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Clinical characteristics and outcomes of COVID-19 long-term nucleic acid positive patients

Abstract

OBJECTIVE:

This study aimed to investigate the clinical characteristics and outcomes of coronavirus disease-19 (COVID-19) long-term nucleic acid positive patients (hereinafter referred to as CLTAPs).

METHODS:

Patients were recruited from the Xiaogan Central Hospital between 16 January 2020 and 28 March 2020. Among the 562 cases of patients with laboratory-identified COVID-19 infection by real-time polymerase chain reaction (qtPCR), 19 cases of COVID-19 patients with more than 41 days from the first to the last time of nucleic acid test were selected as the study group, and 76 cases of age- and gender-matched COVID-19 patients were selected as the control group (hereinafter referred to as C-CLTAPs). Demographic characteristics, clinical symptoms, laboratory examination and computed tomography (CT) imaging characteristics were retrospectively analyzed.

RESULTS:

On admission, among the 562 cases of patients with COVID-19, there were 398 cases of ordinary COVID-19 patients, 99 cases of severe COVID-19 patients and 99 cases of critical COVID-19 patients. CLTAPs had milder clinical symptoms and longer viral shedding time in comparison to C-CLTAPs. Compared to C-CLTAPs, CLTAPs had a lower infection index at admission. CLTAPs used less oxygen therapy and a higher proportion of hydroxychloroquine treatment in comparison to C-CLTAPs. In comparison to C-CLTAPs, CLTAPs showed slower pulmonary CT progression and faster pulmonary CT absorption.

CONCLUSION:

In this study, out of the 562 cases, we found 19 CLTAPs. The clinical differences between CLTAPs and C-CLTAPs were compared and analyzed. We hope that these finding can provide a theoretical basis for the treatment of CLTAPs.

1.Introduction

In December 2019, the 2019 coronavirus disease broke out in Wuhan, Hubei Province, China. The disease caused by the SARS-cov-2 viral infection was named coronavirus disease-19 (COVID-19) by the World Health Organization (WHO) [1, 2, 3, 4]. To date, six kinds of coronavirons have been identified to cause human disease [4] and are inducers of respiratory, intestinal, liver, and neurological diseases [5, 6, 7]. COVID-19 has quickly spread to all parts of China and many countries around the world as it is highly contagious [8, 9, 10, 11, 12]. Studies have confirmed that the pathogen of the COVID-19 outbreak is highly homologous with the SARS virus, and were named SARS-cov-2 by the International Committee of Virology (ICTV) [13]. At present, there are different reports of the SARS-CoV-2 shedding time, indicating the urgent need to study the replication, immunity and infectivity of SARS-CoV-2. Understanding this is crucial for determining the duration of isolation and antiviral treatment. This also indicates that a large number of basic studies on COVID-19 long-term nucleic acid positive patients (CLTAPs) are needed, including studies on the epidemiological and clinical features. At the same time, the CLTAPs with new coronavirus personal, clinical, laboratory, and radiologic characteristics, treatment, and outcome information is of great reference and research value.

In this present study, the aim was to describe the epidemiological, clinical, laboratory and radiological characteristics, treatment, and outcomes of CLTAPs, and to compare the clinical characteristics and outcomes of the control group (C-CLTAPs). We hope that our findings can provide a theoretical basis for the treatment and prevention of CLTAPs.

2.Methods

2.1Patients

A total of 562 confirmed COVID-19 cases at the Xiaogan Central Hospital from 16 January 2020 to 28 March 2020 were collected. The diagnostic criteria meet the requirements of the “Diagnosis and treatment of COVID-19 (7th edition)” issued by the Chinese National Health and Health Committee. This study was approved by the ethics committee of Xiaogan Central Hospital (No. XGLY2020-03-28) and conformed to the Declaration of Helsinki.

2.2Data collection

Patients’ personal, clinical, laboratory and radiologic characteristics, epidemiological, treatment, and outcome information were obtained through standardized data collection from electronic medical records. Data entry into the computer database was independently completed and double-checked by two researchers.

2.3Computed tomography (CT) image collection

Two experienced physicians were employed to review the films and conducted quantitative accounting according to the distribution, location, size, morphology, edge, density, and pulmonary manifestations of the lesions.

Table 1

Demographic and clinical characteristics of the 562 cases with COVID-19

Demographic and clinical characteristicsAll patients (n= 562)
Age (years)-median (IQR)52(43–63)
Age groups (years)-n (%)
39106(18.86)
 40–49114(20.28)
 50–59158(28.11)
 60–6980(14.23)
70104(18.51)
Gender-n (%)
 Male306(54.45)
 Female256(45.55)
BMI (kg/m2) (%)
 BMI < 18.521(3.74)
 18.5 BMI < 24284(50.53)
 24 BMI < 28191(33.99)
 28 BMI < 3252(9.25)
 BMI 328(1.42)
Exposure history-n (%)
 History of residence in Wuhan59(10.50)
 Wuhan tourism history126(22.42)
 Contact history with confirmed patients137(24.38)
 Denied a clear contact history240(42.70)
Comorbidities-n (%)
 Smoking34(6.05)
 Hypertension139(24.73)
 Diabetes64(11.39)
 Cardiovascular disease31(5.52)
 Cerebrovascular disease14(2.49)
 Chronic pulmonary disease26(4.63)
 Chronic kidney disease5(0.89)
 Chronic liver disease37(6.58)
 Rheumatic immune disease9(1.60)
 Malignancies18(3.20)
Clinical symptoms-n (%)
 Fever457(81.32)
 Cough368(65.48)
 Expectoration142(25.27)
 Dyspnea187(33.27)
 Pharyngalgia27(4.80)
 Dizziness8(1.42)
 Myalgia30(5.34)
 Fatigue131(23.31)
 Nausea or vomiting42(7.47)
 Diarrhea24(4.27)
 Temperature ( 37.3) (%)146(25.98)
 SpO2 ( 93) (%)101(17.97)
 HR (> 100) (%)88(15.66)
 BP (SBP 140; DBP 90) (%)107(19.04)
Disease stratification-n (%)
 Ordinary398
 Severe99
 Critically ill65
Median time of viral shedding26(18–36)

Table 2

Demographic and clinical characteristics of C-CLTAPs and CLTAPs

Demographic and clinical characteristicsAll patients (n= 95)C-CLTAPs (n= 76)CLTAPs (n= 19)p value
Characteristics
 Age (years)-median (IQR)57(48–60)56(48–60)57(49–59)0.944
Gender-n (%)
 Male75(78.95)60(78.95)15(78.95)1.000
 Female20(21.05)16(21.05)4(21.05)1.000
Exposure history-n (%)
 History of residence in Wuhan10(10.53)7(9.21)3(15.79)0.403
 Wuhan tourism history17(17.89)13(17.11)4(21.05)0.688
 Contact history with confirmed patients26(27.37)20(26.32)6(31.58)0.645
 Denied a clear contact history42(44.21)36(47.37)6(31.58)0.215
Comorbidities-n (%)
 Smoking5(5.26)5(6.58)0(0.00)N/A
 Hypertension26(27.37)22(28.95)4(21.05)0.490
 Diabetes10(10.53)9(11.84)1(5.26)0.403
 Cardiovascular disease7(7.37)5(6.58)2(10.53)0.556
 Cerebrovascular disease3(3.16)3(3.95)0(0.00)N/A
 Chronic pulmonary disease5(5.26)5(6.58)0(0.00)N/A
 Chronic kidney disease0(0.00)0(0.00)0(0.00)N/A
 Chronic liver disease6(6.32)5(6.58)1(5.26)0.833
 Rheumatic immune disease0(0.00)0(0.00)0(0.00)N/A
 Malignancies2(2.11)2(2.63)0(0.00)N/A
Clinical symptoms-n (%)
 Fever85(89.47)66(86.84)19(100)0.095
 Cough57(60.00)54(71.05)3(15.79)0.000
 Expectoration28(29.47)24(31.58)4(21.05)0.368
 Dyspnea33(34.74)25(32.89)8(42.11)0.451
 Pharyngalgia2(2.11)1(1.32)1(5.26)0.284
 Dizziness2(2.11)2(2.63)0(0.00)N/A
 Myalgia1(1.05)1(1.32)0(0.00)N/A
 Fatigue22(23.16)18(23.68)4(21.05)0.808
 Nausea or vomiting4(4.21)4(5.26)0(0.00)N/A
 Diarrhea5(5.26)5(6.58)0(0.00)N/A
 SpO2 ( 93%)17(17.89)15(19.74)2(10.53)0.349
 HR (> 100)19(20.00)14(18.42)5(26.32)0.442
 Duration of positive time (IQR)28(20–45)24(19–34)54(49–57)0.000

Figure 1.

Dynamic profile of C-CLTAPs and CLTAPs in CT characteristics and SARS-CoV-2 RNA test.

Dynamic profile of C-CLTAPs and CLTAPs in CT characteristics and SARS-CoV-2 RNA test.

Table 3

Laboratory tests of C-CLTAPs and CLTAPs

Laboratory findingsAll patients (n= 95)C-CLTAPs (n= 76)CLTAPs (n= 19)p value
Blood routine
 White blood cell count (× 109/L)5.17(4.21–7.15)5.24(4.14–7.32)4.80(4.40–6.41)0.638
 Red blood cell count (× 1012/L)4.43(4.15–4.81)4.46(4.18–4.81)4.31(4.00–4.80)0.454
 Hemoglobin139(127.50–149)140(128–149.75)133(123–145)0.293
 Neutrophil (× 109/L)3.49(2.56–5.12)3.54(2.56–5.81)3.39(2.61–4.07)0.424
 Lymphocyte (× 109/L)1.02(0.73–1.64)0.96(0.71–1.46)1.35(0.96–1.61)0.093
 Platelet (× 109/L)167(137–222.5)162.50(135–226.25)192(165–209)0.280
Blood coagulation
 Active partial thrombin time (APTT)31.00(28.80–33.85)30.90(28.80–33.90)31.60(29.95–33.50)0.361
 Prothrombin time (PT)12.30(11.70–13.30)12.50(12.20–13.60)11.60(11.30–11.80)0.000
 Fibrinogen (Fib)4.52(3.38–5.34)4.73(3.88–5.56)2.82(2.47–3.84)0.000
 D-dimer (SDD)12.80(12.10–13.80)12.60(12.00–13.70)13.60(13.00–14.55)0.003
Biochemical routine
 Total protein (TP)187.70(138.85–259.50)176.60(128.83–222.68)264(209.95–295.30)0.002
 Albumin propagated (ALB)68.70(64.80–73.80)66.85(63.78–70.65)79.70(72.30–86.45)0.000
 Alanine aminotransferase (ALT)38.20(35.65–40.75)38.05(35.13–40.10)40.90(38.15–43.05)0.002
 Glutamates transaminase (AST)18(11–31)20.00(12.00–33.25)14(8–22.50)0.059
 Total bilirubin23(16.50–30)23.50(17.00–31.50)20(15–26)0.164
 Urea nitrogen11.40(9.50–16.75)11.95(9.50–16.53)11.20(9.20–16.15)0.539
 Creatinine4.70(3.35–5.80)4.50(3.30–5.63)5.40(4.10–5.80)0.340
 eGFR73.30(60.45–88)70.70(59.23–83.30)88(72.75–91.50)0.066
 Lactate dehydrogenase (LDH)69(47–106.25)64.50(45.00–107.75)72.00(60.75–90.50)0.364
 Alkaline phosphatase (ALP)72(65–85)69(63.50–82.25)86(77–106.50)0.005
 Fasting plasma glucose (FPG)5.54(5.05–6.46)5.59(5.18–6.91)5.01(4.28–5.38)0.002
 Total cholesterol (TC)3.60(3.08–4.19)3.50(2.96–4.07)4.23(3.63–4.58)0.005
 Triglyceride (TG)1.35(1.03–1.96)1.28(1.00–1.84)1.46(1.17–2.63)0.023
Four items of chest pain
 Creatinase isoenzyme (CKMB)2.06(1.47–3.01)2.10(1.51–2.88)1.50(1.38–4.71)0.911
 N-terminal brain natriuretic peptide157(51–404)156.50(66–408)214(20–376)0.649
 precursor (BNP)
 Myoglobin (Myo)53.29(40.14–113.60)52.95(40.79–122.23)64.76(30.98–71.56)0.596
 Cardiac troponin (cTnI)0.06(0.03–0.09)0.06(0.04–0.09)0.04(0.02–0.06)0.094
Infection-related index
 PCT0.18(0.13–0.27)0.16(0.12–0.27)0.20(0.18–0.23)0.053
 CRP8.17(2.90–32.05)13.20(3.70–37.51)2.30(1.11–3.52)0.001
 ESR47(31–68.25)47(32–69)19(18–55)0.100

2.4Statistical analysis

Classification variables were expressed as frequency and percentage, continuous variables were expressed as average, and quantitative data of non-normal distribution were calculated by quartile. The Chi-square test and Fisher exact test were used in the two groups of data, and the t-test or Mann-Whitney U test were used to analyze continuous variables. SPSS version 21.0 software was used for all statistical analyses. P< 0.05 was considered statistically significant.

3.Results

3.1Clinical characteristics of the patients on admission

Five hundred and sixty-eight cases of COVID-19 patients were diagnosed at the Xiaogan Central Hospital between 16 January 2020 and 28 March 2020. The demographic and clinical characteristics of the patients are summarized in Table 1. In particular, the median age was 52 years (IQR 43–63), and there were 306 males (54.45%) and 256 females (45.55%). The most common clinical symptoms were fever (81.32%) and cough (65.48%). Dyspnea (65.48%), expectoration (23.31%) and fatigue (25.27%) were the next most common. Diarrhea (4.27%), myalgia (5.34%), dizziness (1.42%), sore throat (2.34%) and conjunctival congestion (0.78%) were relatively uncommon. Most patients had a clear history of contact, including Wuhan travel history (22.42%), Wuhan residential history (10.50%) and contact history with diagnosed patients (24.38%). The proportion of patients who denied a clear contact history was 42.70%. Among these diagnosed patients, hypertension (24.73%) was the most common chronic disease, followed by diabetes (11.39%) and chronic liver disease (6.58%). Disease stratification was 398 ordinary patients (70.81%), 99 severe patients (17.61%) and 65 critical patients (11.56%).

3.2The distinction between CLTAPs and C-CLTAPs

The median time of viral shedding in the 562 cases was 26 (18–36), which was similar to results of Zhou et al. [14]. However, we found that there were 19 patients with a median time of viral shedding of 54 (IQR 49–57), which were considered as CLTAPs. To further explore the characteristics of these 19 CLTAPs, we matched 76 cases of C-CLTAPs of the same gender and age according to a 1:4 ratio, and compared the demographic characteristics, clinical symptoms, laboratory tests, and imaging data between the two groups.

Demographic and clinical characteristics of the CLTAPs and C-CLTAPs are summarized in Table 2. In detail, among the 95 COVID-19 patients, the median age was 57 years (IQR 48–60), and there were 75 males (78.95%) and 20 females (21.05%). There was no significant difference between CLTAPs and C-CLTAPs in exposure history and comorbidities. In terms of clinical symptoms, the symptoms of CLTAPs were milder than those of C-CLTAPs, and the proportion of CLTAPs with cough symptoms was significantly lower than that of C-CLTAPs (15.79% vs 71.05, P< 0.05). In addition, the median duration of viral shedding of CLTAPs was significantly shorter than that of the C-CLTAPs (54 IQR [49–57] vs 24 IQR [19–34], P< 0.05) (Fig. 1). These results suggest that in comparison to C-CLTAPs, CLTAPs had milder clinical symptoms and longer viral shedding time.

Laboratory tests of the CLTAPs and C-CLTAPs are summarized in Table 3. In comparison to C-CLTAPs, white and red blood cells, hemoglobin and neutrophils of CLTAPs decreased and lymphocyte and platelet increased. These results suggest that CLTAPs were more likely to have a lower proportion of inflammatory markers at admission. This was consistent with the result that CLTAPs had a lower infection index in comparison to C-CLTAPs at admission.

Table 4

Treatment and clinic outcomes of C-CLTAPs and CLTAPs

All patients (n= 95)C-CLTAPs (n= 76)CLTAPs (n= 19)p value
Oxygen cure-n (%)
 Oxygen-n31(32.63)28(36.84)3(15.79)0.080
Respiratory support-n (%)
 Non-invasive ventilator5(5.26)5(6.58)0(0.00)N/A
 Invasive ventilator2(2.11)2(2.63)0(0.00)N/A
Drug treatment-n (%)
 Antiviral therapy
 Abidor40(42.11)24(31.58)16(84.21)0.000
 Interferon44(46.32)26(34.21)18(94.74)0.000
 Ganciclovir24(25.26)22(28.95)2(10.53)0.098
 Oseltamivir35(36.84)33(43.42)2(10.53)0.008
 Pironavir ritonavir30(31.58)19(25.00)11(57.89)0.006
 Ribavirin37(38.95)32(42.11)5(26.32)0.207
 Hydroxychloroquine19(20.00)6(7.89)13(68.42)0.000
Antibiotic treatment
 Moxifloxacin48(50.53)43(56.58)5(26.32)0.018
 Levofloxacin15(15.79)14(18.42)1(5.26)0.159
 Piperacillin tazobactam3(3.16)3(3.95)0(0.00)N/A
 Cefoperazone sodium sulbactam sodium1(1.05)1(1.32)0(0.00)N/A
 Glucocorticoid1(1.05)1(1.32)0(0.00)N/A
 Gamma globulin37(38.95)35(46.05)2(10.53)0.005
Complications-n (%)
 Septicemia0(0.00)0(0.00)0(0.00)N/A
 Respiratory failure13(13.68)13(17.11)0(0.00)N/A
 ARDS1(1.05)1(1.32)0(0.00)N/A
 Heart failure2(2.11)2(2.63)0(0.00)N/A
 Septic shock0(0.00)0(0.00)0(0.00)N/A
 Coagulopathy0(0.00)0(0.00)0(0.00)N/A
 Acute kidney injury1(1.05)1(1.32)0(0.00)N/A
 Acute heart injury1(1.05)1(1.32)0(0.00)N/A
Clinical classification
 Ordinary71(74.74)54(71.05)17(89.47)0.098
 Severe16(16.84)14(18.42)2(10.53)0.411
 Critically ill8(8.42)8(10.53)0(0.00)N/A
Clinical outcome-n (%)
 Discharge91(95.79)72(94.74)19(100.00)0.307
 Death4(4.21)4(5.26)0(0.00)0.307

Treatment and clinic outcomes of the CLTAPs and C-CLTAPs are summarized in Table 4. In detail, CLTAPs showed no clinical complications, while C-CLTAPs contained mild clinical complications, including 13 cases of respiratory failure, 1 case of ARDS and 2 cases of heart failure. CLTAPs used less oxygen therapy and had a higher proportion of hydroxychloroquine treatment in comparison to C-CLTAPs. In terms of clinical classification, CLTAPs held more mild patients, which was also the reason for the low proportion of glucocorticoids and globulin use.

Table 5

Radiological data of C-CLTAPs and CLTAPs

All patients (n= 95)C-CLTAPs (n= 76)CLTAPs (n= 19)p value
Lesion distribution-n (%)
 Left lung5(5.26)5(6.58)0(0.00)N/A
 Right lung7(7.37)7(9.21)0(0.00)N/A
 Double lung65(68.42)58(76.32)7(36.84)0.001
Lesion location-n (%)
 Periphery41(43.16)37(48.68)4(21.05)0.030
 Periphery and center36(37.89)33(43.42)3(15.79)0.026
Lesion size (cm)-n (%)
< 15(5.26)5(6.58)0(0.00)N/A
 1 311(11.58)7(9.21)4(21.05)0.149
> 361(64.21)58(76.32)3(15.79)0.000
Lesions form-n (%)
 Patch40(42.11)36(47.37)4(21.05)0.038
 Lung segment20(21.05)18(23.68)2(10.53)0.208
 Lobe17(17.89)16(21.05)1(5.26)0.108
Number of lesions-n (%)
 16(6.32)6(7.89)0(0.00)N/A
 29(9.47)6(7.89)3(15.79)0.293
 3 or more62(65.26)58(76.32)4(21.05)0.000
Lesion margin-n (%)
 Clear4(4.21)4(5.26)0(0.00)N/A
 Vague73(76.84)66(86.84)7(36.84)0.000
Lesion density-n (%)
 Ground glass42(44.21)37(48.68)5(26.32)0.079
 Substantiality1(1.05)1(1.32)0(0.00)N/A
 Mixed type35(36.84)33(43.42)2(10.53)0.008
Extrapulmary manifestations-n (%)
 Mediastinal lymphadenopathy0(0.00)0(0.00)0(0.00)N/A
 Pneumothorax0(0.00)0(0.00)0(0.00)N/A
 Pleural effusion4(4.21)4(5.26)0(0.00)N/A

Radiological data of the CLTAPs and C-CLTAPs are summarized in Table 5. Specifically, according to the distribution characteristics and the range of involvement of COVID-19 lung CTs, we counted the imaging characteristics of lung CTs in the first week of admission. Among all patients, the proportion of lesions involving both lungs was 68.42%, the proportion of lesion distribution simultaneously involving peripheral and central areas was 37.89%, the proportion of the lesion size of > 3 cm was 64.21 %, the proportion of 3 or more lesions was 65.26%, and the proportion of the lesion edge vague was 76.84%. In terms of lung CT lesion involvement location, compared with C-CLTAPs, the proportion of peripheral and central involvement of the CLTAPs was significantly lower (43.42% vs 15.79%, P< 0.05). The proportion of the lesion size of > 3 cm of C-CLTAPs was significantly higher than CLTAPs (76.32% vs 15.79%, P< 0.05). More importantly, we found that C-CLTAPs in the pulmonary CT progression group were much faster than CLTAPs, while the time of pulmonary CT absorption of C-CLTAPs was a lot longer than in the CLTAPs group (Fig. 1). These results indicate that in comparison to C-CLTAPs, CLTAPs showed slower pulmonary CT progression and faster pulmonary CT absorption.

4.Discussion

Scientists have made efforts to reveal the epidemiological, clinical and virological characteristics of SARS-CoV-2 [15, 16, 17, 18, 19, 20]. COVID-19 infection has some similarities with SARS-CoV and MERS-CoV infection [21, 22], but it has obviously strong transmissibility. We are concerned that 2019-nCoV may have acquired efficient human transportation capabilities [23]. In the present study, we reported a cohort of 562 patients with laboratory-confirmed COVID-19 infection. Patients’ personal, clinical, laboratory, radiologic characteristics, epidemiological, treatment, and outcome information was analyzed. The disease stratification was 398 ordinary patients (70.81%), 99 severe patients (17.61%) and 65 critical patients (11.56%).

In addition, we compared 19 cases of CLTAPs with 76 cases of C-CLTAPs in terms of clinical characteristics, treatment, clinic outcomes and CT characteristics. Compared with C-CLTAPs, CLTAPs had a lower infection index at admission (CRP: 13.20 IQR [3.70–37.51] vs 2.30 IQR [1.11–3.52], P< 0.001). The milder clinical symptoms (proportion of cough symptoms: CLTAPs [15.79%] vs C-CLTAPs [71.05%], P< 0.05) and a lower proportion of inflammatory markers of CLTAPs at admission, which indicates that immunity played an important role in the recovery of COVID-19 and the viral shedding time. The median duration of viral shedding of CLTAPs was significantly shorter than that of C-CLTAPs (54 IQR [49–57] vs 24 IQR [19–34], P< 0.05). 17 of the 19 cases tested positive for COVID-19 IgG on March 22 2020. This indicates that although CLTAPs had a lower immune response due to mild clinical symptoms in the early stage of the COVID-19 infection, the immune response of CLTAPs was still activated in the later stage of the disease. This suggests that the COVID-19 shedding time had a relationship with host immunity, which was consistent with the CT results of the CLTAPs, which showed slower pulmonary CT progression and faster pulmonary CT absorption in comparison to C-CLTAPs.

5.Conclusion

In conclusion, we analyzed and discussed the clinical features of 562 cases of COVID-19 patients. We compared and analyzed the clinical differences between CLTAPs and C-CLTAPs, providing a theoretical basis for the treatment of C-CLTAPs and the next stage of prevention and control work.

Author contributions

Y. Yan and M. Wang conceived and designed the study. X. Zhu and F. Yang acquired the data. Q. Li and T. Zhao performed the analysis. Y. Yan wrote the manuscript. W. Li reviewed and edited the manuscript. All authors read and approved the final manuscript and agree to be accountable for all aspects of the research in ensuring that the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Informed consent

All patients provided informed consent for the publication of this study.

Conflict of interest

None of the authors have any conflict of interest to report.

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