative cisplatin dosages were calculated for standard treatment regimens or from individual chemotherapy cycles for nonstandard treatment regimens. If necessary and depending on data availability, dosages were converted to mg/mFor clinical associations besides age and dose of cisplatin, subjects were excluded from the analysis if evaluations and audiometry were done more than 1.2 years (438 days) apart. Age was calculated as the difference in days between date of birth and date of data collection, divided by 365 and rounded to the nearest integer. The association of age with hearing loss is well documented.Distribution and preparation of clinical variables used for clinical association analyses of “self‐reported hearing loss,” “problem hearing in crowds,” tinnitus, peripheral motor neuropathy, peripheral sensory neuropathy, heavy drinking, ever smoking, current smoking, hypertension and hypercholesterolemia are outlined in Figures https://CRAN.R‐project.org/package=MASS; RRID:SCR_019125) was used for association of SRT‐based hearing disability with self‐reported health. Logistic regression was used for other clinical association analyses with SRT‐based hearing disability. For the number of subjects in clinical associations refer to Figure For clinical association analyses, calculated SRTs were transformed to binary with values equal to or greater than 15 dB hearing level placed in the hearing disability group. Ordinal logistic regression from MASS package2.4During the clinical evaluation, peripheral blood samples were collected from subjects and were used for DNA extraction. Genotyping was performed by Regeneron Pharmaceuticals using Infinium Global Screening Array v1.0 (Illumina Inc.).ftp://ftp‐trace.ncbi.nih.gov/1000genomes/ftp/release/20100804/ALL.2of4intersection.20100804.genotypes.vcf.gz) to select for subjects with European ancestry. Variants with minor allele frequency (MAF) lower than 0.05 were filtered out  were excluded. Subjects that deviated from the mean heterozygosity rate by more than three standard deviations were excluded. For filtration based on related genotypes, pi‐hat threshold of 0.0625 was used to select related subjects. Related pairs were determined based on mean identity‐by‐descent  and in each related pair, the subject with higher missing call rate was excluded . bgzip from HTSlibhttps://www.htslib.org, RRID:SCR_002105) and 7‐Zip  were used for compression and decompression of genotype data prior and post imputation. Imputed genotypes were filtered to keep variants with an imputation R2 above 0.8 and to remove variants with MAF below 0.05 or with deviation from HWE (p < 10−6)  Figure .2.5https://CRAN.R‐project.org/package=GenABEL, RRID:SCR_001842). The transformed SRT data were used for linear regression‐based genome‐wide association analysis. Inclusion of the 10 genetic principal components is a common practice to control for population stratification.www.cog‐genomics.org/plink/1.9/, RRID:SCR_021271) which includes implementations of earlier methodhttps://www.ncbi.nlm.nih.gov/snp/) was used to check the details of target variants. LocusZoom webtool,https://my.locuszoom.org, RRID:SCR_021374) was used to generate regional Manhattan plots with LD population set to European. GTEx portal  was used to check if identified SNPs are known expression quantitative trait loci (eQTLs) or splicing quantitative trait loci (sQTLs).To prepare the SRT data for subjects with matching quality‐controlled genotype, the arithmetic mean of SRT measurements for both ears was subjected to rank‐based inverse normal transformation Figure  using Ge2.6https://www.gnu.org/software/bash/, SCR_021268), R , and RStudio  provided the analysis environment. Packages dplyr , tidyrhttps://CRAN.R‐project.org/package=tidyr, RRID:SCR_017102), purrr , sas7bdat (https://CRAN.R‐project.org/package=sas7bdat) were used for data handling in the analysis pipeline. ggplot2https://ggplot2.tidyverse.org, RRID:SCR_014601) was used for plot generation. Rcartocolor  provided the color palette used for genetic ancestry plot.Bash , 1.09; 95% confidence interval (CI), 1.07–1.11; 3.2p < 0.001; “problem hearing in crowds”: OR, 2.68; 95% CI, 1.77–4.06; p < 0.001; Figure p < 0.001; Figure Subjects who reported hearing loss or ‘problem hearing in crowds’ had significantly higher odds of having SRT‐based hearing disability  blocks with p values lower than 10−5, a suggestive threshold for genome‐wide associations in humans  did not identify any variants with s Figure . LocusZos Figure . Among ts Figure . The dis4ATE1, ZFHX3, ENAH, and SRP9) that play important roles in neural development and function.We studied a well‐established cohort of cisplatin‐treated testicular cancer survivors to investigate risk factors for impaired speech recognition threshold. As shown previously in the general population,4.1Consistent with age‐related hearing declines, we observed a significant association between SRT‐based hearing disability and age. Cumulative dose of cisplatin was not associated with SRT‐based hearing disability, suggesting the possibility that SRT deterioration is independent of the ototoxic effect of cisplatin. SRT is highly correlated with low frequency hearing sensitivity measured by PTA of 0.5, 1, and 2 kHz. Thus, our lack of association between SRT and cisplatin dose is consistent with results by others demonstrating cisplatin‐induced hearing loss in the high frequency range,The observed association between self‐reported health and SRT‐based hearing disability could indicate an impact of hearing disability on the subjects' perception of health. However, association does not imply causation, and other underlying conditions influencing health perception could contribute to SRT deterioration and, therefore, to the observed association.4.2p = 0.007; tinnitus: 38% cases/10% controls, p < 0.001).We have previously reported associations of both tinnitus and “self‐reported hearing loss” with SRT deterioration in a subset of The Platinum Study cohort4.3A 2005 meta‐analysis concluded a suggestive positive association between smoking and hearing loss.We did not find a significant association between heavy alcohol consumption and SRT‐based hearing disability, consistent with the reported lack of association between decline of SRT (in noise) and alcohol use in a longitudinal study.We observed significant associations between increasing BMI as well as lower physical activity with SRT‐based hearing disability. Associations between BMI or ‘obesity defined by BMI’ with hearing loss have been reported in both cross sectional4.4We did not observe a significant association between peripheral sensory neuropathy and SRT‐based hearing disability. However, there was a significant association between peripheral motor neuropathy and SRT‐based hearing disability. There is a wide array of identified factors that disproportionately contribute to the development of either peripheral sensory neuropathy or peripheral motor neuropathy.4.5We did not observe an association of hypertension or hypercholesterolemia (defined by taking prescription medications) with SRT‐based hearing disability. There are conflicting reports about the association of hypertension and hearing loss, with presence or lack of association being reported.4.6ATE1 and is an eQTL for it. ATE1 regulated neurite formation during development of the brainZFHX3(ATBF1) which encodes a transcription factor involved in neuronal differentiationZFHX3 is expressed in otic placodeZFHX3 is known to be regulated during development of inner ear in mouse.ENAH, a gene that is highly expressed in the nervous system and encodes a protein that regulates local translation in developing axons.SRP9 and a protein heterodimer that includes SRP9 potentially regulates protein biosynthesis in dendrites.TMEM63A which is expressed in oligodendrocytes and heterozygous missenses mutations in TMEM63A lead to transient hypomyelination during infancy.Suggestively implicated variants were assessed for location  and we used the GTEx portal to check whether the leading variants in each LD block were eQTLs or sQTLs. rs4752613 is located within the intronic sequence of SH2D4B gene which has a noticeable expression in mouse hair cells.We also compared our suggestive SNPs with the list of 51 identified SNPs associated with age‐related hearing loss.4.7A potential limitation for the impact and generalization of our findings to other populations is that 82.3% of the subjects in clinical associations and all of the subjects in genome‐wide association are white.Another limitation of the current study is reliance on questionnaire‐based evaluation of most of the clinical variables. Some of these variables could intrinsically be obtained through self‐assessment . Other life style variables such as smoking and drinking habits are usually self‐reported considering the limitations of real‐life tracking of these behaviors. Biases are intrinsic limitations of cross sectional studies.Lack of information on other ototoxic drugs  is another limitation of the study; however, we do not expect a systematic exposure of the participants (primarily young adults) to other major ototoxic medication.−8 and lack of a replication dataset are limitations of our genome‐wide association study. To the best of our knowledge, there are no datasets currently available that would allow for an accurate replication of our genome‐wide associations. Emergence of new datasets and increased sample size would provide the means for expansion of the current findings on the genetic architecture of SRT decline in cancer survivors.Lack of identification of SNPs reaching significance cutoff of 5 × 104.8Our results improve the current understanding of risk factors for the decline of speech recognition in cancer survivors. Higher BMI, lower physical activity, and smoking are associated with SRT decline.Image Integrity: LocusZoom images are modified to increase legibility and to remove redundant annotations.Mohammad Shahbazi: Conceptualization (lead); formal analysis (lead); investigation ; validation (lead); writing – original draft (lead); writing – review and editing . Xindi Zhang: Conceptualization ; investigation ; methodology ; writing – review and editing . Paul C Dinh: Data curation ; investigation ; methodology ; writing – review and editing . Victoria A Sanchez: Conceptualization ; investigation ; writing – review and editing . Matthew R Trendowski: Investigation ; methodology ; writing – review and editing . Megan Shuey: Formal analysis ; investigation ; writing – review and editing . Tessa Nguyen: Investigation ; writing – review and editing . Darren R. Feldman: Investigation ; writing – review and editing . David J. Vaughn: Investigation ; writing – review and editing . Chunkit Fung: Investigation ; writing – review and editing . Christian K Kollmannsberger: Investigation ; writing – review and editing . Neil E. Martin: Investigation ; writing – review and editing . Lawrence H. Einhorn: Investigation ; writing – review and editing . Nancy J Cox: Investigation ; methodology ; writing – review and editing . Robert D Frisina: Conceptualization ; investigation ; writing – review and editing . Lois B Travis: Conceptualization ; funding acquisition ; investigation ; project administration ; resources ; supervision ; writing – review and editing . Mary Eileen Dolan: Conceptualization ; investigation ; project administration ; writing – original draft ; writing – review and editing .Darren R. Feldman has a relationship with Gilead, Decibel, Astellas, Seattle Genetics, Novartis, and UpToDate. Victoria A. Sanchez reports paid research support and/or consultancy stipends from Autifony Therapeutics Ltd., Oticon Medical, Otonomy Inc., and Boehringer Ingelheim International GmbH (Unrelated to the project). All other authors declare no conflicts of interest.The study was conducted in line with the U.S. Common Rule and was approved by respective Institutional Review Boards. All subjects were >18 years old during enrollment and provided written consent for participation including access to medical records and genetic analysis.Appendix S1Click here for additional data file.


Since the last century, the electrocardiogram (ECG) remains the non‐invasive test, that is, most easily accessible, feasible, and inexpensive for cardiology assessment. In past years, many novel ECG indexes and patterns have been published that allow for a more advanced evaluation of what is currently being done, especially based on subtle QRS changes and patterns.The objective of the study was to provide an update on the evidence and clinical applications of these ECG subtle QRS changes and patterns associated with heart disease.Through the literature review, we will highlight the subtle QRS changes and patterns associated with heart disease, mainly focusing on QRS duration, voltage, morphology, axis, and QT interval.Small increases in QRS duration are associated with a reduction in left ventricular ejection fraction (EF), increased cardiac chamber dimensions, and risk for incident heart failure (HF). Moreover, fragmentation of the QRS complex is associated with myocardial fibrosis and is a substrate for developing arrhythmic events. Besides, low amplitude QRS voltage is associated with congestive HF, and an increase in the voltage of the QRS complexes is associated with the effectiveness of diuresis treatment. Furthermore, small increases in QT interval are associated with diastolic dysfunction due to impaired sarcoplasmic reticulum calcium handling as occurs in myocardial ischemia, hypertension, or diabetes. On the other hand, in patients with left ventricular dysfunction, the QRS area is associated with clinical and echocardiographic response to cardiac resynchronization therapy regardless of the type of bundle branch block. In addition, subtle ECG changes and patterns in the left bundle branch block are associated with concomitant right ventricular dilation, mostly based on the QRS axis and voltage. Notwithstanding, to identify these subtle changes in QRS require exact manual measurements that can take time. In this regard, applying artificial intelligence (AI) to the ECG can make a quicker and more complete assessment, as well as provide a low cost when applied to large populations.We provided an update on the evidence and clinical applications of these subtle QRS changes and patterns associated with diastolic dysfunction, reduced EF, and HF development and therapy responsiveness, as well as their applications for AI to ECG. The QRS duration, QRS amplitude, and QT interval are according to age and sex. Subtle changes seen in the QRS outside of the normal values according age and sex and/or the presence of abnormal QRS morphology such as QRS fragmentation can be used as an evaluation of cardiac chamber dimensions, myocardial fibrosis, low EF, RV dysfunction, diastolic dysfunction, effectiveness of diuresis treatment in HF, better selection for CRT, and arrhythmic risk. Murkofsky et al.  showed c3p = .037) but also demonstrated the association between f‐QRS and ischemic heart disease (IHD) diagnosed by positive stress MRI . After using multivariate analysis adjusted for age, diabetes, hypertension, renal function, and LVEF, f‐QRS remained an independent predictor for positive stress MRI , the patients who subsequently lost weight increased the total 12‐lead QRS voltage  and the sum of leads I and II . Therefore, using the sum QRS voltage of leads I and II constitute a reliable, easy, and more practical than sum all 12‐lead for assessing the effectiveness of diuresis treatment in HF , a competing risk analysis was used to compare the association of several baseline ECG predictors with HF detected during a median follow‐up of 12.1 years. The development of HFrEF was associated with QRS >100 ms, time to intrinsicoid deflection >50 ms (Time to peak R‐wave in V5 and V6), left‐axis deviation −30°, right‐axis deviation −90°, prolonged QT interval, abnormal QRS‐T axis , LVH (Left ventricular hypertrophy) using Cornell criteria , ST/T‐wave abnormalities, and LBBB. The development of HFpEF (Heart failure with preserved ejection fraction) was associated with heart rate per 10‐ms increase, abnormal p‐wave axis (outside the range of 0° and 75°), abnormal QRS‐T axis. The risk of HFrEF versus HFpEF was differently for delayed intrisicoid deflection, prolonged QT interval and ST/T‐wave abnormalities  dilation/dysfunction had been published in recent years. Josephson et al. in the presence of LBBB, the direction of the frontal QRS axis gives information on LV activation and size, as well on the RV. Left‐axis deviation indicates a more delay in activation suggesting LV dilation and a superior axis deviation indicates additional RV dilation  showed that risk factors for acquired prolonged QTc interval were the age, female sex, hypocalcemia, hypokalemia, history of thyroid disease, history of myocardial infarction and taking QT‐prolonging medications , using a cutoff value of QTc ≥ 435 ms had a sensitivity 73% and specificity 74% for detection of diastolic dysfunction, when restricted to patients with known or suspected HF had a sensitivity 80% and specificity 90%.QT interval is measured from the beginning of the QRS complex to the end of the T‐wave and approximates the time it takes the ventricles to repolarize. LQTS is the prolongation of the QT interval. LQTS may be either congenital or acquired  and used a cutoff value of TpTe ≥ 75 ms for detection of abnormal diastolic stress test (Peak exercise E/e' > 13). Moreover, Namdar et al. (n = 204) of patients without coronary artery disease, reported that using this formula [aVL R amplitude × (V1S amplitude + V5R amplitude)/D1 P amplitude] can predict diastolic dysfunction in echocardiography. A ROC analysis showed that the optimal cutoff value to predict diastolic dysfunction was 8.53 mV with 70% sensitivity and 70% specificity . Sauer et al.  demonstrr et al.  showed tr et al. . A retro7R‐squared = 0.7). Major factors seen among patients with a neural networks‐predicted age that exceeded chronologic age by >7 years included: low EF, hypertension, and coronary artery disease (CAD) p < .01  in the medical field, with the use of machine learning techniques as the deep convolutional neural networks (Johnson et al., 8Subtle changes seen in the QRS can be used as an evaluation of cardiac chamber dimensions, myocardial fibrosis, low EF, RV dysfunction, diastolic dysfunction, effectiveness of diuresis treatment in HF, better selection for CRT, and arrhythmic risk Table . Many phArtemio García‐Escobar: Responsible for the concept design, writing and editing artificial intelligence applications in ECG, conclusion, table1, and graphical Abstract; Silvio Vera‐Vera: Writing and editing QRS duration and QRS fragmentation; Alfonso Jurado‐Román: Writing and editing QRS voltage; Santiago Jiménez‐Valero: Writing and editing heart failure; Guillermo Galeote: Writing and editing introduction; Raúl Moreno: Writing and editing diastolic dysfunction.None declared.Not applicable.


P = .024), or monoclonal antibodies  after LM diagnosis, had a statistically significantly longer OS. Presence of neurological symptoms  and not having received radiotherapy  were all associated with poorer OS at multivariate analysis. To summarize, not having neurological symptoms and receiving RT at LM diagnosis were associated with prolonged OS in our cohort. Survival seemed to be prolonged with multimodality treatment, which included targeted therapy, chemotherapy, and RT to the LM sites.In patients with human epidermal growth factor receptor 2 positive (HER2+) breast cancer, leptomeningeal metastases (LM) are a rare but often a fatal clinical scenario. In this multicentric study, clinical and pathologic characteristics of patients with HER2+ breast cancer developing LM were described, as well as survival outcomes. Data were gathered retrospectively from medical records of 82 patients with advanced HER2+ breast cancer and LM treated between August 2005 and July 2020. Following LM diagnosis, 79 (96.3%) patients received at least one line of anti‐HER2 therapy, 25 (30.5%) patients received intrathecal therapy and 58 (70.7%) patients received radiotherapy. Overall survival (OS) was 8.3 months , 1‐year OS was 42%, and 2‐year OS was 21%. At univariate analysis, patients who were treated after 2010, had better Karnofsky performance status, were free of neurological symptoms, had better prognostic, received chemotherapy  breast cancer and leptomeningeal metastasis (LM) are likely to suffer neurological damage. The degree to which neurological symptoms are evident and their impact on survival remain uncertain. Here, investigation of pathological features and survival in a European cohort of HER2+ breast cancer patients with LM shows that preexisting brain metastases are common at LM diagnosis, affecting as many as two‐thirds of patients. Overall survival was longer among patients who lacked neurological symptoms and who received radiotherapy at LM diagnosis. Longer survival was further linked to the use of multimodality therapy. ASCO/CAPAmerican Society of Clinical Oncology/College of American PathologistsB‐GPAbreast‐graded prognostic assessmentCIconfidence intervalsCNScentral nervous systemCNS‐PDcentral nervous system progressive diseaseERestrogen receptorFISHfluorescent in situ hybridizationGhistological gradeHER2+human epidermal growth receptor 2 positiveHRhormonal receptorIHCimmunohistochemistryITintrathecal therapyKPSKarnofsky performance statusLMleptomeningeal metastasesMBCmetastatic breast cancerMRImagnetic resonance imagingnnumberNAnot availableOSoverall survivalPRprogesterone receptorRTradiation therapySS‐BMsimple survival scoreTDM‐1trastuzumab‐emtansine1Leptomeningeal metastases (LM) are a complication of relatively uncommon occurrence in patients with breast cancer. The presence of LM usually alters the course of the metastatic disease, resulting in a bleak prognosis and a reduction in patients' quality of life. The estimated incidence of LM in unselected patients with breast cancer is very low, appearing to be less than 1%, but the percentage increases in patients with advanced breast cancer, reaching 6.6% in clinical studiesBreast cancer tumor biology may play a role in the incidence of LM, time between primary breast cancer diagnosis and LM diagnosis, and subsequent overall survival (OS). The distribution of primary breast cancer surrogate clinical subtypes in LM patients varies significantly. Human epidermal growth receptor 2 positive (HER2+) breast cancer cells may be more neurotropic than other breast cancer cell populations,However, breast cancer subtypes appear to have a different natural propensity to metastasis to the leptomeninges than brain parenchyma.Treatment modalities for LM are usually not supported by data from randomized clinical trials and are often based only on expert opinions.22.1breast‐graded prognostic assessment (B‐GPA),the simple survival score (SS‐BM),INDEX score, which integrates patients' clinical characteristics, breast cancer biological subtype and LM treatment characteristics.Patients' clinical and histopathological characteristics, local and systemic treatments data were retrieved from medical records for patients, aged ≥18 years with histologically proven invasive HER2+ breast cancer and diagnosis of LM, with or without brain metastases. The flow diagram for patients included in our study is shown in Figure 2.2Molecular breast cancer subtypes were identified as HR+/HER2+ , and HR−/HER2+ . Routine diagnostic pathology reports were used to assess the ER, PR, and HER2 receptor status of primary breast cancer tumors or metastatic disease at the time of diagnosis and were evaluated according to then valid American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) recommendations. Hormone receptor‐positive disease was classified as ER+ and/or PR+ disease with a cut off value of 1%. The status of ER or PR were determined using standard immunohistochemistry (IHC) methods as by clinical practice of the participating centers .2.3P values (P < .10) obtained in the univariate analysis to test the variables in the multivariate analysis. To avoid obscuring or confounding the relationship between the independent and dependent variables, prognostic scores were excluded from the multivariate analysis. Overall survival (OS) was defined as time interval from LM diagnosis to date of death or last follow‐up. The binary multivariate logistic regression method was used to identify factors that were significantly associated with the progression of intracranial disease. Statistical analysis also included descriptive statistics. Data were expressed as median with a range for continuous variables, and as counts with frequencies for categorical data. All tests were two‐sided, and the statistical significance level was set at P = .05. The effect sizes [given as hazard ratios with 95% confidence intervals (CI)] were calculated using univariate and multivariate logistic regressions. Figure https://www.medcalc.org; 2020).Data were analyzed using IBM SPSS Statistics software version 26 . A Pearson's chi‐square test was used to compare categorical variables between two groups. The Kaplan‐Meier method was used to calculate estimated survival curves, and the log‐rank test was used to compare two groups. Cox's proportional hazards model was used to calculate additional covariates. To account for variable interactions, we used less stringent 33.1P = .852). The median time from metastatic disease to LM diagnosis was 21.1 months . Imaging alone , imaging and cerebrospinal fluid cytology , and cerebrospinal fluid cytology alone  were used to diagnose LM.In total, 82 patients with HER2+ primary breast cancer and LM were included in the study. Median age at breast cancer diagnosis was 59 years  and median age at LM diagnosis was 64 years . Median time from primary breast cancer diagnosis to LM development was 52.8 months  for HR+/HER2+ breast cancer subtype and 43.2 months  for HR−/HER2+ breast cancer subtype  also had been diagnosed with concurrent brain metastases, while 29 (35.4%) only had LM. When brain parenchymal metastases were diagnosed in patients with LM, they were found concurrently in 26 31.7%) patients, before LM diagnosis in 25 (30.5%) patients and after LM diagnosis in 2 (2.4%) patients. Patients' clinical and pathohistological characteristics are summarized in Table .7% patieHormonal receptor status (HR+ or HR−) was known for 81 (98.8%) patients. Detailed data on systemic treatment received for metastatic disease prior to LM diagnosis is presented in Table Data regarding treatment received after LM diagnosis are summarized in Table P = .002), we found no statistically significant differences in the kind of systemic or local treatment administered based on breast cancer subtype  received methotrexate, 1 patient received cytarabine, 1 patient received trastuzumab‐only, and 1 patient received methotrexate, cytarabine, and trastuzumab. With the exception of endocrine treatment (3.2P = .664). None of the factors tested in the binary multivariate logistic regression model, including HR status (P = .550), de novo vs recurrent disease (P = .611), the presence of brain metastases (P = .162), the receipt of chemotherapy (P = .999), TDM‐1 (P = .828), or lapatinib therapy (P = .551), or local treatments such as brain metastases surgery (P = .999), IT (P = .871), and RT (P = .362), appeared to be significantly associated with intracranial disease progression. Following RT, we observed no improvement in clinical symptoms of LM in 22 (37.9%), improvement in 17 (29.3%), and an unknown clinical response in 19 (32.8%) patients.The median follow‐up from time of LM diagnosis was 8.3 months . The data for the emergence of new CNS metastasis or progression of existing CNS metastasis was available for 64 patients. CNS‐PD was observed in 57 (89.1%) during the follow‐up period. Out of 45 evaluable patients receiving RT, 39 (86.7%) developed CNS‐PD compared to patients who did not receive RT , and the difference was not statistically significant  patients had died. Fifty‐two (63.4%) patients died due to progression of the intracranial disease, 14 (17.1%) patients died due to extracranial disease progression, while the cause of death was not clearly identifiable from medical records for 16 (19.5%) patients.x). The estimated OS rate was 42% at 1 year, 21% at 2 years, and 10% at 3 years, respectively. The impact of several known prognostic factors on OS was investigated using univariate Cox regression (Table P = .434) or in patients with de novo vs recurrent breast cancer . Patients with primary invasive lobular cancer had a shorter OS after LM diagnosis than those with invasive ductal subtypes , but the difference was not statistically significant. Among clinical parameters evaluated at time of LM diagnosis, a poorer Karnofsky performance status (<70) (P = .015) and presence of neurological symptoms at the time of LM diagnosis (P = .011) were significantly associated with a significantly higher risk of death in univariate analysis. Among prognostic indices, two  were significantly associated with a significantly higher risk of death in univariate analysis. Moreover, patient diagnosed with LM prior to 2010 showed a worse prognosis as compared to patients diagnosed in more recent years (P = .036).Median OS from LM diagnosis in the study cohort was 8.3 months (95% CI 5.7‐11P = .024) and receiving monoclonal antibodies . Patients treated with TDM‐1 , intrathecal chemotherapy , or RT after LM diagnosis  showed a longer median OS from time of LM diagnosis, but the difference was not statistically significant. Impact of receiving (any) HER2 targeted treatment could not be assessed as only a limited number of patients did not receive HER2 targeted treatment after LM diagnosis (n = 3). Patients who received multimodality therapy, including targeted therapy, chemotherapy, and RT , had a longer OS  compared to all other patients  who received only two modalities of systemic/local treatment . The difference was statistically significant (P = .040). Kaplan‐Meier survival curves are presented in Figure The impact of treatment received after LM diagnosis on OS was also investigated using univariate Cox regression Table . TreatmeP‐values <.10 at univariate analysis were included in the multivariate analysis. At multivariate analysis, only the presence of neurological symptoms at the time of LM diagnosis  and not receiving RT after LM diagnosis  were confirmed to be statistically significantly and independently associated with worse OS. Conversely, younger age <60 years , LM diagnosis before 2010 , Karnofsky performance status <70 , not receiving chemotherapy  or monoclonal antibodies trastuzumab and/or pertuzumab  following LM diagnosis were not significantly associated with worse OS.The seven clinical variables (excluding prognostic scores) associated with OS with 4The treatment landscape of HER2+ metastatic breast cancer has significantly changed over the last decade. Even if increasing attention is given to the specificities of patients with CNS involvement and several anti‐HER2 targeted agents have demonstrated antitumor activity in the brain,We here report clinical and pathological characteristics, as well as survival outcomes, of 82 patients with HER2+ breast cancer and LM included in our real‐world multicentric retrospective cohort, which is one of the biggest cohorts published to date. In our study cohort, we observed a median OS from LM diagnosis of 8.3 months, which compares favorably to most previous studies,Following LM diagnosis, the majority of patients in our study cohort received multimodality treatment, which included several systemic treatment approaches, IT, and RT. At univariate analysis, patients who were treated after 2010 , or had better Karnofsky performance status, were free of neurological symptoms, had higher scores on the SS‐BM and INDEX prognostic indices, received chemotherapy or monoclonal antibodies (trastuzumab with or without pertuzumab) after LM diagnosis, had a statistically significantly longer OS. At multivariate analysis, absence of neurological symptoms at time of LM presentation, which is consistent with previous reports,In our study cohort, 62.2% of patients were diagnosed with brain metastases prior to or concurrently with LM, and 18.1% underwent brain surgery, before the development of LM, as a direct consequence of brain metastases. At the time of LM diagnosis, 70.7% of patients in our cohort received RT, the majority of which was whole brain RT, and 22.4% of them were previously treated with RT for either brain parenchymal metastases or due to LM. Patients who received the second RT course might have tumor cells that responded better to various therapies, and they lived long enough to be considered for reirradiation due to CNS symptoms or disease progression in the brain. Though RT has the potential to improve quality of life in the short term and is used for the relief of neurological symptoms, the treatment of bulky disease, and the normalization of cerebrospinal fluid flow, data on the effect of RT on survival outcomes are inconsistent,In our study cohort, about one‐third of patients received IT either alone or in combination with systemic chemotherapy and trastuzumab. Only two patients received trastuzumab intrathecally. When compared to patients who did not receive IT, the observed gain in OS was small and not statistically significant. In a recent retrospective analysis of a large contemporary cohort of 312 patients with metastatic breast cancer and LM treated with IT, the authors reported a median OS of 4.5 months and a 1‐year OS rate of 25% for the entire cohort, regardless of HER2 status.Approximately two‐thirds of patients in our study had a preexisting diagnosis of metastatic breast cancer at time of LM diagnosis, which is similar to previous reported cohorts.ClinicalTrials.gov identifiers NCT04420598, NCT04856475, NCT03661424, NCT04457596) and MRI screening .As almost all patients included in our study received at least one line of anti‐HER2 targeted therapy, we were unable to assess the impact of targeted treatment on survival for patients receiving anti‐HER2 therapy  vs those who did not. Nevertheless, in a univariate analysis, the receipt of trastuzumab (with or without pertuzumab) resulted in significantly improved OS. More than a third of patients diagnosed with LM in our study cohort received TDM‐1 or lapatinib, respectively. There was a 1.9‐month difference in survival between those who received TDM‐1 therapy and those who did not, but the difference was not statistically significant. New HER2‐targeted agents have shown extremely promising antitumor activity in patients with HER2+ breast cancer and brain metastases.Our study has several strengths: we analyzed one of the largest studied to date, homogeneous cohort of patients with HER2+ breast cancer diagnosed with LM across three European countries; in addition, patients included were diagnosed and treated in relatively recent years, when several HER2‐targeted agents were already available. Nevertheless, data reported in our study was collected retrospectively and might therefore be subject to potential biases linked to its retrospective nature. Moreover, patients were treated by clinical practice, therefore patients who received treatment may have had better Karnofsky performance status and less advanced disease, resulting in a survival bias.To summarize, LM is a fatal complication of HER2‐positive breast cancer for which the optimal systemic or local treatment still remains to be defined. In our cohort of patients with HER2‐positive breast cancer we observed a median OS of 8.3 months from LM diagnosis, with a significant proportion of patients alive at 1 and 2 years after diagnosis , which is considerably longer than reported by most previous studies. In the univariate analysis, absence of neurological symptoms, good performance status at time of LM diagnosis, receipt of chemotherapy or trastuzumab (with or without pertuzumab), were all associated with longer OS. At a multivariate model, both absence of neurological symptoms and having received RT were associated with longer OS. However, due to the study's retrospective nature, it is impossible to assess the real benefit of each treatment modality as some patients might have received certain therapies because they lived longer and, for example, got local treatment after developing symptoms or because their condition was so good that systemic treatment was possible. The patient's performance status, on the other hand, is a crucial modifying element for therapy decisions. Moreover, the impact of overall HER2‐targeted treatment was not assessable, as almost all patients in our study cohort received at least one line of targeted therapy.In conclusion, treatment of patients with HER2+ breast cancer and LM remains challenging, and until the results of prospective studies are available, a careful evaluation of all possible treatments and an individual approach for each patient is required. Being without neurological symptoms and receiving RT at the time of LM diagnosis were related with a longer OS in our study cohort. Patients with LM who underwent multimodality therapy, which included targeted therapy, chemotherapy, and RT to the LM sites, had a higher rate of OS.The work reported in the paper has been performed by the authors, unless clearly specified in the text: Conceptualization: Ivica Ratosa, Gaia Griguolo, Amélie Darlix, Stéphane Pouderoux, William Jacot; Data curation: Ivica Ratosa, Nika Dobnikar, Tanja Znidaric, Michele Bottosso, Amélie Darlix, Léa Sinoquet; Formal Analysis: Ivica Ratosa, Nika Dobnikar, Tanja Znidaric, Gaia Griguolo, Amélie Darlix, Stéphane Pouderoux, William Jacot; Funding acquisition: none; Investigation: none; Methodology: Ivica Ratosa, Gaia Griguolo, Amélie Darlix, William Jacot; Project administration: Ivica Ratosa, Nika Dobnikar, Domen Ribnikar, Tanja Znidaric, Gaia Griguolo, Amélie Darlix; Resources: Ivica Ratosa, Nika Dobnikar, Domen Ribnikar, Tanja Znidaric, Gaia Griguolo, Amélie Darlix, William Jacot; Software: none; Supervision: Ivica Ratosa, Gaia Griguolo, Amélie Darlix, William Jacot; Validation: Ivica Ratosa, Domen Ribnikar, Tanja Znidaric, Gaia Griguolo, Amélie Darlix, William Jacot; Visualization: none; Writing—original draft: Ivica Ratosa, Nika Dobnikar; Writing—review & editing: Ivica Ratosa, Nika Dobnikar, Michele Bottosso, Maria Vittoria Dieci, William Jacot, Stéphane Pouderoux, Domen Ribnikar, Léa Sinoquet, Valentina Guarneri, Tanja Znidaric, Amélie Darlix, Gaia Griguolo; All authors read, provided feedback and approved the final protocol and manuscript.The authors acknowledge grants from: Istituto Oncologico Veneto projects L04P11 , L02P03 (to Maria Vittoria Dieci), L04P25 (to Maria Vittoria Dieci); University of Padova—Department of Surgery, Oncology and Gastroenterology BIRD 2020 and BIRD 2021 ; 2019 Conquer Cancer Foundation of ASCO/Shanken Family Foundation Young Investigator Award (to Gaia Griguolo); Fondazione AIRC under 5 per mille 2019—ID. 22759 program—G.L. Valentina Guarneri.Ivica Ratosa, Nika Dobnikar, Michele Bottosso, Amélie Darlix, William Jacot, Stéphane Pouderoux, Domen Ribnikar, Léa Sinoquet and Tanja Znidaric report no conflict of interest. Maria Vittoria Dieci reports personal fees from Eli Lilly, MSD, Exact Sciences, Novartis, Pfizer, Seagen, outside the submitted work. Valentina Guarneri reports personal fees from Eli Lilly, Novartis, Roche, MSD, Gilead, Eisai (Advisory Board), and from Eli Lilly, Novartis, GSK, Amgen (Speakers' Bureau) outside the submitted work. Gaia Griguolo reports personal fees from Eli Lilly and Novartis (invited speaker), Gilead (Advisory Board) and from Novartis, Pfizer, Amgen, Daiichi Sankyo (Travel Support) outside the submitted work.All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committees and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Our study was approved by the institutional review board and ethical committee . All study participants provided informed consent for the use of their data for retrospective research purposes, if required by local regulations.Appendix S1 Supporting InformationClick here for additional data file.


Plaque healing may serve a vital function in the natural progression of atherosclerotic disease. This study sought to investigate predictors and morphological characteristics of healed plaque (HP) among angina pectoris (AP) patients.Patients who presented with AP and received preintervention optical coherence tomography (OCT) imaging were consecutively selected for this single‐center retrospective observational study. Patient's demographic and clinical information was collected from the hospital's electronic medical records. Coronary angiograms and OCT images were compared via offline software.p = .01] and 364.22 ± 91.80 vs. 341.53 ± 77.64 µmol/L [p = .01], respectively). Using multivariate analysis, SAP and long lesion length were shown to be stand‐alone indicators of HP. HP presented with more severe stenosis as well as a longer lesion length and had more vulnerable and more complex features. In HP lesions, UAP patients had more plaque ruptures and thrombosis, whereas SAP patients had lower uric acid levels and more multiple HPs(≥3 HPs).A total of 390 patients were chosen as the final study population. HP was identified in 186 patients (47.7%) and was relatively less in cases of unstable angina pectoris (UAP) than in stable angina pectoris (SAP) (89/233 [38.2%] vs. 97/157[61.8%]). The HP group had greater prevalence rates of previous myocardial infarction and SAP and higher levels of triglycerides and uremia (median, 1.67 vs. 1.31 mmol/L [Clinical presentation of SAP and long lesion length were strong predictors for HP in patients with AP. Patients with HP presented with more severe stenosis, longer lesion lengths, greater inflammation, and vulnerability. UAP was defined by the presence of new or developing chest pain on exertion or rest within 2 weeks, in the absence of elevated cardiac enzymes .We collected patient demographic and clinical information, including basic vitals; age and sex; histories of smoking, hypertension, hyperlipidemia, and diabetes mellitus; family history of heart disease; medical history; and laboratory data at admission from the hospital electronic medical record. Percutaneous coronary intervention procedure data and OCT images were also collected. A diagnosis of prior myocardial infarction (MI) was recorded, according to medical documentation, pathological Q‐waves on electrocardiography with regional wall motion abnormalities, and/or presence of localized nonviable myocardium.n= 368) were excluded; 82 patients with low‐quality OCT images caused by artifacts in the blood or too short a pullback were also excluded, and another 48 were excluded because of large thrombi or serious calcifications that impeded plaque visualization of the underlying layer. Those coronary heart disease etiology involving spontaneous coronary artery dissection, spasm, or myocardial bridge (n = 41) were also eliminated. Finally, patients with incomplete data (n = 82) and AMI (n = 78) were excluded from the final analysis. Thus, the final analysis was done on 390 patients . We counted the amount of epicardial coronary arteries carrying stenotic lesions (diameter stenosis [DS] ≥ 50%). The term “eccentric lesions” refers to lesions that have one luminal edge outside the one‐fourth of the apparent vessel lumen. The same criteria were used for concentric lesions as long as they involved both luminal borders. To confirm the classification of lesions, multiple angiographic angles were used whenever possible. When the vessel was visible on moving images during the heart cycle in the absence of contrast injection, the presence of calcification was noted.2.3OCT imaging was conducted with a frequency‐domain OCT system . Intracoronary OCT imaging was performed following standard procedures. All collected OCT images were analyzed via an offline review workstation  by two separate researchers blinded to the study participants' demographic, clinical, and angiographic information. Any disagreements were resolved by consulting a third reviewer to reach a consensus. According to current consensus criteria for OCT imaging,The lipid index was calculated as the product of the average lipid arc and lipid length. Calcification plaques (CPs) were recorded as areas with heterogeneous or low signal attenuation and sharp borders. Macrophage accumulations were defined by the existence of highly backscattering focal granular areas in the fibrous cap. Microvessels were identified by the recognition of small, signal‐poor vesicular or tubular structures in ≥3 contiguous frames. Cholesterol crystals were described as thin and linear regions with high signal intensity in plaques, without backscattering. Thrombus was described by a protrusion of ≥250 mm within the vessel lumen with signal attenuation. Plaque rupture was described by the discontinuity of a fibrous cap and cavity development within the plaque.κ coefficient statistics. The intraobserver variability was calculated in 80 randomly selected plaques 2 weeks apart. The inter‐variability was assessed by two independent physicians at two separate time points. The intra‐ and interobserver κ coefficients were 0.89 and 0.86 for HP, 0.96 and 0.93 for LRPs, 0.95 and 0.94 for CP, and 0.87 and 0.82 for macrophage infiltration, respectively.Inter‐ and intraobserver agreements were evaluated via 2.4t or Mann–Whitney U test. Categorical data are shown as frequency (percentage) values and were analyzed via the chi‐squared or Fisher's exact test. Established cardiovascular disease risk factors  angiographic findings, and variables with p < .10, based on univariate analysis were further analyzed via multivariate analysis.Continuous variables, with normal distribution, are presented as mean ± standard deviation values and those with skewed distribution are presented as median (25th–75th percentiles). We compared continuous data using independent‐samples http://www.R-project.org; The R Foundation for Statistical Computing) and a free statistics analysis platform. A two‐tailed p < .05 was set as the significance threshold.All data analyses employed the R version 3.3.2 software . Healed coronary plaques were less frequently observed in patients with UAP than SAP (89/233 [38.2%] vs. 97/157 [61.8%]) (Table 3.2p = .031), and their levels of triglycerides and uremia were significantly higher . The same laboratory trends could also be seen among UAP patients. In the SAP population, no obvious differences were seen in clinical manifestation between the two patient populations, aside from the level of high‐density lipoprotein cholesterol (HDL‐C) . HP patients in SAP had lower uric acid levels than those in UAP   Figure . No else3.3Quantitative coronary analysis findings are detailed in Table 3.4Univariate analysis showed that SAP, prior MI, lesion length, DS%, type B2/C lesions, triglycerides, and uremia were significant predictors of HP . Whereas SAP patients had more multiple HPs (≥3 HPs), compared with UAP patients   as well as a longer lipid core length. Among UAP patients, HP had more vulnerable and more complex features, demonstrated by higher rates of LRPs, thin cap fibroatheroma (TCFA), cholesterol crystals, macrophage accumulation, plaque rupture, thrombus, and thinner fibrous cap thickness as well as a more severe lipid index, max lipid arc, minimal lumen area, and AS Table . HP pati5) Table .4This study demonstrated that in patients with AP: (1) HP was identified in 47.7% of AP patients, (2) SAP patients had a higher prevalence rate of HP and multiple HPs (≥3 HPs) than UAP patients, (3) the clinical presentation of SAP and lesion length on coronary angiography were predictors for HP in AP patients, (4) HP presented with longer lipid lengths and more severe luminal stenosis. Compared to those in SAP patients, HP in UAP patients had more vulnerable and more complex features and (5) HP patients in UAP had higher uric acid levels, more plaque ruptures, and thrombosis than in SAP.4.1In the past decades, HP could only be observed by pathological examinations performed at autopsy.4.2Here, HP patients displayed an enhanced incidence of both hypertriglyceridemia and hyperuricemia. In SAP patients, the level of HDL‐C was lower in those with HP. In a separate investigation, ACS patients with HP showed enhanced incidence rates of hyperlipidemia and diabetes mellitus.Importantly, MI was more prevalent among patients with HP, in line with other recent OCT studies.4.3HP patients displayed longer lesion lengths, elevated DS, and more complex lesions (Class B2/C). These tendencies were also more pronounced in UAP patients than SAP patients, and the same results could be observed in other studies including ACS patients.In this study, we also observed the impact of other types of B2/C lesions, such as eccentric and calcified lesions, on the HP. One study concluded that lesions with HP had more eccentric lumens after stent implantation.4.4Here, HP patients exhibited longer lesion lengths, further luminal constriction, and more complicated vascular lesions; moreover, lesion length was an independent predictor of HP. Further analyses showed that multiple HPs are related to lesion length. Recent studies have suggested an association of an HP phenotype with lumen narrowing at the culprit and nonculprit locations, which was also confirmed by our study.4.5Here, LRPs, macrophage accumulation, and CP were excessively common in AP patients with HP, and these results match those of previous studies.Our study showed that in HP lesions, UAP patients had more plaque ruptures and thrombosis Whereas SAP patients had more multiple HPs. Some studies found that there was a higher incidence of nonculprit plaque rupture among SAP patients (22%) than those with UAP (12%). However, plaque ruptures were less likely to be covered by thrombus in SAP patients than in UAP patients (21% vs. 33%).However, how to keep the HP stable or avoid repeated plaque rupture and healing is not clear. Intensive antithrombotic therapy was demonstrated to be highly efficacious toward coronary plaque erosion healing. Furthermore, multiple reports validated the numerous benefits of potent lipid‐lowering drugs  on plaque stabilization. Anti‐inflammatory agents are known to lower the risk of cardiovascular events. Although the mechanisms behind these benefits remain unclear, an improvement in plaque‐healing capacity may encourage faster healing. Considering the widely used method involving mechanisms of plaque instability, we should perform more research to further understand the protective mechanisms that convert “poor healers” into “good healers.” Therefore, further prospective studies will be necessary to reveal novel mechanisms of plaque healing and identify more effective means for promoting the stability of plaque healing.4.6Our work encountered certain limitations. First, our study design was retrospective, so inherent selection bias may have been inadvertently introduced. Second, nonculprit plaques were not evaluated using systematic 3‐vessel imaging. This is because this technology is unsuitable in real‐world clinical practice and may bring about undue risk factors. Third, although a prior histology validation study reported elevated OCT specificity in diagnosing HP, diagnosing HP using OCT can still be challenging. Fourth, only a limited number of inflammatory and coagulation indexes were assessed. As such, we cannot say that a definite relationship exists between plaque healing and the inflammation and coagulation systems. In light of this, future investigations must identify more biomarkers to assess the association between plaque rupture and healing to better elucidate related mechanisms and pathology.5The clinical presentation of SAP and lesion length appeared to be strong predictors for HP in patients with AP. Furthermore, OCT analysis showed that HP presented with greater inflammation and vulnerability, more severe AS, and higher rates of macrophage accumulation, LRPs, calcification, cholesterol crystals, plaque rupture, and TCFA.The authors declare no conflict of interest.Supplementary information.Click here for additional data file.


Oxidative stress (OS) occurs in cystic fibrosis (CF).The objective of this work is to evaluate the influence of bacterial infection on biomarkers of OS , markers of oxidative damage , together with the nutritional status and lung function in children with CF.n = 55) and control group , median age: 3.89 and 4.62 years, respectively. CFG was distributed into CFG negative bacteriology  or CFG positive bacteriology , and CFG negative Pseudomonas aeruginosa  or CFG positive Pseudomonas aeruginosa .Cross‐sectional study including CF group  and CFGB+ (P = .042) had lower body mass index‐for‐age z‐score; forced expiratory volume in the first second was lower in CFGB+ and CFGPa+ (both P < .001). After adjusting for confounders and compared with CG: CFG showed higher TBARS (P ≤ .001) and PC (P = .048), and lower CAT (P = .004) and GPx (P = .003); the increase in PC levels was observed in CFGB+ (P = .011) and CFGPa+ (P = .001) but not in CFGB− (P = .510) and CFGPa− (P = .460).Compared with CG, CFG , markers of oxidative damage , together with the nutritional status and pulmonary function in children with cystic fibrosis. Our results demonstrate that there is a systemic oxidative stress in children with cystic fibrosis. The presence of bacterial infection particularly  Subsequently, lungs may be colonized with Pseudomonas aeruginosa and/or Burkholderia cepacia.Burkholderia cepacia complex are very resistant to antibiotic therapy and are associated with the risk of a severe course of the disease. Pseudomonas aeruginosa is one of the main causes of chronic pulmonary infection and OS in CF.The overgeneration of reactive oxygen species and the depletion of antioxidants lead to oxidative stress (OS) in cystic fibrosis (CF).The airway infection leads to progressive damage of the lungs, resulting in increased OS and loss of reduced glutathione (GSH), which occurs through its utilization by the inflammatory process.Pseudomonas aeruginosa, on biomarkers of OS such as CAT, GPx and GSH, and markers of oxidative damage such as protein carbonyl (PC) and thiobarbituric acid reactive substances (TBARS), together with the nutritional status and lung function in the patients.Given the presence of systemic bacterial infection in CF patients, monitoring the progress of the disease through the clinical status of the individuals together with biomarkers of OS play a fundamental role for its understanding and treatment. In this study, we aimed to evaluate, in a pediatric population with CF, the influence of bacterial infection, including 22.1This was a cross‐sectional controlled clinical study (April/2009 to December/2011) carried out at the Joana de Gusmão Children's Hospital, Florianópolis/SC ‐ Brazil. The study was approved by the hospital's Human Research Ethics Committee (#048/2008) and registered in the Australian New Zealand Clinical Trials Registry (#ACTRN12611001217998). Written informed consent was acquired by the parents or guardians before participating in the study.2.2z‐scores (BMI‐z), while exclusion criterion was the presence of CF. Inclusion criteria for CFG were subjects from the Mucoviscidose Support Association of Santa Catarina (Brazil), who were diagnosed with CF by a sweat test (sweat chloride ≥60 mmol/L), and who were 1‐year old or older. Exclusion criteria for both groups were subjects showing fever, diabetes, glucose intolerance, trauma diagnosis, inflammatory disease , degenerative diseases, renal failure, psychiatric disease, cardiovascular disease, and primary or secondary immunodeficiency; and subjects ongoing treatment with antibiotics and/or hormones, anti‐inflammatory, immune suppressant or anti‐histamines drugs, until 30 days before the data collection.A more extensive description of the study population was previously reported.2.3The weight of children ≤2 years of age was taken using a Filizola®/pediatric‐digital scale  (Santo André/SP/Brazil), and in children >2 years of age, a Balmak® 50F/digital scale   was used.2.41),Lung function was evaluated only in children >5 years by the forced expiratory volume at the first second  was assessed by counting colony forming units (CFU).Bacteriological analysis was performed in oropharyngeal secretions from subjects after a 10‐hour fast, using a dry swab, which was evaluated microscopically  by the Gram method. The presence of pathogenic microorganisms for CF , following successive freezing and thawing procedures. A final centrifugation (5000 g for 5 min) supplied the supernatants (hemolysates). Samples were stored at −80°C, except for the plasma samples utilized for TBARS analysis, which were stored in liquid nitrogen (−170°C) until analysis. Aliquots of whole blood were precipitated in trichloroacetic acid (TCA) 12%  and stored immediately in liquid nitrogen until GSH analysis. CAT activity was determined by measuring the decrease in a freshly prepared 10mM hydrogen peroxide solution at 240 nm.Blood was collected from the cubital region in a vacuum system after 10 h of fasting. To carry out determinations of CAT, GPx, PC, and TBARS, samples were collected in tubes containing ethylene diamine tetraacetic acid (EDTA) as anticoagulant. The separation of plasma and erythrocyte was achieved by centrifugation of whole blood at 2,500 2.7Pseudomonas aeruginosa (CFGPa−) or CFG positive Pseudomonas aeruginosa (CFGPa+). Sex and age were included as confounding variables in all models. A Statistical Package for the Social Science® for Windows  was used, and a threshold for significance was set at P < .05.The Kolmogorov–Smirnov test for normality and homogeneity of data was applied. Data are expressed as mean ± standard error of the mean for symmetric distribution and as median and interquartile range (IQR) for asymmetric distribution. Asymmetric variables  were transformed into natural logs before performing multiple linear regression analyses. Multiple linear regression analyses were performed between CG and CFG; between CG and subgroups according to the infection status: CFG negative bacteriology (CFGB−) or CFG positive bacteriology (CFGB+); and according to type of bacterial infection: CFG negative 33.1n = 19 female), with a median age of 4.62 years, (IQR: 3.04–8.91) and BMI‐z of 0.30 ± 1.23. During the study period, the CF outpatient unit assisted 75 subjects, in which 20 were excluded from the study due to: age under one year old (n = 5), undergoing antibiotic treatment (n = 10), showing fever at the time of the study (n = 2), presenting a psychiatric disease (n = 3). Therefore, the CFG consisted of 55 children  with a median age of 3.89 years (IQR: 1.77–8.52) and BMI‐z of −0.26 ± 1.11. The mean age at diagnosis was 1.9 ± 0.39 years.The CG included 31 subjects (n = 55) were further stratified into subgroups in two different ways. (1) Subjects were stratified according to absence or presence of pathogenic microorganisms in CF : CFGB−, n = 27 or CFGB+, n = 28. Nineteen subjects had Pseudomonas aeruginosa infection, 19 had Staphylococcus aureus infection, and three had Burkholderia cepacian infection . (2) Subjects were stratified according to the absence or presence of Pseudomonas aeruginosa: CFGPa−, n = 36 or CFGPa+, n = 19.Subjects with CF (P = .034) and CFGB+  were significantly lower compared with CG (0.30 ± 1.23). FEV1 was significantly higher in CG  compared with CFG . FEV1 was significant lower in CFGB+  and CFGPa+  compared with CG , GPx , and TBARS levels  were significantly different than CFG  and CFGPa+  compared with CG (0.038 nmol/ml) , CFGB+  and CFGPa−  compared with CG  compared with CG  compared with CG  Table . No diff41) and nutritional status (BMI‐z) in children with CF. Additionally, the presence of bacterial infections, particularly Pseudomonas aeruginosa, worsened the oxidative damage to proteins, nutritional status, and lung function in these subjects. While similar findings have been reported in adults with CF,The present study identified higher levels of oxidative damage to proteins and lipids , lower antioxidant defense activities (CAT and GPx), as well as lower lung function .P < .05) compared with 25 healthy control subjects (129.6 ± 12.9 nmol/L).These findings strongly indicate structural and functional oxidative damageP < .05) compared with 17 healthy controls (296.9 ± 57 U/L), although the erythrocytes levels were not different between groups.Regarding the enzymatic antioxidant defenses, our findings showed that CAT and GPx activity were lower in subjects with CF compared with controls. A similar CAT response was found in another large study conducted in 100 pediatric subjects with CF (age range: 1–18 years), compared with 25 healthy controls with same age range, indicating the increased susceptibility of erythrocytes to OS in CF.Concerning the findings obtained for the endogenous and ubiquitous antioxidant GSH,1 and BMI‐z compared with controls. It is suggested that resting energy expenditure is increased by 7–35% in subjects with CF, which may contribute to catabolism and lung function deterioration.Additionally, subjects with CF showed lower FEV1 and BMI‐z. These findings are in agreement with a previous study which demonstrated elevated PC levels in Pseudomonas aeruginosa and Staphylococcus aureus infected CF pediatric subjects  versus controls .Pseudomonas aeruginosa and/or other pathogens.It has been postulated that bacterial infection of the airways may contribute to dysregulation of redox balance in CF. Because subjects participating in this study were categorized based on bacterial colonization, the effect of colonization could be further estimated. We demonstrated that bacterial infections worsened the oxidative damage to proteins, nutritional status, and lung function of subjects with CF by showing increased levels of PC, and decreased FEVThe limitations of this study should be considered when interpreting the results. Although our sample size was similar to others using comparable methods, it is still relatively restricted. Therefore, it is possible that the number of participants may have led to failure to detect other meaningful outcomes. Additionally, the recruitment took place at a single referral center for CF treatment, which could also limit our findings. The study was of cross‐sectional design preventing to derive causal relationships among variables. Notably, this study used a diverse set of blood biomarkers to characterize OS in CF, which are readily available from individuals of any age and with any disease severity.Pseudomonas aeruginosa seems to exacerbate the oxidative damage to proteins and to contribute to progressive lung disease and nutritional status depletion. In this regard, PC may be a useful marker of oxidative modifications of plasma proteins in CF.In conclusion, the present study examined various clinical aspects of the CF disease such as the presence of infection by pathogenic bacteria, lung function, and different ways of grouping individuals. The decrease detected in GPx and CAT activity together with an increase in PC and TBARS contents as well as the apparent inability to maintain higher GSH levels clearly indicate an early evidence of an altered redox response in children with CF. Such chronic oxidative insult associated with bacterial infection particularly The authors have declared that there is no conflict of interest.The study was approved by the hospital's Human Research Ethics Committee (#048/2008), and written informed consent was acquired by the parents or guardians before participating in the study.Conceptualization: GDB and EAMM. Data curation: EAM and YAFM. Formal analysis: GDB, LCRP, and MBF. Investigation: GDB and LCRP. Methodology: GDB, EAMM, LCRP, DLO, JCV, EBP, EBSM, EB, and NLN. Project administration, Resources, Software and Supervision: EAMM. Validation: GDB, YMFM, and EAMM. Roles/Writing ‐ original draft: GDB. Writing ‐ review & editing: LCRP, MBF, EAMM, YMFM, and DWF.Australian New Zealand Clinical Trials Registry (#ACTRN12611001217998).


Klebsiella pneumoniae (CR‐hvKP) that causes nosocomial infection.The purpose of our study is to analyze the microbiological and clinical characteristics of carbapenem‐resistant hypervirulent K. pneumoniae (CRKP) strains that caused nosocomial infection in a hospital in China and collected the relevant clinical data. We characterized these strains for their antimicrobial and virulence‐associated phenotype and genotype and analyzed the clonal relatedness. We screened hypervirulent strains and compared them with non‐hypervirulent strains.We collected the carbapenem‐resistant Galleria mellonella infection model. PFGE showed that ST11‐KL47 CR‐hvKP and ST11‐KL64 CR‐hvKP exhibited a high degree of clonality, while non‐hypervirulent strains were not significant. CR‐hvKP had higher positive rates of blaKPC‐2 and blaCTX‐M‐65 and higher levofloxacin resistance  when compared to the non‐hypervirulent strains. There was no significant difference between the two groups in terms of in‐hospital mortality .We retrospectively analyzed 62 CRKP strains that caused nosocomial infection in a tertiary hospital within 1 year, of which 41  CRKP were considered as CR‐hvKP. All CR‐hvKP strains were multi‐drug resistance (MDR) and the vast majority of isolates  were ST11 KPC‐2‐producing strains. Two hypermucoviscous isolates and 4 capsular types were found in 41 CR‐hvKP. Twenty‐nine isolates  showed hypervirulence in Our research finds that ST11 KPC‐2‐producing CR‐hvKP is the main type of CRKP that caused nosocomial infection, and clonal spread has occurred. We provide more information about CR‐hvKP in health care. Our research finds that ST11 KPC‐2‐producing CR‐hvKP is the main type of CRKP that caused nosocomial infection, which poses a new threat to people's health. And we provide more information about CR‐hvKP in health care. Carbapenem‐resistant K. pneumoniae (CRKP), which can resist almost all clinically used antibiotics and cause serious infections, poses a huge threat to global public health.K. pneumoniae sequence type (ST) 258 has contributed significantly to the dissemination of CRKP in the United States and in European countries, but ST11 is predominant in China,K. pneumoniae strains are significantly different from that of other countries.blaKPC‐2, blaNDM‐1, blaOXA‐48, and ST11 KPC‐2‐producing K. pneumoniae is spreading at an alarming speed.K. pneumoniae (hvKP) is a more virulent variant of K. pneumoniae, known for causing invasive infections among young and relatively healthy individuals. This phenomenon is first observed in community infections and mainly occurs in the Asian Pacific Rim.Hypervirulent K. pneumoniae (CR‐hvKP) infection were increasing, even a fatal outbreak caused by CR‐hvKP in a Chinese hospital had been observed.In the past years, reports on carbapenem‐resistant hypervirulent However, our knowledge of CR‐hvKP is still very limited so far, and more monitoring and research results are urgently needed to fight this pathogen, particularly the pheno‐ and genotypic characteristics of prevalent strains from continually survey in hospitals. This study analyzed the presence of CR‐hvKP among CRKP which caused nosocomial infection in hospitalized patients, and studied the phenotypes and genotypes of the strains, as well as clinical characteristics of the associated patients, which provided more information on understanding CR‐hvKP.22.1K. pneumoniae and resistant to imipenem and/or meropenem (defined as CRKP in this study) were collected. Strains isolated from the same part of the same patient were excluded. Identification results were reconfirmed through VITEK MS . For strains resistant to imipenem or meropenem, the E test method was used to verify their susceptibility. The antimicrobial susceptibility tests of tigecycline and colistin were carried out by the micro‐broth dilution method. The interpretation of the results was carried out according to the FDA guidelines and EUCAST guidelines, respectively.iucA, iroN, prmpA, or prmpA2 in CRKP.A one‐year retrospective study was conducted in Hunan Provincial People's Hospital, the First Affiliated Hospital of Hunan Normal University. This study was approved by the ethics committee of Hunan Provincial People's Hospital. The hospital is located in Changsha, Hunan Province, China. It is a large‐scale comprehensive tertiary hospital with nearly 4000 beds. We used VITEK 2 Compact system  conducting identification and antimicrobial susceptibility test of all strains isolated in Clinical Microbiology Laboratory from January to December 2018. The results of the antimicrobial susceptibility test were interpreted according to the rules provided by the CLSI guidelines.2.2The carbapenem‐resistant phenotype of strains was detected by CLSI recommended modified carbapenem inactivation method (mCIM).2.3blaKPC, blaNDM, blaIMP, blaVIM, and blaOXA‐48) and genes encoding other β‐lactamases .entB, irp‐1, and irp‐2), fimbriae biosynthesis (fimH and mrkD), lipopolysaccharide biosynthesis (wabG), fucose synthesis (wcaG), allantoin metabolism , and putative transporter (peg‐344).https://blast.ncbi.nlm.nih.gov/blast.cgi). We genotyped the capsular polysaccharide synthesis (cps) gene of strains by amplifying and sequencing the wzi gene, as previously described.We detected resistance genes by PCR amplification, including genes encoding carbapenemases . Setting up each strain as an experimental group, each experimental group contained 10 larvae. The mid‐log phase culture was diluted with PBS into a bacterial suspension with a concentration of 106 cfu/ml, and 10 μl of the bacterial suspension was injected with a microsyringe into the left forefoot of each larva. After injection, the larvae were kept at 37°C in dark to observe the 72‐h mortality. Strain which the pathogenicity was similar or stronger than the positive control was assessed as hypervirulence in vivo. NTUH‐K2044, ZR2 (a non‐hypervirulent K. pneumoniae strain identified in our previous study), and PBS were used as positive control, negative control, and blank control, respectively.Further virulence assessment for CR‐hvKP was conducted by 2.5gapA, infB, mdh, pgI, phoE, rpoB, and tonB).https://bigsdb.pasteur.fr/). Genetic correlations among the CRKP strains were subsequently analyzed by PFGE.We conducted MLST by amplifying and sequencing 7 housekeeping genes . Continuous variables were assessed by Student's 33.1K. pneumoniae strains from Hunan Provincial People's Hospital were collected between January 1 and December 31, 2018, by routine monitoring, among which 125 (7.17%) CRKP were identified , 30/41 (73.2%), 3/41 (7.3%), and 19/41 (46.3%), respectively, among which 3 isolates had all four virulence genes . Through our analysis, there were no significant differences between the two groups in terms of age, gender, underlying diseases, invasive treatments, infection sites, length of hospital stay, and in‐hospital mortality  CRKP were CR‐hvKP. The positive rates of 3.2p < 0.001) , trimethoprim/sulfamethoxazole (51.2%), amikacin (41.5%), colistin (0%), and tigecycline (0%) Figure . In term1) Table .blaKPC‐2  and blaIMP‐4 . Most  CR‐hvKP harbored blaKPC‐2, and 1  harbored blaIMP‐4. 1 CR‐hvKP isolate did not carry blaKPC, blaNDM, blaIMP, blaVIM, or blaOXA‐48, but the mCIM phenotype test was positive, indicating that it might harbor other carbapenem resistance genes. Other β‐lactamase genes were detected in CR‐hvKP strains, including blaCTX‐M‐3, blaCTX‐M‐15, blaCTX‐M‐65, blaSHV‐11, blaSHV‐12, and blaTEM‐1. The positive rates of blaKPC‐2 and blaCTX‐M‐65 in CR‐hvKP group were both higher than that of CR‐nhvKP group  . The vast majority of CR‐hvKP belonged to KL64 and KL47, and KL64 was the dominant capsular type , while in the CR‐nhvKP group more diverse capsular types were found. Capsule type KL64  was significantly associated with the CR‐hvKP group when compared to the CR‐nhvKP group  and peg‐344  were significantly associated with the CR‐hvKP group when compared to the CR‐nhvKP group  CR‐hvKP strains showed hypervirulence in vivo  CRKP strains were hypermucoviscous (both were CR‐hvKP). 3.4p < 0.001) was strongly associated with CR‐hvKP when compared to CR‐nhvKP , followed by ST571 (2/62), ST15 (1/62), ST37 (1/62), ST70 (1/62), ST101 (1/62), ST414 (1/62), ST515 (1/62), ST1040 (1/62), ST1779 , ST1933 (1/62), ST2928 (1/62), and new ST (1/62). The majority of CR‐hvKP belonged to ST11  and 1 belonged to ST2928 , while all 10 ST11‐KL47 CR‐hvKP were positive for a combination of iucA‐ prmpA2 genes, suggesting that two different developmental series might have formed. This was confirmed by PFGE analysis. 7 ST11‐KL47 CR‐hvKP which from the PFGE cluster 10 shared the same virulence and resistance characteristics and all isolated from a short period of time, suggested that clonal spread had occurred in our hospital. Interestingly, among ST11‐KL64 CR‐hvKP in PFGE cluster 15 and 18, no consistent characteristics were observed. This might result from the rapid reshaping and diversification of the genome pool of ST11‐KL64 CR‐hvKP.Through MLST and capsular type detection, we found that 41 CR‐hvKP in this study could mainly be divided into two series: 27 ST11‐KL64 isolates and 10 ST11‐KL47 isolates. All 27 ST11‐KL64 CR‐hvKP were positive for a combination of G. mellonella infection model, suggesting complete pLVPK plasmid harboring. Interestingly, KP13, KP145, KP669, and KP1590 shared the same drug resistance type and genotype with KP178, KP213, KP238, and KP1640, but they showed opposite results in the G. mellonella infection model. This might be caused by the presence of undetected virulence factors. In addition, we also found that virulence genes irp‐1 and peg‐344 mainly existed in hypervirulent strains, indicating that these two genes may contribute to the virulence. In future research, the mechanism of hypervirulence is still worthy of attention.In this study, only 3 strains with all the four virulence genes positive were detected; the three all showed high lethality in the K. pneumoniae to obtain exogenous genes encoding resistance and virulence, we need to arouse sufficient vigilance over CR‐hvKP.This study only analyzed CRKP isolated from one hospital in China in one year. The sample size is very limited, and larger‐scale or multi‐center research results are needed to support the above results. In addition, the condition for screening hypervirulent strains in this study is the presence of one or more of virulence gene markers, rather than virulence plasmid, which may cause an overestimation of CR‐hvKP. And, we cannot provide data related to plasmid analysis. Given the excellent ability of 5K. pneumoniae and classical K. pneumoniae in order to perform precise treatment and deal with the spread of CR‐hvKP.ST11 KPC‐2‐producing CR‐hvKP is widespread in our hospital, and two significant lineages of ST11‐KL64 and ST11‐KL47 have emerged and clonal transmission occurred. It is urgent to develop novel rapid and convenient methods to accurately distinguish hypervirulent LX and PO conceived and designed the study. PO, BJ, NP, and JW contributed to data collection and experiments implementation. PO, LC, YW, JY, YC, HY, CT, and LT contributed to data analysis and data interpretation. PO and LX contributed to writing the report and revising the report. All authors read and approved the final version of the manuscript.All authors‐none to declare.Appendix S1Click here for additional data file.Appendix S2Click here for additional data file.


Blood examination revealed markedly elevated troponin T (0.351 ng/mL) and mildly elevated N‐terminal pro‐B‐type natriuretic peptide  and C‐reactive protein , white blood cell 3800/μL, eosinophil 1.7%, hemoglobin 13.8 g/dL, and platelets 152 000/μL. A standard 12‐lead ECG showed ST‐segment elevation at V4–5.The debate over myocarditis following COVID‐19 vaccination is currently a trending topic in medicine. According to the US Centers for Disease Control and Prevention, the frequency of myocarditis/pericarditis following COVID‐19 vaccination is low (12.6 per million doses), and the prognosis is considered good with rapid symptom recovery.Echocardiography showed normal left ventricular contraction with an ejection fraction of 62% and no clinically problematic atrioventricular valve insufficiency. Due to mild symptoms and good physical condition, a decision was made to observe the patient's clinical course without therapeutic intervention. On day 6 of hospitalization (6 days after onset), laboratory data normalized to troponin T at 0.008 ng/mL and NT‐proBNP at 31.0 pg/mL. Cardiac MRI showed slight dyskinesis from the basal septum to the inferior wall. Increased signal from the basal to the middle and lateral inferior wall on black blood T2WI 2‐lumen imaging and similarly increased signal in the apical region were also present (Fig. Previous reports have shown a high rate of abnormal MRI findings in post‐COVID‐19 vaccination myocarditis.Although post‐COVID‐19 vaccination myocarditis has a favorable prognosis and is considered curable, it may leave abnormalities in the myocardium, as observed in this case; it may therefore be premature to declare it as a complication with a good prognosis.In the future, the frequency of residual abnormal findings on cMRI and the timing of subsequent follow up should be re‐examined.The authors declare no conflict of interest.Dr. Konno and Dr. Aso designed the study and drafted the initial manuscript. Dr. Sakurai, Dr. Masumori, Dr. Nakano, and Dr. Osada collected and analyzed the patient data. All the authors have reviewed and revised the manuscript and have approved the final manuscript for submission and agree to be accountable for all aspects of the work.The patient's family provided informed consent for the publication of this case report.