Association of ABO blood group with COVID-19 severity, acute phase reactants and mortality

Uzma Ishaq; Asmara Malik; Jahanzeb Malik; Asad Mehmood; Azhar Qureshi; Talha Laique; Syed Muhammad Jawad Zaidi; Muhammad Javaid; Abdul Sattar Rana

doi:10.1371/journal.pone.0261432

. 2021 Dec 14;16(12):e0261432. doi: 10.1371/journal.pone.0261432

Association of ABO blood group with COVID-19 severity, acute phase reactants and mortality

Uzma Ishaq ¹, Asmara Malik ², Jahanzeb Malik ^3,^4,^*, Asad Mehmood ³, Azhar Qureshi ⁵, Talha Laique ⁶, Syed Muhammad Jawad Zaidi ⁷, Muhammad Javaid ³, Abdul Sattar Rana ^3,⁴

Editor: Robert Jeenchen Chen⁸

PMCID: PMC8670663 PMID: 34905588

Abstract

Introduction

Coronavirus disease 2019 (COVID-19) is the ongoing pandemic with multitude of manifestations and association of ABO blood group in South-East Asian population needs to be explored.

Methods

It was a retrospective study of patients with COVID-19. Blood group A, B, O, and AB were identified in every participant, irrespective of their RH type and allotted groups 1, 2,3, and 4, respectively. Correlation between blood group and lab parameters was presented as histogram distributed among the four groups. Multivariate regression and logistic regression were used for inferential statistics.

Results

The cohort included 1067 patients: 521 (48.8%) participants had blood group O as the prevalent blood type. Overall, 10.6% COVID-19-related mortality was observed at our center. Mortality was 13.9% in blood group A, 9.5% in group B, 10% in group C, and 10.2% in AB blood group (p = 0.412). IL-6 was elevated in blood group A (median [IQR]: 23.6 [17.5,43.8]), Procalcitonin in blood group B (median [IQR]: 0.54 [0.3,0.7]), D-dimers and CRP in group AB (median [IQR]: 21.5 [9,34]; 24 [9,49], respectively). Regarding severity of COVID-19 disease, no statistical difference was seen between the blood groups. Alteration of the acute phase reactants was not positively associated with any specific blood type.

Conclusion

In conclusion, this investigation did not show significant association of blood groups with severity and of COVID-19 disease and COVID-19-associated mortality.

Introduction

Coronavirus disease 2019 (COVID-19) represents a public health emergency causing economic and health care system collapse worldwide. As of April 2021, approximately four million people have died from COVID-19 with the numbers increasing exponentially [1]. With some of the regions surviving through the fourth wave of the pandemic, there has been a multitude of manifestations associated with COVID-19, including the cardiovascular, respiratory, gastrointestinal, and hematological systems [2–4].

Apart from documentary evidence of auto-antigenicity and reporting of hematological complications, many studies have investigated the pathway to viral entry into the human hosts [5, 6]. One such hypothesis resides in the ABO blood group and its association with the severity of diseases such as Hepatitis B Virus (HBV), Middle-Eastern Respiratory Syndrome Coronavirus (MERS), and Severe Acute Respiratory Syndrome Coronavirus (SARS) [7]. Furthermore, several investigations have investigated an association of ABO blood group with COVID-19 [8]. A study on COVID-19 demonstrated a cross-replicating association signal at locus 9q34.2, which coincides with the ABO blood group locus [9]. However, the association between the blood groups and the severity of the disease is still unclear. Several studies have shown an increased risk of infectivity with blood group A while conferring a low risk of COVID-19 infection with blood group O [10]. A couple of systematic reviews demonstrate blood group A individuals’ vulnerability to COVID-19, and blood type AB conferring a lower risk of SARS-COV-2 infection [11, 12].

In South-East Asia however, blood group O and B is prevalent and studies demonstrating the severity of COVID-19 disease and COVID-19-associated mortality in this population subset were lacking [13]. Hence, we conducted a retrospective analysis on a cohort of COVID-19 patients, analyzing their ABO blood types, and observed overall COVID-19-associated mortality and severity of disease in association with the blood type.

Methods

This was a retrospective investigation conducted at Advanced Diagnostics and Liver Center after approval from the ethical review board of our institute (ID: ADC/17/20) according to the Declaration of Helsinki. All participants or their guardians gave written informed consent before data collection. A total of 1067 COVID-19 patients were included in this study from April 2020 through January 2021 and the demographic data, comorbid conditions, epidemiological data, laboratory tests, hospital stay, and mortality rates were extracted via the electronic system of our institute. Every patient was confirmed positive SARS-COV-2 via real-time reverse transcription-polymerase chain reaction (RT-PCR). The severity of COVID-19 was classified into, mild, moderate, and critical according to the Centers for Disease Control (CDC) guidelines. Individuals who have various signs and symptoms of COVID-19 (e.g., fever, cough, sore throat, headache, malaise, nausea, vomiting, loss of taste and smell, etc.) but do not have shortness of breath, dyspnea, or abnormal chest imaging were mild and those showing evidence of lower respiratory illness during clinical assessment or imaging and who have an oxygen saturation (SpO₂) ≥ 94% were labelled moderate disease. Patients with SpO_{2 < 94%} on room air, respiratory rate of > 30 breaths/min, or > 50% lung infiltrates, and those requiring mechanical ventilation were labeled as critical. Patients with known hemoglobinopathies or other blood disorders were excluded [14].

All the tests were carried out in the clinical laboratory of Advanced Diagnostics under the standard procedures according to Punjab Health Commission. Hemoglobin (Hgb), and white blood cells (WBC) were performed on an XN-3100 Sysmex hematology analyzer. C-reactive proteins and D-dimers were analyzed on Cobas® c3011 analyzer (Roche Diagnostics) and interleukin-6 (IL-6), and Procalcitonin was analyzed via electrochemiluminescent immunoassay (ECLIA) in the Elecsys® 2010 immunoassay system. ABO blood group and the cross-match were done manually by an expert hematologist (UI). Group A, B, O, and AB were identified in every participant, irrespective of their RH type and allotted groups 1, 2,3, and 4 respectively.

Statistical analysis was carried out with Statistical Package for the Social Sciences (SPSS) version 26 (IBM Corp, Armonk, NY, USA). After normality adjustments using the Wilk-Shapiro test, quantitative variables were presented as mean ± standard deviation (SD) for normal distribution and median (Interquartile range: IQR) for non-normal distribution. Qualitative variables were presented as frequency and percentages. Comparison of the four groups was analyzed by Student’s t-test and Chi-square test was used for qualitative variables. For outcomes assessment, cumulative incidence and Kaplan Meier curves were plotted for all four groups against the number of days in the hospital and mortality rate. Odds ratio (OR) and 95% confidence interval (CI) were analyzed for the severity of COVID-19 disease, mortality, and hospital stay. Correlation between blood group and lab parameters was presented as histogram distributed among the four groups. Logistic regression was done for predictors of severe COVID-19 disease for ABO blood groups. A p-value of less than 0.05 was considered significant.

Results

A total of 1067 patients were admitted to Advanced Diagnostics and Liver Center from April 2020 through January 2021 who complied with our study criteria for analysis. The mean age of the patients in group 1, 2, 3, and 4 was 47.37 ± 20.21, 47.71 ± 18.45, 47.54 ± 18.84, and 48.87 ± 21.31 years, respectively. The majority of the patients were males 712 (66.7%) with an average body mass index (BMI) of 27.45 ± 3.53. Overall, one-quarter of the patients were diabetic 310 (29%), had hypertension 361 (33.8%), cardiovascular disease (CVD) 282 (26.4%), and 96 (8.9%) had chronic kidney disease (CKD). The majority of blood groups in descending order for this cohort were O (48.8%), B (27.6%), A (18.9%), and 4.5% were AB blood type.

The average median (IQR) hospital stay was 12 (6,25) days. Patients with AB blood group stayed a median (IQR) of 14 (5, 27) days while A blood group cohort stayed 13 (6,27) days. It was statistically non-significant between all four groups. There was overall 10.6% COVID-19-related mortality at our center, with 13.9% in blood group A as the majority of COVID-19 deaths. However, this did not reach statistical significance. Regarding severity of COVID-19 disease, there was a trend towards critical disease in blood group A (n = 83, 41.1%; OR 0.257 (95% CI: 0.167–1.136); p = 0.278) and O (n = 183, 35.1%; OR 0.438 (95% CI: 0.168–1.139); p = 0.090). However, the results were insignificant. Baseline characteristics, patient demographics, the severity of COVID-19, total hospital stay, and mortality rates are presented in Table 1. The overall incidence of the ABO blood type in the COVID-19 cohort and cumulative hazard of cause-specific death is demonstrated in Fig 1 and the levels of acute phase reactants (IL-6, CRP, Procalcitonin, D-dimers) with ABO blood type is exhibited in Fig 2. IL-6 was elevated in blood group A (median [IQR]: 23.6 [17.5,43.8]), Procalcitonin in blood group B (median [IQR]: 0.54 [0.3,0.7]), D-dimers and CRP in group AB (median [IQR]: 21.5 [9,34]; 24 [9,49], respectively).

Table 1. Patient demographics and baseline characteristics of COVID-19 patients with different blood groups.

Variable	Blood Group A (n = 202)	Blood Group B (n = 295)	Blood Group O (n = 521)	Blood Group AB (n = 49)	OR (95% CI)	P-value
Age, years, mean ± SD	47.37 ± 20.21	47.71 ± 18.45	47.54 ± 18.84	48.87 ± 21.31	-	0.444
Gender, n (%)						0.342
Male	138 (62.4%)	239 (69.3%)	283 (67.5%)	52 (63.4%)	-
Female	83 (37.6%)	106 (30.7%)	136 (32.5%)	30 (36.6%)	-
BMI, kg/m ² , mean ± SD	27.34 ± 3.48	27.72 ± 3.67	27.35 ± 3.76	27.48 ± 3.22	-	0.966
Comorbid conditions, n (%)
DM	67 (30.3%)	97 (28.1%)	119 (28.4%)	27 (32.9%)	-	0.744
HTN	80 (36.2%)	106 (30.7%)	146 (34.8%)	29 (35.4%)	-	0.391
CVD	61 (27.6%)	102 (29.6%)	95 (22.7%)	24 (29.3%)	-	0.407
CKD	20 (9%)	33 (9.6%)	38 (9.1%)	5 (6.1%)	-	0.985
COVID-19 severity, n (%)
Mild	51 (25.2%)	82 (27.8%)	156 (29.9%)	30 (61.2%)	6.27 (9.09–9.77)	<0.001
Moderate	68 (33.7%)	128 (43.4%)	182 (34.9%)	14 (28.6%)	4.88 (19.98–21.55)	0.036
Critical	83 (41.1%)	86 (29.2%)	183 (35.1%)	5 (10.2%)	11.34 (46.79–53.22)	<0.001
Hospital stay, median (IQR)	13 (6,27)	12 (6,25)	12 (5,24)	14 (5,27)	3.78 (44.03–50.18)	0.364
Mortality, n (%)	28 (13.9%)	28 (9.5%)	52 (10%)	5 (10.2%)	2.38 (30.28–34.71)	0.412
Lab parameters, median (IQR)
Hgb (g/dl)	12.7 (10.9,13.8)	12.3 (10.7,14.1)	12.7 (11.2,14.8)	12.7 (11.1,15)	-	0.377
WBC (mm³)	12000 (7000,15000)	11000 (6000,14000)	12000 (7000,15000)	10500 (6000,15000)	-	0.707
IL-6 (pg/ml)	23.6 (17.5,43.8)	21.7 (17.5,43.8)	19.7 (16.4,28.7)	19.7 (16.7,32.4)	-	0.001
Procalcitonin (ng/ml)	0.5 (0.3,0.65)	0.54 (0.3,0.7)	0.45 (0.23,0.67)	0.5 (0.23,0.65)	-	0.348
D-dimers (mcg/ml)	15 (8,32)	15 (7,33)	15 (5,28)	21.5 (9,34)	-	0.556
CRP (mg/dl)	17 (11,54)	23 (9,60)	17 (9,54)	24 (9,49)	-	0.146

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Normally distributed variables expressed as mean ± SD, abnormally distributed variables expressed as median (IQR). Categorical variables presented as n (%). P < 0.05 as significant. Standard deviation (SD), interquartile range (IQR), body mass index (BMI), diabetes mellitus (DM), hypertension (HTN), cardiovascular disease (CVD), chronic kidney disease (CKD), hemoglobin (Hgb), white blood count (WBC), C-reactive protein (CRP), interquartile range (IQR), standard deviation (SD), odds ratio (OR), confidence interval (CI).

Multivariate analysis (after adjusting age, gender, and comorbidities) did not show any blood group to be significantly associated with disease severity and mortality in this cohort (Tables 2 and 3). The cause-specific hazards ratio (HR) for survival function was 3.206 (p = 0.361) among all blood groups (Fig 1). More survival was seen with blood group A initially but with a hospital stay of more than approximately 30 days, the survival decreased exponentially in blood group A, while early mortality was observed with blood group AB (Fig 1).

Table 2. Multivariate analysis on ABO blood groups for associated mortality COVID-19 disease.

Blood group	B	SE	Wald (t²)	aOR (95% CI)	P-value
A	-0.576	0.491	3.852	0.257 (0.167–1.136)	0.278
B	-0.680	0.489	1.935	0.507 (0.194–1.321)	0.164
O	-0.826	0.488	2.869	0.438 (0.168–1.139)	0.090
AB	-0.879	0.471	3.479	0.415 (0.165–1.046)	0.062

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Adjusted odds ratio (aOR), confidence interval (CI), beta (B), standard error (SE), chi square distributed with df = 1. P<0.05 as significant.

Table 3. Multivariate analysis on ABO blood groups for severity of COVID-19 disease.

Blood group	B	SE	Wald (t²)	aOR (95% CI)	P-value
A	-0.632	0.563	1.654	0.164 (0.132–0.736)	0.165
B	-0.532	0.163	1.732	0.705 (0.276–1.943)	0.214
O	-0.814	0.254	2.623	0.743 (0.143–1.642)	0.079
AB	-0.632	0.545	2.732	0.154 (0.125–0.953)	0.165

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Adjusted odds ratio (aOR), confidence interval (CI), beta (B), standard error (SE), chi square distributed with df = 1. P<0.05 as significant.

Discussion

Of all the human blood group systems, the most widely used in clinical practice is the ABO blood group and includes four blood types, including A, AB, B, and O. It is located on chromosome 9 in a human DNA (9q34.2) and many studies have demonstrated a vital role of the ABO blood group in some infectious and non-infectious diseases. Histo-blood group antigens (HBGAs) are one of the main antigens expressed on human red blood cells, and differences in blood group antigens can alter host susceptibility to many infections. HBGAs are postulated to decrease the spread of infections through antibodies and ABO antibodies are a part of the innate immune system against many pathogens [10].

In this study, we demonstrated a relationship of COVID-19 severity with ABO blood groups. Blood groups A and O had the majority of severe cases in this cohort of COVID-19 patients. By contrast, we observed mild disease to be prevalent in the O and AB blood groups. Acute phase reactants were not majorly deranged between the blood groups and hospital stay was increased with A and AB blood groups. Overall mortality was high at 10.5% and blood group A was associated with the highest COVID-19-associated mortality. The majority of blood group reported in this cohort was O (48.8%).

There are several studies demonstrating a relationship between ABO blood groups and COVID-19 disease. A study from China tested the association of ABO blood group with COVID-19 infection on 105 COVID-19 cases and 103 controls. Blood group A was prevalent in their population (42.8%) and it was statistically associated with increased infection risk of COVID-19 (OR: 1.33, 95% CI: 1.02–1.73, p = 0.04) in their female population [13]. Two recent studies from the subcontinent: one from Peshawar, Pakistan, and the other from Dhaka, Bangladesh have demonstrated the susceptibility of COVID-19 with the ABO blood groups [15, 16]. The study from Pakistan had a sample size of 1935 patients, with blood group B as the prevalent blood type (35.9%) with an increased susceptibility for COVID-19 infection (OR: 1.195 (95% CI: 1.04–1.36), p = 0.009) while blood groups A and O did not have statistically significant association of positive RT-PCR for SARS-COV-2. The other study from Bangladesh included 381 patients with a prevalence of blood group A in the COVID-19 cohort (32.9%, p<0.001), and no significant differences were observed in the duration of symptoms among other blood types. Our study exhibits contrasting results when compared to these investigations. Blood group O was prevalent in our study cohort (48.8%) and severe disease was associated with blood group A and O (41.1%, 35.1%, respectively). Hospital stay was more with blood type A and AB and higher mortality was associated with blood type A as well (13.9%).

In our previous study and a preprint, we demonstrated altered lipid profiles and thyroid function tests in association with COVID-19 disease and its severity along with acute phase reactants [17, 18]. Acute phase reactants were severely deranged in both study cohorts and there was a positive correlation with the higher classification of severity of COVID-19. A similar conclusion was given in a systematic review of 34 articles, showing the derangement of laboratory parameters with increasing severity of COVID-19 [19]. In this investigation, IL-6 and D-dimers were elevated in blood group A, Procalcitonin in blood group B, and CRP in blood group O. Similarly, a study from Canada reported no difference in acute phase reactants between blood groups A, AB, O, or B [20]. This phenomenon is still unclear with heterogeneous results in different populations and needs further work to understand the underlying mechanisms.

There were several limitations to this study. First, it was a single-center study and the retrospective nature limits the control of confounding factors. Second, due to the limited sample size of COVID-19 in the early stages, the sample size included in this study was not very large. Third, as it represented the population of one province, so a regional selection bias needs to be considered. Third, other comorbidities might influence the severity of the disease. Fourth, outcomes of the patients’ treatment were not examined in this study.

Conclusion

In conclusion, this investigation did not show significant association of blood groups with severity and of COVID-19 disease and COVID-19-associated mortality. Alteration of the acute phase reactants was not positively associated with any specific blood type.

Supporting information

S1 File

(SAV)

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Data Availability

All relevant data are within the paper and its Supporting Information files.

Funding Statement

The author(s) received no specific funding for this work.

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PLoS One. doi: 10.1371/journal.pone.0261432.r001

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21 Jun 2021

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Association of ABO blood group with COVID-19 severity, acute phase reactants and mortality

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3. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

**********

4. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: No

Reviewer #2: No

**********

5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: This study entitled “Association of ABO blood group with COVID-19 severity, acute phase reactants and Mortality” retrospectively analyzed the association between blood ABO groups and disease severity/mortality among the COVID-19 patients.

Some comments and questions were raised for the authors.

1. Many confounding factors would affect the clinical outcome (severity and mortality), such as comorbidities and medical treatment. Therefore, to minimize confounding bias, a multivariate analysis which includes variables of blood groups, comorbidities, and treatment should be performed to determine the risk factors associated with disease severity or mortality. If a certain blood group remains a risk factor for severe disease or mortality after a multivariate analysis, it would be more convincing to state that certain blood group is associated with severe disease and higher mortality.

2. The presentation and interpretation of some statistical results were not precise or not consistent throughout the manuscript. For example,

(1) Abstract, conclusions, “…hospital stay, severity of disease, and mortality were associated with blood group A.” -> However, hospital stay was not different between all four blood groups as mentioned in the Result section “Patients with AB blood group stayed a median (IQR) of 14 (5, 27) days while A blood group cohort stayed 13 (6,27) days. It was statistically non-significant between all four groups.” In addition, the mortality rates among 4 blood groups were not statistically different according to Table 1.

(2) Results: “Regarding severity of COVID-19 disease, there was a trend towards critical disease in blood groups A and O (n=83, 41.1%; n=183, 35.1%; OR, 11.34 (95% CI, 46.79-53.22); p<0.001).” Why was OR ratio here beyond the range of 95% CI? In addition, to determine the effect of blood group A and O on disease severity, blood group A and O should have individual OR.

(3) Discussion, “By contrast, we observed mild disease to be prevalent in the B and AB blood groups.“ -> The statement is not consistent with the data in Table 1.

(4) Discussion, “Acute phase reactants were majorly deranged in blood group O as compared to other groups and hospital stay was associated more with A and AB blood groups”. -> However, according to Figure 2, blood group O appeared to have the highest levels of acute phase proteins, whereas blood group O had the lowest levels of acute phase proteins in Table 1. Please check these data again.

(5) Conclusions, “In conclusion, we demonstrate that male patients with blood group A and O are associated with an increased risk of severe COVID-19 disease after gender stratification while group A is associated with increased hospital stay and mortality.”-> According to the context, the effect of gender was not examined in this study. Furthermore, the association of group A with increased hospital stay and mortality was not evident according to Table 1.

(6) What did “the number of days” mean in the figure 1 (cumulative incidence vs numbers of days)? What’s the unit for incidence here?

Overall, it would be helpful if the statistical analysis of this study is carefully reviewed again by a statistics expert.

Minor comments:

1. Method, “The severity of COVID-19 was classified into, mild, moderate, and critical according to the Centers for Disease Control (CDC) guidelines.” -> Please provide reference here.

2. Please define the headings of Table 3 (B, SE, Wald).

Reviewer #2: Several comments,

I. In general, the English grammar should be checked before submission

II. In the introduction, the authors should clearly describe the current status of studies about the association between ABO blood types and COVID-19. Both pros and cons options about this issue, especially severity and mortality, should also be cited in this section. Moreover, this section also lacks flow and transition sentences between paragraphs.

III. Materials and Methods

A. The definitions of COVID-19 severity are incorrect.

B. How to define COVID-19 related mortality?

IV. Results

A. How about the distribution of comorbidities (other than those described by authors) between different blood types?

B. The therapeutic strategies between patients with different blood types should be pointed out.

V. Discussion

A. The second paragraph only describes the results of this study. No comparison was made with prior studies.

B. In the third paragraph, the authors described different prevalent results of blood types among various studies, including themselves. More discussion should be made about such issues.

VI. Tables and figures

A. Table 2 is not clear

B. The resolution of figures is poor

**********

6. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #2: No

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

PLoS One. 2021 Dec 14;16(12):e0261432. doi: 10.1371/journal.pone.0261432.r002

Author response to Decision Letter 0

16 Jul 2021

Dear editors and reviewers

Thank you for taking out time to comment on this manuscript. Your comments were valuable in making this manuscript better.

Point to point response

Reviewer 1

Issue 1: Many confounding factors would affect the clinical outcome (severity and mortality), such as comorbidities and medical treatment. Therefore, to minimize confounding bias, a multivariate analysis which includes variables of blood groups, comorbidities, and treatment should be performed to determine the risk factors associated with disease severity or mortality. If a certain blood group remains a risk factor for severe disease or mortality after a multivariate analysis, it would be more convincing to state that certain blood group is associated with severe disease and higher mortality.

Response: We re-evaluated the data and did multivariate analysis with adjusting comorbid conditions and age/gender

Issue 2: Abstract, conclusions, “…hospital stay, severity of disease, and mortality were associated with blood group A.” -> However, hospital stay was not different between all four blood groups as mentioned in the Result section “Patients with AB blood group stayed a median (IQR) of 14 (5, 27) days while A blood group cohort stayed 13 (6,27) days. It was statistically non-significant between all four groups.” In addition, the mortality rates among 4 blood groups were not statistically different according to Table 1.

Response: we corrected the abstract as recommended.plz see

Issue 3: Results: “Regarding severity of COVID-19 disease, there was a trend towards critical disease in blood groups A and O (n=83, 41.1%; n=183, 35.1%; OR, 11.34 (95% CI, 46.79-53.22); p<0.001).” Why was OR ratio here beyond the range of 95% CI? In addition, to determine the effect of blood group A and O on disease severity, blood group A and O should have individual OR.

Response: OR corrected and added for both blood groups and mistakes rectified. Plz see

Issue 4: Discussion, “By contrast, we observed mild disease to be prevalent in the B and AB blood groups.“ -> The statement is not consistent with the data in Table 1.

Response: Very avid observation dear sir, we corrected the mistakes. Thank you for commenting. Plz see

Issue 5: Discussion, “Acute phase reactants were majorly deranged in blood group O as compared to other groups and hospital stay was associated more with A and AB blood groups”. -> However, according to Figure 2, blood group O appeared to have the highest levels of acute phase proteins, whereas blood group O had the lowest levels of acute phase proteins in Table 1. Please check these data again.

Response: we rechecked the data and new table is made with mean acute phae reactant values by our statistician. Plz see updated figure

Issue 6: Conclusions, “In conclusion, we demonstrate that male patients with blood group A and O are associated with an increased risk of severe COVID-19 disease after gender stratification while group A is associated with increased hospital stay and mortality.”-> According to the context, the effect of gender was not examined in this study. Furthermore, the association of group A with increased hospital stay and mortality was not evident according to Table 1.

Response: Thankyou dear sir for the observation. You are correct. We rectified the mistake

Minor comments:

1. Method, “The severity of COVID-19 was classified into, mild, moderate, and critical according to the Centers for Disease Control (CDC) guidelines.” -> Please provide reference here.

2. Please define the headings of Table 3 (B, SE, Wald).

Response: updated classification and reference added and table 2 headings dfined in table legend

Reviewer 2

Issue 1: I. In general, the English grammar should be checked before submission

Response: English syntax rechecked

Issue 2: In the introduction, the authors should clearly describe the current status of studies about the association between ABO blood types and COVID-19. Both pros and cons options about this issue, especially severity and mortality, should also be cited in this section. Moreover, this section also lacks flow and transition sentences between paragraphs.

Response: updated investigations added to intro for a better clarity and syntax imporved

Issue 3: Materials and Methods

A. The definitions of COVID-19 severity are incorrect.

B. How to define COVID-19 related mortality?

Response: definition update for severity classification of covid 19, and any death in which no other cause was apparent other than covid 19 was considered as covid associated mortality

Issue 4: IV. Results

A. How about the distribution of comorbidities (other than those described by authors) between different blood types?

B. The therapeutic strategies between patients with different blood types should be pointed out.

Response: dear sit I regret to inform that no other comorbidities were collected in our study and no therapeutic strategy was noted. That data is not available to us unfortunately.

Issue 5: Discussion

A. The second paragraph only describes the results of this study. No comparison was made with prior studies.

B. In the third paragraph, the authors described different prevalent results of blood types among various studies, including themselves. More discussion should be made about such issues.

Response: Discussion altered a little for more clarity

Issue 6; Tables and figures

A. Table 2 is not clear

B. The resolution of figures is poor

Figures cleared and table legends added

Editorial comments

Please include the tables within the main manuscript.

Included in the main text

Please note that in order to use the direct billing option the corresponding author must be affiliated with the chosen institute. Please either amend your manuscript to change the affiliation or corresponding author, or email us at plosone@plos.org with a request to remove this option.

Affiliation amended

Your ethics statement should only appear in the Methods section of your manuscript. If your ethics statement is written in any section besides the Methods, please move it to the Methods section and delete it from any other section. Please ensure that your ethics statement is included in your manuscript, as the ethics statement entered into the online submission form will not be published alongside your manuscript.

Ethics statement added to methods

Attachment

Submitted filename: response to reviewers.docx

Click here for additional data file.^{(15.1KB, docx)}

PLoS One. doi: 10.1371/journal.pone.0261432.r003

Decision Letter 1

Robert Jeenchen Chen

28 Jul 2021

PONE-D-21-18070R1

Association of ABO blood group with COVID-19 severity, acute phase reactants and mortality

PLOS ONE

Dear Dr. Malik,

Please address the issues and revise accordingly.

Please submit your revised manuscript by Sep 11 2021 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.
A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.
An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

We look forward to receiving your revised manuscript.

Kind regards,

Robert Jeenchen Chen, MD, MPH

Academic Editor

PLOS ONE

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: (No Response)

Reviewer #3: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

Reviewer #1: No

Reviewer #3: No

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: No

Reviewer #3: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

Reviewer #1: Yes

Reviewer #3: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

Reviewer #1: No

Reviewer #3: Yes

**********

6. Review Comments to the Author

Reviewer #1: In general, the presentation and interpretation of statistical results was still not precise in this revised manuscript.

Some comments and questions are listed below:

- Abstract: “Acute phase protein reactants” was included in the manuscript title; however, nothing was mentioned in the abstract.

- Abstract (Method): Information provided in the method was very limited.

- Abstract (Results): “Patients with AB blood group stayed a median (IQR) of 14 (5, 27) days while A blood group cohort stayed 13 (6,27) days and overall…” It is difficult to understand why the authors mentioned days of hospital stay for AB blood group and A blood group here, as the days of hospital stay were not significantly different between 4 groups. Why was AB blood group mentioned here in particular?

- Abstract (Results): “…overall 10.6% COVID-19-related mortality was observed at our center, with 13.9% in blood group A as the majority of COVID-19 deaths.” This part could be written as a separate sentence. In addition, although patients of blood group A had a higher proportion of mortality, patients with blood group O contributed to the majority of deaths.

- Abstract & Results: “Regarding severity of COVID-19 disease, there was a trend towards critical disease in blood group A (n=83, 41.1%; OR 0.257 (95% CI:0.167-1.136); p<0.001) and O (n=183, 35.1%; OR 0.438 (95% CI: 0.168-1.139); p<0.001).” The OR (95% CI) presented in this sentence were OR (95% CI) for “mortality” shown in Table 2 (multivariate analysis), but the proportions and p values presented in this sentence were the proportions and p values for critical diseases shown in Table 1 (univariate analysis). The presentation and interpretation of statistical results is confusing.

Result

- Please briefly describe the results of acute phase protein reactants in the text.

- “Multivariate analysis (after adjusting age, gender, and comorbidities) did not show any blood group in this cohort (Table 2).” This sentence was not clear.

- As the study aimed to exam the association between the blood group and disease severity, multivariate analysis should also be performed to identify risk factors associated with severity (as done in Table 2 which examined the association between the blood group and mortality by multivariate analysis.)

Discussion

- “, blood group O was linked to severe derangement of acute-phase reactants.” Data from Table 1 and Figure 2did not support this statement.

Conclusion

- “Alteration of the acute phase reactants is positively associated with blood type A.” Data from Table 1 and Figure 2 did not support this statement, and this statement was not consistent with “blood group O was linked to severe derangement of acute-phase reactants” mentioned in the Discussion section.

Figure

The resolution of Figure 2 was not enough.

Reviewer #3: Reviewer 2 asked

A. How about the distribution of comorbidities (other than those described by authors)

between different blood types?

B. The therapeutic strategies between patients with different blood types should be

pointed out.

Response: dear sit I regret to inform that no other comorbidities were collected in our

study and no therapeutic strategy was noted. That data is not available to us

unfortunately.

These are major confounding factors and should be assessed.

Other confounding factor is the time from the onset of the disease to hospital admission. It should be included to the analysis.

Please provide rationale support to assuring adequate sample power.

The authors stated that p"articipants had blood group O as the prevalent blood type." However this percentage should be compared with the distribution of blood groups in the country.

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #3: No

PLoS One. 2021 Dec 14;16(12):e0261432. doi: 10.1371/journal.pone.0261432.r004

Author response to Decision Letter 1

27 Aug 2021

Dear editors and reviewers

Thank you for taking out time to comment on this manuscript. Your comments were valuable in making this manuscript better.

Point to point response

Abstract: “Acute phase protein reactants” was included in the manuscript title; however, nothing was mentioned in the abstract.

Response: abstract corrected and acute phase protein results added

Abstract (Method): Information provided in the method was very limited.

Response: method info increased as advised

Abstract (Results): “Patients with AB blood group stayed a median (IQR) of 14 (5, 27) days while A blood group cohort stayed 13 (6,27) days and overall…” It is difficult to understand why the authors mentioned days of hospital stay for AB blood group and A blood group here, as the days of hospital stay were not significantly different between 4 groups. Why was AB blood group mentioned here in particular?

Response: results amended. Please see

Abstract (Results): “…overall 10.6% COVID-19-related mortality was observed at our center, with 13.9% in blood group A as the majority of COVID-19 deaths.” This part could be written as a separate sentence. In addition, although patients of blood group A had a higher proportion of mortality, patients with blood group O contributed to the majority of deaths.

Response: statement amended

Abstract & Results: “Regarding severity of COVID-19 disease, there was a trend towards critical disease in blood group A (n=83, 41.1%; OR 0.257 (95% CI:0.167-1.136); p<0.001) and O (n=183, 35.1%; OR 0.438 (95% CI: 0.168-1.139); p<0.001).” The OR (95% CI) presented in this sentence were OR (95% CI) for “mortality” shown in Table 2 (multivariate analysis), but the proportions and p values presented in this sentence were the proportions and p values for critical diseases shown in Table 1 (univariate analysis). The presentation and interpretation of statistical results is confusing.

Response: p values corrected

“Multivariate analysis (after adjusting age, gender, and comorbidities) did not show any blood group in this cohort (Table 2).” This sentence was not clear.

Response: Sentence corrected and Multivariate of disease severity added in table 3

blood group O was linked to severe derangement of acute-phase reactants.” Data from Table 1 and Figure 2did not support this statement.

Response: all statements regarding acute phase reactants corrected please see

Alteration of the acute phase reactants is positively associated with blood type A.” Data from Table 1 and Figure 2 did not support this statement, and this statement was not consistent with “blood group O was linked to severe derangement of acute-phase reactants” mentioned in the Discussion section

Response: all statements regarding acute phase reactants corrected please see

Regards

Attachment

Submitted filename: response to reviewers.docx

Click here for additional data file.^{(13.2KB, docx)}

PLoS One. doi: 10.1371/journal.pone.0261432.r005

Decision Letter 2

Robert Jeenchen Chen

6 Sep 2021

PONE-D-21-18070R2Association of ABO blood group with COVID-19 severity, acute phase reactants and mortalityPLOS ONE

Dear Dr. Malik,

Please address the concerns of the reviewer with unfavorable opinions and revise the manuscript. If not amendable, maybe put into the Limitations.

Please submit your revised manuscript by Oct 21 2021 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.
A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.
An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: https://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols. Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols.

We look forward to receiving your revised manuscript.

Kind regards,

Robert Jeenchen Chen, MD, MPH

Academic Editor

PLOS ONE

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

Reviewer #1: (No Response)

Reviewer #4: All comments have been addressed

Reviewer #5: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

Reviewer #1: No

Reviewer #4: Yes

Reviewer #5: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: I Don't Know

Reviewer #4: Yes

Reviewer #5: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

Reviewer #1: Yes

Reviewer #4: Yes

Reviewer #5: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

Reviewer #1: No

Reviewer #4: Yes

Reviewer #5: Yes

**********

6. Review Comments to the Author

Reviewer #1: All the earlier comments have been addressed by the authors. However, the interpretation and presentation of some results still appeared inaccurate. In many instances, some minor differences existed between groups without statistical differences, but they were presented as meaningful findings. Some expressions are also confusing, for example, “the frequency of acute phase reactants with ABO blood type” in text and “Frequency distribution of acute phase reactants in correlation with ABO blood group” in Figure 2. In addition, the data of acute phase reactants in table 1 looked quite different with those in Figure 2.

Reviewer #4: (No Response)

Reviewer #5: (No Response)

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #4: Yes: Parisa Sabbagh

Reviewer #5: Yes: Hamed Kalani

PLoS One. 2021 Dec 14;16(12):e0261432. doi: 10.1371/journal.pone.0261432.r006

Author response to Decision Letter 2

27 Sep 2021

Dear editors and reviewers

Thank you for taking out time to comment on this manuscript. Your comments were valuable in making this manuscript better.

Point to point response

Question: In many instances, some minor differences existed between groups without statistical differences, but they were presented as meaningful findings.

Response: all minor differences corrected and meaningless findings excluded from the manuscript

Question: Some expressions are also confusing, for example, “the frequency of acute phase reactants with ABO blood type” in text and “Frequency distribution of acute phase reactants in correlation with ABO blood group” in Figure 2.

Response: all confusing statements corrected

Question: In addition, the data of acute phase reactants in table 1 looked quite different with those in Figure 2.

Response: figure and table matched. Please see

Regards

Attachment

Submitted filename: response to reviewers.docx

Click here for additional data file.^{(12.4KB, docx)}

PLoS One. doi: 10.1371/journal.pone.0261432.r007

Decision Letter 3

Robert Jeenchen Chen

22 Nov 2021

PONE-D-21-18070R3Association of ABO blood group with COVID-19 severity, acute phase reactants and mortalityPLOS ONE

Dear Dr. Malik,

Please submit your revised manuscript by Jan 06 2022 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.
A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.
An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: https://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols. Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols.

We look forward to receiving your revised manuscript.

Kind regards,

Robert Jeenchen Chen, MD, MPH

Academic Editor

PLOS ONE

Journal Requirements:

Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

Reviewer #4: (No Response)

Reviewer #5: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

Reviewer #4: Yes

Reviewer #5: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #4: Yes

Reviewer #5: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

Reviewer #4: Yes

Reviewer #5: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

Reviewer #4: Yes

Reviewer #5: Yes

**********

6. Review Comments to the Author

Reviewer #4: Its a good and useful article. And also it has understandable and fluent text. Subject is updated and its one of the most important problem nowadays.

Reviewer #5: 1- Move sentence “Alteration of the acute phase reactants was not positively associated with any specific blood type” from section of Conclusion in Abstract to section of Results.

2- It should be noted in the discussion that the outcome of patients' treatment was not examined in this study and this is one of the limitations of this study.

3- Check for spelling and typographical errors throughout the text.

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #4: Yes: Parisa Sabbagh

Reviewer #5: No

PLoS One. 2021 Dec 14;16(12):e0261432. doi: 10.1371/journal.pone.0261432.r008

Author response to Decision Letter 3

23 Nov 2021

Dear editors and reviewers

Thank you for taking out time to comment on this manuscript. Your comments were valuable in making this manuscript better.

Point to point response

Question: Move sentence “Alteration of the acute phase reactants was not positively associated with any specific blood type” from section of Conclusion in Abstract to section of Results.

Response: Sentence moved to results

Question: It should be noted in the discussion that the outcome of patients' treatment was not examined in this study and this is one of the limitations of this study.

Response: Sentence added to limitations at the end of discussion

Question: Check for spelling and typographical errors throughout the text.

Response: Errors fixed

Regards

Attachment

Submitted filename: response to reviewers.docx

Click here for additional data file.^{(12.4KB, docx)}

PLoS One. doi: 10.1371/journal.pone.0261432.r009

Decision Letter 4

Robert Jeenchen Chen

2 Dec 2021

Association of ABO blood group with COVID-19 severity, acute phase reactants and mortality

PONE-D-21-18070R4

Dear Dr. Malik,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

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PLoS One. doi: 10.1371/journal.pone.0261432.r010

Acceptance letter

Robert Jeenchen Chen

3 Dec 2021

PONE-D-21-18070R4

Association of ABO blood group with COVID-19 severity, acute phase reactants and mortality

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Data Availability Statement

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PERMALINK

Association of ABO blood group with COVID-19 severity, acute phase reactants and mortality

Uzma Ishaq

Asmara Malik

Jahanzeb Malik

Asad Mehmood

Azhar Qureshi

Talha Laique

Syed Muhammad Jawad Zaidi

Muhammad Javaid

Abdul Sattar Rana

Roles

Abstract

Introduction

Methods

Results

Conclusion

Introduction

Methods

Results

Table 1. Patient demographics and baseline characteristics of COVID-19 patients with different blood groups.

Fig 1. Cumulative incidence and survival function Kaplan Meier curve of ABO blood type in COVID-19 cohort.

Fig 2. Levels of acute phase reactants in correlation with ABO blood groups.

Table 2. Multivariate analysis on ABO blood groups for associated mortality COVID-19 disease.

Table 3. Multivariate analysis on ABO blood groups for severity of COVID-19 disease.

Discussion

Conclusion

Supporting information

Data Availability

Funding Statement

References

Decision Letter 0

Robert Jeenchen Chen

Roles

Author response to Decision Letter 0

Decision Letter 1

Robert Jeenchen Chen

Roles

Author response to Decision Letter 1

Decision Letter 2

Robert Jeenchen Chen

Roles

Author response to Decision Letter 2

Decision Letter 3

Robert Jeenchen Chen

Roles

Author response to Decision Letter 3

Decision Letter 4

Robert Jeenchen Chen

Roles

Acceptance letter

Robert Jeenchen Chen

Roles

Associated Data

Supplementary Materials

Data Availability Statement

ACTIONS

PERMALINK

RESOURCES

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