Hypertrophic cardiomyopathy (HCM) is a heterogeneous disease associated with arrhythmias. Non‐sustained ventricular tachycardia (NSVT) is a risk factor for sudden cardiac death and part of the current risk stratification. Furthermore, atrial fibrillation (AF), which increases the risk of stroke, is believed to be common in HCM patients. Routine ambulatory monitoring captures the rhythm only periodically over 24–48 h; thus, the true burden of arrhythmia is unknown. The insertable cardiac monitor (ICM) should help determine a more realistic arrhythmia assessment in HCM patients.The purpose of this study was to ascertain the incidence of NSVT, AF, and bradycardia in unselected HCM patients by the use of an ICM.Thirty adults, mean age 49.9 ± 12.3 years, 25 (83.3%) males were implanted with a Confirm Rx ICM. The monitoring application was installed on the patient's smartphone, which allowed for patient activation in case of symptoms. The ICM was programmed as follows: ventricular tachycardia (VT) ≥ 160 beats per minute (bpm) for ≥8 intervals, AF ≥ 2 min of duration, and bradycardia ≤ 40 bpm or pause ≥ 3.0 s.The mean calculated 5‐year risk was 2.3%, and 29/30 of the patients had a risk <4%. During follow‐up, AF was found in nine patients (30.0%). At least one episode of NSVT was detected in seven patients (23.3%). In 13 patients (43.3%), sinoatrial block/sinus arrest/sinus bradycardia were seen. No arrhythmia was detected in nine patients (30.0%).In this first prospective study using an ICM, the arrhythmia burden in HCM patients yielded 30.0% AF and 23.3% NSVT. AFatrial fibrillationHCMhypertrophic cardiomyopathyICMinsertable cardiac monitorNSVTnon‐sustained VTVTventricular tachycardia12DS2‐VASc risk factors, is an indication for anticoagulation.The hypertrophic cardiomyopathy (HCM) phenotype in adults requires at least 15 mm thickness in any segment of the myocardial wall, which is not explained by other myocardial diseases or abnormal loading conditions due to hypertension or aortic stenosis.Sudden cardiac death is mainly caused by ventricular tachycardia (VT) or ventricular fibrillation, even though bradycardia may be implicated as well. An implantable cardioverter‐defibrillator (ICD) effectively restores rhythm with an annual rate of appropriate therapy of 4.8%, according to a meta‐analysis.The insertable cardiac monitor (ICM) Confirm Rx  provides long‐term monitoring of atrial and ventricular arrhythmias in addition to bradycardia.22.1This prospective longitudinal study recruited 30 patients, aged 18–65 years, 25 (83.3%) males, with an unequivocal diagnosis HCM from the Region Gävleborg and University Hospital of Umeå in Sweden. The patients were identified from hospital databases using the diagnostic codes I42.1 and I42.2 and subsequently validated by the investigators using medical records. An estimated 5‐year risk of sudden cardiac death <6% according to the risk calculator was a prerequisite, since with higher risk an ICD should be considered, based on ESC guidelines.2.2All patients were implanted between August and December 2017. The implantation procedure was performed under local anesthesia (carbocaine with epinephrine) using the standard operation kit for Confirm Rx via a subcutaneous incision at the level of the fourth rib on the left side. The monitoring application, connected to home monitoring site Merlin, was installed on the patients' own or borrowed smartphone. The patient was instructed on how to use the application and report symptoms.2.3The ICM programming was standardized. VT detection was defined as 160 bpm during ≥8 intervals with high electrogram (EGM) priority, and the discriminator “sudden onset” was activated (onset delta 18%), and a bigeminy qualifier was programmed off. A potential AF episode was recorded based on ≥2 min duration (the shortest programmable duration). Bradycardia was recorded if the rate was ≤40 bpm or there was a pause ≥3.0 s. Patient‐activated recordings for symptoms had a high EGM priority and were set to record 6 min of pre‐trigger and 1 min of post‐trigger rhythms, with the first eight EGMs stored in memory. The maximal ventricular sensitivity was typically 0.15 mV but could be adjusted as necessary if R waves were low. The threshold start was programmed at 75%, sense refractory period 250 ms, and decay delay 60 ms.2.4All participants completed the study with 18 months follow‐up as predefined. Technical support was sometimes requested when the patient wanted to change phones and reinstallation of the application was necessary. In a few patients, the study period had to be prolonged due to the temporary device disconnection. After the study period, all devices were explanted except in three cases, in which the clinician took over the continued monitoring.2.5All episodes were scrutinized by an expert review and categorized into atrial arrhythmia , ventricular tachycardia (sustained VT and NSVT), sinoatrial block/arrest, and atrioventricular block (second or third degree). The differentiation between supraventricular arrhythmias and VT were based on general principles such as rate, regularity, sudden onset, and change in QRS morphology compared to a normal rhythm.2.6n), percentages, ranges, percentiles, means, and standard deviations (SDs). To analyze the association between variables and outcomes, the χ2 test and t test were employed, as appropriate. A two‐sided p‐value < .05 was considered significant, whereas associations with p‐values between .05 and .10 were considered a tendency. Kaplan–Meier estimates were used to describe the time from implant to the outcome, AF, and NSVT, respectively. For statistical analyses, SPSS version 25 (IBM) was used.Data were described as numbers  and registered at Clinical Trial Registration NCT03259113. Each patient was informed about the study in both oral and written form by a physician and included after written consent.33.1SD 12.3) years. The vast majority were males  with a similar mean age (p = .796). Most patients had the maximum wall thickness localized in the septum  and the remaining in the apex. Patient characteristics are summarized in Table Before the study, the patients had been evaluated and followed‐up according to clinical routine, including echocardiography and Holter‐monitoring, typically every 1–2 years. The mean age of the 30 patients at the time of the ICM implant was 49.9 (3.2n = 9) of patients. In one of these patients, two episodes of atrial flutter were observed. The cumulative incidences of first device‐detected AF at 6 and 12 months were 26.7% and 30.0%, respectively, that is, the first episode was diagnosed within 1 year in all cases. In two of these patients, AF had been previously diagnosed before the implant. Thus, the device detected AF in 25% (n = 7) of patients without a history of AF. In one of the patients with a previously known AF, recurrent episodes occurred frequently and permanent AF developed despite treatment. In the remaining patients, the number of AF‐episodes ranged from 1 to 8 episodes with a total of 35 episodes, but they were all self‐terminating. Except for the patient who developed permanent AF, two patients reported symptomatic AF, of which one episode resulted in syncope . Patients with premature atrial complexes during 24‐hour ambulatory monitoring at baseline did not have significantly more AF than those without.During the 18‐month follow‐up, AF was detected in 30.0% (3.3n = 7) of the patients, all of the low‐risk patients with a 5‐year estimated risk score <4%. NSVT had been previously detected on Holter monitor in two patients, in whom NSVT was likewise detected in this study. Thus, the device detected NSVT in 5 of the 28 patients without a history of NSVT (17.9%). No episode of sustained VT (above 30 s) was reported. The cumulative incidences of first device‐detected NSVT at 6 and 12 months were 13.3% and 20.0%, respectively. Altogether, a total of 21 episodes occurred in all patients. Four patients had only 1 episode of NSVT ; in two patients 2 episodes occurred, of which one was reported as symptomatic (presyncope); and in one patient a total of 11 episodes clustered during the same day followed by 2 episodes a few months later. Notably, in this latter patient, after the storm of NSVT, almost daily patient‐activated symptom recordings were transmitted, but with no correlation to any arrhythmia.At least one NSVT was diagnosed in 23.3% (3.4n = 13) of the patients, sinoatrial block/arrest or sinus bradycardia was observed at about 30–40 bpm. The longest pause was 3.1 s. Most episodes occurred during nighttime hours, and were asymptomatic. No atrioventricular block, second‐ (Mobitz type I/II) or third‐degree block was detected in any patient. No arrhythmias were detected in nine patients, and among the patients with arrhythmias there was some overlap. An example of arrhythmias are depicted in Figures In 43.3% n = 3 of the 44.1Among patients with HCM deemed at low risk according to the ESC risk calculator, a considerable arrhythmia burden was discovered by continuous long‐term monitoring. The ICM offers a complete, uninterrupted monitoring period in comparison to external loop recorders, where disconnections can occur, requiring follow‐up and technical support. The Confirm Rx, with its smartphone application for remote monitoring and symptom registration, proved to be feasible in this setting. The use of an ICM in HCM patients has been proposed in statements of research priorities4.2Thirty percent of the cohort was diagnosed with at least one episode of AF; a quarter of the cohort had newly diagnosed AF. The functional and structural abnormalities of the myocardium, especially low‐flow in the left atrial appendage, predispose patients to a prothrombotic condition, such that even AF of short duration implies stroke risk.4.3A fifth of HCM patients who were considered low risk for sudden cardiac death turned out to have at least one episode of NSVT. Fortunately, no sustained ventricular arrhythmias occurred. In patients who likely represent more selected HCM patients with higher risk, similar prevalence has been observed on 24–48 h ambulatory ECG monitoring, and NSVT is considered to be a more pronounced risk factor at a younger age.4.4Sinoatrial block/sinus arrest or sinus bradycardia were common, especially during nighttime, but did not meet the criteria for pacemaker implantation.4.5It is important to stress that diagnostic yield reflects patient selection. In an ICM study of 16 highly selected patients with advanced Anderson‐Fabry disease, significant arrhythmias were remarkably common.Future research of larger series of HCM patients would be welcomed, using ICMs allowing for analysis of subgroups or subsets, like patients who have undergone myectomy or alcohol septal ablation. Nowadays, an ICM can be easily implanted outside the electrophysiological laboratory and connected to a smartphone application for remote monitoring, which reduces cost compared to other monitoring systems.4.6This is the first study on arrhythmia detection in HCM using an ICM, which allows the evaluation of the true incidence of arrhythmias. Still, an ICM offers single lead tracings, which may limit differentiation between supraventricular tachycardia and VT. ICM insertion is invasive and costly, so they are limited to selected patients in clinical practice. The findings in this study of unselected low‐risk patients need to be confirmed in larger cohorts and subgroups of HCM in different settings.5In unselected HCM patients deemed at low or intermediate risk for sudden cardiac death, 18 months evaluation using an ICM found that a considerable proportion of patients had arrhythmias: 30.0% AF, 23.3% NSVT, and 43.3% sinoatrial block/arrest or sinus bradycardia.Peter Magnusson: idea, design, recruitment, data collection, ECG‐analyses, writing, and project management. Stellan Mörner: design, recruitment, data collection, critical revision, and project management.The study was approved by Ethical Review Board in Umeå (document number 2017/13‐31) and registered at Clinical Trial Registration NCT03259113.


Pupillary evaluation is a crucial element of physical exams. Noting size, reactivity, and consensual response is critical in assessing for optic nerve dysfunction. We aim to establish normative data for scotopic pupillary size and function in the pediatric population in a clinical setting.Pupillometry was obtained prospectively for consecutive, normal patients < 18 years old being evaluated by Lurie Children’s Ophthalmology. Quantitative data included maximum (MAX) and minimum (MIN) diameters, constriction percentage (CON), latency (LAT), average (ACV) and maximum (MCV) constriction velocities, average dilation velocity (ADV), and 75% recovery time (T75). Iris color was noted as light, intermediate, or dark.196 eyes of 101 participants  were analyzed. Mean MAX was 6.6 mm (5.1–8.1 mm 95% CI); MIN was 4.7 mm (3.1–6.1 mm 95% CI); CON was 30% (17–42 95% CI); LAT was 230 milliseconds (160–300 ms 95% CI); ACV was 3.70 mm/sec (2.21–5.18 mm/sec 95% CI); and ADV was 0.88 mm/sec (0.38–1.38 mm/sec 95% CI). Age had a positive correlation with MAX, MIN, and CON. 84.2 and 95.8% of participants showed resting pupil asymmetry of ≤0.5 mm and ≤ 1.0 mm, respectively.p < 0.05). Also, age had a positive correlation with MAX, MIN, and CON.Quantitative pupillometry can be a useful tool for screening pediatric patients. We sought to establish normative data in this group. We found males to have significantly greater MCV and CON than females ( The pupillary exam is a crucial element of ophthalmologic and neurologic evaluations. In particular, observation of pupillary size, reactivity, and consensual response is critical in the assessment of optic nerve dysfunction. In the early 1990’s, some studies showed pupillometry as a more sensitive method to measure autonomic nerve function in adolescents with type 1 diabetes compared to cardiovascular reflexes . More reThis study was approved by the Institutional Review Board of Ann & Robert H. Lurie Children’s Hospital of Chicago (Lurie Children’s) and conformed to the requirements of the United States Health Insurance Portability and Privacy Act with adherence to the tenets of the Declaration of Helsinki.Based on the lead author’s availability, pupillometry and informed consent were obtained in a prospective manner for consecutive normal patients younger than 18 years old  who were being evaluated at the Ophthalmology Clinic of Lurie Children’s. Exclusion criteria for controls included: inability to sit for testing, developmental delay, genetic syndromes, neurologic pathology , or intraocular pathology that would affect pupillary function .Among the 143 patients consented, 42 patients were excluded due to inability to cooperate with the exam (34), inability to perform the exam due practicalities of clinic work flow after consenting , or pathPupillometry data were measured using the handheld NeurOptics PLR-200TM Pupillometer . The pupillometer employs an 850 nm infrared illumination to collect measurements on the eye before, during, and after presentation of a full-field white light stimulus with peak wavelengths comprised of red, green, and blue. An opaque rubber interface that can be sanitized places the device in contact with the orbital rim of the eye to be measured, thus occluding outside light from entering the measured eye and allowing direct measurement. The device highlights an outline of the pupil and graphs its displacement over time with accuracy of 0.05 mm. Data were obtained in a dark clinic room throughout regular clinic hours (8:00 AM – 5:00 PM) to emulate routine clinical testing. Scotopic conditions were verified prior to exam by measurement of luminance of less than 2 Lumens with a luminometer  at the level of the patient’s eyes. The right eye was measured first in each patient. Data from each eye exam were recorded prior to examination of the second eye. Recorded data included maximum (MAX) and minimum (MIN) diameters, constriction percentage (CON) — the calculated percentage difference between MAX and MIN, latency (LAT), average (ACV) and maximum (MCV) constriction velocities, average dilation velocity (ADV), and 75% recovery time (T75).Iris color was noted as light (blue), dark (brown) or intermediate. Study data were managed using REDCap electronic data capture tools hosted at Northwestern University .p < 0.05. Statistical analyses were conducted using SAS version 9.4 .Categorical variables are reported as frequencies, and percentages and continuous variables are reported in means and standard deviations. Pearson correlations were used to describe relationships between two continuous variables: age and eye measurements. To account for the random effect of two-eye measurements per patients, mixed effect models were run to determine differences between independent variables including eye color, race, ethnicity, and gender. All tests were two-sided, and significance was defined as n = 134 and 102, respectively). The self-identified demographic distribution of the population is shown in Table Data from 196 eyes of 101 participants were analyzed with the exception of average dilation velocity and 75% recovery time, which could not be measured in 62 and 94 eyes, respectively . Males had significantly greater constriction percentage and maximum constriction velocity than females (p < 0.05). There were no statistically significant differences between the parameters measured in Hispanic and non-Hispanic subjects . Race  was self-reported for 49/101 subjects, and there were no statistically significant differences shown between the parameters measured.Table r = 0.26 p = 0.0002), minimum diameter (r = 0.28 p < 0.0001), and constriction percentage (r = 0.23 p = 0.0015). Without quantitative pupillometry, anisocoria has been defined as asymmetry of 1 mm or greater [There was a positive correlation with age and maximum diameter . Other studies in light [It is well established that, throughout childhood, the eye and visual pathway have significant growth and development, which may expectantly lead to pupillary changes over time. Although under ambient light conditions, Brown et al. measured data similar to our results that suggested a weak, yet statistically significant, correlation between pupil size and age  and red (unreliable). It will only display as green if it generates reliable data in at least six out of the eight variables measured. This explains the discrepancies in n values of ADV and T75 from the remainder of the data. Adhikari et al. showed that pupil diameter measured by an infrared camera is affected by fixation eccentricity, introducing at least a 0.07-mm error once eye movements deviate more than 5° from the central fixation axis . While fp = 0.0179 and p = 0.0105, respectively). In contrast to Fan et al., our findings might be attributable to differences in population sampling: ours having a higher n and lower ages than their population [Previous studies have been equivocal on the association between gender and pupillary reaction, showing weak differences  or no dipulation . Our datVia self-reporting, demographic data was obtained for all subjects on ethnicity but for only 49/101 subjects with regards to race. There were no statistical differences for any measured variable by ethnicity or by race. However, Brown et al. measured a population that was 64% white and 24% African American, finding statistical differences in pupil size and function (MCV and ADV) between the eyes of White and African American subjects when measure in ambient light. Due to differences in demographics between the two studies, direct comparisons cannot be made.Anisocoria has been clinically defined as asymmetry of 1 mm or greater , 5. InteThe clinical nature of this study provides both strengths and limitations to the data and analysis presented above. As mentioned earlier, fixation eccentricity and exact interstimulus interval provide a more standardized approach to data collection. Furthermore, data were collected throughout the clinic day, thus preventing consistent time measurements to limit effects from circadian rhythm on pupillary function . FinallyIn conclusion, the authors offer quantitative pupillometry measurements in children to be compared against the gender-matched data presented in this manuscript. Children falling outside of normal ranges may warrant further evaluation.


WBC count increased from 7.2 × 109/L pregame to 10.1 × 109/L 2 h postgame (p < 0.001). The median OFF-hr score decreased from 99.5 to 94.2 immediately postgame and remained significantly lower than baseline at 2 h postgame . Looking at individual results, the highest OFF-hr score increased from 120 at baseline to 124 at 2 h postgame. Our findings suggest that participation in a floorball game affects several hematological parameters and consequently can affect health assessment and antidoping testing.Assessment of hematological parameters is common in sports medicine. Although physical exercise is an important preanalytical variable, data about acute hematological changes after high-intensity intermittent exercise are scarce. This study aimed to examine floorball as a potential preanalytical variable for hematological parameters used in health assessment and antidoping testing. Twenty-three professional male floorball players participated in a floorball game. Hematological parameters including hemoglobin, erythrocyte count and erythrocyte indices, reticulocytes, white blood cells (WBC), platelets, reticulocytes, and OFF-hr score were assessed at baseline, immediately postgame, and at 2 h postgame. Median hemoglobin concentration decreased significantly from 146 g/L pregame to 141 g/L immediately postgame ( Blood collection through venipuncture with subsequent laboratory analysis is a common medical procedure . The comThe preanalytical phase is an essential component of laboratory quality, and several variables affect the result of a blood sample . PhysicaHematological parameters also play another important role in sports medicine. CBC is frequently used in antidoping testing for the detection of blood doping . The Worrd IOC meeting in Durban, South Africa, in 2011 and is a candidate for inclusion in the Olympic Games. Therefore, the International Floorball Federation has adopted the WADA antidoping code.Floorball is a rapidly growing sport that contains episodes of high-intensity intermittent exercise of alternating aerobic and anaerobic character, and it can cause transient elevation of cardiac biomarkers , 12. It Few studies have examined the effect of high-intensity intermittent exercise on hematological and biochemical parameters , 5. WithIn this prospective, observational study, 23 male players from a professional floorball team participated in a floorball game, played in 3 × 20 minutes effective time , for evaluation of acute alterations in hematological parameters. The game was conducted in March 2014 in Sundsvall, Sweden, starting at 10 : 00AM. All players were competitive athletes from the same floorball team and had previously been screened for cardiovascular abnormalities. They were eligible for inclusion in the study if both ECG and echocardiogram were unremarkable. No player had taken any medications and no player had a history or illicit drug use. No player had donated blood or received blood transfusion, and there was no history of altitude training or simulation. All players were nonsmokers.Oral and written information about the procedures was given before the study. Consent forms were obtained from all study participants and their parents/legal guardians if under 18 years. The study was approved by the regional ethics committee and all procedures complied with the ethical standards of the Declaration of Helsinki.ad libitum before, during, and after the game. Ingestion of food was not allowed from 2 h before the time of the first blood sampling until completion of the last blood sampling 2 h postgame. Blood was drawn at three time points: pregame (09 : 30AM), 0 h postgame (11 : 30AM), and 2 h postgame (01 : 30PM). Five players were also tested after 24 h to follow alterations for a longer time. Blood sampling was performed from an antecubital vein using a 21 G needle within 30 seconds of tourniquet application and under aseptic conditions. The players rested in a sitting position 10 minutes before and during each collection. Two experienced phlebotomists collected the samples.The participants refrained from exercise 24 h prior to the study to get adequate resting parameters. The study was conducted at sea level. Water intake was allowed 2-EDTA  to measure hematological parameters, and into 4 mL vacutainer tubes containing lithium heparin  to measure biochemical parameters. Subsequent to sampling, the tubes were mixed 10 times on a blood mixer, and all samples were immediately transported in an insulated cooler box to an accredited laboratory (SS-EN ISO/IEC 17025 and SS-EN ISO 15189) and analyzed within 30 minutes. No blood sample was discarded due to unsatisfactory venipuncture attempts.Blood was collected into 3 mL vacutainer tubes containing KLaboratory testing was performed on calibrated instruments. Analytical quality was monitored by means and standard deviation of an internal quality control system and by participation in an external quality assurance program. Blood samples were inverted 20 times prior to analysis. Full blood count was determined using an automated hematology analyzer , according to the manufacturer's specifications. The CBC included hemoglobin (Hb), hematocrit (Hct), red blood cells (RBC), mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), red cell distribution width (RDW-CV), platelet count (PLT), and leukocyte count including a quantitative differential count of lymphocytes, monocytes, neutrophils, eosinophils, and basophils. Reticulocyte count and percentage of reticulocytes were also obtained. No samples required manual review. The assays showed coefficients of variation (CV) < 5% for Hb, Hct, RBC, erythrocyte indices and reticulocytes, <6% for PLT, and <8% for leukocyte and differential count.g to separate plasma from blood cells. Plasma albumin, sodium, potassium, total calcium, creatinine, and lactate dehydrogenase (LD) were analyzed using assays from Roche Diagnostics on a fully automatic Cobas 6000 analyzer . Indices of hemolysis, icterus, and lipemia (HIL indices) were assessed for lithium heparin plasma to assure sample quality. The total CV was <5% for all assays.Blood samples were centrifuged for 7 minutes at 2000 ×p-values. A p-value <0.05 was indicative of statistical significance. Statistical analyses were performed using IBM SPSS 26.0 .Data from all parameters were tested for normality using the Shapiro–Wilk test and verified by visual inspection of histograms. Normally distributed data are reported as mean and 95% confidence intervals (95% CI). Nonnormally distributed data are reported as median with interquartile range (IQR) values. The OFF-hr Score, which is an index of stimulation, was calculated as “Hb [g/L] – 60 ∗ √(Reticulocytes [%])”. At sea level, the normal range was 85–95, levels ≥104.6 require further investigation of an athlete, and levels ≥125.6 denote a start prohibition meaning that an athlete is not allowed to participate in any competitive events , 14. TheAnthropometric measurements were conducted at enrollment, summarized in The body mass was measured in all players pregame and immediately postgame. The mean pregame body mass was 77.3 kg (72.8–81.8 kg). The mean body mass did not change significantly immediately postgame .p < 0.001) and returned to baseline (146 g/L) 2 h postgame. The median percentage difference pregame compared to 0 h postgame was 3.7% (IQR 1.5–4.7%). For the erythrocyte indices, only MVC were significantly altered immediately postgame and 2 h postgame compared to baseline. The mean WBC (leukocyte) concentration increased from 7.2 × 109/L pregame to 8.6 × 109/L (p=0.002) and 10.1 × 109/L (p < 0.001) immediately postgame and 2 h postgame, respectively. Leukocyte differential count (p < 0.001) and 2 h postgame (p < 0.001). Also, monocytes increased significantly 0 h and 2 h postgame (p=0.029 and p < 0.001). There was a significant decrease in lymphocyte count 0 h postgame (p=0.010), and a decrease in eosinophils 0 h and 2 h postgame (p < 0.001 and p=0.003). No significant difference was shown after 24 h compared to baseline for Hb, Hct, RBC, leukocyte count, and PLT in five players tested.Levels of hematological parameters are presented in al count  showed aNo significant difference was shown immediately postgame and 2 h postgame compared to baseline for reticulocyte count. The percentage of reticulocytes displayed a nonsignificant increase from 0.70% to 0.75% immediately postgame, which returned to baseline 2 h postgame (0.70%).p < 0.001) immediately postgame and remained significantly lower than baseline 2 h postgame . Looking at individual results, the highest OFF-hr score was 120 at baseline, increasing to 124 at 2 h postgame. Three players with an OFF-hr score that was within the reference (85–95) pregame had levels below the normal range at 2 h postgame, and two players had levels >104.6 2 h postgame.Hb and percentage of reticulocytes are used for calculation of the OFF-hr score. The median baseline OFF-hr score was 100. The Median OFF-hr score decreased to 94 (p=0.009) but not immediately postgame compared to baseline. There was no significant difference in levels of sodium and total calcium postgame compared to baseline. Potassium levels decreased from 3.9 mmol/L at baseline to 3.6 mmol/L at 0 h postgame (p < 0.001), normalizing to 3.7 mmol/L at 2 h were no statistical difference could be observed (p=0.137). Creatinine levels increased significantly from a median concentration of 84 µmol/L pregame to 94 µmol/L immediately postgame (p < 0.001) and returned to 84 µmol/L 2 h postgame (p=0.279). Levels of LD were significantly lower at both 0 h  and 2 h postgame  compared to baseline (3.4 µcat/L).Biochemical parameters are presented in In the present study, we assessed the impact on hematological parameters in 23 professional floorball players after a floorball game. Some variables included in the CBC were significantly altered after the game. These findings are, to our knowledge, the first observed after intermittent high-intensity exercise and have two important implications to be considered, primarily in sports medicine, hematology, and laboratory medicine.First, with increasing participation in floorball, physicians and laboratory staff should acknowledge participation in a floorball game as a preanalyical variable altering several hematological parameters. CBC is assessed in clinical routine for screening and diagnosis of several disorders or to assess treatment progress and thus plays a significant role in clinical decision making . Levels We found that Hb concentrations decreased significantly immediately postgame. It has been suggested to be the result of mechanically induced damage to the erythrocytes, known as mechanical hemolytic anemia . HoweverThe second important point is the impact on the hematological module of the Athlete Biological Passport (ABP) for antidoping testing, as limited data on how exercise affects ABP in the acute phase exist. There are mainly three types of blood doping, namely, blood transfusions, erythropoietin (EPO), and synthetic oxygen carriers. All methods enhance exercise performance in aerobic sports . As therAlthough the long-term effects of different types of exercise on hematological variables are well studied, data on the acute variation of Hb and reticulocytes induced by exercise are scarce . In the Most players had false low OFF-hr score levels postgame concluding that intermittent high-intensity exercise acutely reduces the OFF-hr score significantly, thus reducing the sensitivity of the ABP hematological module. However, a fraction of players also had an increased OFF-hr score postexercise. There might be a risk of misinterpreting these physiological variations induced by exercise as false-positives, which would have drastic consequences for an individual athlete. According to the WADA rules, antidoping testing can be performed two hours after training or competition. Furthermore, it is stated that all testing is performed in the morning. Obviously, these rules are not always followed . Thus, oPhysicians in the field of laboratory medicine and hematology are likely to become involved in the evaluation of an athlete's hematological parameters and must be able to distinguish whether an abnormality is the result of an acute disorder, doping or a preanalytical error source. To assure analytical accuracy, floorball should be documented and referenced as a preanalytical variable when evaluating laboratory results in sports medicine.Our study has some limitations to consider. The number of participants was small, and the general conclusions might not be applicable to a larger cohort. Another limitation is the timing of blood sampling. According to WADA guidelines, there should be no blood collection for 2 h following the competition. Although the 2 h postgame testing falls within these recommendations, we suggest that a future study of the same rationale should test different sampling times >2 h postexercise in order to test the validity of the ABP for a longer period postexercise. We did not analyze the blood samples twice as recommended, making our results somewhat uncertain.In summary, we found that several hematological parameters are significantly altered after a floorball game in professional players. This can have serious consequences for health assessment and antidoping testing. It is important that an athlete serves as its own reference, as conventional reference intervals and cutoffs might not be appropriate.


Diabetes mellitus (DM) is associated with increased cardiovascular (CV) risk. We compared health‐related quality of life (HRQoL), healthcare resource utilization (HRU), and clinical outcomes of stable post‐myocardial infarction (MI) patients with and without DM.In post‐MI patients, DM is associated with worse HRQoL, increased HRU, and worse clinical outcomes.The prospective, observational long‐term risk, clinical management, and healthcare Resource utilization of stable coronary artery disease study obtained data from 8968 patients aged ≥50 years 1 to 3 years post‐MI . Patients with ≥1 of the following risk factors were included: age ≥65 years, history of a second MI >1 year before enrollment, multivessel coronary artery disease, creatinine clearance ≥15 and <60 mL/min, and DM treated with medication. Self‐reported health status was assessed at baseline, 1 and 2 years and converted to EQ‐5D scores. The main outcome measures were baseline HRQoL and HRU during follow‐up.P < .0001) was higher; mean number of hospitalizations  and mean length of stay  were lower in patients without vs with DM. All‐cause death and the composite of CV death, MI, and stroke were significantly higher in DM patients, with adjusted 2‐year rate ratios of 1.43 (P < .01) and 1.55 (P < .001), respectively.DM at enrollment was 33% . Mean baseline EQ‐5D score  had poorer EQ‐5D scores, higher hospitalization rates and LoS, and worse clinical outcomes vs those without DM. Strategies focusing specifically on this high‐risk population should be developed to improve outcomes.ClinicalTrials.gov: NCT01866904 . Janzon et al demonstrated that patients deemed to be at high risk after MI contributed to a substantial burden on HRU.Therefore, we sought to contribute to a better understanding of these issues in patients with DM in the TIGRIS  registry, which includes a unique international population with MI 1 to 3 years prior to enrollment.22.1TIGRIS was a prospective, observational study that included 9208 patients from 25 countries in Asia‐Pacific/Australia, Europe, North America, and South America. The main objective was to better understand the long‐term outcomes and associated HRU in stable individuals with MI 1 to 3 years prior to study enrollment. A list of principal investigators for the TIGRIS study is provided in Table ClinicalTrials.gov, NCT01866904) enrollment criteria as well as patient characteristics and treatment patterns have been published previously.TIGRIS  with three levels of severity  was completed by every individual at each visit.A standardized electronic case report form was used for data collection, which included medical history, demographics, variables from routine examination (at baseline), medication use, HRU, and clinical events (ischemic and hemorrhagic), during follow‐up.In the present study, 8968 patients  with complete data on DM status were analyzed. Data on self‐reported health status were available in 7260 patients, and data on HRU were available in 7838 patients. The main focus of this study was HRQoL at baseline and HRU during follow‐up.2.2P‐values were based on a 2‐sample t‐test, χ2 test, and test for trend for quantitative, binary, and ordinal variables, respectively.Comparisons of patient characteristics by DM status were summarized by mean and SD for quantitative variables and by frequency/percentage for categorical variables. For the EQ‐5D‐3L self‐reported health questionnaire, the United Kingdom (UK)‐weighted index has been used as the most widely accepted summary of overall health status.Hospitalizations and other HRU items were based on 6‐monthly patient recall during follow‐up at 6, 12, 18, and 24 months after enrollment. These have been totaled to summarize each patient's HRU over 24 months of follow‐up.The 2‐year percentage incidence of clinical outcomes is reported by DM status, using Kaplan‐Meier estimates to account for patients lost to follow‐up. Poisson regression models were used to adjust for other baseline influences on risk of event. Variables included in the adjustment were those in the TIGRIS risk index model,32). Patients with DM also had a higher prevalence of peripheral artery disease (5.2% vs 9.8%), HF (10.0% vs 14.6%), anemia (2.3% vs 4.1%), angina (8.9% vs 12.2%), and stroke (3.7% vs 5.9%). Moreover, patients with DM also had higher CV event‐related hospitalization rates in the 6 months prior to enrollment (5.0% vs 6.4%). All these measures were more pronounced in patients with insulin‐dependent DM, which comprised both patients with type 1 (N = 86) and type 2 (N = 783) DM  had DM, of whom 869 (29%) were treated with insulin  was independently associated with a 50% increase in hospitalization.Our study has some limitations. First, although clinical endpoints were verified in medical records, they were not centrally adjudicated in the TIGRIS registry. It is reassuring that the increased risk of MACE and other clinically relevant events in patients with DM in the TIGRIS registry was consistent with that observed in the PEGASUS‐TIMI 54 trial, where all events were centrally adjudicated by a clinical events committee.5In stable outpatients' post‐MI, the presence of DM is associated with decreased long‐term survival and an increased risk for ischemic events. In addition, DM is associated with a higher HRU and worse HRQoL. These results could help inform healthcare system planning internationally in view of the global DM pandemic.José C. Nicolau, conception and design, analysis and interpretation of data, and drafting and writing the final version of the manuscript; Stuart J. Pocock and Ruth Owen, data analysis and interpretation and drafting and revision of the manuscript; Remo H.M. Furtado, data analysis and revision of the manuscript; David Brieger, Shaun G. Goodman, Mauricio G. Cohen, Tabassome Simon, Dirk Westermann, Christopher B. Granger, Richard Grieve, Satoshi Yasuda, Jiyan Chen, Katarina Hedman, Carl Mellström, and Gunnar Brandrup‐Wognsen, conduct of the registry and revision of the manuscript.Appendix S1 Supporting information.Click here for additional data file.Figure S1 Supporting information.Click here for additional data file.Figure S2 Supporting information.Click here for additional data file.


SON gene . There are only 33 cases and 26 causative SON variants reported to date since the first report in 2015. Here, we report a new case of ZTTK syndrome and a de novo disease‐causing SON variant.Zhu‐Tokita‐Takenouchi‐Kim  syndrome is a rare, autosomal dominant genetic disorder caused by heterozygous variants in the We conducted whole‐exome sequencing (WES) to obtain genetic data of the patient. The clinical and genetic data of the patient were analyzed.SON causes an amino change (p.Ser1766Leufs*7).The clinical features of our patient were strikingly similar to previously reported cases. Notably, our patient had unique presentations, including a bridged palmar crease in the left hand and growth hormone deficiency. The c.5297del de novo variant in SON gene and refines the genotype‐phenotype map of ZTTK syndrome. Our findings also highlighted the importance of WES for early diagnosis of ZTTK syndrome, which may improve diagnostic procedures for affected individuals.Our report expands the mutant spectrum of the  There are only 33 cases and 26 causative variants in SON of ZTTK syndrome have been reported to date worldwide, and we reported 1 additional case of ZTTK syndrome and revealed 1 de novo disease‐causing variants in SON. Our patient had unique presentations, including a bridged palmar crease in the left hand and growth hormone deficiency. Our report expands the mutant spectrum of SON gene and refine the genotype‐phenotype map of ZTTK syndrome. There are only a few cases reported to date , and 26 causative SON variants have been identified so far  syndrome is an autosomal dominant hereditary disease caused by heterozygous variants in the SON, c.5297del (p.Ser1766Leufs*7), detected using diagnostic whole‐exome sequencing  in height. The target height of the patient is 152.76 ± 3 cm .Our patient was an 11 years and 4 months old girl born at full‐term through spontaneous labor, with oligohydramnios and placenta senility. The propositus was small‐for‐gestational‐age (SGA) infant with a birth weight of 2200 g and a body length at birth of 47 cm. Feeding difficulties occurred shortly after birth. Her psychomotor and language development were significantly delayed. The patient began walking and saying “mummy” and “daddy” at about 2 years of age. She still has severe dysarthria and was 128.2 cm  were also normal. Her fasting insulin (FI) level was 1.1 uIU/mL , insulin‐like growth factor‐1 (IGF‐1) level was 51.8 ng/mL , and IGF‐1 bp3 level was 2.72 µg/mL ; all these levels were decreased compared with the respective references. The growth hormone provocation test revealed a peak value of 8.1 ng/mL . The Wechsler intelligence scale measured her intelligence quotient (IQ) at the age of 9 as 43, meaning she has hypophrenia. The Child Behavior Checklist (CBCL) revealed that the proband had severe maladjusted behavior, including obvious social withdrawal, schizoid personality disorder, inattention, hyperactivity, destructive behavior, and maltreatment. Her skeletal age was 9 years and 11 months old, which lagged her actual age. The complete blood count, routine urine‐check, routine excrement examination, adrenocorticotropic hormone, plasma cortisol level, blood lipid level, HbA1c, the thyroid function test, electroencephalogram (EEG), ultrasonic testing of the abdomen and urinary systems, and brain CT were all normal. The anterior‐posterior and lateral films of the whole spine were normal. Her parents were both healthy. She has a 24‐year‐old half‐brother with the same father who was diagnosed with epilepsy. Our patient has never suffered from epileptic seizures. The proband's parents denied any history of inherited metabolic disease.33.1Our study was approved by the Ethics Committee of West China Second Hospital of Sichuan University. We obtained written informed consent from the patient's parents prior to conducting the WES. Informed consents were obtained from patient's parents for inclusion of her clinical and imaging details in the manuscript for the purpose of publication.3.2The umbilical cord blood or fetal tissue genomic DNA was extracted using the Blood Genome Column Medium Extraction Kit  according to the manufactural instructions. The extracted DNA samples were subjected to quality controlling using Qubit 2.0 fluorimeter and electrophoresis with 0.8% of agarose gel for further protocol.3.3Protein‐coding exome enrichment was performed using the xGen Exome Research Panel v1.0 (IDT), consisting of 429,826 individually synthesized and quality‐controlled probes, targeting 39 Mb protein‐coding regions  of the human genome and covering 51 Mb of end‐to‐end tiled probe space.3.4High‐throughput sequencing was performed using the Illumina NovaSeq 6000 series sequencer (PE150). Nothing less than 99% of the target sequence was sequenced.Quality control. Raw data were processed using fastp for adapters removing and low‐quality reads filtering.Variants calling. The paired‐end reads were performed using the Burrows–Wheeler Aligner (BWA) to the Ensembl GRCh37/hg19 reference genome. Base quality score recalibration, together with single‐nucleotide variants (SNPs), short indel calling, and CNVs were conducted using GATK. High quality and reliable variants were obtained according to the sequence depth and variant quality, SNPs, Indels, and CNVs.www.chigene.org) was used to annotate the database‐based minor allele frequencies (MAFs) and ACMG  practice guideline‐based pathogenicity for every gene variant. The system also provided serial software packages for conservative analysis and protein product structure prediction. The databases for the annotation of MAFs include 1,000 genomes, dbSNP, ESP, ExAC, and Chigene in‐house MAFs database; Provean, Sift, Polypen2_hdiv, Polypen2_hvar, MutationTaster, M‐Cap, and Revel software packages were used to predict protein product structure variation. The prioritized pathogenicity annotation of ACMG guidelines, the OMIM, HGMD, and ClinVar databases were used as conferences for pathogenicity of every variant. To predict the functional changes associated with splice variants, the MaxEntScan, dbscSNV, and GTAG software packages were used instead of the product structure prediction software.Variant annotation and pathogenicity prediction. The online system independently developed by Chigene  cases of ZTTK syndrome had intellectual disability, developmental delay, and facial dysmorphism. Brain malformations  were observed in 85.9% of the subjects. Neurological features such as hyper‐or hypotonia, epilepsy or other EEG abnormalities, and autism spectrum disorder occurred in 62.0% of the subjects. Musculoskeletal abnormalities  were identified in 77.3% of the subjects. Approximately 69.6% of the cases had eye and/or vision abnormalities, of which strabismus was the most common. Others include hyperopia, cortical visual impairment, and optic atrophy. Short stature occurred in 51.8% of the cases. Other manifestations include heart defects , urogenital malformations , intestinal atresia, high position or cleft palate, craniosynostosis. Several subjects have feeding difficulties early after birth, some even require a gastrostomy feeding tube. Immunoglobulin deficiency and abnormal coagulation also occur in several patients (Kim, Baddoo, et al., SON gene consists of 12 exons, with the size of exon 3 accounting for 82% of the entire‐coding region (Khan et al., SON is 1.88, meaning that it belongs to the 2% of the most intolerant human protein‐coding genes (Petrovski, Wang, Heinzen, Allen, & Gold‐stein, SON was knocked down in HeLa and human embryonic stem cells, a group of genes essential to neuronal cell migration, embryonic survival, metabolism, and mitochondrial function, including TUBG1, FLNA, PNKP, WDR62, PSMD3, HDAC6, PCK2, PFKL, IDH2, ACY1, and ADA showed significantly decreased expression (Ahn et al., SON result in severe and extensive multi‐systematic detriments.The SON knockdown in mouse neural progenitors resulted in defective migration during corticogenesis and reduced the spine density of mature cortical neurons. The induction of human wild‐type SON expression rescued these neural abnormalities, confirming that the abnormalities were caused by SON insufficiency. In addition, this data supports the idea that the neural abnormalities in ZTTK syndrome are caused by SON haploinsufficiency rather than functional or dysfunctional proteins resulting from different types of mutations (Ueda et al., Recently, Ueda et al. demonstrated that SON. Also, we emphasize the importance of WES for early diagnosis of ZTTK syndrome, which can speed up the diagnostic procedure, sparing patients from unnecessary investigations and ineffective, or even harmful treatments. Our report expands the mutant spectrum of the SON gene and refines the genotype‐phenotype map of ZTTK syndrome.In conclusion, we report an additional case of ZTTK syndrome and reveal a novel disease‐causing variant in We declare that we have no competing interests.Our study was approved by the Ethics Committee of West China Second Hospital of Sichuan University. With written informed consent from parents of the patient, we conducted the genetic tests. Informed consent was obtained from the parents of our patient for inclusion of her clinical and imaging details in the manuscript for the purpose of publication.Table S1Click here for additional data file.


Data on clinical, laboratory, and radiographic characteristics and risk factors for in‐hospital mortality of lung cancer patients with COVID‐19 are scarce. Here, we aimed to characterize the early clinical features of lung cancer patients with COVID‐19 and identify risk factors associated with in‐hospital mortality.All consecutive lung cancer patients with laboratory‐confirmed COVID‐19 admitted to 12 hospitals in Hubei province, China, from 3 January to 6 May 2020 were included in the study. Patients without definite clinical outcomes during the period were excluded. Data on initial clinical, laboratory and radiographic findings were compared between survivors and nonsurvivors. Univariable and multivariable logistic regression analyses were used to explore the risk factors associated with in‐hospital mortality.P = 0.0497) and elevated high sensitivity cardiac troponin I (hs‐TNI)  were associated with an increased risk of in‐hospital mortality.Of the 45 lung cancer patients  included, 34 (75.6%) discharged and 11 (24.4%) died. Fever (73.3%) and cough (53.3%) were the dominant initial symptoms, and respiratory symptoms were common. Lung cancer patients also presented atypical appearances of COVID‐19. In the multivariable analysis, prolonged prolongation prothrombin time (PT) (OR = 2.1, 95% CI: 1.00–4.41, Lung cancer patients with COVID‐19 have high in‐hospital mortality. Prolonged PT and elevated hs‐TNI are independent risk factors for in‐hospital mortality of lung cancer patients with COVID‐19.Lung cancer patients with COVID‐19 have atypical early symptoms and imaging features.The prolonged prothrombin time and elevated high sensitivity cardiac troponin I are independent risk factors for in‐hospital mortality of lung cancer patients with COVID‐19.This study characterizes the early clinical features of lung cancer patients with COVID‐19 in China, and identifies the risk factors associated with in‐hospital mortality of lung cancer patients with COVID‐19. Lung cancer patients with COVID‐19 have high in‐hospital mortality with unique early symptoms and imaging features. Prolonged PT and elevated hs‐TNI are independent risk factors for in‐hospital mortality of lung cancer patients with COVID‐19. They may be used to help clinicians predict prognosis at an early stage for lung cancer patients with COVID‐19. All consecutive hospitalized patients diagnosed with lung cancer at any time and COVID‐19 on admission, or during hospitalization from 3 January to 6 May 2020, were identified. Patients with laboratory‐confirmed COVID‐19 and a definite clinical outcome (discharge or death) were included in the analysis. Laboratory‐confirmed COVID‐19 was defined when SARS‐CoV‐2 nucleic acid was positive as detected by reverse transcription‐polymerase chain reaction (RT‐PCR) assay, as described previously.A trained team of physicians collected data from the electronic medical records using a standardized data collection form. Data included age, sex, smoking status, comorbidities, laboratory, radiographic, and electrocardiographic findings, pathology of lung cancer, active anticancer therapy (within four weeks of COVID‐19 diagnosis), cancer status (present vs. in remission), onset date, clinical manifestations and treatment of COVID‐19 and outcomes. Current lung cancer patients included all cases with newly diagnosed, partial remission, progressive, or recurrent cancer, while lung cancer patients in remission included those treated who went into complete remission.Chest computed tomography (CT) images were independently assessed for the presence and distribution of abnormalities by three chest radiologists. Ground‐glass opacity (GGO) was defined as hazy increased opacity in the lung, with the preservation of bronchial and vascular margins.Outcomes included in‐hospital mortality and discharge. The criteria for discharge were normal body temperature for at least three days, clinical remission of respiratory symptoms, substantial resolution of inflammation as shown by chest radiography, and two consecutive negative results for SARS‐CoV‐2 RNA obtained at least 24 hours apart.Continuous variables are presented as median and interquartile ranges (IQR), and categorical variables are expressed as counts and percentages. Continuous variables to compare the differences between survivors and nonsurvivors were assessed using a Wilcoxon sum test, and categorical variables were analyzed using Chi‐square analysis or Fisher's exact test as appropriate; odds ratio (OR) and 95% confidence interval (CI) were calculated.P‐value of <0.2 in univariate analysis, and then limiting final multivariate models to risk factors or confounders that were statistically significant in analyses. No imputation was made for missing data. If the RT‐PCR assay for SARS‐CoV‐2 was positive when the patient died, the date of death was used as the end date. All statistical tests were two‐sided, and a P‐value of <0.05 was considered statistically significant. For all analyses, SAS 9.3  was used.To explore the risk factors for in‐hospital mortality, univariate and multivariate logistic regression models were used. Multivariate logistic regression was performed, first by adjusting for the factors with a From 3 January 2020, to 6 May 2020, 50 patients with lung cancer were identified from 11 660 patients clinically diagnosed with COVID‐19 and admitted to 12 hospitals in Hubei Province. Due to the newly constructed hospitals during the epidemic of COVID‐19, some patients, including lung cancer patients with COVID‐19, were transferred to the new hospitals for a reasonable allocation of medical resources. Five patients were then excluded, and thus 45 patients were included in the analysis. As of 6 May 2020, 34 patients were discharged, and 11 died, with an in‐hospital mortality rate of 24.4%.P = 0.0207), but no difference in the sex ratio (P = 0.1318). Comorbidities were present in 30 (66.7%) patients, with hypertension being the most common comorbidity, followed by coronary artery disease and diabetes. The prevalence of hypertension was higher in nonsurvivors than in survivors .Demographic, clinical, and tumor characteristics for patients are shown in Table The two most common early symptoms of COVID‐19 were fever (33 [73.3%]), and cough (24 [53.3%]). Other early symptoms of COVID‐19 included chest tightness (8 [17.8%]), shortness of breath (7 [15.6%]), fatigue (6 [13.3%]) and sputum production (5 [11.1%]), dyspnea (2 [4.4%]), loss of appetite (2 [4.4%]), myalgia (1 [2.2%]), nausea (1 [2.2%]), diarrhea (1 [2.2%]), seizure (1 [2.2%]), dysphagia (1 [2.2%]), headache (1 [2.2%]), and dizziness (1 [2.2%]). Among them, a 68‐year‐old man with a history of epilepsy and small cell lung cancer had a seizure on admission. He presented with respiratory symptoms (sputum production and dyspnea) during hospitalization and died 10 days following admission. There were no significant differences in the early symptoms of COVID‐19 between nonsurvivors and survivors (Table The most common lung cancer was lung adenocarcinoma (10 [22.2%]), followed by lung squamous cell cancer (5 [11.1%]) and small cell lung cancer (2 [4.4%]). The lung cancer types of 28 patients were not available in the electronic medical records. There were 31 (68.9%) current lung cancer patients and 14 (31.1%) patients in remission. There was no difference between the survivors and nonsurvivors in terms of cancer status and anticancer therapy . Other findings included pleural effusion, nodule, thoracic lymphadenopathy, pleural thickening, and pericardial thickening Table . The medA total of 14 (31.1%) patients presented with ECG abnormalities on admission. There was no significant difference in ECG abnormalities between survivors and nonsurvivors Table .P < 0.0001); More patients needed noninvasive and invasive mechanical ventilation in nonsurvivors than survivors . More patients were admitted to the intensive care unit (ICU) in nonsurvivors than survivors .Treatment of COVID‐19 patients and outcomes are shown in Table Respiratory failure was the most frequently observed complication (26.7%), followed by acute cardiac injury (22.2%), secondary infection (24.4%), ARDS (20.0%), heart failure 13.3%), acute kidney injury (8.9%), and sepsis (8.9%). The incidence of all comorbidities in nonsurvivors was significantly higher than survivors, except for secondary infection , with hypertension , prolonged prothrombin time (PT) on admission , and elevated high sensitivity cardiac troponin I (hs‐TNI) on admission  were associated with an increased risk of in‐hospital mortality, whereas elevated platelet count (≥125 × 109/L)  was associated with a decreased risk. In the multivariable analysis, only prolonged PT   (Fig Univariable analyses revealed that patients who were older (OR = 1.07, 95% CI: 1.01–1.14, Our study suggests that the early clinical manifestations, laboratory, and radiographic findings of COVID‐19 in lung cancer patients were similar to those previously reported in patients without cancer in Hubei, especially Wuhan city, China.Our results show that the in‐hospital mortality rate in lung cancer patients with COVID‐19 in China was 24.4%, while previous studies reported that the fatality rate of noncancer patients in the same age groups with confirmed COVID‐19 in China ranged from 1.3% to 8.0%.The lung cancer symptoms may overlap with symptoms of COVID‐19, since they both directly impair lung function. In our lung cancer cohort, fever and cough were the dominant initial symptoms, and respiratory symptoms were common. Lung cancer patients with COVID‐19 also presented with some nonspecific symptoms, which have been reported in older people or immunosuppressed patients.The main CT findings of lung cancer patients with COVID‐19 have been reported to be similar to radiological findings, commonly reported in patients with COVID‐19.More importantly, we identified that prolongation of PT on admission was associated with an over two‐fold increased risk of in‐hospital mortality in lung cancer patients with COVID‐19. This finding is in agreement with a previous study demonstrating that coagulation abnormalities may be associated with an increased risk of death in patients with COVID‐19.et al. in which the targeted disruption of ACE2 in mice resulted in a severe heart contractility defect, increased angiotensin II levels, and upregulation of hypoxia‐induced genes in the heart.Several studies have reported that cardiac injury is a common condition among hospitalized patients with COVID‐19, and is associated with a higher risk of in‐hospital mortalityet al.This study has several limitations. First, the number of patients involved in this observational study is relatively small, and thus one should take this limitation into account when interpreting the results and conclusions. Second, from this dataset, we found that lung resection surgery, chemotherapy, and treatment with immune checkpoint inhibitors given within four weeks before the diagnosis of laboratory‐confirmed COVID‐19 were not associated with increased risk with in‐hospital mortality. Similar observations were reported for chemotherapy, immunotherapy, hormonal therapy, targeted therapy, and radiotherapy in cancer patients with COVID‐19 in a study by Lee In conclusion, lung cancer patients with COVID‐19 have high in‐hospital mortality. Prolonged PT and elevated hs‐TNI are independent risk factors for in‐hospital mortality of lung cancer patients with COVID‐19. They may be used to assist clinicians predict prognosis at an early stage for lung cancer patients with COVID‐19.All authors have no conflict of interest to declare.


Despite a high prevalence of obesity among women, it remained constant in women but showed an increasing trend in men; moreover, the trends of low physical activity and current smoking were better for women. Despite some improvement in CVH metrics, < 4% of Iranian adults meet ≥ 6 CVH metrics in 2016; this issue needs intervention at the public health level using a multi-component strategy.To examine the trends of 7 cardiovascular health metrics (CVH metrics) incorporate of smoking, physical activity, diet, body mass index (BMI), fasting plasma glucose (FPG), total cholesterol (TC), and blood pressure (BP) level during three cross-sectional STEPwise approaches to surveillance (STEPS), 2007–2016, among Iranian adults. The study population consisted of 19,841 women and 17,243 men, aged 20–65 years. The CVH metrics were categorized as ‘ideal’, ‘intermediate’, and ‘poor’. The sex-stratified weighted prevalence rate of each CVH metrics was reported. The conditional probability of each poor versus combined intermediate and ideal metric was analyzed using logistic regression. In 2016 compared to 2007, the prevalence of poor BP level (20.4% vs. 23.7%), smoking (13.7% vs. 23.8%), TC ≥ 240 mg/dl (2.4% vs. 11.2%) and FPG < 100 mg/dl (75.6% vs. 82.3%) declined, whereas poor physical activity level (49.7% vs. 30%), poor healthy diet score (38.1% vs. 4.1%), BMI levels ≥ 25 kg/m Smoking, physical inactivity, high blood pressure, high cholesterol level, unhealthy diet alongside obesity, and glucose intolerance status contribute to persistent CVD. Achieving favorable changes in healthy lifestyle factors (even slightly) can have a considerable effect on decreasing the epidemiologic and economic health burden2.Cardiovascular Disease (CVD) persists as a critical public health problem despite the great global effort to reduce cardiovascular risk factors through primary prevention3. There is convincing evidence that a more ideal CVH metrics is accompanied by reduced risk of CVD and non-CVD outcomes such as cancer, depression, cognitive impairment, and diabetes5.Based on evidence from randomized clinical trials, the American Heart Association (AHA) established the 2020 strategic impact goals, which incorporated 7 cardiovascular health metrics (CVH metrics), consisting of four health behaviors  and three health factors  for improvement of cardiovascular health5. Among the seven CVH metrics, the highest and lowest prevalence for ideal CVH metrics was attributed to smoking status and diet, respectively5. However, survey data showing the trends of CVH metrics among the general population are very limited. To the best of our knowledge, few population-based studies have been conducted among US, Canadian and Korean populations that examined the trends of all 7 ideal cardiovascular health metrics. Accordingly, two American National Health and Nutrition Examination Surveys (NHANES) between 1998 and 2010, the Korean National Health and Nutrition Examination Survey (KNHANES) between 2005 and 2009, and a Canadian study carried out from 2003 to 2011 showed no improvement in the prevalence of ideal CVH metrics7.Several cross-sectional studies have focused on the prevalence of CVH metrics in different populations. The distribution of ideal CVH metrics  between 2010 and 2015 was reported to be as low as 0.5–12% in the United States (US) and 0.3–10% in the non-US population8. Ischemic heart disease, the most important cause of death in Iran in the year 2016, was responsible for 40% and 44% of all deaths in men and women, respectively9. Our previous cross-sectional study among Tehranian residents showed a very low prevalence of ideal CVH metrics in 1999–201110.The Middle East and North Africa (MENA) region is considered to carry a high absolute burden of CVD. Risk factors such as rapid urbanization, changing lifestyle including physical inactivity and nutritional transition to high caloric intake, political instability, social conflict, terrorism, and lack of comprehensive preventive programs over the past decades are the main problems in this regionTo the best of our knowledge, this is the first nationwide gender-specific report on the trend of CVH metrics in the MENA region, using the AHA’s 2020 impact goals among Iranian adults in the scope of the STEPwise approach to surveillance (STEPS) during 2007–2016.13. We confirm that all research was performed following relevant guidelines, and confirming that informed verbal consent was obtained from all participants and/or their legal guardians. This study was approved by the Institutional Review Board (IRB) of the Research Institute for Endocrine Sciences (RIES), Shahid Beheshti University of Medical Sciences, Tehran, Iran, and all participants provided written informed consent.This study is secondary data analysis on the World Health Organization (WHO) STEPS surveys. Data was collected using a random multistage cluster sampling method in non-hospitalized and non-institutionalized Iranian adults, by trained interviewers during a household meeting. The STEPS survey was conducted in seven stages, between 2004 and 2016, four of which included laboratory measurements on a subsample population. In the current study, we used three STEPS, 2007, 2011, and 2016; which had similar methods for the measurement of all needed CVH metrics variables. Despite slight differences in sampling designs between the 3 surveys, and the smaller sample size in 2011 , samples were representative of the Iranian adult population in all 3 surveys. Further details regarding STEPS have been previously publishedFor trends in CVH metrics, we used data from STEPS 2007 , 2011 (n = 9967), and 2016 . FPG and TC values were available for a subsample of adults aged 20–65 years . After removing subjects with missing data on all 7 CVH metrics, 37,091 adults  remained for data analysis  were recorded after at least 10 min of rest, three times within 5 min of each other, in a seated position from the right arm, using an appropriately-sized standard cuff sphygmomanometer . The mean value was considered as the subject’s SBP and DBP. Height was measured with a portable, inflexible measuring bar in standing position with no shoes on, with a precision of 0.1 cm. Weight was measured using a digital scale in light clothing without shoes on and recorded to the nearest 0.1 kg. BMI was calculated as weight in kilograms divided by height in meters squared. For biochemical measurements, according to the standard protocol, 10–12 ml of the venous blood sample was drawn from each participant after at least 8 h of overnight fasting. Samples were sent to collaborating centers in 2007 and 2011, but in 2016 samples were sent to the Central Reference Laboratory of the Ministry of Health of Iran  under cold chain conditions(4–8 °C). All samples were promptly centrifuged (1500 rpm for 10 min at standard room temperature: 21 °C). FPG was measured via enzymatic colorimetric method using glucose oxidize and TC level was checked via enzymatic photometric method using cholesterol esterase and cholesterol oxidase in 2007 and 2011, whereas the auto analyzer (Cobas C311 Hitachi High-Technologies Corporation. Tokyo Made in Japan) was used in 2016.Demographic information on sex, age, education, occupation as well as cigarette smoking, physical activity, and drug consumption were obtained from participants using a standard questionnaire based on the STEPS survey16. The subgroup of smoking status consists of current, former, and never-smokers, which were attributed ‘poor’, ‘intermediate’, and ‘ideal’ status, respectively. The AHA’s definition of ‘ideal’ smoking status includes never or quit smoking > 12 months, ‘intermediate’ groups include quit smoking less than 12 months ago, and ‘poor’ groups include smoking daily or occasionally. In the questionnaire, we categorized the ‘current’ smoker as a participant who smoked daily or occasionally, any amount of all kinds of tobacco  at the time of the interview and ‘former’ as someone who had a history of smoking but had since quit. According to our questionnaire, we used average metabolic equivalent tasks score (METs) to define physical activity instead of using the duration of physical activity , which were calculated based on the global physical activity questionnaire (GPAQ). The GPAQ is a standardized questionnaire of physical activity developed by the WHO15. ‘ideal’, ‘intermediate’, and ‘poor’ physical activity was defined as physical activity of ≥ 1500 MET mins/wk, 600–1500 MET mins/wk, and < 600 MET mins/wk, respectively. The corresponding metrics for BMI were ‘ideal’ (< 25.0 kg/m2), ‘intermediate’ (25.0–29.9 kg/m2) and ‘poor’ (≥ 30.0 kg/m2). AHA’s healthy diet score was defined by the sum of the following 5 components, allocating 1 point each for the consumption of fruits and vegetables (≥ 4.5 cups/d), fish (≥ two 3.5-oz servings/wk), fiber-rich whole grains , sodium(< 1500 mg/d), and sugar-sweetened beverages(< 36 oz./wk)16. Considering the limited data in our questionnaire, the modified healthy diet score was used based on only two components, daily fruits and vegetables, and fish servings in all 3 surveys. Participants were placed in the ’ideal’ group if their fruit and vegetable consumption was ≥ 4 cups/d, and consumption of fish ≥ two 3.5-oz servings/wk. The ‘poor’ group comprised participants who consumed less than 2 cups/d fruits and vegetables, and without consumption of fish. All other participants were categorized as the ‘intermediate’ group. Statin therapy for high cholesterol level was recorded only for STEPS 2016, therefore we modified AHA’s definition of TC status, without considering treatment information in 2007 and 2011. We categorized participants as ‘ideal’ if TC < 200 mg/dl, ‘intermediate’ if TC level was 200–239 mg/dl, and ‘poor’ if they had a TC level equal or greater than 240 mg/dl. According to FPG level, participants were ranked as ‘ideal’ if untreated FPG was lower than 100 mg/dl, ‘intermediate’ if untreated FPG was 100–125 mg/dl or treated to lower than 125 mg/dl, and ‘poor’ if they had an FPG level equal or greater than 126 mg/dl. Subgroup classification of blood pressure level consisted of ‘ideal’ , ‘intermediate’ , and ‘poor’ (SBP ≥ 140 mmHg/DBP ≥ 90 mmHg). To calculate the total CVH metrics score, in the first step we recoded each metric as a binary variable, assigning a score of 1 point to the ‘intermediate’ or ‘ideal’ category versus 0 points for the ‘poor’ category. A CVH metric total score was attained by summing up the newly defined variables. A total CVH metric score was categorized as ‘‘ideal’ if the total CVH metric score was 6–7, ‘intermediate’ if the score was 3–5, and ‘poor’ if the CVH metric score was less than 2.We used AHA’s 2020 Impact Goals which defined three CVH metrics categories; ‘ideal’, ‘intermediate’, and ‘poor’Table16. The sp value < 0.05 was considered statistically significant.In the current study, we used STEPs with a complex sampling design. To achieve a representative estimation of the Iranian population, a survey analysis was performed and weights were generated using categories of age, sex, area of residence , and 30 provinces, according to the national population of Iran . All data from 2007, 2011, and 2016 STEPs were pooled. The weighted prevalence rates (95% CI) of each health metric were estimated using Taylor-linearized variance estimation. The conditional probability of each poor vs. combined intermediate and ideal metric was analyzed by logistic regression, wherein the STEPs cycles were considered a continuous independent variable, and linear trends in the probability of each health metric were examined. Differences across the sexes were examined by using interaction terms . All analyses were performed using STATA 14, and Demographic characteristics of the study participants are described in Table As shown in Table Tables Figure In the current study, we examined the trends of poor, intermediate, and ideal levels of CVH metrics during 3 consecutive national surveys from 2007 to 2016. Throughout these surveys, the prevalence of BP level ≥ 140/90 mmHg, TC ≥ 240 mg/dl, and current smoking status decreased in both genders. However, overweight and obesity status increased among men, and physical activity of less than 600 MET mins/wk and modified poor diet score increased in both genders. Moreover, the prevalence of prediabetes (but not diabetes state) increased significantly in both genders. Unfortunately, only about 6% and 3.8% of the total population met 6 or more ideal CVH metrics in 2007 and 2016, respectively.8. To the best of our knowledge, 4 studies conducted in developing countries , exhibited a low prevalence of ≥ 6 ideal CVH metrics (0.3–4%)5. Similarly, in the current study, although this prevalence reached about 7.2% in 2011, it again decreased to < 4% in 2016. The consistently low trends of ideal CVH metrics were also confirmed in national studies conducted in the US (i.e. < 10%)4, Canada (< 8.8%)7, and Korea (< 14%)6. Moreover, the intermediate categories of CVH metrics  had the highest prevalence in both genders in this study (≈ 70%). Comparable values in NHANES and KNHANES were 64.4–66.3% and 66.7–71%, respectively6.The low prevalence of ideal CVH metrics is a global health problem, notably in low-and middle-income countries5. This reduction rate was more pronounced among women, a finding similar to that observed in the KNHANES and Canadian study7. Moreover, it is important to note that Iranian women are more likely to underreport smoking behaviors, given the social shame of smoking17. Unfortunately, in 2016, about 1 out of 4 Iranian men were current smokers. Importantly, more than 19% of the population attributable fraction (PAF) of premature CVD among men was attributed to current smoking18. This risk might be minimized by effective programs such as raising taxes on cigarettes as well as the development of a workplace smoking regulation and smoking restriction at the national level.The trend of current smoking status was shown to decline from 23.8 to 13.7%. The trend analysis of previous studies in the US and non-US population also reflect the improvement of smoking status4 and Korea (5.4% in 2005 to 7.6% in 2009)6. The decreasing trend in lipid levels in our data registry could hardly be explained by lifestyle changes  since it was shown that low physical activity increased from 30.0 to 49.7% during this period, or by the use of lipid-lowering medications (only 5.6% in 2016). Despite this, due to extensive media advertising against the consumption of saturated fatty acids, it was shown that over 30% of Iranian families now consume less hydrogenated oil than they used to in the past19, which could explain the favorable lipid trend in the Iranian population during our surveys.The favorable trend of poor total cholesterol level in our study (11.2% in 2007 to 2.4% in 2016) was significantly better than a comparable change in the US (20.6% in 1988–1994 to 14.2% in 2005–2010)20. Our results were in line with nutritional status worldwide, with a healthy diet score being reported to be the poorest CVH metrics in the previous US and non-US studies5. According to Global Burden of Disease results, the consumption of whole-grain in the MENA region was about one-third of the global average8; hence, this downward shift in nutritional status would be more pronounced if this item had been included in our study. From 2007 to 2016, rising living costs and rising inflation that might be attributable to the country's long years of sanctions reduced people's access to healthy diets that contain enough vegetables and fruits. This issue, along with the numerous preoccupations of people to earn enough income, has led to not allocating enough time to prepare healthy diets, in other words, the food pattern has increasingly changed to a Western diet incorporating caloric dense and sucrose-enriched drinks21. Also, the occurrence of natural disasters such as floods, earthquakes, and droughts frequently during these years along with political instability in the region, especially in neighboring countries, has become an important reason for the growing decline in healthy nutrition in the people22.Poor diet scores stemming from low consumption of fruits, vegetables, and fish demonstrated a significant increase from 4.1% in 2007 to 38.1% in 2016 in our study. The average daily consumption of fruits and vegetables among the Iranian adult population in 2007 (2.58 servings per day) was reported to be lower than the average value recommended by WHO (5 or more servings per day)8. This low physical activity level might be explained by rapid urbanization, industrialization, and a sedentary lifestyle due to occupational and transport facility changes in the region21. On the other hand, in contrast to the results of NHANES and KNHANES, the trend of low physical activity increased from 2007 to 2016, with a significantly higher slope in men, although women had significantly higher values of physical inactivity across all three surveys. The higher prevalence of physical inactivity among women may be linked to their role as caregiver to another family member in the house, their lower-income, and cultural issues that limit the participation of women in some sports23. To promote physical activity, public health agencies should reinforce appropriate public health education and organize strategic intervention programs among adults in Iran, such as the development of public sports facilities.Recent reports have shown that the mean physical activity level in the MENA region was approximately 1000 MET mins/wk less than the average global value for both genders19, continued until 2016. Despite this, in 2016, 3 out of 5 adults had pre-hypertension/hypertension. Accordingly, among the participants of the Tehran Lipid and Glucose Study (TLGS), the highest PAF for CVD among potential risk factors was attributed to hypertension, reaching 21.6%24. Unfortunately, the prevalence of pre-hypertension remained constant at about 43% during this period. Importantly, the presence of prehypertension was shown to be significantly associated with CVD and mortality26. The slight favorable trend of hypertension in contrast to low physical activity, poor diet status, and high salt intake27 might be justified by other contributing factors such as the increase in the use of antihypertensive drugs. The high prevalence of intermediate and poor BP levels among Iranian residents requires immediate preventive programs, consisting of encouraging physical activity, reducing salt intake, as well as increasing the consumption of fruits, vegetables, and a potassium-rich diet.Regarding pre-hypertension and hypertension status, the favorable trend observed in 2005–20112 and FPG ≥ 100 mg/dl (including drug-treated patients) in the study population increased from about 58 to 63%, and 18 to 24%, respectively from 2007 to 2016. Based on the study in 2011, it was estimated that the age-standardized prevalence of IFG and type 2 diabetes among the Iranian population aged ≥ 20 years was 14.4% and 11.3%, respectively28. Data from the 9th edition of the International Diabetes Federation reported that 463 million people suffer from diabetes around the world. Without effective national advocacy, this will be expected to increase by 51%, reaching 700 million in 2045; most of this increase is expected to arise from the MENA region29. The significant increase in abnormalities in glucose metabolism could be related to an aging population, unhealthy lifestyle, and physical inactivity due to a growing urban population. In our study, the prevalence of obesity in each survey was higher among women than in men, similar to other countries in the MENA region30. The high prevalence of obesity among Iranian women might be attributable to the high prevalence of low physical activity as discussed above; moreover, the high parity rate among women was addressed as an underlying factor of obesity in this gender31. Among Iranians, the PAF of BMI ≥ 25 kg/m2 for type 2 diabetes among women and men was 34.6% and 27.1%, respectively28. The TLGS demonstrated that among modifiable risk factors, the PAF of diabetes for CVD and all-cause mortality were about 14% and 24%, respectively, while the PAF of CVD attributed to being overweight or obese was about 24%24. Hence, the significant increase in the prevalence of being overweight/obese and impaired glucose intolerance could negate the favorable trend of hypercholesterolemia, smoking, and hypertension. To address these paradoxical trends, implementing public health interventions that target lifestyle change by educating people regarding the advantages of a healthy diet and increasing physical activity is seriously advised; the impact of which was shown for up to 6 years in reducing metabolic syndrome among Tehranian residents.The prevalence of BMI ≥ 25 kg/m32. As a successful example, in a community-based study in Tehran, it was shown that family–school and community based educational sessions resulted in about 20% decrease incidence of metabolic syndrome during 6 years follow up33.Implementing multicomponent community-based prevention strategies in the form of NGOs and charitable organizations, health marketing strategies to raise public awareness about health behaviors, using community health workers (Behvarz) especially in deprived rural areas, applying smartphone preventive program to improve the quality of health care, adopting general practitioners and other health workers to assign community members to a link worker, and finally preventive, diagnostic, and therapeutic services may improve cardiovascular health status. Major gains will likely achieve from public health strategies targeting incorrect diet, physical inactivity, and preventing or stopping cigarette smokingTo the best of our knowledge, this is one of the few studies examining the trends of CVH metrics . Moreover, the fact that this study measured 7 CVH metrics over 10 years and examined trends in each gender is another strong point. However, our study had some limitations. First, we used a subsample of the STEPS population; namely those with complete data on CVH metrics, which might diminish the exact assessment of CVH metrics trends in the Iranian population. Second, the sampling method performed in 2016 differed slightly from 2007 and 2011; however, all samples taken in the three surveys were representative of the Iranian population. Third, self-reporting of physical activity, cigarette smoking, and dietary records in our surveys could cause recall bias and imprecise estimation of cardiovascular health status. Fourth, only 2 components of a healthy diet were used for assessment of nutritional status and our modified diet score may not reflect the complete effect of diet on cardiovascular health status.The prevalence of ideal CVH metrics remained very low during 2007–2016 and in the last survey, less than 4% of Iranian adults met the criteria of 6 or more ideal CVH metrics. Although the levels of smoking, TC, and BP had improved slightly, the unfavorable trends of physical activity, unhealthy diet, obesity, and ideal FPG need immediate attention at a public health level using a multi-component strategy.


The optimal use of intracardiac echocardiography (ICE) may reduce fluoroscopy time and procedural complications during endocardial ablation of cardiac arrhythmias. Due to limited evidence in this area, we conducted the first systematic literature review and meta‐analysis to evaluate outcomes associated with the use of ICE.g −1.06; 95% confidence interval [CI] −1.81 to −0.32; P < .01), fluoroscopy dose , and procedure time  vs ablation without ICE. A 6.95 minute reduction in fluoroscopy time and a 15.2 minute reduction in procedure time was observed between the ICE vs non‐ICE groups. These efficiency gains were not associated with any decreased effectiveness or safety. Sensitivity analyses limiting studies to an atrial fibrillation (AF) only population yielded similar results to the main analysis.Studies reporting the use of ICE during ablation procedures vs without ICE were searched using PubMed/MEDLINE. A meta‐analysis was performed on the 19 studies (2186 patients) meeting inclusion criteria, collectively representing a broad range of arrhythmia mechanisms. Use of ICE was associated with significant reductions in fluoroscopy time (Hedges' The use of ICE in the ablation of cardiac arrhythmias is associated with significantly lower fluoroscopy time, fluoroscopy dose, and shorter procedure time vs ablation without ICE. These efficiency improvements did not compromise the clinical effectiveness or safety of the procedure. Preprocedural images can also be merged into three‐dimensional electroanatomical mapping (EAM) systems to visualize the esophagus and its location along the posterior wall of the left atrium, and reduce radiation exposure during the ablation procedure.Intracardiac echocardiography (ICE) has multiple real‐time applications during catheter ablation, including the ability to guide transseptal puncture, visualize the location of the esophagus, provide guidance of cardiac anatomy, and detect microbubbles as a result of overheating, thereby preventing complications.2a priori.We conducted a systematic literature review following typical best practices, including the use of a prospective protocol specifying search terms and study eligibility.2.1We searched PubMed/MEDLINE to identify studies published in English between 1 January 1996 and 31 October 2018, that assessed the use of ICE during the ablation of cardiac arrhythmias vs ablation without ICE. The electronic search was supplemented by manually searching reference lists of recent review articles. Search terms used in the literature search are detailed in Table S1.2.2Studies were screened for eligibility using a two‐step process and prespecified criteria. During “level I” review, studies were screened for eligibility by a single reviewer, based on their title and abstract. Potentially eligible studies with an eligible patient population and some indication that ICE was evaluated were reviewed in full text. During “level II” screening, full‐text articles were reviewed for use of the technology of interest and for eligible comparative data. At level II screening, two reviewers independently assessed each study for fit with the selection criteria.TM Catheter, Biosense Webster, Inc; Ultra ICETM Catheter, Boston Scientific; or ViewFlexTM Catheter, St. Jude Medical) catheters compared to each other, or to ablation procedures without the use of ultrasound. We deliberately included reports of ablation for any form of cardiac arrhythmia to broadly assess the use of ICE according to real‐world clinical practice. Studies were excluded if they did not include a procedure of interest, did not use real‐time guidance during ablation , or did not report any outcomes of interest .Included studies were required to be in English‐language, comparative , and with at least 10 patients undergoing endocardial ablation with either sensor‐based  or non‐sensor‐based  level of evidence.2.4The primary endpoint for the meta‐analysis was fluoroscopy time. Secondary outcomes were fluoroscopy dose, procedure time, acute procedure success, peri‐procedural complications, and freedom from arrhythmia at 6 months follow‐up or longer.2.4.1g adjustment). The standardized mean difference allows the analysis of studies assessing the same outcome, but with different outcome definitions, data reporting formats, or measurement scales. Absolute Hedges' g values <0.2 indicate a small effect, 0.5 a medium effect, and >0.8 a large effect.g values are desirable. Mean difference  analysis was also performed on fluoroscopy and procedure time outcomes. In studies with three arms, we chose the two arms with the cleanest ICE vs non‐ICE comparison . Since the choice was not always clear‐cut, we also performed a sensitivity analysis using the alternate comparator arm.Intention‐to‐treat results were extracted for all binary outcomes, with between‐group effect sizes compared using a risk ratio (RR). Continuous and time outcomes were compared using standardized mean difference , and use of an alternate comparator arm. For fluoroscopy time, sensitivity associated with the use of a sensor‐based ICE catheter (SOUNDSTAR® Catheter) was also performed. In particular, extensive post‐hoc sensitivity analyses were conducted for studies restricted to an AF population across all endpoints of interest, after our systematic review revealed that a majority of reports focused on this arrhythmia type. Doing so eliminated all studies with a pediatric cohort, as well as those with substrates distinctive from AF.P‐values were two‐sided, and values ≤.05 were considered statistically significant.Data manipulation and statistical analyses were performed using SAS Software, Version 9.4 and the R meta‐package, Version 4.9‐4. All 3Our initial search retrieved 1349 articles .3.23.2.12 = 97%).g −1.06; 95% CI −1.81 to −0.32; P < .01)  . The funnel plot and Egger's test of asymmetry (P = .9670) suggested no publication bias or small‐study effects .Data for fluoroscopy time were available from 14 studies, with significant heterogeneity among studies I = 97%.g g −1.25; 95% CI −2.14 to −0.36; P < .01).P < .01),P < .01),P = .04),P < .01), or used only sensor‐based ICE catheters (P = .02),The significant reduction in fluoroscopy time demonstrated in the main analysis was robust in all sensitivity testing, including studies with only AF patients (Hedges' 3.2.22 = 93%) and no evidence of publication bias or small study effects.g −1.27; 95% CI −1.91 to −0.62; P < .01) ,P < .01),P = .01). Similar results were found when limiting studies to an AF population  (Table S4).Ten studies reported fluoroscopy dose data, with significant heterogeneity among studies (I) Figure . This re3.2.32 = 86%) and no evidence of publication bias or small study effects.g −0.35; 95% CI −0.64 to −0.05; P = .02)  . These results were consistent in a sensitivity analysis restricting studies to an AF population . Other sensitivity analyses including use of the HKSJ method (P = .10), removal of one outlying and influential study (P = .09),P = .09),P = .07),Data for procedure time were available from 14 studies, with significant heterogeneity among studies (I) Figure . This co3.33.3.12 = 30%). Acute success was high in all studies and not significantly different in ablation procedures using ICE vs those without  . Sensitivity performed on AF only patients yielded consistent results .Thirteen studies were included in the analysis,3.3.22 = 0%).P = .24) . No outlying or influential studies were identified to include in a sensitivity analysis. Sensitivity analyses using an alternate group for the 3‐arm studyP = .33) and using the HKSJ difference method (P = .23) did not demonstrate any significant differences in freedom from arrhythmia between groups (Table S5).Eleven studies reported freedom from arrhythmia outcomes, with no observable heterogeneity among studies (I3.42 = 0%).P = .08) . In the sensitivity analysis that included an alternate group for 3‐arm studies,P < .01). There was no significant difference among the groups when restricting studies to only AF ablations (P = .24) (Table S5).Six studies reported zero (0) peri‐procedural complications in one or both arms3.52 = 0%).P = .14) . No studies with an alternate group for 3‐arm studies were available for sensitivity analysis, and limiting reports to an AF population yielded nonsignificant results consistent with the main analysis (P = .21) (Table S6).Five studies reported zero (0) venous access complications in one or both arms4To the best of our knowledge, this is the first meta‐analysis comparing ICE‐guided ablation with procedures using fluoroscopy or other mapping/navigation systems that do not use ICE. Our study highlights that catheter ablation of a range of cardiac arrhythmias using real‐time imaging with ICE is associated with significant reductions in fluoroscopy time (primary outcome), fluoroscopy dose, and procedure time compared with ablation without the use of ICE. These reductions were not accompanied by an evident decrease in effectiveness or safety.Prolonged fluoroscopic guidance during ablation exposes the patient to significant levels of radiation.Operators and staff who perform many ablation procedures over time accumulate significant exposure to radiation; therefore, these individuals are also highly susceptible to the risks associated with heavy fluoroscopy use, which may be even greater than that experienced by patients.Because of the risks of radiation, technological strategies including the use of ICE have been developed to reduce hazardous exposure to patients and operators. This meta‐analysis demonstrates that the use of ICE during ablation results in significantly lower duration and a dose of fluoroscopy compared to ablation without ICE. The planned sensitivity analyses for these endpoints found the results to be robust. Ablation procedures using ICE were associated with a 6.95 minute shorter fluoroscopy time compared to ablation without the use of ICE. Significant reductions in fluoroscopy time with a sensor‐based ICE catheter were also observed in a mean difference analysis demonstrating a 12.74 minute reduction.Real‐time guidance and visualization of cardiac anatomy is critical for procedural efficiency in catheter ablation procedures. ICE provides additional information to the operator beyond angiography or other forms of imaging, by not only producing accurate procedural imaging of the cardiac anatomy but also providing guidance for the trans‐septal puncture to ensure safe and reliable access to the left atrium.P = .24). In clinical practice, the use of ICE throughout the ablation procedure varies from physician to physician. Studies meeting the selection criteria for our meta‐analysis provided limited methodological descriptions on their use of ICE; therefore, it is not clear how precisely ICE was used during ablation, and whether the full extent of potential benefits was realized. Regardless, hospitals or operators that do not routinely integrate CT/MRI into their ablation workflow should see a compelling value for the use of ICE.In this study improved efficiency  using ICE did not compromise effectiveness. Based on the main analyses, freedom from arrhythmia was not significantly different for ICE vs comparators (P = .08). A significantly lower RR was also found in the alternate‐arm sensitivity analysis . Beyond the transseptal puncture, ICE can provide benefits through different stages of catheter ablation, and may reduce the incidence of complications such as pericardial effusion, tamponade, thrombus formation, or pulmonary veins stenosis.P = 0.14). In our meta‐analysis, peri‐procedural complications were rare, with many studies reporting no events in one or both comparator arms. Due to such rarity, it is difficult to definitively assess a statistical difference in the rate of complications among procedures that use ICE vs those that do not. In a 2013 systematic review examining complications of catheter ablation in AF, the incidence of peri‐procedural complications was reported at 2.9%.Reductions in fluoroscopy and procedure times with ICE were also not accompanied by any evident increase in risk. In fact, non‐venous access complications trended lower for ICE vs comparators  and occupational hazards (for clinicians) may contribute to lower downstream treatment costs. However, it is difficult to generalize the determination of “cost‐effectiveness” from country to country. Each healthcare system is subject to diverse perspectives of value, influenced by current cultural and political factors, existing healthcare financing models, level of economic development, and local unmet medical needs. Robust and nuanced analysis is needed to further explore this topic.5Our study included 19 publications in the first meta‐analysis comparing the endocardial ablation of any cardiac arrhythmia with ICE vs procedures using fluoroscopy or other mapping/navigation systems. However, there were several limitations to our work, many of which are inherent to any meta‐analysis. First, our systematic literature search only included English‐language published evidence indexed within PubMed/MEDLINE or discoverable by manual reference checks. Most of the included studies were conducted in North America and Europe. Second, we included comparative data from both randomized and non‐randomized studies due to the limited number of RCTs available, and among the included RCTs, three studies were downgraded from level 2 to level 3 due to confounding/quality issues. Third, the comparator group was broad and included EAM, fluoroscopy, or other/mixed imaging modalities without the use of ICE. Fourth, the time period of the included studies (>20 years) was also broad. Technological advances in ablation of arrhythmias have dramatically improved over the past 5 to 10 years. Procedures and techniques, as well as diagnostic and ablation catheters have become more sophisticated, which has led to improved safety, efficacy, and efficiency. Lastly, there was significant heterogeneity among studies in analyses examining efficiency outcomes , which might reflect different study periods, hospital workflows, or individual operator skills. Nevertheless, there was no evidence of publication bias or small‐study effects, and the treatment effects were robust in a sensitivity analysis.6Ablation of various cardiac arrhythmias using ICE is associated with significant reductions in fluoroscopy time, fluoroscopy dose, and procedure time when compared to ablation without the use of ICE. These efficiency improvements did not appear to negatively impact clinical effectiveness or safety of the ablation procedure.Conception and design: DF, LG, YI, LG, and SL. Collection and assembly of data: DF and LG. Data analysis and interpretation, manuscript writing and final approval of manuscript: All authors.Supporting informationClick here for additional data file.