Hepatocellular carcinoma (HCC) with portal vein tumor thrombus (PVTT) predicts a poor prognosis. The aim of the present study was to evaluate the efficacy and safety of using lenvatinib and camrelizumab combined with transarterial chemoembolization (TACE) to treat HCC with PVTT.This was a single‐arm, open‐label, multicenter, and prospective study. Eligible patients with advanced HCC accompanied by PVTT were enrolled to receive TACE combined with lenvatinib and camrelizumab. The primary endpoint was progression‐free survival (PFS), while the secondary endpoints included objective response rate (ORR), disease control rate (DCR), overall survival (OS), and safety.Between April 2020 and April 2022, 69 patients were successfully enrolled. With a median follow‐up time of 17.3 months, the median age of the patient cohort was 57 years (range: 49–64 years). According to modified Response Evaluation Criteria in Solid Tumors, the ORR was 26.1%  and the DCR was 78.3% . The median PFS (mPFS) and median OS (mOS) were 9.3 and 18.2 months, respectively. And tumor number >3 was identified as an adverse risk factor for both PFS and OS. The most common adverse events across all grades included fatigue (50.7%), hypertension (46.4%), and diarrhea (43.5%). Twenty‐four patients (34.8%) experienced Grade 3 toxicity that was relieved by dose adjustment and symptomatic treatment. No treatment‐related deaths occurred.TACE combined with lenvatinib and camrelizumab is a well‐tolerated modality treatment with promising efficacy for advanced HCC with PVTT. Patients with a clinical diagnosis of HCC based on histological examination or American Association for the Study of Liver Diseases (AASLD) guidelines, irrespective of PVTT types, were enrolled in this study. Other inclusion criteria were: (1) age 18–75 years; (2) at least one measurable lesion defined by modified Response Evaluation Criteriain Solid Tumors (mRECIST); (3) ECOG‐PS 0 or 1; (4) Child–Pugh score ≤7; (5) adequate cardiac, hepatic, renal, bone marrow, and hematologic function; and (6) predicted life expectancy >12 weeks. Key exclusion criteria included: (1) uncontrolled hypertension; (2) active autoimmune diseases; (3) combined with other untreated malignancies; (4) pregnancy or lactation; (5) HCC with complete portal vein trunk obstruction; or (6) prior history of systemic and locoregional therapy for PVTT. Although subjects were allowed to have extrahepatic tumor spread, brain metastases or complete obstructive invasion of the primary branches of the biliary duct need to be ruled out. PVTT type was defined by Cheng‘s classification, Type I refers to tumor thrombus distant to the second or second grade branch of the portal vein, Type II refers to tumor thrombus found in the left or the right branch of the hepatic portal vein, Type III refers to tumor thrombus in the main portal vein lumen, and tumor thrombus found in the superior mesenteric vein is Type IV.Written approval was obtained from the Institutional Review Board of Beijing Ditan Hospital, Capital Medical University before starting the study . The study was conducted in accordance with good clinical practice, with the principles outlined in the Declaration of Helsinki and local laws. All participants provided written informed consent prior to enrollment.2.2The prospective study was performed in three hospitals in Beijing from April 2020 to April 2022: Beijing Ditan Hospital, Capital Medical University; Beijing Youan Hospital, Capital Medical University; and The Fifth Medical Center of Chinese PLA General Hospital. According to the literature, the PFS of BCLC‐C HCCs treated with TACE combined with lenvatinib and ICIs is about 8 months, and the PFS of HCCs treated with TACE and lenvatinib is about 5 months. The PASS15.0 software was used, with α‐value = 0.05, β‐value = 0.1, time = 12 months, follow‐up = 12 months, and the calculated sample size = 64 cases.2.3TACE was performed by two professional radiologists, and all patients underwent lipiodol‐based TACE. The chemoembolization emulsion was prepared by mixing the chemotherapeutic drugs  with 6–10 mL of lipiodol and an appropriate amount of contrast medium through the catheter. Some patients with rich tumors or arteriovenous shunts had solid embolic agents (300–500 μm) such as gelatin sponge or polyvinyl alcohol particles until the artery supplying the tumor was occluded and the tumor staining disappeared. TACE was performed on demand, subsequent TACE would be repeated when viable lesions or incomplete lipiodol uptake of liver tumor were demonstrated on the test of computed tomography (CT) or magnetic resonance imaging (MRI). The interval of repeat TACE was 8–12 weeks. Lenvatinib was administered orally at 12 mg/day for patients weighing ≥60 kg and 8 mg/day for patients weighing <60 kg, starting 7 days before the first cycle of TACE after enrollment. The drug was stopped on the day of TACE. The first dose of camrelizumab 200 mg was given intravenously on day 5 ± 2 after the initial TACE procedure and then every 3 weeks (Q3W). Both of lenvatinib and camrelizumab were continued until disease progression or intolerable toxicity. Dose reductions or interruptions were permitted for drug‐related adverse events.2.4Efficacy assessments were performed every 8 weeks for the first 6 months and then every 12 weeks until disease progression or treatment discontinuation. Survival follow‐up was performed every 4 weeks until death, inability to follow‐up, or study completion. Tumor response was assessed according to mRECIST and classified as complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD). The initial tumor assessment was at week 8 based on radiographic images of contrast‐enhanced CT or MR. The best tumor response was recorded as the final results of evaluation. Progression‐free survival (PFS) was defined as the primary endpoint. The secondary endpoints included ORR, disease control rate (DCR), overall survival (OS), and safety. PFS was defined as the time from the date of the first dose of lenvatinib until disease progression or death from any cause. ORR was calculated as the percentage of patients with CR and PR. DCR was estimated as the percentage of patients with CR, PR, and SD. OS referred to the time from the start of treatment until death from any cause or last follow‐up. Safety was assessed and graded using CTC‐AE (Version 5.0).2.5T‐test or Mann–Whitney U‐test. Categorical variables were presented in frequencies (proportions) and compared using the chi‐square test or Fisher's exact test. PFS and OS were calculated by the Kaplan–Meier method and the differences between groups were assessed via the log‐rank test. A univariable and multivariable Cox proportional hazards model was used to predict prognostic factors for PFS and OS. A value of p < 0.05 was considered statistically significant.Statistical analysis was conducted using R version 4.0.5. Continuous variables were expressed as mean ± standard deviation or median (interquartile range) and analyzed using the 33.1n = 54), predominantly infected with hepatitis B virus (HBV) ; 72.5% of the patients had an ECOG PS score of 0 (n = 50). Eighteen (26.1%) patients had multiple tumors, and the median tumor diameter was 8 cm (ranging from 5.2 to 11.0 cm) in all cohorts. The number of patients with PVTT type I/II, and extrahepatic metastasis was 42 (60.9%), and 24 (34.8%), respectively. Alpha‐fetoprotein (AFP) was stratified at 400 ng/mL and 27 (39.1%) patients exceeded this cutoff. Most patients had good liver function, while 91.3% (n = 63) of patients had albumin–bilirubin (ALBI) class 1–2 and 60.9% (n = 42) had Child–Pugh Grade A.Between April 2020 and April 2022, a total of 81 HCC with PVTT were screened at three centers. Eight patients who had protocol violations  were excluded, and the remaining 73 participants received TACE combined with lenvatinib and camrelizumab. In addition, 3 patients were intolerant to treatment, 1 patient was lost to follow‐up, and finally 69 participants were enrolled, as shown in Figure 3.2p = 0.72) nor OS  was significantly different  and the median OS was 18.2 months . The Kaplan–Meier curves of PFS and OS are shown in Figure t Figure .The waterfall plot of changes in tumor size was assessed according to mRECIST criteria Figure : 18 (26.p = 0.006) was identified as an independent adverse factor for PFS  and tumor size ≥8 cm  were independent risk factors for death , which in turn regulates other pro‐angiogenic factors, such as VEGF.In addition, multiple tumors are closely related to patient recurrence and survival. In the above studies, HCC patients with >3 liver tumors could benefit more from TACE with lenvatinib.The safety profile of TACE combined with lenvatinib and camrelizumab observed in this study is consistent with the previously reported AEs of TACE, lenvatinib or camrelizumab alone.This study has several limitations, including the single‐arm design and the small sample size, which preclude more analysis and may bias toward patients who can benefit from the therapy. This study was conducted at three centers in Beijing, China but geographic variation in patients may affect treatment outcomes. Therefore, large‐scale multicenter prospective trials with randomized controls are needed for validation.5TACE combined with lenvatinib and camrelizumab achieved excellent efficacy in HCC patients with all types of PVTT. Importantly, the comprehensive therapy did not add other treatment‐related toxicities, and most adverse reactions could be controlled by dose adjustment and symptomatic treatment.Xiaomi Li: Data curation ; project administration ; writing – original draft . Xiaoyan Ding: Data curation ; project administration ; writing – original draft . Mei Liu: Data curation ; project administration ; writing – original draft . Jingyan Wang: Formal analysis ; writing – review and editing . Wei Sun: Formal analysis ; writing – review and editing . Ying Teng: Formal analysis ; writing – review and editing . Yawen Xu: Software ; supervision . Hongxiao Wu: Validation ; visualization . Wendong Li: Investigation ; methodology . Lin Zhou: Conceptualization ; project administration . Jinglong Chen: Conceptualization ; project administration .All authors declare no conflicts of interest.The study was conducted according to the guidelines of the Declaration of Helsinki, and approved by the Ethics Committee of Beijing Ditan Hospital, Capital Medical University (BJDT CMU IRB), (ethic code: JDLKZ 2021–003‐02).


Peripheral blood vessels in pigs are not easily accessible, making placement of intravenous catheters difficult. Alternative methods to intravenous administration of fluids, such as administering fluids via the rectum (proctoclysis), are warranted in pigs.Administration of polyionic crystalloid fluids via proctoclysis results in hemodilution changes similar to intravenous administration. The objectives of this study were to evaluate the tolerance for proctoclysis in pigs and compare analytes before and after intravenous or proctoclysis therapy.Six healthy, growing, academic institution‐owned pigs.0, T3, T6, T9, and T12. Effects of treatment and time on analytes were determined by analysis of variance.Randomized, cross‐over design clinical trial, with 3 treatments  with a 3‐day washout period. The pigs were anesthetized and jugular catheters were placed. A polyionic fluid (Plasma‐Lyte A 148) was administered at 4.4 mL/kg/h during the intravenous and proctoclysis treatments. Laboratory analytes, including PCV, plasma, and serum total solids, albumin, and electrolytes were measured over 12 h at T0 and T6 . Proctoclysis did not significantly affect any laboratory analytes at any time points (P > .05).Proctoclysis was tolerated by pigs. Albumin concentrations decreased during the IV treatment between TProctoclysis did not demonstrate hemodilution similar to intravenous administration of polyionic fluids. Proctoclysis might not be an effective alternative to the intravenous administration of polyionic fluids in healthy euvolemic pigs. Handling and restraining pigs for placement of intravenous catheters is challenging because pigs are excitable, might bite, and are usually unwilling to tolerate such manipulation. Although fractious sick pigs can be sedated or anesthetized for the placement of intravenous catheters, adverse outcomes associated with sedation or anesthesia, such as respiratory impairment including decreased ventilation, aspiration, or death, might occur. While orogastric or nasogastric administration of fluids is clinically valuable and safe for use in horses and ruminants, the method is not tolerated by awake pigs and is unsafe in anesthetized pigs. Therefore, effective and less stressful alternative methods to intravenous administration of fluids, such as administering fluids via the rectum (proctoclysis), are warranted in pigs.Proctoclysis is technically simple to perform and requires similar equipment as an enema. Except in scenarios where rapid fluid volume resuscitation is required, proctoclysis might be an inexpensive, safe, effective, and less stressful alternative to intravenous fluid administration. Proctoclysis is used effectively in rabbits,22.1The sample size was estimated to detect a change in PCV of at least 5%, using an anecdotal mean PCV of 30% in healthy pigs to 25%, after initiation of fluid therapy by either route, similar to studies in horses,A clinical trial with 6 healthy, growing pigs was performed. Five pigs were Yorkshire barrows, and 1 was a Hampshire gilt. The study was a cross‐over design with 3 treatments and a 3‐day washout period between treatments. The 3‐day washout was chosen based on the half‐life of crystalloid fluids in humans undergoing anesthesia and surgery.2.2Before placing catheters, feed and water were withheld from the pigs for 12 and 8 hours, respectively. Anesthesia was induced with a combination of tiletamine and zolazepam  administered intramuscularly. Anesthesia was maintained with isoflurane  dosed to effect (1%‐5%) and oxygen (4 L/min) using a mask. The pigs were monitored for depth of anesthesia by using a capnometer and monitoring of heart rate, respiratory rate, mucus membrane color, and capillary refill time by trained personnel. The pigs were positioned in dorsal recumbency, and the forelimbs extended caudally and secured on the surgical table with soft ropes. An area measuring 15 × 15 cm on the ventral and lateral left and right neck was clipped to expose the area over the jugular groove and aseptically prepared for the intravenous catheter placement. An over‐the‐wire 2‐ or 3‐port, 4 French × 13 cm, long‐term intravenous catheter  was placed in the right and left jugular vein as previously described.2.32.3.10) and 3 (T3), 6 (T6), 9 (T9), and 12 (T12) hours after the beginning of the treatment into a blood tube containing heparin as an anticoagulant . Blood was also collected in a tube containing no anticoagulant  at T0, T6, and T12 hours. Monitoring and sample collection procedures were the same among the 3 treatments.Feed and water were withheld from pigs for 12 hours during the treatment procedures. The feed and water withholding procedures for the pigs were the same for all 3 treatments. All wood shavings bedding was removed to prevent consumption by the pigs. When possible, feces were collected from the floor of pen and weighed during the treatment procedures. Respiratory rate, heart rate, and demeanor (agitation and restlessness) were monitored every 3 hours. Blood was collected at 0  was lubricated and inserted into the rectum. The length of the feeding tube inserted into the rectum ranged from 25 to 30 cm. The catheter was secured and taped to the pig's tail.Sterile polyionic crystalloid fluid  was administered continuously at 4.4 mL/kg/h for 12 hours using a fluid pump  and a coiled administration set . The dose rate of 4.4 mL/kg/h (2 × maintenance rate) was based on previous studies and recommendations in ruminants and pigs.2.3.3Intravenous administration of polyionic fluids was performed via 1 of the jugular venous catheters. The coiled administration set was secured on the back of the pigs with adhesive tape to prevent the pigs from chewing the set. Intravenous fluid type, administration rate, use of a fluid pump, and monitoring of fluid administration procedures were similar to fluid administration per rectum.2.3.40, T3, T6, T9, and T12 hours. Packed cell volume and plasma total solids were determined within 15 minutes after collection. Blood collected into tubes containing no anticoagulant at T0, T6, and T12 hours was centrifuged at 2800 × g, and serum was harvested. The serum was submitted to University of California Davis Veterinary Medical Teaching Hospital Clinical Pathology laboratory to determine serum total solids, sodium, chloride, ionized magnesium, potassium, blood urea nitrogen, creatinine, and albumin using a chemistry analyzer  within 12 hours after collection. Serum total solids, albumin, creatinine, and blood urea nitrogen measurements were measured because these analytes might be altered with hemodilution or hemoconcentration. Sodium, chloride, ionized magnesium, and potassium concentrations were measured because these electrolytes are present in Plasma‐Lyte A 148.The PCV and plasma total solids were measured using a microhematocrit reader  and an optic refractometer  from samples collected in tubes with heparin as an anticoagulant collected at T2.4The Shapiro‐Wilk test was used to test the data for normality. Mean ± SD was reported when data were normally distributed, whereas median (range) was reported when data were not normally distributed. Descriptive data, including body weight, dropout rate, and complications associated with the treatment procedures, were reported.P < .05 was considered significant.The effect of treatment  and time on clinical laboratory analyte measurements were compared using a 2‐factor repeated measures of analysis of variance (ANOVA). In the analysis of variance, treatment and time were considered fixed effects, whereas the subject (pig) was considered a random effect. When differences were present among treatments or time points, post hoc analysis was performed using the Tukey test. Because multiple analytes concentrations were determined from every sample collected, a 2‐factor multiple analysis of variance (MANOVA) was also performed to compare to the results of the ANOVA. In the MANOVA, treatment and time were also considered fixed effects, whereas the subject (pig) was considered a random effect. Interactions between treatment and time were considered for ANOVA and MANOVA analyses. Commercial statistical software was used to analyze the data . 33.1Actinobacillus spp., presumably secondary to catheter site infection, based on necropsy findings. Both intravenous catheters from the pig that was euthanized required a replacement after the first treatment (day 6 after the beginning of the procedures).Data were normally distributed; therefore, mean ± SD was reported. All pigs were considered healthy before treatment based on clinical examination, CBC, and serum biochemical analysis. The mean ± SD weight for the pigs was 43.1 ± 5.7 kg. The mean duration from induction of anesthesia with tiletamine‐zolazepam to full recovery  from anesthesia was 4 hours. Assuming a half‐life of 4 hours for Plasma‐Lyte A,All pigs subjectively tolerated proctoclysis (median score 0), and no consistent agitation, restlessness, or straining to remove the red rubber tubing inserted in the rectum was observed during the procedures. There was minimal external leakage (<2 mL) of administered fluid per rectum. One (59.1 g), 2 , and 5 pigs  defecated during the RECT, CONT and IV treatment procedures, respectively. It was difficult to collect feces from pigs under proctoclysis when leakage was observed because of the liquid consistency. Due to the inconsistency of fecal output and difficulty in weighing feces during proctoclysis, further comparison of fecal output among treatments was not performed.3.23.2.1P = .006) and interactions between treatment and time (P = .03) had a significant effect on albumin concentrations. Albumin concentrations at T6 were lower than T0  for the IV treatment. Albumin concentrations were not significantly different between any time points for the RECT treatment (P > .05); concentrations were 3.7, 3.7, and 3.7 g/dL at T0, T6, and T12, respectively. Similarly, albumin concentrations were not significantly different (P > .05) at any time point for the CONT treatment; concentrations were 3.9, 4.0, and 4.1 g/dL at T0, T6, and T12, respectively. Time had no significant effect (P = .09) on albumin concentrations. The analysis of variance model (fixed effects) for albumin concentrations as a function of treatment, time, and interaction between treatment and time is summarized in Table Treatment (P = .09), time (P = .99), and interactions between treatment and time (P = .42) had no significant effect on the PCV. Treatment (P = .09), time (P = .31), and interactions between treatment and time (P = .09) had no significant effect on plasma total solids. Time had a significant effect on serum total solids (P = .009), with total serum solids lower at T6 than at T0 . In contrast, time had no significant effect (P > .05) on serum total solids concentrations between T0 and T12  or T6 and T12 . Treatment (P = .13) or interactions between treatment and time (P = .06) had no significant effect on serum total solids. Packed cell volume, plasma total solids, and serum total solids concentrations for the CONT, IV, and RECT treatments at different time points are summarized in Table Treatment . Sodium concentrations for RECT treatment were lower than the IV treatment . Time (P = .57) or interactions between treatment and time (P = .40) had no significant effect on sodium concentrations. Treatment (P = .06), time (P = .79), and interactions between treatment and time (P = .97) had no significant effect on chloride concentrations. Treatment (P = .81), time (P = .48), and interactions between treatment and time (P = .53) had no significant effect on ionized magnesium concentrations. Treatment (P = .22), time (P = .51), and interactions between treatment and time (P = .31) had no significant effect on potassium concentrations.Treatment had a significant effect on sodium concentrations (P = .46) and interaction between treatment and time (P = .09) had no significant effect on creatinine concentrations. In contrast, time (P = .0007) had a significant effect on creatinine concentrations. Creatinine concentrations at T6 were lower than at T0 . Treatment (P = .87) had no significant effect on blood urea nitrogen concentrations. In contrast, time (P = .03) and interactions between treatment and time (P = <.0001) had a significant effect on blood urea nitrogen concentrations. Blood urea nitrogen concentrations at T12 were lower than T0 . Blood urea nitrogen concentrations at T6  and T12  were lower than at T0 for the IV treatment. The concentrations of sodium, chloride, ionized magnesium, potassium, creatinine, and blood urea nitrogen for the CONT, IV, and RECT treatments at different time points are summarized in Table Treatment P = .6 and int46 compared to T0 with the IV treatment, consistent with hemodilution. In horses, a reduction in albumin concentrations after 6 hours was reported only with intravenous administration of fluids but not with proctoclysis,Continuous fluid infusion per rectum did not significantly affect serum biochemical analytes compared to intravenous administration of fluids in healthy pigs. Our results suggest that hemodilution due to the absorption of fluids from the rectal or distal colonic mucosa was not evident, inconsistent with our hypothesis. In contrast, serum albumin concentrations significantly decreased at TThe rectum in pigs is <5 cm in length, whereas the entire colon measures 5 m in length.The anatomy of the colon in pigs is comparable to humans,0 and T6 but not between T6 and T12. A possible reason for this might be that the pigs enrolled in our study were healthy; therefore, normal physiological responses, such as increased fluid loss via urination, compensated for the hemodilution observed between T0 and T6. The significant effect of time on serum total solids, creatinine, and blood urea nitrogen or the higher sodium concentrations in the IV compared to the RECT treatments are of minimal practical clinical significance.A significant difference in the albumin concentrations for the IV treatment was detected between TThe pigs tolerated proctoclysis, and no complications associated with proctoclysis were recorded during the procedures. It is essential to note the intravenous catheter site infection associated with sepsis and endocarditis that we reported in 1 pig. The replacement of both catheters in this animal likely increased the likelihood of catheter site infection.Although routinely performed in our clinical practice when venous access is unsuccessful, our study results suggest that proctoclysis does not demonstrate hemodilution comparable to the intravenous administration of polyionic fluids in healthy pigs. Despite being tolerated well in pigs, proctoclysis using polyionic fluids at a rate of 4.4 mL/kg/h might not be a sufficient alternative to the intravenous administration of fluids.Our study limitations include a lack of performing a urinalysis. Urine collection was not performed because of the difficulty in maintaining urine collection bags in pigs for 12 hours; Despite removing all bedding, the pigs were observed chewing on the metal fencing on the pens while feed and water were withheld. Therefore, the pigs were likely to chew the urine collection bags. The scoring system adaptation described in our study was subjective, not validated, and the reliability of the scale is unknown. No further analysis of the scoring system analysis such as ordinal regression was performed because of the small sample size.5Pigs tolerated proctoclysis with a polyionic fluid, but the changes in analytes consistent with hemodilution were absent. Our results suggest that proctoclysis might not be an effective alternative to the intravenous administration of polyionic fluids in healthy, euvolemic pigs.Munashe Chigerwe serves as Associate Editor for the Journal Veterinary Internal Medicine. He was not involved in review of this manuscript. No other authors declare a conflict of interest.Approved by the University of California, Davis IACUC, protocol: #21935.The authors declare that human ethics approval was not needed for this study.


The study aimed to collect and compare clinical and laboratory findings of children with severe and nonsevere COVID‐19 in Kermanshah City, located in the west of Iran.The study was conducted on 500 children with COVID‐19 hospitalized in Mohammad‐Kermanshahi Hospital in Kermanshah City. Pediatric COVID‐19 was confirmed by reverse transcription‐polymerase chain reaction (RT‐PCR) test using respiratory secretion samples. Medical records were reviewed and information related to demographic characteristics, underlying diseases, clinical manifestations, laboratory findings, and chest computed tomography (CT) scans were all extracted from electronic and paper records. Patients were divided into three groups according to the severity of the disease: mild, moderate, and severe. Clinical and laboratory findings were compared between the groups and the collected data were analyzed by statistical methods.Out of 500 patients, 286 were boys and 214 were girls. Of the patients, 321 cases were only COVID‐19, while 179 patients were diagnosed as Multisystem Inflammatory Syndrome in Children (MIS‐C) positive. The average age of COVID‐19 patients was 3.85 ± 4.48 and of MIS‐C patients was 3.1 ± 3.5. In order, fever, cough, and heart disorders were the most common symptoms in patients with COVID‐19 and MIS‐C, respectively. In terms of disease severity, 246 patients had mild disease, 19 patients had moderate disease, and 56 patients had severe disease. In severe patients, the average number of white blood cells (WBC) was higher, while the average number of lymphocytes was lower. Also, in these patients, the average age was lower, and most of them had respiratory distress. In mild patients, often cough, diarrhea, and vomiting were observed.The results of our study showed that laboratory factors such as WBC count, lymphocyte count, CT findings, Respiratory distress, cough, diarrhea, and vomiting can be used to evaluate the severity of COVID‐19 in children. Inclusion criteria included age less than 18 years and a positive result of the COVID‐19 reverse transcription‐polymerase chain reaction (RT‐PCR) test of respiratory secretions obtained through the nasopharyngeal or oropharyngeal swab. Exclusion criteria included incomplete clinical/laboratory data and diagnosis of other pulmonary infections.Medical records were reviewed and all data related to laboratory findings and other information including demographic characteristics, disease severity, date of onset of symptoms, date of diagnosis, the history of contact with COVID‐19 patients, date of hospitalization, and clinical outcome were extracted. Information on underlying diseases, clinical manifestations , laboratory findings , and chest CT scans were all extracted from electronic medical records.The patients included in the study were classified into three groups according to the severity of the disease. Severity was defined according to the report provided by the new coronavirus pneumonia prevention and control program (6th edition) published by the National Health Commission of China.The study was approved by the Institutional Review Board and Ethical Committee of Kermanshah University of Medical Sciences .2.1t test/Mann–Whitney U test. Categorical variables were presented as counts (percentages) and analyzed with Fisher's test. All tests were two‐sided and p < 0.05 was considered statistically significant.All analyses were done using SPSS software version 23.0. The normality distribution of the data was checked using the Kolmogorov–Smirnov test. Continuous variables were presented as mean ± standard deviation and analyzed using an independent 3In total, out of 500 children with suspected COVID‐19 and/or MIS‐C disease hospitalized in Mohammad‐Kermanshahi Hospital, 286 patients (57.2%) were boys and 214 patients (42.8%) were girls. The average age of the patients was 3.85 ± 4.48 years. In terms of age distribution, 146 patients (29.2%) were under 1 year old, 223 patients (44.6%) were between 1 and 5 years old, 103 patients (20.6%) were between 6 and 12 years old, and 28 patients (5.6%) were 12 years old and older.Out of 500 patients, 321 (64.2%) were COVID‐19 patients and 179 (35.8%) were MIS‐C cases. Clinical manifestations and laboratory findings in patients with COVID‐19 and MIS‐C are presented in Tables In terms of laboratory factors, the average white blood cells (WBC) and D‐dimer were higher in patients with MIS‐C compared with COVID‐19 patients.The COVID‐19 patients 321 cases) were classified according to the severity of the disease as follows: 246 cases (76.6%) were mild, 19 cases (5.9%) were moderate, and 56 cases (17.4%) were severe. Critical diseases was not observed in any of the pediatrics. The comparison of clinical and laboratory characteristics based on the severity of the disease is presented in Tables 21 cases p = 0.001).A significant difference was observed between the severe and mild groups in terms of age, The average age children in the severe group (2.3 ± 4.3) were significantly longer had a lower than in mild patients (4 ± 4.35) (p = 0.001).The mean hospitalization days in severe patients (5.3 ± 4.2 days) were significantly longer than in mild patients (3.4 ± 3 days)  .The findings obtained from the chest CT scan according to the severity of the disease are presented in Table In patients with MIS‐C, a chest X‐ray was performed on 36 patients, 15 of whom had abnormal symptoms and 21 had no symptoms.Antiviral anticoagulant drugs used in patients included aspirin (ASA) in 168 patients (33.6%), IVIG in 71 patients (14.2%), prednisolone in 190 patients (38%), enoxaparin in 30 patients (6%), and remdesivir in 24 patients (4.8%).The sensitivity and specificity indices for a number of variables to predict the severity of the disease are shown in Table 4Considering the limited information on the clinical characteristics and laboratory findings of COVID‐19 in children, here we conducted a retrospective study of COVID‐19 in people less than 18 years of age in Kermanshah City. In our study, most children (44.6%) were in the age group of 1–5 years. Similarly, in the Martinez‐Garcia study, the 1–5‐year‐old group had the highest prevalence of COVID‐19 compared with other children.Previous studies showed that the clinical symptoms in infants under 1 year were more severe than in other children's age groups.The findings of our study showed that boys are slightly more affected by COVID‐19 disease, so that the COVID‐19 incidence rate in boys was 57.2% and in girls was 42.8%. Similar to our study, other studies reported more COVID‐19 cases in boys.A history of contact with family members who were infected with COVID‐19 or going to an epidemic area are among the causes of the disease spread in children.In children, the clinical course of COVID‐19 is mild and has a wide clinical spectrum.In our study, decreased sense of smell and taste was not seen in any of the patients. These symptoms are usually less investigated in children. In Goktug et al.'s study, there was a loss of smell in 3.5% and a loss of taste in 4.3%, and all patients were over 10 years old.In the severe group, higher chest pain, respiratory distress, breathing rate, pulse rate, underlying disease, cardiac involvement, oxygen therapy, longer hospitalization time, and lower oxygen saturation percentage were observed. In the mild group, cough, diarrhea, and vomiting were more prevalent. Similar to our study, the results of Hosseini Yazdi et al.'s study also showed that patients in the severe group had longer hospital stays and lower oxygen saturation than nonsevere respiratory distress patients.In the present study, the inflammatory markers of CRP and ESR were not predictive factors for the severity of the COVID‐19 disease. In the study of Najafinejad et al., like our study, half of the people with COVID‐19 had positive CRP, but no correlation was observed between CRP and the severity of the disease.3/µL) was 13.8 and 10.16 in MIS‐C and COVID‐19 patients, respectively. Compared with COVID‐19 patients, the amount of D‐dimer was higher in MIS‐C patients. In the study by Yasuhara et al., patients with MIS‐C usually had cardiac involvement, elevated inflammatory markers, gastrointestinal symptoms, and skin manifestations.Studies reported that COVID‐19 is more common in younger children and children with respiratory dysfunction. However, patients with MIS‐C who often present with cardiac dysfunction and gastrointestinal symptoms do not have a specific underlying disease.Antiviral treatments and supportive care are essential for patients with COVID‐19.In our study, the death rate was eight cases (1.6%). Using the data of the national COVID‐19 registry for all positive COVID‐19 cases in Iran, Madani et al. reported a 5.3% mortality rate in people under the age of 18 from January 2020 to October 2020.Among the limitations of this study, the following can be mentioned: (1) This study only included a short 3‐month observational design with a retrospective nature, (2) The information was based on patient records and there was some missing data, (3) CT scan and imaging was only performed in a few patients and these results cannot reflect the results of all patients, (4) Not all the laboratory tests were performed in all patients.5The results of our study showed that laboratory factors such as WBC count, lymphocyte count, CT findings, Respiratory distress, cough, diarrhea, and vomiting can be used to evaluate the severity of COVID‐19 in children.Fatemeh Nemati Zargaran: Data curation; writing—original draft. Mosayeb Rostamian: Writing—original draft. Saeed Alimoradi: Data curation. Shahab Rezaeian: Formal analysis; software. Etrat Javadirad: Writing—review and editing. Roya Chegene Lorestani: Data curation; writing—original draft; writing—review and editing. Hajar Motamed: Writing—review and editing. Mahtab Hasanpourshahlaei: Data curation. Elham Rostami: Data curation. Keyghobad Ghadiri: Conceptualization; Writing—review and editing.The authors declare no conflict of interest.The lead author Keyghobad Ghadiri affirms that this manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned  have been explained.Supporting information.Click here for additional data file.


Systemic lupus erythematosus (SLE) is a multisystem autoimmune disorder exhibiting variable disease courses and multiple clinical manifestations. SLE's aetiology remains unclear; however, different environmental , genetic, and hormonal factors are potentially involved. A positive family history and history of having other autoimmune illnesses are considered high‐risk factors for SLE; nevertheless, most SLE cases are scattered. The 2019 European League Against Rheumatism/American College of Rheumatology classification criteria for SLE include at least one positive antinuclear antibody test as a mandatory entry criterion, followed by additive weighted standards grouped in seven clinical  and three immunological  domains weighted from 2 to 10, with patients accumulating ≥10 points being diagnosed with SLE. Herein, we report a case of neuropsychiatric lupus, a rare and severe form of SLE. Main steps at the management of a 16‐year‐old girl with history of neuropsychiatric lupus. Furthermore, the patient exhibited a photosensitive malar rash, alopecia, lymphadenopathy, and thyroid nodules. Other neurological examination findings were normal, and examination of other systems also revealed no other abnormalities. Investigations yielded the following: a complete blood count decrease in white blood cells [2700/µL (4.1–11.6)], an increase in monocytes [14.4% (3.8–11.2)], a normal red blood cell count, and a normal haemoglobin level. Liver function testing revealed a mild elevation of the alanine aminotransferase level [44 (0–40)] and a normal albumin level, while other findings were normal. Kidney function testing yielded creatinine and urea levels of 33 µmol/L (44–80) and 1.95 mmol/L (2.1–7.1), respectively, while other findings were normal. Urine analysis revealed negative blood, protein, and glucose results, and other findings were normal. The erythrocyte sedimentation rate was 7 mm/h (0–20), C‐reactive protein was positive, and rheumatoid factor and anti‐cyclic citrullinated peptide were negative. Antiphospholipid, anti‐SM, and anti‐RNP antibodies were negative. However, anti‐dsDNA antibodies were positive [81.7 IU/mL (positive >35)]. C3 and C4 complement levels were 90 mg/dL (90–180) and 12 mg/dL (12–40), respectively. Thyroid function testing revealed a mild decrease in free thyroid hormone 3 as well as normal thyroid‐stimulating hormone and free thyroid hormone 4 levels. Electrocardiography showed sinus tachycardia. Brain magnetic resonance imaging (MRI) revealed prominent sulci, mainly of the Sylvian fissure; corpus callosum atrophy; and bilaterally prominent temporal horns with relatively symmetrical increased fluid‐attenuated inversion recovery signal intensities of both hippocampal formations  antibody positivity. s Figure . Thyroid2.1The patient commenced SLE treatment on December 30, 2020, 2 months after initial symptom onset. The patient was initially administered pulse steroid (1000 mg of methylprednisolone) daily for 5 days, followed by oral prednisone 60 mg daily. Subsequently, the patient was administered Plaquenil 400 mg PO OD and cyclophosphamide 2 mg/kg PO OD as well as phenytoin as an antiepileptic medication. However, the patient developed an allergic reaction to phenytoin and was consequently shifted to levetiracetam, became increasingly agitated, and was gradually shifted to Lamictal 25 mg PO BID while being weaned off levetiracetam, thus resolving the agitation. The patient was prescribed Bisoprolol 5 mg PO BID for sinus tachycardia. After 3 months, the patient's medical situation improved, with no more seizures or psychosis. On June 8, 2021, cyclophosphamide was discontinued, CellCept 1000 mg PO BID was commenced, and the steroid dose was gradually reduced to 15 mg PO OD. Since the patient was on steroids, her weight increased, and her lipid profile revealed an increase in total cholesterol and low‐density lipoprotein levels; therefore, she was prescribed atorvastatin and provided with dietary advice. The patient's thyroid‐antibody test result was negative; hence, fine needle aspiration of the thyroid was recommended to check for malignancy, and the biopsy results were unremarkable for malignancy. By the 2nd of March 2022, the patient was on prednisolone 5 mg PO OD, CellCept 1000 mg PO BID, Plaquenil 400 mg PO OD, atorvastatin 10 mg PO OD, Lamictal 25 mg PO BID, Bisoprolol 5 mg PO PD, and Ca and vitamin D tablets. The patient presented no active complaints and appeared to fare well.2.2Based on clinical, laboratory, and radiological findings, the diagnosis is SLE manifested primarily with neuropsychiatric symptoms. Lumbar puncture, which had previously been performed, revealed normal cyto‐biochemical markers. Cerebrospinal fluid bacteriological, mycological, and mycobacteriological cultures that had previously been conducted came out negative. On March 7, 2022, the patient was followed up with MRI and electroencephalography (EEG) as well as anti‐dsDNA and C3 and C4 complement assessments. MRI revealed similar changes to those that had initially been observed, with mild signal reductions. Follow up EEG which was done later after recovery revealed no abnormal brain activity. The anti‐dsDNA antibody level decreased to 1.9 IU/mL compared with its initial value of 81.7 IU/mL. The C3 and C4 levels increased to 135 and 26 mg/dL compared with their initial values of 90 and 12 mg/dL, respectively. The patient has been undergoing regular follow‐up with neurology and rheumatology teams. The plan is to taper down the patient's steroid dose to zero. The neurology team will monitor the patient to adjust her antiseizure medication. The patient developed morbid obesity (body mass index >40) and became a candidate for obesity management; therefore, the obesity team will monitor her. Moreover, the patient will also be closely monitored by the rheumatology team for any disease reactivation and medication adjustment.3This case's diagnosis was initially difficult to establish because the main symptoms of central nervous system (CNS) lupus can be diffuse  or focal .4Continued efforts to further elucidate the pathologic mechanisms underlying various manifestations of SLE and neuropsychiatric features are ongoing to aid in diagnosing and treating neuropsychiatric SLE. In our patient, the combination of clinical features, radiological findings, and positive immunological titres facilitated diagnosis. The patient's symptoms and response to treatment along with her laboratory findings improved, thus ensuring us that we were on the right track. Further studies are obligatory to help rheumatologists appropriately deal with and manage patients with CNS lupus.Abdulrahman Ali M. Khormi: conceptualization; formal analysis; investigation; project administration; resources; supervision; visualization; writing—original draft; writing—review & editing. Faisal Taher Hijazi: data curation; methodology; resources; writing—review & editing.The authors declare no conflicts of interest.The patient consented to the publishing of this case report.


As a complex and acute brain dysfunction, if postoperative delirium (POD) occurs in the postoperative period, it will lead to a prolonged length of stay in the critical care unit, with increased hospitalization costs and higher mortality. A few case reports inspired us to pay close attention to pituitary tumor‐associated delirium. We hypothesized that the changes in hormone levels after pituitary tumor resection might be associated with POD occurrence.Retrospective analysis was performed on data from a single‐center cohort study conducted at Southwest Hospital between January 2018 and May 2022. A total of 360 patients with pituitary tumors who underwent endoscope‐assisted transsphenoidal pituitary tumor resection were divided into two groups at a 1:3 ratio, with 36 patients in the POD group and 108 patients in the non‐POD group matched by propensity score, age, sex, and tumor size. Basic characteristics, pituitary adenoma features, endocrine levels and other biochemical indicators, and Confusion Assessment Method for the Intensive Care Unit (CAM‐ICU) for postoperative delirium were documented for further analysis.p = .024) and corticotropin‐releasing hormone  levels were closely associated with postoperative delirium and with high levels of blood glucose  after surgery. Subsequent analysis indicated that serum potassium , sodium , CRH , and GLU  levels in the perioperative period were independent risk factors for delirium.Lower insulin‐like growth factor‐1  after surgery. Logistic regression analysis indicated that serum potassium , serum sodium levels , CRH levels , and blood glucose  in the perioperative period were independent risk factors for delirium. In accordance with the progress of neuroendoscopy technology, endoscope‐assisted transsphenoidal surgery for pituitary tumors and other basicranial tumors has led to more radical excision with fewer complications. A recent meta‐analysis showed that the most frequently reported postoperative complications included cerebrospinal fluid leakage (12.8%), diabetes insipidus (12.8%), postoperative hypopituitarism (9.2%), and secondary hematoma (8.5%) . Informed consent to participate was waived due to the observational nature of the study. This study was conducted in accordance with the ethical guidelines of the Helsinki Declaration and reported in accordance with the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) checklist.We retrospectively enrolled all patients with pituitary tumors admitted to the Department of Neurosurgery, Southwest Hospital between January 2018 and May 2022. The present study was approved by the Ethics Committee of Southwest Hospital of Army Medical University (No. (B)KY2021035) and registered in the Chinese Clinical Trial Registry  age ≥ 18 years old, no sex limitation; (2) pituitary adenoma confirmed by preoperative magnetic resonance imaging (MRI), endocrinology and postoperative pathology and treated by endoscope‐assisted transsphenoidal pituitary tumor resection; (3) GCS score ≥12 on admission; (4) no history of intracranial surgery; and (5) stay in the NICU > 24 h.Exclusion criteria: (1) previously diagnosed with Alzheimer's disease or other cognitive impairments; (2) communication difficulties, such as speech impairment or language barrier; (3) schizophrenia history or routine use of antipsychiatry drugs; (5) unable to complete delirium assessment due to coma or other reasons; (6) autoimmune diseases, glucocorticoid therapy or use of other hormone drugs; (7) preoperative upper respiratory infection; and (8) patients with unstable vital signs or hemodynamics after surgery.2.2The diagnostic criteria for postoperative delirium according to The Diagnostic and Statistical Manual of Mental Disorders, published by the American Psychiatric Association, are as follows: (1) altered mental status represented by a change from baseline or fluctuations in the previous 24 h; (2) inattention; (3) altered consciousness; and (4) disorganized thinking. Postoperative delirium can be diagnosed if the patient has both (1) and (2), plus (3) or (4)  Training Manual performed the delirium evaluation by using the CAM‐ICU Worksheet and Flowsheet (Mandarin Version)  and 108 patients in the non‐POD group. The flow diagram of cohort matching is also illustrated in Figure 2.4We retrieved the characteristics and clinical data of those matched cohorts via medical records, categorized as (1) basic characteristics, including age, sex, length of stay, operation duration; (2) pituitary adenoma features, including pituitary adenoma classification and size, invasive or not; (3) endocrine levels, including thyroid‐stimulating hormone (TSH), thyroxin (T4), insulin‐like growth factor‐1 (IGF‐1), growth hormone (GH), blood prolactin (PRL), follicle‐stimulating hormone (FSH), estradiol (E2), testosterone, progesterone, adrenocorticotropic hormone (ACTH), and plasma cortisol; (4) other biochemical indicators, including blood sodium, blood potassium, blood glucose, blood chlorine, albumin; and (5) CAM‐ICU for postoperative delirium, intensive care delirium screening checklist (ICDSC) and Richmond agitation‐sedation scale (RASS) for severity of delirium.2.5t test or the Mann‒Whitney U test. Regression analysis dominantly considered the variables with significant differences in two‐group comparisons. p < .05 was regarded as statistically significant, and SMD < 0.1 was considered to indicate that the difference between two groups could be ignored.The 1:3 propensity score match was performed by R version R 4.2.1  on the enrolled subjects via the nearest‐neighbor method without replacement, and the caliper value was set as 0.2 Figure . The dat33.1p = .604, 0.190, 0.729, Table The difference in tumor size between the delirium and nondelirium groups could not be ignored before propensity score matching (PSM), and the standard mean difference (SMD) was 0.249. However, there was an obvious decrease in the SMD value and no significant differences in age, female sex, or tumor size between the two matched groups  score at discharge, and all the enrolled subjects scored 0 or 1. Thus, we regarded patients with a mRS score = 1 as having a poor prognosis. A larger proportion of postoperative delirium patients had a poor prognosis at discharge than those without delirium , corticotropin‐releasing hormone (CRH), insulin‐like growth factor 1 (IGF‐1), growth factor (GH), prolactin (PRL), follicle‐stimulating hormone (FSH), estradiol (E2)) were compared between the delirium and nondelirium groups. The results showed that compared to the delirium group, patients without delirium had a higher secretion of IGF within 72 h of surgery, as well as CRH after 72 h of surgery . Conversely, the GLU level in the blood of the delirium group was higher than that in the nondelirium group 72 h after surgery . The two‐group comparisons of other variables showed no significant difference , serum chloride ion, serum potassium ion, serum sodium ion, glucose (GLU)) and hormonal variables , tetraiodothyronine T, corticop = .038), serum sodium ions within 72 h of surgery , GLU after 72 h of surgery , and CRH after 72 h of surgery  might be associated with the occurrence of delirium. Therefore, based on the above results, multivariate analysis confirmed that the elevation of GLU 72 h after surgery  independently increased the risk of delirium in postoperative pituitary adenoma patients  after surgery. Logistic regression analysis indicated that serum potassium and sodium levels and blood glucose levels in the perioperative period were independent risk factors for delirium.Postoperative delirium is one of the most severe complications after surgery, with an acute confusion status characterized by inattention, cognitive dysfunction and an altered consciousness. It has been reported that delirium is an independent risk factor for the subsequent development of dementia .The present study was registered in the Chinese Clinical Trial Registry (https://publons.com/publon/10.1002/brb3.3041.The peer review history for this article is available at Supplemental Figure S1. Comparison of the standard mean difference of baseline data before and after propensity scoring matching.Click here for additional data file.


Emerging evidence has shown that leukocyte telomere length (LTL) is associated with various health‐related outcomes, while the causality of these associations remains unclear. We performed a systematic review and meta‐analysis of current evidence from Mendelian randomization (MR) studies on the association between LTL and health‐related outcomes. We searched PubMed, Embase, and Web of Science up to April 2022 to identify eligible MR studies. We graded the evidence level of each MR association based on the results of the main analysis and four sensitive MR methods, MR‐Egger, weighted median, MR‐PRESSO, and multivariate MR. Meta‐analyses of published MR studies were also performed. A total of 62 studies with 310 outcomes and 396 MR associations were included. Robust evidence level was observed for the association between longer LTL and increased risk of 24 neoplasms , six genitourinary and digestive system outcomes of excessive or abnormal growth, hypertension, metabolic syndrome, multiple sclerosis, and clonal hematopoiesis of indeterminate potential. Robust inverse association was observed for coronary heart disease, chronic kidney disease, rheumatoid arthritis, juvenile idiopathic arthritis, idiopathic pulmonary fibrosis, and facial aging. Meta‐analyses of MR studies suggested that genetically determined LTL was associated with 12 neoplasms and 9 nonneoplasm outcomes. Evidence from published MR studies supports that LTL plays a causal role in various neoplastic and nonneoplastic diseases. Further research is required to elucidate the underlying mechanisms and to bring insight into the potential prediction, prevention, and therapeutic applications of telomere length. This systematic review and meta‐analysis found that genetically determined telomere length was robustly associated with increased risk of neoplasms, hypertension, metabolic syndrome, multiple sclerosis, and clonal hematopoiesis of indeterminate potential and decreased risk of coronary heart disease, chronic kidney disease, rheumatoid arthritis, juvenile idiopathic arthritis, idiopathic pulmonary fibrosis, and facial aging. The following search items were used: “telomere” OR “telomere length” OR “leukocyte telomere length” OR “LTL” for the exposure and “Mendelian randomization” OR “instrumental variable analysis” for the study design. Detailed search strategy is shown in Supplementary Method. We also identified potentially eligible studies according to the reference lists of included studies and relevant reviews.Studies to be included needed to (1) use MR; (2) use LTL as the exposure; and (3) measure the causal association between the exposure and one or more health‐related outcomes. Studies met any of the following criteria were excluded: (1) nonhuman studies; (2) conference abstracts, editorials, or reviews; (3) not written in English or Chinese; or (4) full text was not available. If more than one study reported the same outcome in the same population, we included the one with the most participants.All articles were exported to Endnote  after the literature search and duplicated records were removed. Two independent reviewers (BC and YY) assessed the articles according to the inclusion and exclusion criteria, and any disagreement was arbitrated by a third reviewer (HW). Articles were first selected by titles and abstracts and then full texts.2.2p value  for the main and sensitive analyses, data source, ancestry, and quality‐associated information .One author (BC) extracted the information from each article and assessed the quality of included studies, and the extracted information and quality assessment were checked by two authors (YY and HW). The following information was extracted and filled into the predefined tables: the family name of the first author, year of publication, study design , the number of instrumental variables, sample size (exposure and outcome), exposure (longer or shorter telomere length), health‐related outcome, analysis for effect estimation, odds ratio (OR) or hazard ratio (HR) per 1 standard deviation (SD) increase in telomere length with 95% CI and There are no formal tools for the assessment of the risk of bias for MR studies. The quality of studies included in the current systematic review was discussed according to the main analysis to estimate the effect size of telomere length on health‐related outcomes as well as the tests of three key assumptions of each MR study.2.3p value threshold was used. For the sensitive analysis, p value of 0.05 was considered significant. An MR association was graded non‐evaluable when only the main analysis was performed. For evaluable associations, when all the methods achieved statistical significance and the direction of the effect sizes were concordant, the evidence level was graded robust. When at least one method achieved statistical significance and the direction of the effect sizes were concordant, the evidence level was graded probable. When at least one method achieved statistical significance and the direction of the effect sizes were not concordant, the evidence level was graded suggestive. When none of the methods achieved statistical significance, the evidence level was graded insufficient. We also performed an additional grading by excluding the MR Egger method from the analysis due to the low power.We evaluated the evidence level for causality through the criteria raised by Markozannes et al. . Briefly2.4I2 test. I2 < 25%, between 25% and 50%, between 50% and 75%, and >75% was considered low, mild, moderate, and high heterogeneity, respectively. p‐Values were corrected for multiple testing via false discovery rate (FDR). FDR‐corrected p < 0.05 was considered statistically significant.Stata  software was used to perform meta‐analysis of included MR associations. ORs per 1 SD increase in telomere length with 95% CIs for each health‐related outcome were pooled using a random‐effect model. Only the outcomes reported by two or more studies and with the same ancestry were analyzed. Associations with overlapping population were not pooled. Because there were no restrictions on validation for the key assumptions of MR, we performed sensitivity analyses by removing studies that did not select instrumental variables from GWAS, studies without tests for horizontal pleiotropy, or studies with evidence of pleiotropy. The heterogeneity between studies was determined by 33.1The initial search yielded 1245 records, of which 954 remained after removing duplicates. Sixty‐two MR studies with 310 outcomes were enrolled in the systematic review and 52 outcomes were included in the meta‐analysis  used summary‐level MR approach, 26 (41.9%) studies used individual‐level approach, and 15 (24.2%) studies used both individual‐level and summary‐level MR approaches. The first MR study was published in 2012, while the majority were published after 2019 . Most studies  included participants of European ancestry, while the remaining studies included East Asian (or Asian), Black, Hispanic, or mixed individuals. One study did not state the ancestry of participants.−8 in most studies, while several studies did not report the significance level. F‐statistics were reported in 19 studies (30.6%), which were all above 10 except 1, indicating the presence of weak instrument bias. All the individual‐level MR studies adjusted for potential confounders, while 29 (56.9%) of the summary‐level MR studies did not report the adjustment. However, this did not mean the violation of the second assumption, because covariates might have been adjusted in the GWASes of outcomes and genetic instruments are not susceptible to potential confounders due to the random allocation at conception. There is no appropriate strategy to test pleiotropy in individual‐level MR analyses. As a result, pleiotropy was tested in only a few individual‐level studies by excluding potentially pleiotropic SNPs. In contrast to individual‐level MR studies, most summary‐level studies  tested the pleiotropy by “gtx” package, heterogeneity, asymmetry of funnel plots, goodness‐of‐fit test, or more formal techniques such as MR Egger and MR‐PRESSO. Detailed description of the study quality is shown in Table All studies used full instrumental variable analyses, such as the use of weighted genetic score for individual‐level MR studies and inverse variance weighted for summary‐level MR studies. Three of the included studies were GWASes of LTL with MR analyses exploring the causal links between LTL and disease outcomes. The remaining studies all identified instrumental variables from published GWASes of LTL, except for one that identified SNPs based on their biological function. The significance level for identifying instrumental variables was 5 × 103.3A total of 396 associations were included in the systematic review, with 258 (65.2%) of them not graded because only the main analysis was performed. Among these non‐evaluable associations, 24 (9.3%) used an individual‐level approach, 172 (66.7%) used a summary‐level approach, and 62 (24.0%) used both individual‐level and summary‐level approaches. Thirty‐five (13.6%) of the non‐evaluable associations had a statistically significant main analysis result. In the graded 138 (34.8%) associations, there were 40  with robust evidence, 34  with probable evidence, 2  with suggestive evidence, and 62  with insufficient evidence Table . After rN = 2), lung cancer (N = 2), lung adenocarcinoma (N = 2), soft tissue sarcoma, kidney cancer (N = 2), leukemia, chronic lymphocytic leukemia, melanoma, lymphoma, multiple myeloma, all cancers (N = 2), breast cancer, ER‐positive breast cancer, and basal cell carcinoma. Additionally, the associations for adolescent‐onset ependymoma, neuroblastoma, and serous low‐malignant‐potential ovarian cancer were upgraded to robust after removing MR Egger , while analyses for other outcomes were not pooled  were robust, pertaining to increased risk of benign breast lump, benign prostatic hyperplasia, breast cyst, uterine fibroid, uterine polyps, and decreased risk of chronic kidney disease , in respiratory system outcomes. Additionally, longer LTL with decreased risk of interstitial lung disease (ILD) was upgraded from probable to robust evidence after removing MR Egger Figure . In the Only one robust association in endocrine system pertained to metabolic syndrome. Additionally, longer LTL with increased risk of chronic kidney disease in T2D patients was upgraded from probable to robust evidence after removing MR Egger Figure . Meta‐anFor neurological/psychiatric outcomes, the association for multiple sclerosis was robust. After excluding MR Egger, dementia (Alzheimer's) was upgraded to robust Figure . Meta‐anI2 = 81.2%)  Figure . In the ) Figure .For outcomes of other systems, the associations for rheumatoid arthritis and juvenile idiopathic arthritis were robust, with corresponding meta‐analyses results of 0.80 0.72–0.90) and 0.72 (0.55–0.94), respectively. Other robust associations were those for clonal hematopoiesis of indeterminate potential and facial aging  (0.97 [0.95–0.99]), which was upgraded to robust after excluding MR Egger, and impaired general cognitive function (0.92 [0.86–0.99]). However, the evidence level of two MR analyses for general cognitive function were non‐evaluable. A previous study investigated the causal relationship of longer LTL on metabolic syndrome and found that the forward association was primarily driven by blood pressure and upper‐body fat distribution  and Knowledge Innovation Program of the Chinese Academy of Sciences (JH2022007).We declare no conflicts of interest.Data S1.Click here for additional data file.Table S1.Click here for additional data file.


Hepatocellular carcinoma (HCC) is a common cancer threatening the public health globally. Although HCC has been associated with the telomere length (TL), the causal relationship between them is not well understood. Therefore, we attempted to explore the linear causal relationship between TL and HCC through Mendelian randomization (MR) analysis among Asian and European populations.N = 23,096). The data of TL‐associated SNPs in the European population  and the GWAS summary statistics of HCC in the Asian population  as well as the European population  were downloaded from the public GWAS database. Two‐sample MR was performed using inverse variance weighting (IVW), weighted median estimate, MR–Egger regression, weighted‐mode estimate, and simple‐mode estimate methods. Sensitivity analysis was performed to text the primary results' robustness.The summary statistics of TL‐associated single nucleotide polymorphisms (SNPs) were obtained from a genome‐wide association study (GWAS) in the Asian population (p = 0.887) and European populations . Other methods also achieved similar outcomes. Sensitivity analysis was performed and revealed no heterogeneity and horizontal pleiotropy.Nine SNPs associated with TL in Asian populations and 98 SNPs in European populations were selected as instrumental variables. No linear causal relationship between heritable TL and the HCC risk was recorded in the Asian (IVW analysis odds ratio [OR] = 1.023, 95% confidence interval [CI] 0.745, 1.405, No linear causal association was recorded between heritable TL and HCC in Asian and European populations. elomere length and hepatocellular carcinoma in Asian and European populations using mendelian randomization. While exploring the causality, MR uses single nucleotide polymorphisms (SNPs) associated with factors such as instrumental variables (IVs) and is usually unaffected by confounding and reverse causality that are commonly observed in observational studies.Our study evaluated the linear causal relationship between TL and HCC by using SNPs that are robustly associated with TL as IVs in Asian and European populations through a two‐sample MR analysis.22.1N = 23,096).N = 472,174; study ID “ieu‐b‐4879”) and the GWAS summary statistics of HCC in the Asian population , and the European population . The quality‐control procedure undertaken and the pipeline of HCC GWAS produced by the IEU GWAS database associated with the full UK Biobank has been described in detail elsewhere.The summary statistics of SNPs were obtained from a meta‐GWAS that identified nine SNPs in the linkage equilibrium with significantly associated with TL in the Asian population (2.2p < 5 × 10−8) as the inclusion criteria. In order to accurately identify the effect alleles in the exposure and outcome GWAS datasets, palindromic SNPs, representing alleles with the same pair of letters  in the forward and reverse strands of DNA double‐helix structure, with allele frequency close to 50% were pruned.http://www.phenoscanner.medschl.cam.ac.uk/) was employed to detect pleiotropic SNPs associated with known HCC risk factors, such as hepatitis B, cirrhosis, obesity, and prune, if present.F = R2 (n − k − 1)/k (1 − R2), where, R2, n, and k represent the TL variation explained by IVs, the sample size, and the IVs numbers, respectively.R2 can be calculated by using the following formula: .β, N, and se(β) represent the effect allele frequency, the estimated genetic effect on TL, the sample size, and the standard error, respectively. If the F‐statistic was >10, we considered it to be less likely to be weak IV. Next, the information on these SNPs of HCC from the IEU GWAS dataset was extracted. Among Europeans, particularly, we converted the bolt‐linear mixed model effect sizes and SE of HCC statistical data into an approximate OR scale using a Taylor transformation expansion series.p < 5 × 10−8). Second, the SNPs in linkage disequilibrium  were removed. Then, we detected pleiotropic SNPs, identified palindromic SNPs, calculated F statistics, and extracted the corresponding HCC data using the same methods as for the Asian population.To satisfy the three assumptions of MR analysis, a series of strict quality‐control measures were practiced for selecting SNPs. Among Asians, we first adopted a strict threshold of genome‐wide significance (2.3We combined the summary statistics (βSNP–TL and βSNP–HCC) in Asians and Europeans, respectively, to estimate the linear causal relationship between heritable TL and the risk of HCC. The inverse variance weighting (IVW) is an effective analysis under the assumption that all genetic variants are valid IVs, specifically requiring that genetic variants affect the target outcome (HCC) only through the pathway by which exposure (TL) affects the outcome (HCC) .2.4Q test was applied to assess the heterogeneity of IVs, and p < 0.05 was considered significantly heterogeneous. If the genetic variants used as IVs are found to be associated with risk factors other than the exposure of interest and have a causal effect on the outcome, there are bias caused by horizontal pleiotropy; as such, the MR assumptions 2 and 3 are violated. MR–Egger regression can be applied to evaluate the bias caused by horizontal pleiotropy. When the intercept is close to 0 (p > 0.05), horizontal pleiotropy is considered absent.The IVW analysis and MR–Egger regression were tested for heterogeneity. Cochran's 2.5p < 0.05 considered to indicate statistical significance.All statistical analyses were performed in this study using the “Two‐sample MR” package in the R version 4.0.1, with a two‐sided 3F‐statistics of all SNPs were >10. The MR analysis performed using the IVW analysis, weighted median estimate, MR–Egger regression, weighted‐mode estimate, and simple‐mode estimate revealed no significant evidence of a linear causal relationship between heritable TL and HCC in Asians  and Europeans   12.144 (8) p = 0.145; MR–Egger, Q (df) 10.811 (7), p = 0.147] and Europeans . Moreover, the obtained results were less likely to be affected by any potential bias  and Europeans . Furthermore, the “leave‐one‐out” analysis was performed by eliminating each SNP sequentially, which suggested that no particular IV had a driving effect on the linear causal relationship in Asians .When we performed MR analysis using the above‐mentioned five methods, each of which offers unique merits and performed sensitivity analyses to ensure the robustness of the results, no linear causal relationship was observed between the TL and HCC risk. Previous observational studies showed an association between TL and HCC risk in the Asian population. A case–control study  reported that, when compared to the healthy controls, individuals with a relatively long TL had a significantly increased risk of HBV‐related HCC after adjusting for factors such as age and sex .In addition, an MR analysis conducted on TL and HBV‐related HCC risk (1538 HBV‐positive cases and 1465 HBV‐positive controls) in the Asian population reported individual‐level data for analysis along with a U‐shaped relationship.Our study offers several advantages. The nine SNPs in Asians and 98 SNPs in Europeans stringently selected were all independent and rigidly associated with TL, which avoids the effect of linkage disequilibrium on the causal estimate. Considering that both MR analyses were based on either all Asians or all Europeans, bias arising due to population stratification was minimized. Therefore, the SNPs selected in this study and the corresponding research results are significant and reliable. Similar conclusions obtained across two different ethnic groups despite their environmental differences increase the generalization of our conclusions at the global level.Although the methodology of MR analysis is valuable in causal inference, it has only a few limitations. The MR analysis assumed a linear relationship between the two elements being studied in the causal relationship, even when the possibilities of other nonlinear relationships such as J or U‐shape existed, thereby weakening the power of causal inference. Owing to the limitation of public data, we could not explore the non‐linear relationships of TL and HCC. Furthermore, subgroup analyses based on gender, age, and comorbidities were limited and caution was exercised when extending the conclusions to the individual level because summary‐level statistics were obtained.In conclusion, our two‐sample MR analysis revealed no significant linear causal relationship between human TL and the risk of HCC in the Asian and European populations.Chenglei Yang: Conceptualization ; investigation ; methodology ; project administration ; supervision ; validation ; writing – review and editing . Xi Wu: Data curation ; formal analysis ; investigation ; methodology ; resources ; software ; visualization ; writing – original draft ; writing – review and editing . Siyu Chen: Data curation ; investigation ; methodology ; visualization . Bangde Xiang: Funding acquisition ; project administration ; supervision ; validation .This work was supported by the High‐level Innovation Team and Outstanding Scholar Program in Guangxi Colleges and Universities, Innovation Project of Guangxi Graduate Education (No. YCBZ2022089); College Students' Innovation and Entrepreneurship Training Program (S202210598055); and Guangxi Key Research and Development Program .The authors declare no conflicts of interest.The data used in our study were obtained from published studies or public databases, and no original data were sourced from patients. Therefore, no ethics committee approval was required.Figure S1.Figure S2.Click here for additional data file.Table S1.Click here for additional data file.


Immune checkpoint inhibitors (ICIs) have emerged as a standard treatment for various malignancies. However, research indicates blocking the immune checkpoint pathway may exacerbate atherosclerotic lesions.We aimed to investigate whether ICI therapy increases the risk of arterial thromboembolic events (ATEs).A retrospective cohort study was conducted on patients with histologically confirmed cancer at our institution between 2018 and 2021, using the propensity score matching method. The primary endpoint was ATEs occurrence, comprising acute coronary syndrome, stroke/transient ischemic attack, and peripheral arterial thromboembolism. Subgroup analyses assessed whether the ICI treatment effect on ATEs varied over time by limiting the maximum follow‐up duration. Logistic regression analysis identified ATE risk factors in ICI‐treated patients.n = 2877) demonstrated an ATEs risk 2.01 times higher than the non‐ICI group ]; p < 0.001). Subgroup analysis revealed no significant increase in ATEs risk for ICI‐treated patients within 1 year . However, ATEs risk in the ICI group rose by 41% at 1 year (p = 0.010) and 97% at 4 years (p ≤ 0.001). Age, diabetes, hypertension, peripheral atherosclerosis, atrial fibrillation, chronic ischemic heart disease, distant cancer metastasis, and ICI treatment cycles contributed to ATEs risk elevation in ICI‐treated patients.Overall, the ICI group  treatment does not increase the risk of arterial thromboembolic events (ATEs) within the first year, but the risk significantly increases after 1 year of treatment and becomes more prominent as the follow‐up duration extends. Beyond the established traditional risk factors  for ATEs, distant cancer metastasis and an increasing number of ICI cycles are emerging risk factors for ATEs in ICI‐treated patients. Over the past few years, immune checkpoint inhibitors (ICIs) have revolutionized cancer therapeutics, representing a milestone in oncology. By binding to immune checkpoints, ICI therapy restores and enhances the ability of effector T cells to recognize and kill tumor cells, thereby augmenting the antitumor immune response. Currently, the clinical utilization of ICI agents primarily involves inhibitors targeting the programmed cell death protein 1 (PD‐1), programmed death ligand 1 (PD‐L1), cytotoxic T lymphocyte‐associated antigen 4 (CTLA‐4), and lymphocyte‐activation gene 3 (LAG‐3) pathways.ICI therapy has demonstrated remarkable efficacy in both solid and hematological tumors. Presently, nine checkpoint inhibitors targeting the PD‐1/PD‐L1, CTLA‐4, and LAG‐3 pathways have been approved by the United States Food and Drug Administration for the treatment of subsets of patients with 17 different types of cancer, such as head and neck cancer, breast cancer, lung cancer, liver cancer, esophageal cancer, stomach cancer, colorectal cancer, kidney cancer, bladder cancer, uterine  cancer, cervical cancer, Merkel cell carcinoma, skin squamous cell carcinoma, basal cell carcinoma, melanoma, lymphoma, and mesothelioma, as of May 2023.Nevertheless, the therapeutic blockade of the immune checkpoint pathway by ICI disrupts the balance between immunity and tolerance in the immune system. Consequently, the activated immune system may attack other nontumor tissues, causing immune‐related adverse events (IRAEs). Studies have reported that up to 94.9% of cancer patients treated with ICIs experience at least one IRAE, with 55.5% encountering at least one severe IRAE (grades 3 and 4).Considering the widespread clinical use of ICI therapy and its potential impact on the incidence of ATEs in patients with malignant tumors, we designed a propensity score matching (PSM) cohort study to determine whether the administration of ICIs results in an increase in ATEs.22.1We conducted a retrospective cohort study to investigate the association between ICI treatment and the incidence of ATEs in cancer patients. We included patients diagnosed with malignant tumors at Chongqing University Cancer Hospital between 2018 and 2021. The exclusion criteria were2.2The study's primary outcome was the occurrence of ATEs, which encompassed ischemic stroke, transient ischemic attack (TIA), acute coronary syndrome (ACS), and peripheral arterial thrombosis and embolism (PATE), including thromboembolism of the renal, mesenteric, and splenic arteries. The secondary endpoints were the individual components of the ATEs. We verified endpoint event occurrences by retrieving the corresponding International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD‐10) codes from the medical records of hospitalized patients at our institution. Specifically, the ACS codes used were I20.0, I20.1, I21, I22, and I23, while codes for stroke were I63.0‐I63.6 and I63.9. TIA was represented by the code G45.900. The codes for PATE were I74.0–I74.5, I74.8, and I74.9, and thromboembolisms of the mesenteric, renal, and splenic arteries were coded as K55.003, N28.0, and D73.500, respectively. Specific endpoint events ICD‐10 codes are summarized in Tables 2.3Three researchers independently collected data using preestablished forms to reduce selection bias through our cancer center's big data platform for digital medical records. One investigator collected baseline demographic data , cardiovascular history , atrial flutter or atrial fibrillation (AF), and cardiovascular risk factors . Another researcher gathered cancer‐related data . All cardiovascular histories, cardiovascular risk factors, and cancer types involved in disease diagnoses were retrieved and verified using ICD‐10 codes. Distant metastasis of cancer was confirmed through detailed TNM(tumor (T), node (N), and metastasis (M)) staging. A third investigator performed data collection of the primary and secondary outcomes. Consultations with a fourth investigator resolved disputes over the data collection procedure.2.4To mitigate selection bias and obtain more accurate causal effect estimates, propensity score matching (PSM) was employed using the “MatchIt” package in R software . Initially, a binomial distribution model with a generalized linear model was fitted to calculate the propensity scores for each observed unit. The model was based on the relationship between the treatment variable  and potential confounders  that could influence treatment assignment and outcomes. This enabled the prediction of the probability of each observed unit receiving the treatment given their covariates. Subsequently, the “matchit” function from the “MatchIt” package in R was applied to perform matching based on the propensity scores.2.5t‐tests were applied to examine normally distributed and nonnormally distributed measurements, respectively. The relative risk (RR) and 95% confidence interval (CI) for the primary and secondary outcomes in the matched cohort were estimated using a modified Poisson regression methodp value less than 0.10 in the univariate logistic analysis were included in the multivariate analysis. Considering the high mortality rate among cancer patients, which may introduce competing risks for endpoint events, we conducted a competing risk analysis with death as a competing risk event. For univariate analysis, the Fine‐Gray test was employed. All statistical tests were two‐tailed, and p values less than 0.05 were deemed statistically significant.Patient demographics and clinical characteristics were assessed using descriptive statistics. Categorical variables were summarized using counts and percentages and analyzed with the chi‐square test. Mean and standard deviation were presented for continuous variables. Descriptive statistics were utilized to assess the distribution of patient demographics and clinical characteristics. Counts and percentages were used to summarize categorical variables, which were then analyzed using the chi‐square test. Mean and standard deviation were presented for continuous variables. Independent sample t‐tests and corrected 33.1At our institution, from January 1, 2018 to December 31, 2021, a total of 51,174 patients were diagnosed with malignant tumors. The baseline characteristics of these patients are summarized in Table 3.2p < 0.001) in matched cohort. The competing risk analysis, with death as a competing risk event, demonstrated that even when accounting for competing risk events, the cumulative risk of ATEs in the ICI group remained significantly higher than that in the non‐ICI group (p < 0.001). Figure p < 0.001), whereas the risk of ACS and PATE in the ICI group increased by 1.70 times ]; p < 0.001) and 1.36 times ]; p = 0.006), respectively.The overall incidence of ATEs was 3.4% among the cohort of 50,761 individuals. In contrast, the incidence of ATEs was 7.8% in the subset of patients who received ICI treatment. The risk of ATEs in the ICI group was 2.01 times higher than that in the non‐ICI group ]; 3.3p = 0.52; 9‐month follow‐up: RR, 1.30 [95% CI (0.97–1.72)], p = 0.075). However, the risk of ATEs in the ICI group increased significantly at 1 year ]; p = 0.010) and became increasingly evident with the extension of the follow‐up duration ], p ≤ 0.001; 3‐year follow‐up: RR, 1.90 [95% CI (1.52–2.38)], p ≤ 0.001; 4‐year follow‐up: RR, 1.97 [95% CI (1.58–2.46)], p ≤ 0.001). Table p < 0.001) and the cohort receiving ICIs as subsequent lines ]), p < 0.001). The results are displayed in Figures The subgroup analysis showed that ICI treatment did not significantly increase the incidence of ATEs in cancer patients within 1 year ], 3.4p = 0.045), diabetes mellitus ]; p < 0.001), hypertension ]; p < 0.001), peripheral arterial atherosclerosis ]; p < 0.001), AF ]; p = 0.026), chronic ischemic heart disease ]; p = 0.040), distant metastasis of malignant tumor ]; p < 0.001), and cycles of ICIs use ]; p = 0.002) were independent risk factors for ATEs in cancer patients treated with ICIs. Table The baseline characteristics with a P value less than 0.10 in the univariate logistic regression analysis in the ICI cohort were included in the multivariate analysis. The multivariate analysis showed that age ]; 4The present study was a large‐scale, real‐world retrospective cohort study focusing on the association between ATEs and ICI treatment. Our study had two main conclusions. First, our research has unveiled the novel discovery that ICI treatment does not increase ATEs in cancer patients within 1 year, but the risk significantly increases after 1 year and becomes more pronounced with increased follow‐up. Second, the risk factors for ATEs in cancer patients treated with ICIs were age, diabetes mellitus, hypertension, peripheral arterial atherosclerosis, AF, chronic ischemic heart disease, distant metastasis of malignant tumors, and cycles of ICIs use.Immune checkpoint molecules are expressed on immune cells and can regulate immune activation, playing a critical role in preventing autoimmune responses. Abnormal expression or function of immune checkpoint molecules can lead to various diseases. For instance, excessive expression of immune checkpoint molecules can increase the risk of malignant tumors by inhibiting immune function. Conversely, defects or low expression of immune checkpoint molecules can cause autoimmune diseases by causing the body's immune response to go out of control. Monoclonal antibody drugs targeting CTLA‐4, PD‐1, and PD‐L1 can regulate the immune response, exerting anticancer effects. Thus, ICI agents are considered broad‐spectrum anticancer drugs that have shown remarkable clinical efficacy in treating various types of cancer. As the indications of ICIs rapidly expand and the treatment gradually switches from second‐line to first‐line, ICIs may become the primary treatment for various types of cancer in the near future, as well as aspirin or statins for cardiovascular diseases. Unfortunately, ICI agents have a variety of unique adverse reactions related to their mechanism of action, which are called IRAEs. Clinicians have gradually emphasized the importance of ICI cardiovascular adverse events after continuing reports of ICI‐related severe myocarditis.The most meaningful finding of this study was that the hazard of ATEs increased significantly in cancer patients treated with ICIs after 1 year and became more pronounced with increased follow‐up. Previous preclinical studies have shown that immune checkpoints have a protective effect on atherosclerosis. Abatacept, a syngeneic analog of CTLA‐4, prevented CD4+ T‐cell activation and reduced atherosclerosis progression by 78% in the femoral artery of mice.A large retrospective clinical study matched 2842 cancer patients treated with ICIs with patients not treated with ICIs at a 1:1 ratio based on age, cancer type, and cardiovascular history. After more than 2 years of follow‐up, the study found that ICI treatment was associated with an over 3‐fold progression of aortic plaques; more importantly, using ICIs increased the risk of complex cardiovascular events  by more than fourfold.Additionally, our research showed that the risk of ATEs in the ICI group increased significantly after 1 year and became increasingly evident with the extension of the follow‐up duration. The reason might be that atherosclerosis is a long‐term, progressive process. Atherosclerosis is a chronic inflammatory disease that can be quantified using positron emission tomography (PET) imaging to assess the degree of inflammation.A pharmacovigilance study (using the VigiBase database) showed that the incidence of myocardial infarction and cerebral arterial ischemia in cancer patients treated with ICIs was only 0.53% and 0.62%, respectively, which was even lower than the data reported in the complete database.The incidence of ATEs was reported to be extremely low in preclinical ICI drug trials, but recent retrospective studies found a significant increase in ATEs. One of the prominent reasons was that early clinical drug trials excluded patients with atherosclerotic cardiovascular disease; however, a significant portion of patients who received ICI therapy in the real world had a variety of atherosclerotic cardiovascular diseases. For instance, Drobni et al. found that approximately 20.5% of cancer patients with ICI therapy had a history of atherosclerotic cardiovascular disease.5First, although we performed PSM for demographic characteristics, baseline cardiovascular risk factors, cancer types, and other types of cardiotoxic anticancer therapy, there may be additional unmeasured confounding factors influencing the risk of ATEs in cancer patients. Our database, for example, lacked data on smoking, obesity, antiplatelet, anticoagulant, and anti‐atherosclerosis treatments. In addition, our study showed that 66.9% of patients treated with ICIs had distant organ metastasis, and these patients might have poor adherence to anti‐thrombotic and anti‐atherosclerosis therapy due to expected short survival, high risk of bleeding, and liver and kidney dysfunction. This could potentially overestimate the incidence of ATEs. Second, our study was based on information in the medical records of hospitalized patients at our institution; the true incidence of ATEs might be underestimated if cancer patients had ATEs and subsequently visited another institution for management. Third, this was a single‐center study, which might lead to regional bias.6There is a higher risk of ATEs in patients undergoing ICI treatment, and the risk increases significantly after 1 year of treatment. Close monitoring of ATEs is recommended during and after ICI therapy for cancer patients who have hypertension, peripheral arterial atherosclerosis, AF, chronic ischemic heart disease, older age, diabetes, distant metastases, and an increased number of ICI therapy cycles.Jie Zhu: Conceptualization ; data curation ; investigation ; methodology ; project administration ; software ; validation ; writing – original draft (lead); writing – review and editing . Yue Chen: Conceptualization ; data curation ; formal analysis ; methodology ; software ; writing – original draft ; writing – review and editing . Yuanlong Zhang: Conceptualization ; data curation ; formal analysis ; funding acquisition ; methodology ; project administration ; software ; writing – original draft ; writing – review and editing . Wei Wang: Conceptualization ; data curation ; methodology ; software ; writing – review and editing . Yujue Wang: Conceptualization ; data curation ; methodology ; project administration ; visualization ; writing – review and editing . Zhuo Lu: Conceptualization ; data curation ; investigation ; methodology ; writing – review and editing . Yulin Zhang: Conceptualization ; data curation ; methodology ; project administration ; supervision ; writing – review and editing . Haike Lei: Conceptualization ; data curation ; methodology ; project administration ; supervision ; writing – review and editing . Dairong Li: Conceptualization ; formal analysis ; investigation ; methodology ; project administration ; supervision ; writing – review and editing . Bo Long: Conceptualization ; funding acquisition ; methodology ; project administration ; supervision ; writing – review and editing . Haixia Liu: Conceptualization ; funding acquisition ; investigation ; methodology ; project administration ; supervision ; writing – original draft ; writing – review and editing .This research received support from a decision‐making consultation and management innovation project in the Shapingba District of Chongqing, China (grant no. Jcd202276). and funded by the Chongqing Natural Science Foundation (grant no. CSTB2022NSCQ‐MSX1482). These funding sources are unrelated to the work submitted.The authors declare that they have no potential conflict of interest.This study was conducted in accordance with the Helsinki Declaration and was approved by the Ethics Committee of Chongqing University Cancer Hospital (CZLS2023021‐A). Due to the retrospective cohort design of our study, the Ethics Committee granted a waiver of informed consent from the patients.Figure S1.Click here for additional data file.Figure S2.Click here for additional data file.Figure S3.Click here for additional data file.Table S1.Click here for additional data file.Table S2.Click here for additional data file.Table S3.Click here for additional data file.