Assessment of sub-maximal aerobic capacity in North African patients with chronic hepatitis B: a pilot case-control study

Jihene Bergaoui; Imed Latiri; Sawssen MRAD; Houda Chaouch; Salma Amous; Jihene Ben Abdallah; Samia Ernez Hajri; Helmi Ben Saad

doi:10.12688/f1000research.160390.2

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Research Article

Revised

Assessment of sub-maximal aerobic capacity in North African patients with chronic hepatitis B: a pilot case-control study

[version 2; peer review: 2 approved]

Jihene Bergaoui¹, Imed Latiri¹, Sawssen MRAD², [...] Houda Chaouch³, Salma Amous², Jihene Ben Abdallah², Samia Ernez Hajri¹, Helmi Ben Saad ¹

Jihene Bergaoui¹, Imed Latiri¹, [...] Sawssen MRAD², Houda Chaouch³, Salma Amous², Jihene Ben Abdallah², Samia Ernez Hajri¹, Helmi Ben Saad ¹

PUBLISHED 08 Apr 2025

Author details Author details

¹ Hospital Farhat HACHED, Research laboratory “Heart Failure, LR12SP09, Universite de Sousse Faculte de Medecine de Sousse, Sousse, Sousse, 4000, Tunisia
² Biochemistry Research Laboratory (LR18ES47), Farhat Hached University Hospital of Sousse, Sousse, Sousse, 4000, Tunisia
³ Department of Infectious Diseases, Viral Hepatitis Research Unit (UR12SP35), Farhat Hached University Hospital of Sousse, Sousse, Sousse, 4000, Tunisia

Jihene Bergaoui
Roles: Conceptualization, Formal Analysis, Investigation, Methodology, Validation, Visualization, Writing – Original Draft Preparation, Writing – Review & Editing

Imed Latiri
Roles: Conceptualization, Methodology, Validation, Visualization, Writing – Original Draft Preparation, Writing – Review & Editing

Sawssen MRAD
Roles: Data Curation, Validation, Visualization, Writing – Original Draft Preparation

Houda Chaouch
Roles: Data Curation, Validation, Writing – Original Draft Preparation, Writing – Review & Editing

Salma Amous
Roles: Data Curation, Visualization, Writing – Original Draft Preparation, Writing – Review & Editing

Jihene Ben Abdallah
Roles: Data Curation, Validation, Writing – Original Draft Preparation, Writing – Review & Editing

Samia Ernez Hajri
Roles: Data Curation, Project Administration, Writing – Original Draft Preparation, Writing – Review & Editing

Helmi Ben Saad
Roles: Conceptualization, Data Curation, Formal Analysis, Investigation, Methodology, Project Administration, Resources, Supervision, Validation, Visualization, Writing – Original Draft Preparation, Writing – Review & Editing

OPEN PEER REVIEW

REVIEWER STATUS

Abstract

Background

Studies assessing sub-maximal aerobic capacity in non-cirrhotic chronic hepatitis B (CHB) patients are scarce. This study aimed to evaluate sub-maximal aerobic capacity in CHB patients compared to apparently healthy participants (control-group (CG)).

Methods

A 6-min walk test (6MWT) was performed. The 6-min walk distance (6MWD) was recorded, along with heart-rate (HR), oxy-hemoglobin saturation (SpO₂), blood-pressure, and dyspnea ( ie ; visual analogue scale) at rest (Rest) and at the end (End) of the 6MWT. Additionally, the 6-min walk work (6MWW), and “estimated cardiorespiratory and muscular chain age” were calculated. Signs of physical intolerance were determined including abnormal 6MWD ( ie ; 6MWD < lower limit of normal), chronotropic insufficiency (ie ; HREnd < 60% of maximal predicted HR (MPHR)), high dyspnea ( ie ; dyspneaEnd > 5), and desaturation ( ie ; drop in SpO₂> 5 points).

Results

Compared to the CG (n=28), the CHB-group (n=26) exhibited significantly lower 6MWD by 61 meters (8%), lower 6MWW by 10%, and lower HR_End by 21% (when expressed in bpm) and 17% (when expressed in %MPHR). The CHB-group, compared to the CG, included higher percentages of participants with chronotropic insufficiency and abnormal 6MWD (23.08% vs. 3.57%, and 34.61% vs. 3.57%, respectively). The CHB-group was 8.1 and 14.3 times more likely to have chronotropic insufficiency and abnormal 6MWD than the CG, respectively. CHB accelerated the aging of the “cardiorespiratory and muscular chain” by 11 years.

Conclusion

Non-cirrhotic CHB may contribute to reduced submaximal aerobic capacity and acceleration of “cardiorespiratory and muscular chain” aging.

Keywords

Aerobic Capacity; Aging; Chronic Disease; Exercise Test; Physical Fitness; Physical Intolerance

Corresponding author: Helmi Ben Saad

Competing interests: No competing interests were disclosed.

Grant information: The author(s) declared that no grants were involved in supporting this work.

Copyright: © 2025 Bergaoui J et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

How to cite: Bergaoui J, Latiri I, MRAD S et al. Assessment of sub-maximal aerobic capacity in North African patients with chronic hepatitis B: a pilot case-control study [version 2; peer review: 2 approved]. F1000Research 2025, 14:98 (https://doi.org/10.12688/f1000research.160390.2) First published: 16 Jan 2025, 14:98 (https://doi.org/10.12688/f1000research.160390.1) Latest published: 08 Apr 2025, 14:98 (https://doi.org/10.12688/f1000research.160390.2)

Revised Amendments from Version 1

The major differences between this revised version of our article and the previously published version are as follows:
We calculated the odds ratio (OR) to assess the risk of CHB on aerobic capacity and the acceleration of aging in the cardiorespiratory and muscular systems. Specifically, we determined the OR for two key variables: abnormal 6MWD and chronotropic insufficiency.
For quantitative data, we calculated the mean percentage change between the two groups and the delta percentage change for variables measured at rest and at the end of the walk, including heart-rate, oxy-hemoglobin saturation, blood-pressure, and dyspnea.
We removed several 6MWD indices from statitical analysis.
We removed Figure 2 to avoid redundancy with Table 2.
We clarified the recruitment method of the control group and acknowledged convenience sampling as a study limitation.
We discussed the significant differences between the two groups in terms of age, education level, and socioeconomic status.
We recommended that future studies assess the physiological cost index, which is determined by dividing the difference between end-exercise and resting heart rates by walking speed.
We modified and improved our conclusion.
We revised the English version using a generative AI tool.

See the authors' detailed response to the review by Khadija Ayed
See the authors' detailed response to the review by Kaouther MASMOUDI

Introduction

Viral hepatitis B (VHB) induces significant morbidity and mortality in the general population.¹ VHB can progress to chronicity if it persists for more than six months and can induce systemic manifestations.¹^–³ In addition to hepatic conditions such as cirrhosis or hepatocellular carcinoma, chronic hepatitis B (CHB) causes extrahepatic effects, which can impact exercise capacity [ eg ; myocardial damage and alterations in pulmonary and muscle function]⁴^–⁸ and significantly worsen the morbidity and mortality associated with CHB,² with potential social disadvantages.⁶^,⁸^,⁹ Some studies have reported the harmful impacts of CHB on the main elements of the chain involved during adaptation to both maximal effort ( eg ; maximal oxygen consumption ( $\dot{V} O_{2}$ max))⁹^,¹⁰ and sub-maximal aerobic exercise ( eg ; 6-min walk test (6MWT))¹⁰^,¹¹, namely the cardiorespiratory and muscular chain (CRMC).³^,⁴^,⁸^,¹⁰ First, it “seems” that the resting cardiovascular system of CHB patients is altered, with 3% of them having cardiovascular disease.¹² Second, CHB induces a decrease in resting lung function, such as the forced vital capacity and/or forced expiratory volume in one second.⁸ Third, CHB causes weakness of respiratory muscles with low maximal inspiratory and expiratory pressures,⁸ and can affect muscle fibers leading to muscle injuries.⁵^,¹³

Exercise tolerance is commonly quantified through the measurement of oxygen consumption ( $\dot{V} O_{2}$ ) during a cardiopulmonary exercise testing, which necessitates advanced and expensive equipment, highly skilled personnel for its operation, and substantial financial resources.¹⁴ These limitations have led to the adoption of simpler assessments, such as the 6MWT.¹⁵^,¹⁶ The latter offers several advantages including enhanced safety, ease of administration, closer alignment with everyday activities, cost-effectiveness, and ready implementation on a large scale.¹⁵^,¹⁶ Over the past two decades ( ie ; 2004-2024), the 6MWT has been extensively utilized in assessing functional exercise performance across diverse populations, including those with pulmonary, cardiac, and neuromuscular diseases.¹⁷^–²⁰ Studies assessing CHB-related incapacity in terms of maximal and sub-maximal aerobic exercise impairment are scarce.⁹^–¹¹ As of late March 2025, it “seems” that only two studies have assessed $\dot{V} O_{2}$ in CHB patients,⁹^,¹⁰ and only one Saudi study has compared the 6MWT data of CHB patients to those of healthy participants.¹¹ On the one hand, $\dot{V} O_{2}$ at peak of exercise ( $\dot{V} O_{2}$ peak) was a predictor of mortality, as patients with a low $\dot{V} O_{2}$ peak ( ie ; < 17 ml/kg) had a survival rate of 55%,¹⁰ and it is significantly correlated with maximal inspiratory pressure (r = 0.64) and with the model for end-stage liver disease (r = 0.91).⁹ On the other hand, the authors of the Saudi study reported that compared to healthy participants (n=45), patients with CHB (n=49) had a significantly lower 6-min walk distance (6MWD) by 31 m.¹¹ The Saudi study had some methodological weaknesses that can “slightly” modify the findings.¹¹ First, the inclusion of patients with diverse liver diseases ( eg ; non-cirrhotic chronic hepatitis B (NC-CHB) or C, cirrhotic), is a source of ‘perplexity’ since the clinical outcomes are different.⁶ Second, the absence of sample size determination is a statistical flaw.²¹ Third, the expression of the main outcome ( ie ; 6MWD) only in absolute value, and the lack of its standardization according to participants’ characteristics ( eg ; sex and anthropometric data), could lead to misinterpretation.⁸^,¹⁰^,¹¹ The standardized 6MWD allows a more objective comparison between the diverse groups.²² Fourth, the use on the quantitative significance approach with a “p value” < 0.05 is criticized, and the qualitative significance approach is recommended in medical exercise research.²³

To the finest of the authors’ knowledge, no previous study has explored the aerobic incapacity via the 6MWT in a homogeneous group of NC-CHB patients compared to a control-group (CG) of “apparently” healthy participants. The main aim of this case-control study was to compare the 6MWT data of the CHB-group and CG. The null hypothesis was that the two groups would have a comparable 6MWD ( ie ; the main outcome).

Methods

The present study is part of a larger project, involving two groups (CHB patients and “apparently” healthy controls) and comprising three parts. The project’s methodology was published as a “protocol in progress”.⁶ The first part of the project evaluated muscle-mass and strength in CHB patients.⁷ The main conclusion was that NC-CHB does not affect muscle-mass and strength.⁷ The second part, which is the focus of this study, examines sub-maximal aerobic capacity. The third and fourth parts will evaluate the quality-of-life and oxidative status of the two aforementioned groups, respectively.

Study design

This project is a case-control study conducted during the decline of the coronavirus disease (COVID-19) pandemic in Tunisia ( eg ; September 2020). The study was conducted in collaboration with the department of physiology at the faculty of medicine of Sousse (Sousse, Tunisia) and three departments from Farhat HACHED hospital in Sousse ( ie ; infectious diseases, biochemistry, and hematology). The study was conducted following the guidelines established by the STROBE statement.²⁴

Each participant received comprehensive information about the study’s objectives, procedures, potential risks, and other pertinent details. After this thorough briefing, we obtained written informed consent from all participants, confirming their voluntary involvement in the study. Additionally, each participant was provided with a report of his/her individual evaluations.

Study population

Two groups of participants ( ie ; cases and controls) were recruited (Figure 1).

Figure 1. Study flow chart.

CHB: chronic hepatitis B. M: man. W: woman.

Cases were selected from patients followed for VHB infection, who had undergone histological evaluation by liver-biopsy or fibroscan within the last four years prior to inclusion in the study at the above infectious diseases department. Diagnosis of hepatitis B virus (HBV) infection was based on a positive result for hepatitis B surface antigen (HBsAg) for at least six months. Patients were eligible for inclusion if they were aged between 25 and 55 years, had an HBV-DNA viral load higher than 2000 IU/ml confirmed at least one year prior to inclusion, and showed no significant pathological fibrosis, as indicated by a fibroscan score less than 6 kPa and/or a “meta-analysis of histological data in viral hepatitis” score less than A2F2. Exclusion criteria were as follows: physical or mechanical impairments that could interfere with the 6MWT such as a history of orthopedic or rheumatologic diseases, contraindications for the 6MWT like signs of unstable angina or myocardial infarction within the previous month, resting heart-rate (HR) higher than 120 bpm, and abnormal blood-pressure (BP) (ie; systolic BP (SBP) > 180 mmHg, or diastolic BP (DBP) > 100 mmHg),¹⁶ comorbidities such as respiratory or cardiovascular diseases, systemic conditions that could influence blood test results like diabetes mellitus²⁵ or renal failure, consumption of alcohol, co-infection with other viruses, liver damage, or the requirement for CHB treatment during the study period.

Controls were “apparently” healthy participants, non-alcohol consumers, aged between 25 and 55 years, without any chronic disease, physical problems, COVID-19 infection, or 6MWT contraindications.¹⁶

Files of participants, from both groups, with missing biological data were excluded from the final statistical analysis.

Sample size

The sample size was calculated using this equation²⁶:

N = ((r + 1) {(Z_{α / 2} + Z_{1 - β})}^{2} s^{2}) / ({rd}^{2});

where

• “ N ” is the required number of participants (N = n₁ + n₂, such as n₁ and n₂ are the sample sizes for the case and control groups);
• “ Z _α/2” is the normal deviate at a level of significance (1.96 for a 5% level of significance);
• “ Z _1-β” is the normal deviate at 1- β% power with β% of type II error (1.28 at 90% statistical power);
• “ r ” (= n₁/n₂) is the ratio of sample sizes required for the two groups (r = 1 gives a 1:1 sample size distribution for the two groups); and
• “ s ” and “ d ” are the pooled standard-deviation (SD) and difference of 6MWD means between the two groups. These values were derived from a previous Saudi case-control study comparing the 6MWD of CHB patients to healthy participants.¹¹ The controls and cases had 6MWD means of 421 and 390 m, respectively, with a mean SD of 50 m.

Inserting these values into the predictive equation resulted in a total sample size of 54 participants (27 in each group). Assuming a 10% loss of biological data, a revised sample size of 60 participants was determined (60 = 54/(1-0.10)).

Study protocol

The explorations were conducted indoor between 8:00 AM and 12:00 PM, with four participants examined per day, and an average time of 60 minutes per participant. The study protocol included the following steps:

• Signing of consent and completion of medical questionnaires.
• Collection of anthropometric data and blood samples.
• Bioelectrical impedance analysis.
• Consumption of a food snack of choice.
• Measurement of handgrip-strength.
• Performance of the 6MWT.

Applied questionnaires

A questionnaire comprising three parts was administered by one qualified examiner ( JB in the authors’ list). The mean duration of the questionnaire was approximately 20 minutes.

The first part was a standard medical questionnaire (widely used in the infectious diseases and physiology departments) aiming at collecting clinical and socioeconomic data. Questions were asked in Arabic. Clinical histories, such as previous hospitalization, comorbidities, and viral co-infections were recorded. Cigarettes smoking was evaluated in pack-years, and participants were classified into two groups (non-smoker: <5 pack-years; smoker³: ≥5 pack-years).⁶ Depending on alcohol consumption habits, participants were classified into two groups (consumer/non-consumer).⁶ Socioeconomic-level was determined according to the participant’s profession, with two levels defined ( ie ; unfavorable and favorable).⁶ Schooling level was arbitrarily defined as low and high.⁶ Parity (the number of children born to a woman) was noted. Since the 2023 Tunisian global fertility rate was 2.09 children per woman, a parity greater than two was considered “high”.²⁷^,²⁸

The second part of the questionnaire was linked to the physical-activity (PA) level, which was estimated using the Voorrips questionnaire.²⁹ This questionnaire is reproducible, and its score is positively related to the 24-hour measurement of the PA as assessed by a pedometer.²⁹ While the Arabic version is not validated, it has been widely used in previous studies.³⁰^–³² This questionnaire contains 51 items assessing various scores, which are divided into three categories of PA ( ie ; daily, sports, and leisure activities). The sum of the three scores represents the total PA score. According to the total score, participants were divided into two groups: sedentary (score <9.42) and active (score ≥9.42).²⁹

The third part of the questionnaire was related to the evaluation of quality-of-life using the chronic liver diseases questionnaire.³³ Data from this part will be analyzed in a subsequent study.

Sex and anthropometric data

Age (in years) and sex (man; woman) were documented for each participant. Height was measured in centimeters using a Siber Hegner ^® standing stadiometer, with participants standing upright, without shoes, heels together, and back straight. Weight (in kilograms), muscle-mass (in percentage), and body fat (in percentage) were assessed using a Beurer BF-600 (Beurer GmbH, Germany) bioelectrical impedance analyzer in the morning after an overnight fast, with participants in a standing position.³⁴ Body mass index (BMI, kg/m²) was determined. Participants corpulence status was categorized as follows³⁵: underweight (BMI < 18.5 kg/m²), normal weight (BMI: 18.5–24.9 kg/m²), overweight (BMI: 25–29.9 kg/m²), and obesity (BMI ≥ 30 kg/m²). All measurements were conducted by a single qualified examiner ( JB in the authors’ list).

Biological data

Some biological data ( eg ; hemoglobin, erythrocyte-sedimentation-rate, C-reactive-protein, interleukin-6, alkaline-phosphatase, alanine-aminotransferase, aspartate-aminotransferase, gamma-glutamyl-transpeptidase, total-bilirubin, non-conjugated-bilirubin, ( ie ; antioxidant stress marker),³⁶ albumin ( ie ; antioxidant stress marker),³⁷^,³⁸ and uric-acid ( ie ; oxidant-antioxidant balance marker)³⁹ were collected by a nurse. Some of these biological data and their technical aspects were detailed elsewhere.⁶^,⁷

Handgrip strength

Handgrip-strength, the technique and findings of which were detailed elsewhere,⁶^,⁷ was performed by one qualified examiner ( JB in the authors’ list). For this study, the highest absolute handgrip-strength value (kg) between the two hands of each participant was retained.

6-min walk test

Sub-maximal aerobic capacity was evaluated using the 6MWT, supervised by one qualified examiner ( IL in the authors’ list). Participants were asked to wear comfortable clothing and appropriate footwear for walking, and to avoid strenuous exercise in the two hours preceding the 6MWT.¹⁶ A single 6MWT was performed in a 40 m flat corridor indoor ( ie ; physiology department), which was marked every meter with start and end indicators.⁴⁰ Instructions given before the 6MWT followed the most updated guidelines,¹⁶^,⁴⁰ that included “walk as far as possible for 6 minutes”. Participants were informed that they could slow down, stop, rest as needed, and resume walking when able.¹⁶^,⁴⁰ Participants were instructed not to run under any circumstances, and no encouragement or walking aids were provided during the 6MWT.¹⁶^,⁴⁰ The remaining time was announced every minute ( eg ; you have × minutes left).¹⁶^,⁴⁰ The examiner did not walk with the participants to avoid influencing their walking speed.

The following 6MWT data were recorded: HR [bpm, % of maximal predicted HR (MPHR (bmp) = 208-0.7 × Age (year))],⁴¹ dyspnea (absolute value), BP (mmHg), oxy-hemoglobin saturation (SpO₂, %), number of stops while walking, and 6MWD (m, %). The 6-min walk work (6MWW, m.kg), the product between 6MWD and weight was calculated.⁴² HR, SpO₂, SBP, DBP, and dyspnea were measured while the participant was seated at rest (_Rest) and immediately at the end (_End) of the 6MWT.¹⁶^,⁴⁰ The HR and SpO₂ were measured using a handheld pulse oximeter (M700, Biolight CO., LTD. China), and BP was measured using a manual tensiometer and a stethoscope. Dyspnea was measured on a visual analog scale (VAS) ranging from 0 (no dyspnea) to 10 (maximum dyspnea).⁴³

The 6MWD was expressed both in absolute value (m) and as a percentage of the predicted 6MWD.²²^,⁴⁴ For participants under 40 years of age, the following predictive equation for 6MWD specific to the North African population was applied: 6MWD (m) = 800.05-64.71 × Sex (0: Man; 1: Woman) - 10.23 × BMI (kg/m²) - 1.63 × Age (years) + 2.05 × Weight (kg).⁴⁴ For this group, the lower limit of normal (LLN) was calculated by subtracting 74.31 m from the predicted 6MWD value.⁴⁴ For participants older than 40 years of age, the following predictive equation for 6MWD specific to the North African population was applied: 6MWD (m) = 720.50-160.27 × Sex (0: Man; 1: Woman) - 5.14 × Age (years) - 2.23 × Weight (kg) + 271.98 × Height (m).²² For this group, the LLN was calculated by subtracting 89 m from the predicted 6MWD value.²²

Since the 6MWT assesses the integrated response of the CRMC,⁴⁰^,⁴⁵^,⁴⁶ the estimated CRMC (ECRMC) age was calculated using the following formulas: ECRMC (years) = 184.25-0.36 × measured 6MWD (m) + 44.39 × Height (m) - 13.87 × Sex (0: Man; 1: Woman); for participants under 40 years of age⁴⁴; and ECRMC (years) = 140.17-0.19 × measured 6MWD (m) - 31.18 × Sex (0: Man; 1: Woman) - 0.43 × Weight (kg) + 52.91 × Height (m); for participants aged 40 years and more.²²

The following definitions were applied based on previous studies²²^,⁴⁷^,⁴⁸:

i) Signs of walking intolerance: abnormal 6MWD ( ie ; 6MWD < LLN), stopping while walking, high dyspnea ( ie ; dyspnea _End >5/10);
ii) Clinically significant desaturation: drop in SpO₂ >5 points; and
iii) Chronotropic insufficiency: HR _End <60%.

Statistical analysis

The distribution of quantitative data was analyzed using the Shapiro-Wilk W test. Data were expressed as means±SD (and 95% confidence intervals) when the normality test was met. If not, data were presented as medians (interquartile range). For quantitative data, mean percentage changes (%) between the two groups were calculated [mean percentage change = 100 × (CHB-group mean value minus CG mean value)/CHB-group mean]. For each group, percentage delta changes (∆) between data determined at _Rest and _End walk were calculated for HR, SpO₂, SBP, DBP, and dyspnea VAS [ ie ; ∆HR (%) = 100 × (HR_End – HR_Rest)/HR_Rest, ∆SpO₂ (%) = 100 × (SpO_2End − SpO_2Rest)/SpO_2Rest, ∆SBP (%) = 100 × (SBP_End – SBP_Rest)/SBP_Rest, and ∆DBP (%) = 100 × (DBP_End – DBP_Rest)/DBP_Rest].

The Wilcoxon matched-pairs test was used to compare chronological and ECRMC ages within each group. To compare data between the two groups, two significant approaches were applied. The quantitative (statistical) approach consists in using the Mann-Whitney U and Chi-2 tests to compare quantitative and categorical data, respectively, between the two groups. The qualitative (clinical) approach consists in comparing percentages of participants with walking intolerance signs, desaturation, chronotropic insufficiency using the 2-sided Chi-2 test. Moreover, to confirm the risk of CHB on aerobic capacity, odds ratios were calculated for abnormal 6MWD and chronotropic insufficiency. Hedge’s unbiased d value was used to measure the effect size of the main outcome ( ie ; 6MWD).⁴⁹ The effect size was described as small (≤0.2), medium (around 0.5), large (around 0.8), or very large (³1.30).⁴⁹

All statistical procedures were performed using. STATISTICA (data analysis software system, version 12. www.statsoft.com, RRID: SCR_014213). The significance level was set at p<0.05.

Results

Out of the 128 participants assessed, data from 54 participants [26 cases (15 men/11 women) and 28 controls (15 men/13 women)] were retained for the final dataset (Figure 1).

Table 1 presents the characteristics of the two groups of participants. Compared to the CG, the CHB-group was ≈5 years older and included higher percentages of participants with low schooling-level, and unfavorable socioeconomic-level. The two groups had comparable handgrip-strength values and PA scores and included comparable percentages of smokers and sedentary participants. No participant consumed alcohol.

Table 1. Characteristics of the chronic hepatitis B (CHB, n=26) and control (CG, n=28) groups.

Data	Unit/category	CHB-group	CG	Mean change (%)	p-value
Sex and anthropometric data
Sex^b	woman	11 (42.31)	13 (46.43)	-	0.761
Chronological age^a	year	42±6 (40 to 45)	37±7 (34 to 39)	12%	0.006^*
ECRMC age^a	year	53±26 (43 to 64)	25±28 (14 to 36)	53%	0.001^*
Delta age (chronological age – ECRMC age)^a	year	-11±24 (-21 to -2)^#	12±25 (2 to 22)^#	209%	0.001^*
Age range < 40^b	years	10 (38.46)	20 (71.43)	-	0.015^*
Height^a	cm	171±10 (167 to 175)	173±10 (169 to 176)	-1%	0.822
Weight^a	kg	82±18 (74 to 89)	82±14 (76 to 87)	0%	0.634
Muscle-mass^a	%	34±8 (6 to 10)	35±7 (6 to 10)	-1%	0.883
Body fat^a	%	33±15 (11 to 20)	31±13 (10 to 17)	6%	0.863
Body mass index^a	kg/m²	27.8±5.8 (25.5 to 30.2)	27.5±4.1 (25.9 to 29.1)	1%	0.979
Corpulence status^b	normal weight	9 (34.61)	7 (25.00)	-	0.728
	overweight	10 (38.46)	13 (46.42)	-
	obesity	7 (26.92)	8 (28.57)	-
Parity, habits, socioeconomic data
Parity^a		2±1 (1 to 2)	1±1 (1 to 2)	50%	0.247
High parity^b	>2	1 (3.84)	1 (3.57)	-	0.969
Smoker^b	yes	10 (38.46)	5 (17.85)	-	0.091
Schooling-level^b	low	8 (30.76)	1 (3.57)	-	0.007^*
Socioeconomic-level^b	unfavorable	9 (34.61)	3 (10.71)	-	0.035^*
Physical activity scores and levels
Daily activities^a		1.77±0.45 (1.58 to 1.95)	1.76±0.81 (1.45 to 2.08)	0	0.436
Sports activities^a		0.72±2.03 (-0.10 to 1.54)	2.13±3.88 (0.62 to 3.63)	-196%	0.279
Leisure activities^a		0.75±1.63 (0.0 to 1.41)	0.38±0.84 (0.05 to 0.71)	49%	0.653
Total score^a		3.24±3.18 (1.95 to 4.52)	4.27±4.45 (2.55 to 6.00)	-32%	0.616
Sedentary^b		25 (96.15)	25 (89.29)	-
Muscle function
Handgrip strength (highest absolute value)^a	kg	41±10 (8 to 14)	43±13 (11 to 18)	-5%	0.697
Viral charge, liver-biopsy puncture and fibroscan score
Viral charge^c	IU/mL	5230 (3180-12786)	-	-	-
Liver-biopsy puncture^α, b	A0F0	4 (30.77)	-	-	-
	A0F1	3 (23.07)	-	-	-
	A1F0	1 (7.69)	-	-	-
	A1F1	5 (38.46)	-	-	-
Fibroscan score^β, a	KPa	4.67±1.15	-	-	-

a Mean±standard deviation (95% confidence interval);

b Number (%);

c Median (interquartile range).

* p-value < 0.05 (Mann-Whitney U test or 2-sided Chi-2): CHB group vs. CG.

# p-value < 0.05 (Wilcoxon matched pairs test): Chronological age vs. ECRMC age for each group.

α Liver biopsy puncture was performed in 13 patients.

β Fibroscan score was performed in 21 patients.

The CHB-group and the CG had comparable values of hemoglobin (14.51±1.92 vs. 14.54±1.79 g/dL, respectively), erythrocyte-sedimentation-rate (6.96±7.13 vs. 7.36±6.95, respectively), C-reactive-protein (5.39±0.98 vs. 5.93±1.54 mg/L, respectively), alkaline-phosphatase (50.61±16.60 vs. 41.64±16.07 UI/L, respectively), alanine-aminotransferase (16.26±6.58 vs. 16.89±11.54 UI/L, respectively), aspartate-aminotransferase (21.77±5.09 vs. 20.89±13.02 UI/L, respectively), gamma-glutamyl-transpeptidase (15.54±9.55 vs. 15.46±10.76 UI/L, respectively), non-conjugated-bilirubin (12±16 vs. 9±5 μmol/L, respectively), total-bilirubin (14±16 vs. 10±5 μmol/L, respectively), albumin (44±3 vs. 44±3 g/L, respectively), uric-acid (258±82 vs. 253±60 μmol/L, respectively), and interleukin-6 (1.7±0.9 vs. 1.9±1.7, respectively.

Table 2 presents the 6MWD and the 6MWW values of the two groups of participants. Compared to the CG, the CHB-group covered a statistically significantly shorter distance by 10% when expressed in m (702±60 vs. 641±57 m, respectively) and by 8% when expressed in percentage of predicted value (103±8 vs. 95±12%, respectively). The Hedge’s unbiased d for the 6MWD (m, %) were small at -1.026 and -0.980, respectively. Compared to the CG, the CHB-group had statistically lower 6MWW by 10%.

Table 2. 6-min walk distance (6MWD) and 6-min walk work (6MWW) values of the chronic hepatitis B (CHB, n=26) and control (CG, n=28) groups.

Data	Unit	CHB-group	CG	Mean change (%)	p-value
6MWD	m	641±57 (618 to 664)	702±60 (678 to 725)	-10%	0.001^*
6MWD	%	95±12 (90 to 100)	103±8 (100 to 106)	-8%	0.003^*
6MWW	m.kg	52194±12001 (9412 to 16567)	57459±11121 (8792 to 15137)	-10%	0.070^*

* p-value < 0.05 (Mann-Whitney U test or 2-sided Chi-2): CHB-group vs. CG.

Table 3 presents the HR values of the two groups of participants. Compared to the CG, the CHB-group had statistically lower HR _End by 21% (when expressed in bpm) and 17% (when expressed in %MPHR), and ∆HR by 48%, and included a higher percentage of participants with chronotropic insufficiency. The CHB-group was 8.1 times more likely to have chronotropic insufficiency than the CG.

Table 3. Heart rate (HR) data of the chronic hepatitis B (CHB, n=26) and control (CG, n=28) groups.

Data	Unit	CHB group	CG	Mean change (%)	p-value
HR _Rest^a	bmp	67±8 (64 to 71)	68±11 (64 to 72)	-1%	0.843
HR _Rest^a	%MPHR	38±4 (36 to 40)	37±6 (35 to 40)	3%	0.737
HR _End^a	bpm	127±27 (116 to 138)	153±22 (145 to 162)	-21%	0.001^*
HR _End^a	%MPHR	71±14 (65 to 77)	83±13 (78 to 88)	-17%	0.005^*
Delta HR = 100 x (HR _End - HR _Rest)/HR_Rest^a	%	88±33 (75 to 102)	130±47 (112 to 148)	-48%	0.001^*
Chronotropic insufficiency^b	-	6 (23.08)	1 (3.57)	-	0.033^*

a Mean±standard deviation (95% confidence interval) .

b Number (%).

* p-value < 0.05 (Mann-Whitney U test or 2-sided Chi-2): CHB-group vs. CG.

All participants completed the 6MWT and none stopped during the test. Table 4 presents the values of BP, SpO₂, and dyspnea, and exercise intolerance’ signs of the two groups of participants. The two groups had comparable BP, SpO₂, and dyspnea, and included comparable percentages of participants with desaturation and high dyspena _End. Compared to the CG, the CHB-group had a statistically higher ∆SpO₂ by 180% and included a significantly higher percentage of participants with an abnormal 6MWD. The CHB-group was 14.3 times more likely to have an abnormal 6MWD than the CG.

Table 4. Blood-pressure, oxy-hemoglobin saturation (SpO₂), dyspnea, and exercise intolerance’ signs of the chronic hepatitis B (CHB, n=26) and control (CG, n=28) groups.

Data (unit)	Phase or applied definitions	CHB-group	CG	Mean change (%)	p-value
Blood-pressure, SpO₂, and dyspnea
SBP (mmHg)^a	_Rest	119±13 (114 to 125)	114±12 (109 to 119)	4%	0.130
	_End	148±21 (139 to 156)	147±20 (139 to 154)	1%	0.972
	∆ = 100 x (SBP_End - SBP_Rest)/SBP_Rest	24±16 (17 to 31)	29±15 (23 to 35)	-21%	0.283
DBP (mmHg)^a	_Rest	77±11 (72 to 82)	73±11 (69 to 78)	5%	0.257
	_End	79±9 (75 to 83)	77±13 (72 to 82)	3%	0.341
	∆ = 100 x (DBP_End - DBP_Rest)/DBP_Rest	4±16 (-2 to 11)	6±15 (-0 to 12)	-50%	0.795
SpO₂ (%)^a	_Rest	97.9±0.9 (97.5 to 98.3)	98.3±0.8 (97.9 to 98.6)	0%	0.188
	_End	98.4±0.9 (98.0 to 98.7)	97.9±1.2 (97.4 to 98.4)	1%	0.177
	∆ = 100 x (SpO_2End - SpO_2Rest)/SpO_2Rest	0.52±1.20 (0.03 to 1.00)	-0.36±1.42 (-0.91 to 0.19)	180%	0.005^*
VAS dyspnea^a	_Rest	0	0	-	-
VAS dyspnea^a	_End	1.6±1.2 (1.1 to 2.1)	1.1±0.8 (0.8 to 1.5)	31%	0.156
Exercise intolerance’ signs
Drop in SpO₂^a	SpO_2End - SpO_2Rest	0.50±1.17 (0.03 to 0.97)	-0.36±1.39 (-0.90 to 0.18)	180%	0.007^*
Desaturation^b	Drop in SpO₂ > 5 points^b	0	0	-	-
High dyspnea_End^b	Dyspnea_End > 5^b	0	0	-	-
Abnormal 6MWD^b	6MWD < LLN^b	9 (34.61)	1 (3.57)	-	0.003^*

a Mean±standard deviation (95% confidence interval).

b Number (%).

* p-value < 0.05 (Mann-Whitney U test or 2-sided Chi-2): CHB-group vs. CG.

Compared to the CG, the CHB-group had a higher ECRMC age by 28 years (25±28 vs. 53±26 years, respectively) (Table 1). The comparison of chronological and ECRMC ages revealed accelerated aging of the CRMC by 11 years in the CHB-group, and decelerated aging in the CG by 12 years (Table 1).

Discussion

This case-control study reveals that CHB impacts sub-maximal aerobic capacity. Specifically, compared to the CG, the CHB-group demonstrated statistically significant reduction in 6MWD by 61 m (8%). Consequently, the null hypothesis that the two groups would have comparable 6MWD was rejected. Moreover, compared to the CG, the CHB-group demonstrated statistically significant lower 6MWW by 10%, and HR_End by 21% (when expressed in bpm) and 17% (when expressed in %MPHR). Additionally, the CHB-group was 8.1 and 14.3 times more likely to have chronotropic insufficiency and abnormal 6MWD than the CG, respectively. Furthermore, CHB was found to accelerate the aging of the CRMC by 11 years.

As of late March 2025, and to the best of the authors’ knowledge, only one Saudi study,¹¹ detailed in Appendix 1 has compared 6MWT data of patients with hepatic pathologies, including 49 CHB patients, to those of a CG.

Discussion of results

The CHB-group had a lower 6MWD by approximately 61 m compared to the CG, aligning with the Saudi study,¹¹ which reported a difference of about 41 m. Additionally, the CHB-group exhibited an approximately 8% lower 6MWD expressed as a percent of predicted value ( Table 2). No previous study have expressed the 6MWD as a percent of a predicted value. Compared to the CG, the CHB-group had lower 6MWW by 10%. The 6MWW index in CHB patients have not been previously evaluated. The 6MWW, reflecting the work done during the 6MWT, has been assessed in conditions such as human immunodeficiency virus infection and chronic obstructive pulmonary disease, which reported lower 6MWWs in chronic patient.⁵⁰^–⁵²

No previous studies have compared HR, SpO₂, BP, and dyspnea data between CHB and CGs. Compared to the CG, our CHB-group had lower HR_End (bpm and %MPHR) by 21% and 17%, respectively, and ΔHR by 48%, and included a higher percentage of patients exhibiting chronotropic insufficiency (4% vs. 23%). Despite being “apparently” free from cardiovascular diseases, chronotropic insufficiency in CHB patients could be a preclinical sign of incipient cardiovascular pathology, as 3% of CHB patients are reported to develop cardiovascular diseases.¹²

Compared to the CG, the CHB-group had a higher ΔSpO₂ by 180%, but comparable SpO_2Rest and SpO_2End. The higher ΔSpO₂ observed in our CHB-group lacks clinical significance as both groups had comparable SpO₂ values, and no participant experienced “clinically significant desaturation”. This suggests that the alveolo-capillary membrane of CHB patients remains intact.

Both groups had comparable BP and VAS dyspnea, indicating that CHB does not significantly affect BP or dyspnea.

Compared to the CG, the CHB-group had a higher ECRMC’ age by 23 years (Table 1). The ECRMC age for the CHB and control groups was higher by 11 years and lower by 12 years compared to chronological age, respectively. This indicates accelerated CRMC aging, similar to findings reported in diabetic patients.²⁵

Factors explaining the decline in 6MWD and acceleration of CRMC aging in NC-CHB patients

Several factors may explain the decline in 6MWD and the acceleration of CRMC aging in NC-CHB patients, including comorbidities ( eg ; cardiac, respiratory, and/or muscular diseases), patient characteristics ( eg ; age, corpulence status, schooling-level, socioeconomic-level, sedentary lifestyle), parity, and smoking habits.

Chronotropic insufficiency may partly explain the 6MWD decrease, as seen in previous studies involving obstructive sleep-apnea-hypopnea-syndrome (OSAHS) patients,⁴⁶ diabetic patients,²⁵ or narghile-smokers.³² Although the impact of CHB on sinus node activity during walking was not documented, it affects sinoatrial node function.⁵³ Concerning the respiratory system, possible explanations for the 6MWD decrease include alterations in the alveolo-capillary membrane, bronchial airway, and respiratory muscle strength. The absence of SpO₂ alterations suggests that the alveolo-capillary membrane is intact (Table 4). However, lung function data alteration and respiratory muscle weakness indicate that these factors may contribute to the decrease in 6MWD.⁸ Muscle function was not a factor in our study, as both groups had comparable muscle-mass and handgrip-strength (Table 1). Previous studies have reported no impairment in muscle strength in CHB patients,⁵⁴^,⁵⁵ but handgrip-strength is a strong predictor of 6MWD,⁵⁶ and CHB can cause muscle injuries.⁵^,¹³

The 5-year age gap between the CHB and control groups is unlikely to account for the differences in 6MWD and HR, as adjustments were made for age. Literature presents conflicting results regarding the effect of age on 6MWD.²²^,²⁵^,³²^,⁴⁶ While age has been identified as an independent predictor of 6MWD in diabetic patients,²⁵ it was a non-independent predictor in OSAHS patients⁴⁶ and narghile-smokers.³² In healthy adults, age is a dependent predictor of 6MWD.²²

The corpulence status was not a factor in our study, as the two groups had comparable BMI values and comparable corpulence statuses (Table 1). Literature also provides conflicting conclusions about the effect of BMI and corpulence status on 6MWD.²²^,²⁵^,³²^,⁴⁶ While some studies consider BMI an independent predictor of 6MWD in OSAHS patients,⁴⁶ narghile-smokers,³² and healthy adults,²² others do not.²⁵ While some studies consider corpulence status an independent 6MWD predictor in diabetic patients,²⁵ others do not in OSAHS patients,⁴⁶ narghile-smokers,³² and healthy adults.²²

In our study, the CHB-group encompassed higher percentages of participants with lower schooling-level and unfavorable socioeconomic-level (Table 1). The effect of schooling-level and socioeconomic-level on 6MWD is also controversial in literature.²²^,²⁵^,³²^,⁵⁶^,⁵⁷ Schooling-level was an independent predictor in some studies of healthy adults,⁵⁷ but not in others.²²^,²⁵^,³²^,⁴⁶^,⁵⁶ Socioeconomic-level was an independent predictor in healthy adults²² and diabetic patients,²⁵ but not in others including OSAHS patients⁴⁶ or narghile-smokers.³²

Since the two groups were matched for PA (Table 1), PA levels cannot explain the 6MWD decrease. Literature on PA’s effect on 6MWD is mixed.²²^,²⁵^,³²^,⁴⁶ While one study considered PA an independent 6MWD predictor in diabetic patients,²⁵ two others considered it a non-independent 6MWD predictor in OSAHS patients⁴⁶ or narghile-smokers.³² In healthy adults,²² the PA level was identified as a dependent 6MWD predictor.

Since the women of both groups were matched for parity data (Table 1), the latter cannot explain the 6MWD decrease. In literature, parity is recognized as a 6MWD influencing factor in healthy adults,²²^,⁵⁸ and patients with chronic conditions.²⁵^,⁴⁶

The matched smoking status (Table 1), also eliminates smoking as a cause for the 6MWD decrease, with conflicting literature results,²⁵^,⁴⁶ While one study considered it an independent 6MWD predictor in diabetic patients,²⁵ but not in others including OSAHS patients.⁴⁶

Pathophysiological mechanisms explaining 6MWD decline and CRMC aging acceleration

Several mechanisms may explain the 6MWD decline and CRMC aging acceleration in NC-CHB patients, including anemia, inflammation, liver dysfunction, oxidative stress, and apoptosis.⁵⁹^–⁶⁹

Anemia,⁵⁹ inflammation,⁶⁰^,⁶¹ and certain liver function markers (aspartate-aminotransferase, alkaline-phosphatase, and bilirubin)⁶²^,⁶³ are associated with exercise capacity. Nonetheless, since both groups were matched for hemoglobin, inflammation, and liver function data, these factors alone do not fully explain the 6MWD decline.

CHB interferes with apoptosis signaling pathways,⁶⁴^,⁶⁵ and oxidative stress may contribute to liver disease progression in CHB patients.⁶⁶^–⁶⁸ Similar to chronic obstructive pulmonary disease, apoptosis in the quadriceps of CHB patients might impair muscle function,⁶⁹ while oxidative stress could affect functional capacity.³⁰^,⁶⁰ Although albumin, non-conjugated-bilirubin, and uric-acid values were comparable between the two groups, suggesting maintained oxidant-antioxidant balance, the oxidative stress factor cannot be completely ruled out in explaining the 6MWD decline.

Discussion of methods

Several methodological points, which may influence our results, require discussion. The following paragraphs will discuss the sample and effect sizes, participants’ characteristics, statistical analysis approaches, recruitment methods, 6MWT practice, and data collection.

Sample and effect sizes

In contrast to the Saudi study,¹¹ we calculated both sample and effect sizes. Determining an adequate sample size is crucial for ensuring sufficient power to detect statistical effects.⁷⁰ The effect size provides a quantitative measure of the strength and magnitude of the observed association between exposure and outcome variables.⁴⁹ Unlike p-values, which indicate only whether an association is statistically significant, the effect size offers a more comprehensive understanding of the practical significance of the relationship.⁴⁹ Our calculated sample size ( ie ; CHB-group = 26, CG = 28) was smaller than that of the Saudi study ( ie ; CHB-group = 49, CG = 45),¹¹ and the effect size for the 6MWD was small.

Participants’ characteristics

Several factors can influence the 6MWD, including anthropometric data ( eg ; age, height, weight, BMI, corpulence status, and muscle-mass), sex, biological data ( eg ; hematological, inflammatory, and biochemical data), parity, schooling-level, socioeconomic-level, PA level, and muscle strength. The influence of these factors will be discussed below.

Age, height, weight, BMI, corpulence status, muscle-mass, and sex are known independent predictors of 6MWD.⁷¹^–⁷⁴ Compared to our study, the Saudi study¹¹ included participants with a broader age range (25-55 vs. 18-80 years), which could introduce confusion, as 6MWD is negatively correlated with age.⁷¹^–⁷³ In our study, the CG was younger than the CHB-group by 5 years. To account for this, we applied two corrective actions. We used North African 6MWD reference equations to standardize 6MWD by age,²²^,⁴⁴ and we expressed HR as a percentage of MPHR, accounting for age.⁴¹ Our corrective measures are effective strategies for accounting for the impact of age.²²^,⁴¹^,⁴⁴ For instance, expressing the 6MWD as a percentage of the predicted value—calculated using a reference equation that includes age as an independent factor—helps standardize results across different age groups.⁵⁷ This approach adjusts for expected age-related variations in 6MWD, enabling a more equitable comparison between the two groups.⁵⁷ However, while this adjustment minimizes the direct influence of age on 6MWD, it may not entirely eliminate all potential confounding effects, particularly if other age-related factors ( eg ; motivation) affect performance.²²^,⁴⁴ It was better to perform additional statistical adjustments, such as analysis of covariance with age as a covariate, to further enhance the accuracy of the comparison. Anthropometric data ( ie ; height, weight, BMI, corpulence status, and muscle-mass), and sex were comparable between our two groups. The Saudi study¹¹ reported comparable age, height, and weight but did not compare BMI or corpulence status (Appendix 1). This omission could lead to misinterpretation, as high BMI is associated with reduced functional capacity⁷⁵ and 6MWD.²² Additionally, muscle-mass, an important factor influencing 6MWD⁷⁴ was comparable between our two groups. As done by Alameri et al.,¹¹ comparable percentages of men and women were included in our study. Sex also influences 6MWT results, with women generally showing lower 6MWD than men.⁷⁶

The two groups were matched for all biological data. Our sample of CHB patients represents a real-life cohort. For instance, the mean hemoglobin value in our study (14.51±1.92 g/dL) is similar to that reported by Alameri et al.¹¹ (12.87±4.41 g/dL).

We reported data on parity, which was comparable between the two groups, with no women having high parity. Parity negatively correlates with 6MWD, with multiparous women showing lower 6MWD compared to nulliparous women.²² This effect may be due to hormonal changes, biochemical modifications, or respiratory muscle impairment.²²

We reported schooling-level and socioeconomic-level data for our participants (Table 1). First, the unfavorable socioeconomic-level among our NC-CHB patients reflects findings in African CHB patient.⁷⁷ Second, compared to the CG, the CHB-group had higher percentages of participants with low schooling-level, and unfavorable socioeconomic-level (Table 1). On the one hand, the schooling-level was highlighted to contribute slightly but significantly to the variability of the 6MWD, accounting for an additional 2.2% of its variance.²² In the study by Masmoudi et al.,⁵⁷ it was observed that “the higher the schooling-level was, the longer the 6MWD was”. However, in an American study,⁵⁶ a high schooling-level was identified as a non-significant independent predictor of 6MWD. On the other hand, socioeconomic-level was also recognized as a factor that slightly but significantly influenced 6MWD variability, explaining an additional 0.2–1.5% of its variance.²² In the study by Masmoudi et al.,⁵⁷ urban participants demonstrated a significantly higher 6MWD compared to their rural counterparts.

We assessed PA level and handgrip-strength, finding comparable data between the two groups. In our study 96% of the CHB-group had a sedentary status (Table 1), which aligns with a study reporting 60% of CHB patients as sedentary.⁷⁸ Reduced PA often leads to altered muscle metabolism, decreased muscle-mass, and reduced physical capacity.⁷⁴ Handgrip-strength is a strong, independent predictor of 6MWD.⁵⁶

While the Saudi study.¹¹ employed only a quantitative approach to compare measured data, our study utilized both quantitative and qualitative approaches. The qualitative approach, such as comparing percentages of patients with abnormal 6MWD, is recommended in medical exercise research.²³

Recruitment methods of the two groups

Like what has been done by Alameri et al.,¹¹ our CHB patients were recruited from those followed at outpatient clinics. The main limitation of such method is the potential for selection bias.⁷⁹ Outpatient clinics typically serve individuals with less severe or milder forms of illness compared to those admitted to hospitals.⁸⁰ This bias may affect the generalizability of the results to the broader population, including those not seeking regular medical care or those treated in other healthcare settings.⁷⁹

Contrary to the Saudi study,¹¹ where healthy participants were recruited from hospital employees and medical students, in our study, the “apparently” healthy participants were recruited via a convenience sampling from relatives of CHB patient and from the announcement on social media account. On the one hand, the method applied by Alameri et al.¹¹ may consist of more highly educated individuals with a higher socioeconomic-level, which are more likely to come from the broader general population. On the other hand, some relatives of CHB patients could be unknowingly carrying HBV. Our use of convenience sampling, a nonprobability sampling method based on the investigator’s judgment,⁸¹ could introduce a confounding factor. This approach may result in the underrepresentation or overrepresentation of certain groups within the sample, potentially limiting the generalizability of the findings to the broader population.⁸¹ However, despite these limitations, convenience sampling remains a widely preferred method among researchers due to its affordability and ease of implementation.⁸¹

6MWT practice

Since the information about 6MWT practice and data collection during the test allow better interpretation and comparison of results among different studies, many details such as applied guidelines, corridor length, place, number of tests, day-time, encouragement and walking aids during the 6MWT, and number of investigators need to be discussed. First, as done in the Saudi study,¹¹ we applied the most updated available guidelines ( ie ; 2002,⁴⁰ and 2014 guidelines, respectively).¹⁵^,¹⁶ Using updated guidelines in medical research lies in the promotion of scientific rigor, patient safety, relevance, consistency, regulatory compliance, and improved clinical decision-making. Second, as done in the Saudi study,¹¹ we reported the corridor’ length ( ie ; 30¹¹ and 40 m, respectively). The corridor length is essential for precise comparisons of 6MWT results⁸² and can influence performance.¹⁵^,⁴⁰ Although it was recommended that the walking course must be 30 m in length,⁴⁰ research has shown that there are no significant differences in outcomes when tracks of lengths ranging from 15 to 50 m are used.⁸² Third, unlike the Saudi study,¹¹ we reported the 6MWT practice place ( ie ; indoor as recommended).⁴⁰ Research has indicated that there is little difference in 6MWD ( ie ; mean difference 4 m) between indoor and outdoor courses.⁸³ Fourth, as done by Alameri et al.¹¹ we performed only one 6MWT. Although repeated testing is recommended to account for the familiarization effect on 6MWD,²²^,⁷¹^,⁷³^,⁸⁴^–⁸⁷ the 6MWT is more appropriate for clinical settings, where the test is typically performed once.⁸⁸ Fifth, contrary to the Saudi study,¹¹ we reported the day-time of the 6MWT ( ie ; between 8 and 11 am).²²^,⁸⁵ This period is characterized by a stable ambient temperature and humidity which can minimize the intraday effects.⁸⁹ Intraday variability can be a source of biased data.⁴⁰ Sixth, contrary to the Saudi study,¹¹ we mentioned that no encouragement or walking aids during the 6MWT was given to participants. The latter can influence the 6MWD.¹⁵^,¹⁶^,⁹⁰^,⁹¹ Finally, contrarily to the Saudi study,¹¹ where 6MWT was supervised by several investigators, only one investigator was implicated in our study. In patients with chronic conditions, the 6MWT data can be compared when conducted by different investigators.⁹²

Collected data

Similar to the Saudi study,¹¹ we reported the main outcome of the 6MWT (ie; 6MWD). Contrary to the Saudi study, we reported additional 6MWT data (Appendix 1).

The 6MWT main outcome, which is the 6MWD, is reported frequently in meters,¹⁵^,¹⁶ which could be a source of misinterpretation.⁸^,¹⁰^,¹¹ In our study, 6MWD was expressed as percentage of predicted 6MWD, and the LLN was calculated from predicted values. Comparing measured 6MWD to predicted values derived from norms is an important point since norms are essential to guide the diagnostic and prognostic use of the 6MWT and the success in medical decision-making depends as much on selecting and properly using norms and their limits.¹⁵^,⁴⁰

In our study, we reported some 6MWT secondary outcomes, including HR, SpO₂, BP, dyspnea, ECRMC’ age, and 6MWW. The following sentences will discuss their clinical importance. First, HR was reported in pbm and as percentage of MPHR in order to avoid the age effect, and ΔHR was calculated. Expressing HR as percentage of MPHR accommodates individual variations in fitness levels and age, allowing for personalized exercise intensity assessment.⁴² ΔHR calculation is essential since it correlated with 6MWD.⁸⁷^,⁹³^,⁹⁴ Second, SpO₂ and drop in SpO₂ were reported. Oxygen desaturation during a 6MWT provides information regarding exercise-induced desaturation, disease severity and disease progress.¹⁵^,¹⁶ Third, BP was mentioned. Measuring BP during the 6MWT is valuable for assessing cardiovascular health, exercise responses, and overall patient safety.²²^,⁴⁶^,⁹⁵ It can aid in diagnosis, risk assessment, exercise prescription, and patient care in cardiovascular conditions.²²^,⁴⁶^,⁹⁵ Fourth, dyspnea was evaluated. On the one hand, dyspnea is a clinical sign of walking intolerance.²²^,⁴⁷^,⁴⁸ On the other hand, it reflects both the physiology of exercise limitation, and the impact of exercise limitation on daily life.¹⁵^,¹⁶ Fifth, we calculated the ECRMC’ age, which reflects acceleration of ageing.⁴⁰^,⁴⁵ Finally, we calculated the 6MWW in order to better estimate the work required to perform the 6MWT than 6MWD alone.⁴² For example, since weight directly affects the energy required to complete the 6MWT, the 6MWW can offer valuable insights into patients’ functional capacity.¹⁵^,¹⁶ The 6MWW correlates strongly with $\dot{V} O_{2}$ peak and is suggested as a parameter of patients’ fitness evaluation when gas exchange measurements are unavailable.⁹⁶ In future research, it would be valuable to assess the physiological cost index.⁹⁷^,⁹⁸ The latter (expressed as heartbeats per meter), determined by dividing the difference between ending and resting HRs by walking speed, represents the additional HR demand during walking.⁹⁷^,⁹⁸ Studies have shown that healthy adults typically exhibit mean physiological cost index values ranging from 0.23 to 0.42.⁹⁷^,⁹⁸

Study limitations

This study has two major limitations. First, the CG did not undergo HBV-DNA testing or fibroscan to confirm the absence of HBV infection and hepatic fibrosis, respectively. These tests were challenging to perform due to economic constraints and ethical considerations. Second, the study did not include spirometry testing, despite its known predictive value for 6MWD.²²^,⁴⁰^,⁵⁶^,⁸⁴^,⁸⁵^,⁹⁴ Spirometry tests were not feasible due to the COVID-19 pandemic and the associated restrictions.⁹⁹

Conclusion

Our study reveals that NC-CHB impairs sub-maximal aerobic capacity, with patients showing reduced 6MWD and 6MWW compared to controls. Chronotropic insufficiency and accelerated cardiorespiratory-muscular aging suggest systemic dysfunction beyond liver disease. Our study contributes to the limited literature on CHB-related functional impairment and calls for integrated management strategies addressing both hepatic and extrahepatic manifestations of the disease. Future research should explore mechanisms and interventions to address these impairments.

Ethical approval

This study was approved by the ethics committee of Farhat HACHED Hospital (Approval number FH/3010/2020) on August 15, 2020. All procedures in the study adhered to the ethical standards of the 1964 Helsinki Declaration.

Informed consent

Written informed consent was obtained from all patients after receiving an explanation of the study.

Data availability

Zenodo: Excel data of the 54 participants (26 patients and 28 controls) included in the pilot case-control study titled “Assessment of sub-maximal aerobic capacity in North African patients with chronic hepatitis B”, https://doi.org/10.5281/zenodo.14542662.¹⁰⁰

The project contains the following underlying data:

• [Excel data of the 2 groups (26 patients and 28 controls).xlsx] (Excel file including the numerical data of the 54 participants).¹⁰⁰

Data are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).

Extended data

Zenodo: Appendix 1: Methodologies and results of studies comparing 6-min walk test (6MWT) data of chronic hepatitis B (CHB) patients and healthy participants, https://doi.org/10.5281/zenodo.15095971 ¹⁰¹

The project contains the following extended data:

• [Appendix 1: Methodologies and results of studies comparing 6-min walk test (6MWT) data of chronic hepatitis B (CHB) patients and healthy participants].¹⁰¹

Data are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).

Reporting guidelines

Zenodo: STROBE checklist for [Assessment of sub-maximal aerobic capacity in North African patients with chronic hepatitis B: A pilot case-control study]. https://doi.org/10.5281/zenodo.14542795.¹⁰²

Data are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).

Acknowledgments

The primary findings of this paper were showcased as a poster at the 5 ^th International Congress of Physiology and Integrative Biology Society, held in June 2022 in Lyon, France. A revised abstract entitled “The assessment of submaximal aerobic capacity in North African patients with chronic hepatitis B (CHB): A case– control study” derived from this work was subsequently published in the Journal of Acta Physiologica.¹⁰³

Authors want to thank Prs. Salima FERCHICHI, Khalifa LIMEM, and Mondher KORTAS for their invaluable contribution to the analysis of biochemical and hematological markers. The authors would like to express their sincere gratitude to the two reviewers for their excellent feedback, which has substantially improved the quality of this work. Their insightful comments and constructive suggestions were invaluable in refining our manuscript.¹⁰⁴

In preparing this paper, the authors used ChatGPT ephemeral, to revise some passages of the manuscript, to double-check for any grammar mistakes or improve academic English only. After using this tool, the authors have reviewed and edited the content as necessary and take full responsibility for the content of the publication.¹⁰⁵

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VERSION 2 PUBLISHED 16 Jan 2025

Author details Author details

Jihene Bergaoui
Roles: Conceptualization, Formal Analysis, Investigation, Methodology, Validation, Visualization, Writing – Original Draft Preparation, Writing – Review & Editing

Imed Latiri
Roles: Conceptualization, Methodology, Validation, Visualization, Writing – Original Draft Preparation, Writing – Review & Editing

Sawssen MRAD
Roles: Data Curation, Validation, Visualization, Writing – Original Draft Preparation

Houda Chaouch
Roles: Data Curation, Validation, Writing – Original Draft Preparation, Writing – Review & Editing

Salma Amous
Roles: Data Curation, Visualization, Writing – Original Draft Preparation, Writing – Review & Editing

Jihene Ben Abdallah
Roles: Data Curation, Validation, Writing – Original Draft Preparation, Writing – Review & Editing

Samia Ernez Hajri
Roles: Data Curation, Project Administration, Writing – Original Draft Preparation, Writing – Review & Editing

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No competing interests were disclosed.

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Bergaoui J, Latiri I, MRAD S et al. Assessment of sub-maximal aerobic capacity in North African patients with chronic hepatitis B: a pilot case-control study [version 2; peer review: 2 approved]. F1000Research 2025, 14:98 (https://doi.org/10.12688/f1000research.160390.2)

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Reviewer Report 23 Apr 2025

Kaouther MASMOUDI, University of Sfax, Sfax, Tunisia

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https://doi.org/10.5256/f1000research.179982.r376729

I would like to thank the authors for the choice of this original study which aimed to evaluate sub-maximal aerobic capacity in CHB patients compared to apparently healthy participants (control-group).

In literature, a few articles interested in physical activity evaluation and CHB.
The 6MWT is a valid and safe test which is largely accepted by patients and can evaluate their daily activity.

One of the strengths of this article is the evaluation of several important indexes from simple results such 6MWD, BMI, SpO2, height, weight, sex, such as 6-min walk work (6MWW), 6MWDxBMI, 6MWDxSpO2End, estimated age (ECRMC)

The weaknesses of this study is the lack of spirometry tests due to the COVID-19 pandemic and the associated restrictions such as explained by authors .

Authors have considered all my comments and revised this article , particularly , they have advanced arguments for explanation of differences between the study and control groups.

Competing Interests: No competing interests were disclosed.

Reviewer Expertise: respiratory functional exploration

I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard.

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Author Response 07 May 2025

Helmi BEN SAAD, Hospital Farhat HACHED, Research laboratory “Heart Failure, LR12SP09, Universite de Sousse Faculte de Medecine de Sousse, Sousse, 4000, Tunisia

07 May 2025

Author Response

Dear Reviewer,
I want to express my sincere gratitude on behalf of all the authors for your nice remarks and your favorable evaluation of our work.
We sincerely appreciate your ... Continue reading Dear Reviewer,
I want to express my sincere gratitude on behalf of all the authors for your nice remarks and your favorable evaluation of our work.
We sincerely appreciate your insightful remarks and helpful criticism during the review process, which have significantly raised the caliber and readability of our work.
Once again, we appreciate your insightful comments and your support in getting our updated paper accepted.
Pr. Helmi Ben Saad
Dear Reviewer,
I want to express my sincere gratitude on behalf of all the authors for your nice remarks and your favorable evaluation of our work.
We sincerely appreciate your insightful remarks and helpful criticism during the review process, which have significantly raised the caliber and readability of our work.
Once again, we appreciate your insightful comments and your support in getting our updated paper accepted.
Pr. Helmi Ben Saad
Competing Interests: None Close
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COMMENTS ON THIS REPORT

Author Response 07 May 2025

Helmi BEN SAAD, Hospital Farhat HACHED, Research laboratory “Heart Failure, LR12SP09, Universite de Sousse Faculte de Medecine de Sousse, Sousse, 4000, Tunisia

07 May 2025

Author Response

Dear Reviewer,
I want to express my sincere gratitude on behalf of all the authors for your nice remarks and your favorable evaluation of our work.
We sincerely appreciate your ... Continue reading Dear Reviewer,
I want to express my sincere gratitude on behalf of all the authors for your nice remarks and your favorable evaluation of our work.
We sincerely appreciate your insightful remarks and helpful criticism during the review process, which have significantly raised the caliber and readability of our work.
Once again, we appreciate your insightful comments and your support in getting our updated paper accepted.
Pr. Helmi Ben Saad
Dear Reviewer,
I want to express my sincere gratitude on behalf of all the authors for your nice remarks and your favorable evaluation of our work.
We sincerely appreciate your insightful remarks and helpful criticism during the review process, which have significantly raised the caliber and readability of our work.
Once again, we appreciate your insightful comments and your support in getting our updated paper accepted.
Pr. Helmi Ben Saad
Competing Interests: None Close
Report a concern

Views

Reviewer Report 14 Apr 2025

Khadija Ayed, PHYSIOLOGY, Faculty of medicine of Tunis, Tunis, Tunisia; Physiology and functional testing, Center of expertise in aeronautical medicine, Tunis, Tunisia; Physiology and functional testing, National Center for Sports Medicine and Science, Tunis, Tunisia

Approved

https://doi.org/10.5256/f1000research.179982.r376730

CITE

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Author Response 26 Apr 2025

Helmi BEN SAAD, Hospital Farhat HACHED, Research laboratory “Heart Failure, LR12SP09, Universite de Sousse Faculte de Medecine de Sousse, Sousse, 4000, Tunisia

26 Apr 2025

Author Response

Dear Reviewer,
On behalf of all the authors, I would like to sincerely thank you for your kind words and your positive assessment of our work. We are truly grateful ... Continue reading Dear Reviewer,
On behalf of all the authors, I would like to sincerely thank you for your kind words and your positive assessment of our work. We are truly grateful for your thoughtful comments and constructive feedback throughout the review process, which have greatly contributed to improving the quality and clarity of our manuscript. Your recognition of the potential contribution of our study to the understanding of liver disease, particularly viral hepatitis during exercise, is deeply appreciated. Thank you once again for your valuable input and for supporting the acceptance of our revised manuscript. With kind regards,
Pr. Helmi Ben Saad
Dear Reviewer,
On behalf of all the authors, I would like to sincerely thank you for your kind words and your positive assessment of our work. We are truly grateful for your thoughtful comments and constructive feedback throughout the review process, which have greatly contributed to improving the quality and clarity of our manuscript. Your recognition of the potential contribution of our study to the understanding of liver disease, particularly viral hepatitis during exercise, is deeply appreciated. Thank you once again for your valuable input and for supporting the acceptance of our revised manuscript. With kind regards,
Pr. Helmi Ben Saad
Competing Interests: No competing interests. Close
Report a concern
Respond or Comment

COMMENTS ON THIS REPORT

Author Response 26 Apr 2025

Helmi BEN SAAD, Hospital Farhat HACHED, Research laboratory “Heart Failure, LR12SP09, Universite de Sousse Faculte de Medecine de Sousse, Sousse, 4000, Tunisia

26 Apr 2025

Author Response

Dear Reviewer,
On behalf of all the authors, I would like to sincerely thank you for your kind words and your positive assessment of our work. We are truly grateful ... Continue reading Dear Reviewer,
On behalf of all the authors, I would like to sincerely thank you for your kind words and your positive assessment of our work. We are truly grateful for your thoughtful comments and constructive feedback throughout the review process, which have greatly contributed to improving the quality and clarity of our manuscript. Your recognition of the potential contribution of our study to the understanding of liver disease, particularly viral hepatitis during exercise, is deeply appreciated. Thank you once again for your valuable input and for supporting the acceptance of our revised manuscript. With kind regards,
Pr. Helmi Ben Saad
Dear Reviewer,
On behalf of all the authors, I would like to sincerely thank you for your kind words and your positive assessment of our work. We are truly grateful for your thoughtful comments and constructive feedback throughout the review process, which have greatly contributed to improving the quality and clarity of our manuscript. Your recognition of the potential contribution of our study to the understanding of liver disease, particularly viral hepatitis during exercise, is deeply appreciated. Thank you once again for your valuable input and for supporting the acceptance of our revised manuscript. With kind regards,
Pr. Helmi Ben Saad
Competing Interests: No competing interests. Close
Report a concern

Version 1

VERSION 1

PUBLISHED 16 Jan 2025

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Reviewer Report 03 Mar 2025

Kaouther MASMOUDI, University of Sfax, Sfax, Tunisia

Approved with Reservations

https://doi.org/10.5256/f1000research.176281.r363571

Thank you for this original study.
You have clearly respond to Objectives mentioned in the introduction.
Methodology is globally well described.
The only remark is the description of the method of recruitment of the control group: among health personnel, or visitor of patients or invitation to participate via social media.
Results:
- The significant difference between the two groups in age, schooling level and socioeconomic level is an important factor that can influence results of six min walk test and its comparison between the two groups
- Redondance of results between fig 2 and table 2
- Tables 2, 3 and 4 can be regrouped in the same table.

Is the work clearly and accurately presented and does it cite the current literature?

Yes
Is the study design appropriate and is the work technically sound?

Partly
Are sufficient details of methods and analysis provided to allow replication by others?

Yes
If applicable, is the statistical analysis and its interpretation appropriate?

Yes
Are all the source data underlying the results available to ensure full reproducibility?

Yes
Are the conclusions drawn adequately supported by the results?

Yes

Competing Interests: No competing interests were disclosed.

Reviewer Expertise: respiratory functional exploration

I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above.

CITE

Report a concern

Author Response 08 Apr 2025

Helmi BEN SAAD, Hospital Farhat HACHED, Research laboratory “Heart Failure, LR12SP09, Universite de Sousse Faculte de Medecine de Sousse, Sousse, 4000, Tunisia

08 Apr 2025

Author Response

The authors sincerely thank the reviewer for her thorough and insightful feedback on our manuscript. We have carefully considered each comment and made the necessary revisions to address her concerns. ... Continue reading The authors sincerely thank the reviewer for her thorough and insightful feedback on our manuscript. We have carefully considered each comment and made the necessary revisions to address her concerns. We believe these changes have significantly improved the manuscript.

Below are our specific responses to the reviewer's positive comments/suggestions.

COMMENT 1.
.Thank you for this original study.
.You have clearly respond to Objectives mentioned in the introduction.
RESPONSE
            .We sincerely appreciate your positive feedback and recognition of our work.
.We are pleased that the study successfully addresses the objectives outlined in the introduction.
.Thank you for your thoughtful review.

COMMENT 2.
Methodology is globally well described.
The only remark is the description of the method of recruitment of the control group: among health personnel, or visitor of patients or invitation to participate via social media.
RESPONSE
.We appreciate your valuable feedback on our methodology.
.Regarding the recruitment of the control group, we have clarified this aspect as suggested. Additionally, we have added the following sentence to the study limitation subsection to address the potential impact of convenience sampling: “Our use of convenience sampling, a nonprobability sampling method based on the investigator's judgment, ⁸¹ could introduce a confounding factor. This approach may result in the underrepresentation or overrepresentation of certain groups within the sample, potentially limiting the generalizability of the findings to the broader population. ⁸¹ However, despite these limitations, convenience sampling remains a widely preferred method among researchers due to its affordability and ease of implementation. ⁸¹.”
.We hope this addition enhances the clarity and completeness of our methodological discussion. Thank you for your insightful review.

COMMENT 3
Results: The significant difference between the two groups in age, schooling level and socioeconomic level is an important factor that can influence results of six min walk test and its comparison between the two groups
RESPONSE
.Thank you for your valuable observation. We acknowledge that differences in age, schooling level, and socioeconomic status between the two groups could influence the results of the 6MWT and its comparison. We appreciate your insightful feedback, which has helped improve the clarity and robustness of our study. We have carefully considered this point in our analysis and discussion.
.Concerning AGE, we have applied two corrective actions by using North African 6MWD reference equations to standardize 6MWD by age, and by expressing heart-rate as a percentage of maximal predicted heart-rate, accounting for age. Our corrective actions are valid approaches to account for the effect of age. For example, expressing the 6MWD as a percentage of the predicted value derived from a reference equation that includes age as an independent factor helps normalize the results across different age groups. This method adjusts for expected age-related differences in 6MWD and allows for a fairer comparison between the two groups. However, while this adjustment reduces the direct impact of age on 6MWD, it may not completely eliminate all potential confounding effects, especially if other age-related factors (eg, motivation) influence performance. If possible, conducting additional statistical adjustments (such as ANCOVA with age as a covariate) could further refine the comparison. We have added the following paragraph: “In our study, the CG was younger than the CHB-group by 5 years. To account for this, we applied two corrective actions. We used North African 6MWD reference equations to standardize 6MWD by age, ^{22, 44} and we expressed HR as a percentage of MPHR, accounting for age. ⁴¹ Our corrective measures are effective strategies for accounting for the impact of age. ^{22, 41, 44} For instance, expressing the 6MWD as a percentage of the predicted value—calculated using a reference equation that includes age as an independent factor—helps standardize results across different age groups. ⁵⁷ This approach adjusts for expected age-related variations in 6MWD, enabling a more equitable comparison between the two groups. ⁵⁷ However, while this adjustment minimizes the direct influence of age on 6MWD, it may not entirely eliminate all potential confounding effects, particularly if other age-related factors ( eg ; motivation) affect performance. ^{22, 44} It was better to perform additional statistical adjustments, such as analysis of covariance with age as a covariate, to further enhance the accuracy of the comparison”
.Concerning the SCHOOLING LEVEL, and SOCIOECONOMIC STATUS, we have added the following paragraph: “First, the unfavorable socioeconomic-level among our NC-CHB patients reflects findings in African CHB patient. ⁷⁷ Second, compared to the CG, the CHB-group had higher percentages of participants with low schooling-level, and unfavorable socioeconomic-level (Table 1). On the one hand, the schooling-level was highlighted to contribute slightly but significantly to the variability of the 6MWD, accounting for an additional 2.2% of its variance. ²² In the study by Masmoudi et al., ⁵⁷ it was observed that "the higher the schooling-level was, the longer the 6MWD was". However, in an American study, ⁵⁶ a high schooling-level was identified as a non-significant independent predictor of 6MWD. On the other hand, socioeconomic-level was also recognized as a factor that slightly but significantly influenced 6MWD variability, explaining an additional 0.2–1.5% of its variance. ²² In the study by Masmoudi et al., ⁵⁷ urban participants demonstrated a significantly higher 6MWD compared to their rural counterparts.

COMMENT 4.
Redundancy of results between fig 2 and table 2
RESPONSE
.We agree with the reviewer, and we have deleted figure 2.

COMMENT 5.
- Tables 2, 3 and 4 can be regrouped in the same table.
RESPONSE
            .Thank you for your suggestion regarding Tables 2, 3, and 4. We appreciate your effort to improve the clarity of the manuscript.
.However, after your permission we would like to keep each table separate to maintain clarity and readability.
.We hope this explanation is satisfactory and appreciate your understanding.

COMMENT 6.
Is the work clearly and accurately presented and does it cite the current literature? Yes
Is the study design appropriate and is the work technically sound? Partly
Are sufficient details of methods and analysis provided to allow replication by others? Yes
If applicable, is the statistical analysis and its interpretation appropriate? Yes
Are all the source data underlying the results available to ensure full reproducibility? Yes
Are the conclusions drawn adequately supported by the results? Yes
RESPONSE
.We sincerely thank you for your thorough review and valuable feedback.
.We are pleased that you found our work well-presented, appropriately cited, and methodologically sound.
.Regarding the study design, we have carefully addressed the necessary improvements and have implemented all the requested changes.
.We appreciate your insightful comments, which have helped enhance the clarity and quality of our manuscript.
.We have added this sentence in the ACKNOWLEDGMENTS subsection: “The authors would like to express their sincere gratitude to the two reviewers for their excellent feedback, which has substantially improved the quality of this work. Their insightful comments and constructive suggestions were invaluable in refining our manuscript. ¹⁰⁴”
The authors sincerely thank the reviewer for her thorough and insightful feedback on our manuscript. We have carefully considered each comment and made the necessary revisions to address her concerns. We believe these changes have significantly improved the manuscript.

Below are our specific responses to the reviewer's positive comments/suggestions.

COMMENT 1.
.Thank you for this original study.
.You have clearly respond to Objectives mentioned in the introduction.
RESPONSE
            .We sincerely appreciate your positive feedback and recognition of our work.
.We are pleased that the study successfully addresses the objectives outlined in the introduction.
.Thank you for your thoughtful review.

COMMENT 2.
Methodology is globally well described.
The only remark is the description of the method of recruitment of the control group: among health personnel, or visitor of patients or invitation to participate via social media.
RESPONSE
.We appreciate your valuable feedback on our methodology.
.Regarding the recruitment of the control group, we have clarified this aspect as suggested. Additionally, we have added the following sentence to the study limitation subsection to address the potential impact of convenience sampling: “Our use of convenience sampling, a nonprobability sampling method based on the investigator's judgment, ⁸¹ could introduce a confounding factor. This approach may result in the underrepresentation or overrepresentation of certain groups within the sample, potentially limiting the generalizability of the findings to the broader population. ⁸¹ However, despite these limitations, convenience sampling remains a widely preferred method among researchers due to its affordability and ease of implementation. ⁸¹.”
.We hope this addition enhances the clarity and completeness of our methodological discussion. Thank you for your insightful review.

COMMENT 3
Results: The significant difference between the two groups in age, schooling level and socioeconomic level is an important factor that can influence results of six min walk test and its comparison between the two groups
RESPONSE
.Thank you for your valuable observation. We acknowledge that differences in age, schooling level, and socioeconomic status between the two groups could influence the results of the 6MWT and its comparison. We appreciate your insightful feedback, which has helped improve the clarity and robustness of our study. We have carefully considered this point in our analysis and discussion.
.Concerning AGE, we have applied two corrective actions by using North African 6MWD reference equations to standardize 6MWD by age, and by expressing heart-rate as a percentage of maximal predicted heart-rate, accounting for age. Our corrective actions are valid approaches to account for the effect of age. For example, expressing the 6MWD as a percentage of the predicted value derived from a reference equation that includes age as an independent factor helps normalize the results across different age groups. This method adjusts for expected age-related differences in 6MWD and allows for a fairer comparison between the two groups. However, while this adjustment reduces the direct impact of age on 6MWD, it may not completely eliminate all potential confounding effects, especially if other age-related factors (eg, motivation) influence performance. If possible, conducting additional statistical adjustments (such as ANCOVA with age as a covariate) could further refine the comparison. We have added the following paragraph: “In our study, the CG was younger than the CHB-group by 5 years. To account for this, we applied two corrective actions. We used North African 6MWD reference equations to standardize 6MWD by age, ^{22, 44} and we expressed HR as a percentage of MPHR, accounting for age. ⁴¹ Our corrective measures are effective strategies for accounting for the impact of age. ^{22, 41, 44} For instance, expressing the 6MWD as a percentage of the predicted value—calculated using a reference equation that includes age as an independent factor—helps standardize results across different age groups. ⁵⁷ This approach adjusts for expected age-related variations in 6MWD, enabling a more equitable comparison between the two groups. ⁵⁷ However, while this adjustment minimizes the direct influence of age on 6MWD, it may not entirely eliminate all potential confounding effects, particularly if other age-related factors ( eg ; motivation) affect performance. ^{22, 44} It was better to perform additional statistical adjustments, such as analysis of covariance with age as a covariate, to further enhance the accuracy of the comparison”
.Concerning the SCHOOLING LEVEL, and SOCIOECONOMIC STATUS, we have added the following paragraph: “First, the unfavorable socioeconomic-level among our NC-CHB patients reflects findings in African CHB patient. ⁷⁷ Second, compared to the CG, the CHB-group had higher percentages of participants with low schooling-level, and unfavorable socioeconomic-level (Table 1). On the one hand, the schooling-level was highlighted to contribute slightly but significantly to the variability of the 6MWD, accounting for an additional 2.2% of its variance. ²² In the study by Masmoudi et al., ⁵⁷ it was observed that "the higher the schooling-level was, the longer the 6MWD was". However, in an American study, ⁵⁶ a high schooling-level was identified as a non-significant independent predictor of 6MWD. On the other hand, socioeconomic-level was also recognized as a factor that slightly but significantly influenced 6MWD variability, explaining an additional 0.2–1.5% of its variance. ²² In the study by Masmoudi et al., ⁵⁷ urban participants demonstrated a significantly higher 6MWD compared to their rural counterparts.

COMMENT 4.
Redundancy of results between fig 2 and table 2
RESPONSE
.We agree with the reviewer, and we have deleted figure 2.

COMMENT 5.
- Tables 2, 3 and 4 can be regrouped in the same table.
RESPONSE
            .Thank you for your suggestion regarding Tables 2, 3, and 4. We appreciate your effort to improve the clarity of the manuscript.
.However, after your permission we would like to keep each table separate to maintain clarity and readability.
.We hope this explanation is satisfactory and appreciate your understanding.

COMMENT 6.
Is the work clearly and accurately presented and does it cite the current literature? Yes
Is the study design appropriate and is the work technically sound? Partly
Are sufficient details of methods and analysis provided to allow replication by others? Yes
If applicable, is the statistical analysis and its interpretation appropriate? Yes
Are all the source data underlying the results available to ensure full reproducibility? Yes
Are the conclusions drawn adequately supported by the results? Yes
RESPONSE
.We sincerely thank you for your thorough review and valuable feedback.
.We are pleased that you found our work well-presented, appropriately cited, and methodologically sound.
.Regarding the study design, we have carefully addressed the necessary improvements and have implemented all the requested changes.
.We appreciate your insightful comments, which have helped enhance the clarity and quality of our manuscript.
.We have added this sentence in the ACKNOWLEDGMENTS subsection: “The authors would like to express their sincere gratitude to the two reviewers for their excellent feedback, which has substantially improved the quality of this work. Their insightful comments and constructive suggestions were invaluable in refining our manuscript. ¹⁰⁴”
Competing Interests: No competing interests. Close
Report a concern
Respond or Comment

COMMENTS ON THIS REPORT

Author Response 08 Apr 2025

Helmi BEN SAAD, Hospital Farhat HACHED, Research laboratory “Heart Failure, LR12SP09, Universite de Sousse Faculte de Medecine de Sousse, Sousse, 4000, Tunisia

08 Apr 2025

Author Response

The authors sincerely thank the reviewer for her thorough and insightful feedback on our manuscript. We have carefully considered each comment and made the necessary revisions to address her concerns. ... Continue reading The authors sincerely thank the reviewer for her thorough and insightful feedback on our manuscript. We have carefully considered each comment and made the necessary revisions to address her concerns. We believe these changes have significantly improved the manuscript.

Below are our specific responses to the reviewer's positive comments/suggestions.

COMMENT 1.
.Thank you for this original study.
.You have clearly respond to Objectives mentioned in the introduction.
RESPONSE
            .We sincerely appreciate your positive feedback and recognition of our work.
.We are pleased that the study successfully addresses the objectives outlined in the introduction.
.Thank you for your thoughtful review.

COMMENT 2.
Methodology is globally well described.
The only remark is the description of the method of recruitment of the control group: among health personnel, or visitor of patients or invitation to participate via social media.
RESPONSE
.We appreciate your valuable feedback on our methodology.
.Regarding the recruitment of the control group, we have clarified this aspect as suggested. Additionally, we have added the following sentence to the study limitation subsection to address the potential impact of convenience sampling: “Our use of convenience sampling, a nonprobability sampling method based on the investigator's judgment, ⁸¹ could introduce a confounding factor. This approach may result in the underrepresentation or overrepresentation of certain groups within the sample, potentially limiting the generalizability of the findings to the broader population. ⁸¹ However, despite these limitations, convenience sampling remains a widely preferred method among researchers due to its affordability and ease of implementation. ⁸¹.”
.We hope this addition enhances the clarity and completeness of our methodological discussion. Thank you for your insightful review.

COMMENT 3
Results: The significant difference between the two groups in age, schooling level and socioeconomic level is an important factor that can influence results of six min walk test and its comparison between the two groups
RESPONSE
.Thank you for your valuable observation. We acknowledge that differences in age, schooling level, and socioeconomic status between the two groups could influence the results of the 6MWT and its comparison. We appreciate your insightful feedback, which has helped improve the clarity and robustness of our study. We have carefully considered this point in our analysis and discussion.
.Concerning AGE, we have applied two corrective actions by using North African 6MWD reference equations to standardize 6MWD by age, and by expressing heart-rate as a percentage of maximal predicted heart-rate, accounting for age. Our corrective actions are valid approaches to account for the effect of age. For example, expressing the 6MWD as a percentage of the predicted value derived from a reference equation that includes age as an independent factor helps normalize the results across different age groups. This method adjusts for expected age-related differences in 6MWD and allows for a fairer comparison between the two groups. However, while this adjustment reduces the direct impact of age on 6MWD, it may not completely eliminate all potential confounding effects, especially if other age-related factors (eg, motivation) influence performance. If possible, conducting additional statistical adjustments (such as ANCOVA with age as a covariate) could further refine the comparison. We have added the following paragraph: “In our study, the CG was younger than the CHB-group by 5 years. To account for this, we applied two corrective actions. We used North African 6MWD reference equations to standardize 6MWD by age, ^{22, 44} and we expressed HR as a percentage of MPHR, accounting for age. ⁴¹ Our corrective measures are effective strategies for accounting for the impact of age. ^{22, 41, 44} For instance, expressing the 6MWD as a percentage of the predicted value—calculated using a reference equation that includes age as an independent factor—helps standardize results across different age groups. ⁵⁷ This approach adjusts for expected age-related variations in 6MWD, enabling a more equitable comparison between the two groups. ⁵⁷ However, while this adjustment minimizes the direct influence of age on 6MWD, it may not entirely eliminate all potential confounding effects, particularly if other age-related factors ( eg ; motivation) affect performance. ^{22, 44} It was better to perform additional statistical adjustments, such as analysis of covariance with age as a covariate, to further enhance the accuracy of the comparison”
.Concerning the SCHOOLING LEVEL, and SOCIOECONOMIC STATUS, we have added the following paragraph: “First, the unfavorable socioeconomic-level among our NC-CHB patients reflects findings in African CHB patient. ⁷⁷ Second, compared to the CG, the CHB-group had higher percentages of participants with low schooling-level, and unfavorable socioeconomic-level (Table 1). On the one hand, the schooling-level was highlighted to contribute slightly but significantly to the variability of the 6MWD, accounting for an additional 2.2% of its variance. ²² In the study by Masmoudi et al., ⁵⁷ it was observed that "the higher the schooling-level was, the longer the 6MWD was". However, in an American study, ⁵⁶ a high schooling-level was identified as a non-significant independent predictor of 6MWD. On the other hand, socioeconomic-level was also recognized as a factor that slightly but significantly influenced 6MWD variability, explaining an additional 0.2–1.5% of its variance. ²² In the study by Masmoudi et al., ⁵⁷ urban participants demonstrated a significantly higher 6MWD compared to their rural counterparts.

COMMENT 4.
Redundancy of results between fig 2 and table 2
RESPONSE
.We agree with the reviewer, and we have deleted figure 2.

COMMENT 5.
- Tables 2, 3 and 4 can be regrouped in the same table.
RESPONSE
            .Thank you for your suggestion regarding Tables 2, 3, and 4. We appreciate your effort to improve the clarity of the manuscript.
.However, after your permission we would like to keep each table separate to maintain clarity and readability.
.We hope this explanation is satisfactory and appreciate your understanding.

COMMENT 6.
Is the work clearly and accurately presented and does it cite the current literature? Yes
Is the study design appropriate and is the work technically sound? Partly
Are sufficient details of methods and analysis provided to allow replication by others? Yes
If applicable, is the statistical analysis and its interpretation appropriate? Yes
Are all the source data underlying the results available to ensure full reproducibility? Yes
Are the conclusions drawn adequately supported by the results? Yes
RESPONSE
.We sincerely thank you for your thorough review and valuable feedback.
.We are pleased that you found our work well-presented, appropriately cited, and methodologically sound.
.Regarding the study design, we have carefully addressed the necessary improvements and have implemented all the requested changes.
.We appreciate your insightful comments, which have helped enhance the clarity and quality of our manuscript.
.We have added this sentence in the ACKNOWLEDGMENTS subsection: “The authors would like to express their sincere gratitude to the two reviewers for their excellent feedback, which has substantially improved the quality of this work. Their insightful comments and constructive suggestions were invaluable in refining our manuscript. ¹⁰⁴”
The authors sincerely thank the reviewer for her thorough and insightful feedback on our manuscript. We have carefully considered each comment and made the necessary revisions to address her concerns. We believe these changes have significantly improved the manuscript.

Below are our specific responses to the reviewer's positive comments/suggestions.

COMMENT 1.
.Thank you for this original study.
.You have clearly respond to Objectives mentioned in the introduction.
RESPONSE
            .We sincerely appreciate your positive feedback and recognition of our work.
.We are pleased that the study successfully addresses the objectives outlined in the introduction.
.Thank you for your thoughtful review.

COMMENT 2.
Methodology is globally well described.
The only remark is the description of the method of recruitment of the control group: among health personnel, or visitor of patients or invitation to participate via social media.
RESPONSE
.We appreciate your valuable feedback on our methodology.
.Regarding the recruitment of the control group, we have clarified this aspect as suggested. Additionally, we have added the following sentence to the study limitation subsection to address the potential impact of convenience sampling: “Our use of convenience sampling, a nonprobability sampling method based on the investigator's judgment, ⁸¹ could introduce a confounding factor. This approach may result in the underrepresentation or overrepresentation of certain groups within the sample, potentially limiting the generalizability of the findings to the broader population. ⁸¹ However, despite these limitations, convenience sampling remains a widely preferred method among researchers due to its affordability and ease of implementation. ⁸¹.”
.We hope this addition enhances the clarity and completeness of our methodological discussion. Thank you for your insightful review.

COMMENT 3
Results: The significant difference between the two groups in age, schooling level and socioeconomic level is an important factor that can influence results of six min walk test and its comparison between the two groups
RESPONSE
.Thank you for your valuable observation. We acknowledge that differences in age, schooling level, and socioeconomic status between the two groups could influence the results of the 6MWT and its comparison. We appreciate your insightful feedback, which has helped improve the clarity and robustness of our study. We have carefully considered this point in our analysis and discussion.
.Concerning AGE, we have applied two corrective actions by using North African 6MWD reference equations to standardize 6MWD by age, and by expressing heart-rate as a percentage of maximal predicted heart-rate, accounting for age. Our corrective actions are valid approaches to account for the effect of age. For example, expressing the 6MWD as a percentage of the predicted value derived from a reference equation that includes age as an independent factor helps normalize the results across different age groups. This method adjusts for expected age-related differences in 6MWD and allows for a fairer comparison between the two groups. However, while this adjustment reduces the direct impact of age on 6MWD, it may not completely eliminate all potential confounding effects, especially if other age-related factors (eg, motivation) influence performance. If possible, conducting additional statistical adjustments (such as ANCOVA with age as a covariate) could further refine the comparison. We have added the following paragraph: “In our study, the CG was younger than the CHB-group by 5 years. To account for this, we applied two corrective actions. We used North African 6MWD reference equations to standardize 6MWD by age, ^{22, 44} and we expressed HR as a percentage of MPHR, accounting for age. ⁴¹ Our corrective measures are effective strategies for accounting for the impact of age. ^{22, 41, 44} For instance, expressing the 6MWD as a percentage of the predicted value—calculated using a reference equation that includes age as an independent factor—helps standardize results across different age groups. ⁵⁷ This approach adjusts for expected age-related variations in 6MWD, enabling a more equitable comparison between the two groups. ⁵⁷ However, while this adjustment minimizes the direct influence of age on 6MWD, it may not entirely eliminate all potential confounding effects, particularly if other age-related factors ( eg ; motivation) affect performance. ^{22, 44} It was better to perform additional statistical adjustments, such as analysis of covariance with age as a covariate, to further enhance the accuracy of the comparison”
.Concerning the SCHOOLING LEVEL, and SOCIOECONOMIC STATUS, we have added the following paragraph: “First, the unfavorable socioeconomic-level among our NC-CHB patients reflects findings in African CHB patient. ⁷⁷ Second, compared to the CG, the CHB-group had higher percentages of participants with low schooling-level, and unfavorable socioeconomic-level (Table 1). On the one hand, the schooling-level was highlighted to contribute slightly but significantly to the variability of the 6MWD, accounting for an additional 2.2% of its variance. ²² In the study by Masmoudi et al., ⁵⁷ it was observed that "the higher the schooling-level was, the longer the 6MWD was". However, in an American study, ⁵⁶ a high schooling-level was identified as a non-significant independent predictor of 6MWD. On the other hand, socioeconomic-level was also recognized as a factor that slightly but significantly influenced 6MWD variability, explaining an additional 0.2–1.5% of its variance. ²² In the study by Masmoudi et al., ⁵⁷ urban participants demonstrated a significantly higher 6MWD compared to their rural counterparts.

COMMENT 4.
Redundancy of results between fig 2 and table 2
RESPONSE
.We agree with the reviewer, and we have deleted figure 2.

COMMENT 5.
- Tables 2, 3 and 4 can be regrouped in the same table.
RESPONSE
            .Thank you for your suggestion regarding Tables 2, 3, and 4. We appreciate your effort to improve the clarity of the manuscript.
.However, after your permission we would like to keep each table separate to maintain clarity and readability.
.We hope this explanation is satisfactory and appreciate your understanding.

COMMENT 6.
Is the work clearly and accurately presented and does it cite the current literature? Yes
Is the study design appropriate and is the work technically sound? Partly
Are sufficient details of methods and analysis provided to allow replication by others? Yes
If applicable, is the statistical analysis and its interpretation appropriate? Yes
Are all the source data underlying the results available to ensure full reproducibility? Yes
Are the conclusions drawn adequately supported by the results? Yes
RESPONSE
.We sincerely thank you for your thorough review and valuable feedback.
.We are pleased that you found our work well-presented, appropriately cited, and methodologically sound.
.Regarding the study design, we have carefully addressed the necessary improvements and have implemented all the requested changes.
.We appreciate your insightful comments, which have helped enhance the clarity and quality of our manuscript.
.We have added this sentence in the ACKNOWLEDGMENTS subsection: “The authors would like to express their sincere gratitude to the two reviewers for their excellent feedback, which has substantially improved the quality of this work. Their insightful comments and constructive suggestions were invaluable in refining our manuscript. ¹⁰⁴”
Competing Interests: No competing interests. Close
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Reviewer Report 08 Feb 2025

Approved with Reservations

https://doi.org/10.5256/f1000research.176281.r363568

This is a rare and original study, focusing on The assessment of sub-maximal aerobic capacity in North African patients with chronic hepatitis B (CHB) through a case-control study. This is a study that could provide a great benefit to the management of chronic diseases, but also to the importance of integrating adapted physical activity as an effective and promising therapeutic means in these diseases. However, this scientific work requires a review at certain points :
In the introduction :
Page 2 : Some studies have reported the harmful impacts of CHB on the main elements of the chain involved during adaptation to both maximal (eg; oxygen consumption ( _VO2)) and sub-maximal (eg; 6-min walk test (6MWT)) aerobic exercise…..

This example is not suitable, it is the maximal oxygen consumption (V'O2 max) which rather evaluates the tolerance to maximum effort

Page 3 : Exercise tolerance is commonly quantified through the measurement of _VO2 during a cardiorespiratory test (à cardiopulmonary exercise testing CPET)
Page 3 : (On the one hand, _VO2 at peak of exercise ( _VO2peak) was a predictor of mortality, as patients with a low _VO2peak (ie; < 17 ml/kg) had a survival rate of 55%,10 and it is significantly correlated with maximal inspiratory pressure (r = 0.64) and with the Model for End-Stage Liver Disease (r = 0.91).9 On the other hand, the authors of the Saudi study reported that compared to healthy participants (n=45), patients with CHB (n=49) had a significantly lower 6-min walk distance (6MWD) by 31 m.11 The Saudi study had some methodological weaknesses that can “slightly” modify the findings.11 First, the inclusion of patients with diverse liver diseases (eg; non-cirrhotic chronic hepatitis B (NC-CHB) or C, cirrhotic), is a source of ‘perplexity’ since the clinical outcomes are different.6 Second, the absence of sample size determination is a statistical flaw.21 Third, the expression of the main outcome (ie; 6MWD) only in absolute value, and the lack of its standardization according to participants’ characteristics (eg; sex and anthropometric data), could lead to misinterpretation.8,10,11 The standardized 6MWD allows a more objective comparison between the diverse groups.22 Fourth, the use on the quantitative significance approach with a “p value” < 0.05 is criticized, and the qualitative significance approach is recommended in medical exercise research.23)

This whole part should be mentioned in the discussion and not in the introduction

In the methods
Page 4 : To the finest of the authors’ knowledge, no previous study has explored the incapacity (aerobic capacity) via the 6MWT in a homogeneous group of NC-CHB patients….
Page 5 : co-morbidities such as respiratory or cardiovascular diseases, systemic conditions that could influence blood test results like diabetes mellitus or renal failure, consumption of alcohol….

Why did you exclude diabetics from this study knowing that diabetes does not contraindicate 6MWT?

Page 6 : (non-smoker: <5 pack-years; smoker3: 5 pack-years or over )

There is a mistake in the formula for the predicted value of the 6-minute walking distance for subjects under 40 years old

For patients under 40 years of age, you used the following formula:
6MWD (m) = 800.05-64.71 x Sex (0: Man; 1: Woman) - 10.23 x BMI (kg/m2) - 1.63 x Age (years) + 2.05 x Weight (kg)
But, according to reference 43 The formula which allows the theoretical DM6 to be calculated is as follows:
6MWD (m) = 800.05 + 64.71 x Sex (men:1/women:0) - 10.23 x BMI (kg/m2) - 1.63 x Age (years) + 2.05 x Weight (kg).
So you need to correct your formula and precise coefficient for gender.
Page 7 : For the ECRMC, reference 45 only contains the formula for calculating this parameter in patients over 40 years old, so it is necessary to specify the reference of the other formula which allows the calculation of the ECRMC for patients under 40 years old.
In the Statistical analysis:
In this study it was necessary to calculate the Odds ratio to confirm the risk of hepatitis on aerobic capacity and the acceleration of aging of the cardiorespiratory and muscular chain”Results
Page 7 :
Out of the 128 participants assessed, data from 54 participants [26 cases (15 m/11w) and 28 controls (15m/13w)] were retained for the final dataset…
Table 1, 2, 3 and 4 : mean change should be mentioned for each group and the change in the measured value should be expressed as a percentage change from the baseline value (mean % change CHB Group and mean % change CG) and in this case the significance of the difference between the percentage change of the parameter for each group should be sought.
Then, the comparison between the percentages of change will allow to evaluate the effect of the groups in the statistical analysis

In the Discussion :
Discussion of methodology should come before discussion of results
Why you did not evaluate the physiological cost index of walking (ICP). This index is defined by the difference in heart rate at the end of the 6MWT and that at rest reported to the walking speed during the 6MWT. It is an index that was created and validated by J. MacGregor and which evaluates the cost of cardiac work deployed in walking and which could have interesting correlations with the ECRMC.
You justified the use of 6MWW by the fact that it has strong correlations with peak VO2 and this is very interesting in the absence of a technical platform allowing the measurement of peak VO2. However, the strong and significant correlations between DM6 and SpO2 are still known and validated in the literature, thus, the use of the multiplication of 6MWD by the SpO2End is useless in this work especially since you have not shown in this work correlations between this parameter and other measured parameters which could justify its usefulness.
The same remarks for the “6MWDxBMI”, “6MWDxmuscle-mass” and “6MWDxbody-fat” especially given the lack of references and scientific validity for these parameters even in your study.

The English version of this work leaves something to be desired.

The conclusion :
The conclusion should be better structured, it should respond to the objectives of the study in a clear and precise manner and not contain references.

Is the work clearly and accurately presented and does it cite the current literature?

Yes
Is the study design appropriate and is the work technically sound?

Yes
Are sufficient details of methods and analysis provided to allow replication by others?

Yes
If applicable, is the statistical analysis and its interpretation appropriate?

I cannot comment. A qualified statistician is required.
Are all the source data underlying the results available to ensure full reproducibility?

Partly
Are the conclusions drawn adequately supported by the results?

No

Competing Interests: No competing interests were disclosed.

Reviewer Expertise: exercise physiology and pulomonary functionnal testing

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Author Response 08 Apr 2025

Helmi BEN SAAD, Hospital Farhat HACHED, Research laboratory “Heart Failure, LR12SP09, Universite de Sousse Faculte de Medecine de Sousse, Sousse, 4000, Tunisia

08 Apr 2025

Author Response

The authors sincerely thank the reviewer for her thorough and insightful feedback on our manuscript. We have carefully considered each comment and made the necessary revisions to address her concerns. ... Continue reading The authors sincerely thank the reviewer for her thorough and insightful feedback on our manuscript. We have carefully considered each comment and made the necessary revisions to address her concerns. We believe these changes have significantly improved the manuscript. Below are our specific responses to the reviewer positive comments/suggestions.

COMMENT 1.
This is a rare and original study, focusing on the assessment of sub-maximal aerobic capacity in North African patients with chronic hepatitis B (CHB) through a case-control study. This is a study that could provide a great benefit to the management of chronic diseases, but also to the importance of integrating adapted physical activity as an effective and promising therapeutic means in these diseases.
RESPONSE
            Thank you so much for your kind and thoughtful comments. We are grateful for your recognition of the originality and potential impact of our study. We fully agree that integrating adapted physical activity can offer significant therapeutic benefits for patients with chronic diseases like chronic hepatitis B, and we hope our work contributes meaningfully to the ongoing discussions in this field. Your encouragement is highly appreciated.

COMMENT 2.
In the introduction: Page 2 : Some studies have reported the harmful impacts of CHB on the main elements of the chain involved during adaptation to both maximal (eg; oxygen consumption ( _VO2)) and sub-maximal (eg; 6-min walk test (6MWT)) aerobic exercise…..
This example is not suitable, it is the maximal oxygen consumption (V'O2 max) which rather evaluates the tolerance to maximum effort
RESPONSE
            .We agree with the reviewer.
            .The sentence was changed as: “Some studies have reported the harmful impacts of CHB on the main elements of the chain involved during adaptation to both maximal effort ( eg ; maximal oxygen consumption ( V̇O2max)) ^{9, 10} and sub-maximal aerobic exercise ( eg ; 6-min walk test (6MWT)) ^{10, 11}^”

COMMENT 3
In the introduction: Page 3: Exercise tolerance is commonly quantified through the measurement of _VO2 during a cardiorespiratory test (à cardiopulmonary exercise testing CPET)
RESPONSE
            .We agree with the reviewer.
            .The sentence was changed as: “Exercise tolerance is commonly quantified through the measurement of oxygen consumption (V̇O2) during a cardiopulmonary exercise testing,”

COMMENT 4
In the introduction: Page 3: (On the one hand, _VO2 at peak of exercise ( _VO2peak) was a predictor of mortality, as patients with a low _VO2peak (ie; < 17 ml/kg) had a survival rate of 55%,10 and it is significantly correlated with maximal inspiratory pressure (r = 0.64) and with the Model for End-Stage Liver Disease (r = 0.91).9 On the other hand, the authors of the Saudi study reported that compared to healthy participants (n=45), patients with CHB (n=49) had a significantly lower 6-min walk distance (6MWD) by 31 m.11 The Saudi study had some methodological weaknesses that can “slightly” modify the findings.11 First, the inclusion of patients with diverse liver diseases (eg; non-cirrhotic chronic hepatitis B (NC-CHB) or C, cirrhotic), is a source of ‘perplexity’ since the clinical outcomes are different.6 Second, the absence of sample size determination is a statistical flaw.21 Third, the expression of the main outcome (ie; 6MWD) only in absolute value, and the lack of its standardization according to participants’ characteristics (eg; sex and anthropometric data), could lead to misinterpretation.8,10,11 The standardized 6MWD allows a more objective comparison between the diverse groups.22 Fourth, the use on the quantitative significance approach with a “p value” < 0.05 is criticized, and the qualitative significance approach is recommended in medical exercise research.23)
This whole part should be mentioned in the discussion and not in the introduction
RESPONSE
.Thank you for your valuable feedback. We understand your suggestion to move the long paragraph from the introduction to the discussion.
.However, we believe that this would complicate the comprehension of the introduction, as this paragraph represents the core of our introduction. In this part of the introduction, we addressed certain methodological weaknesses observed in a Saudi study (eg; inclusion of patients with diverse liver diseases, absence of sample size determination, expression of the 6MWD only in absolute value, and the lack of its standardization according to participants’ characteristics, use on the quantitative significance approach with a “p value” < 0.05), which were important, and can modify the Saudi authors’ findings. By numbering these limitations, we aim to highlight the originality and unique aspects of our study and inform readers that we have avoided some confusion factors noted in the Saudi study.
.We hope that this explanation clarifies our reasoning, and we appreciate your understanding.

COMMENT 5.
In the methods: Page 4: To the finest of the authors’ knowledge, no previous study has explored the incapacity (aerobic capacity) via the 6MWT in a homogeneous group of NC-CHB patients….
RESPONSE
.We agree with the reviewer.
            .The sentence was changed as: “To the finest of the authors’ knowledge, no previous study has explored the aerobic incapacity via the 6MWT in a homogeneous group of NC-CHB patients compared to a control-group (CG) of “apparently” healthy participants. The main aim of this case-control study was to compare the 6MWT data of the CHB-group and CG. The null hypothesis was that the two groups would have a comparable 6MWD ( ie ; the main outcome).”

COMMENT 6.
In the methods Page 5: co-morbidities such as respiratory or cardiovascular diseases, systemic conditions that could influence blood test results like diabetes mellitus or renal failure, consumption of alcohol….
Why did you exclude diabetics from this study knowing that diabetes does not contraindicate 6MWT?
RESPONSE
.Thank you for this remark.
.A previous Tunisian study (Latiri I, et al.: Six-minute walk test in non-insulin-dependent diabetes mellitus patients living in Northwest Africa. Diabetes Metab. Syndr. Obes. 2012;5:227–245) concluded that diabetes mellitus seems to accelerate the decline of the submaximal aerobic capacity evaluated through the 6MWD. For that reason, we have excluded diabetics from our study.
.We have added the aforementioned reference inside the text after diabetes mellitus (diabetes mellitus ²⁵)

COMMENT 7.
In the methods Page 6: (non-smoker: <5 pack-years; smoker3: 5 pack-years or over )
RESPONSE
.Thank you for this remark.
.Correction done inside the paper: ³5 pack-years

COMMENT 8.
There is a mistake in the formula for the predicted value of the 6-minute walking distance for subjects under 40 years old
For patients under 40 years of age, you used the following formula:
6MWD (m) = 800.05-64.71 x Sex (0: Man; 1: Woman) - 10.23 x BMI (kg/m2) - 1.63 x Age (years) + 2.05 x Weight (kg)
But, according to reference 43 The formula which allows the theoretical DM6 to be calculated is as follows:
6MWD (m) = 800.05 + 64.71 x Sex (men:1/women:0) - 10.23 x BMI (kg/m2) - 1.63 x Age (years) + 2.05 x Weight (kg).
So you need to correct your formula and precise coefficient for gender.
RESPONSE
.Thank you for your remark.
.Sorry to let you know that there is no mistake in the formula for the predicted value of the 6MWD for subjects under 40 years old. We have simply have simply inverted codes for sex [ie; (0: Man; 1: Woman) by (men:1/women:0)] and therefore we have changed “-64.71 x Sex” by “+ 64.71 x Sex”. We have changed the signs in order to make the formulas of subjects aged more and less than 40 years homogenized.
.Therefore, our 6MWD results are correct. Thank you for your comprehension.

COMMENT 9.
In the methods Page 7: For the ECRMC, reference 45 only contains the formula for calculating this parameter in patients over 40 years old, so it is necessary to specify the reference of the other formula which allows the calculation of the ECRMC for patients under 40 years old.
RESPONSE
.Thank you for this remark.
.Correction done inside the paper.

COMMENT 10.
In the Statistical analysis:
In this study, it was necessary to calculate the Odds ratio to confirm the risk of hepatitis on aerobic capacity and the acceleration of aging of the cardiorespiratory and muscular chain.
RESPONSE
            .Thank you for your remark.
            .We have calculated the odds ratio (OR) to confirm the risk of hepatitis on aerobic capacity and the acceleration of aging of the cardiorespiratory and muscular chain. Mainly we have calculated the OR for the following two data: abnormal 6MWD and Low HR (we do not calculated the OR for Desaturation and High dyspnea_End since no participant from both groups exhibited Desaturation or High dyspnea_End (see Table 4).
.We have added the following sentences inside the paper:
*Abstract:
“The CHB-group was 8.1 and 14.3 times more likely to have chronotropic insufficiency and abnormal 6MWD than the CG, respectively”
*Manuscript:
“Moreover, to confirm the risk of CHB on aerobic capacity, odds ratios were calculated for abnormal 6MWD and chronotropic insufficiency”.
“The CHB-group was 8.1 times more likely to have chronotropic insufficiency than the CG.”
“The CHB-group was 14.3 times more likely to have an abnormal 6MWD than the CG.”

COMMENT 11.
”Results Page 7: Out of the 128 participants assessed, data from 54 participants [26 cases (15 m/11w) and 28 controls (15m/13w)] were retained for the final dataset…
RESPONSE
.Thank you for this remark.
.Correction done inside the paper: “Out of the 128 participants assessed, data from 54 participants [26 cases (15 men/11 women) and 28 controls (15 men/13 women)] were retained for the final dataset.”

COMMENT 12.
”Results Page 7: Table 1, 2, 3 and 4 : mean change should be mentioned for each group and the change in the measured value should be expressed as a percentage change from the baseline value (mean % change CHB Group and mean % change CG) and in this case the significance of the difference between the percentage change of the parameter for each group should be sought. Then, the comparison between the percentages of change will allow to evaluate the effect of the groups in the statistical analysis.
RESPONSE
            .We failed to correctly understand your comment.
            .Inside the statistical analysis subsection, we have added the following sentence: For quantitative data, mean percentage changes (%) between the two groups were calculated [mean percentage change = 100 x (CHB-group mean value minus CG mean value)/CHB-group mean]. For each group, percentage delta changes (∆) between data determined at _Restand _End walk were calculated for HR, SpO₂, SBP, DBP, and dyspnea VAS [ ie ; ∆HR (%) = 100 x (HR_End – HR_Rest)/HR_Rest, ∆SpO₂ (%) = 100 x (SpO_2End - SpO_2Rest)/ SpO_2Rest, ∆SBP (%) = 100 x (SBP_End – SBP_Rest)/SBP_Rest, and ∆DBP (%) = 100 x (DBP_End – DBP_Rest)/DBP_Rest].
            .We have not calculated percentage delta changes (∆) for Dyspnea VAS, since all _Restvalues were equal to zero.
.In tables 1, 2, and 3, mean changes were calculated between the two groups for quantitative data. We cannot calculate mean percentage changes for each group because there is no baseline and after intervention data. We have applied all needed changes in Table 1.
            .In tables 3 and 4, we have calculated, for each group, the change (∆) in HR, SBP, DBP, and VAS. Then we have compared the changes between the two groups.
            .Please consult all changes inside the abstract, text and tables.

COMMENT 13.
In the Discussion: Discussion of methodology should come before discussion of results
RESPONSE
            .Thank you for your suggestion. We understand that there is two approaches related to the subjects you raised: should we begin with the discussion of results or methods?
.In an original medical article, it is generally recommended to begin the Discussion section by interpreting and discussing the key results of the study. This approach helps maintain a logical flow, as readers are usually most interested in understanding the study’s findings before delving into methodological considerations.
.Thank you for your comprehension.

COMMENT 14.
In the Discussion: Why you did not evaluate the physiological cost index of walking (ICP). This index is defined by the difference in heart rate at the end of the 6MWT and that at rest reported to the walking speed during the 6MWT. It is an index that was created and validated by J. MacGregor and which evaluates the cost of cardiac work deployed in walking and which could have interesting correlations with the ECRMC.
RESPONSE
            .Thank you for your remark concerning the physiological cost index (PCI).
.We have consulted the paper by MacGregor J ‘The evaluation of patient performance using long-term ambulatory monitoring technique in the domiciliary environment. Physiotherapy. 1981 Feb 10;67(2):30-3. PMID: 7312961”.
            .The PCI, created and validated by J. MacGregor, is a metric used to quantify the energy cost or efficiency of walking, particularly in individuals with mobility impairments or disabilities. It is designed to provide a standardized way to assess walking performance by considering factors such as speed, energy expenditure, and physiological effort. The PCI is often used in clinical and rehabilitation settings to evaluate the effectiveness of interventions, such as prosthetics, orthotics, or physical therapy, on walking ability. This was not the aim of our study.
.The PCI i) measures the energy cost of walking, typically expressed as the amount of energy expended per unit distance walked (e.g., oxygen consumption per meter); ii) often normalizes energy expenditure to body weight or other physiological parameters to allow for comparisons across individuals, iii) is useful for identifying inefficiencies in walking patterns and guiding interventions to improve mobility. Again, this was not the main aim of our study.
            .The PCI is calculated using data from walking tests, often involving measures of: i) Oxygen consumption during walking, ii) Walking speed (distance over time), and iii) Body weight or other anthropometric data. Its formula typically involves dividing the energy expenditure (e.g., oxygen consumption) by the product of walking speed and body weight, though the exact formula may vary depending on the study or application. In our study, we cannot calculate the PCI, since we have not all needed data.
            .In practice, the PCI can be calculated as PCI (bpm*min/m) = (HR_End (bpm) minus HR_Rest) (bpm)/walk speed (m/min). Mean PCI values for healthy adults have been reported to be between 0.23 and 0.42 (MacGregor J. The evaluation of patient performance using long-term ambulatory monitoring technique in the domiciliary environment. Physiotherapy. 1981 Feb 10;67(2):30-3. PMID: 7312961. 13-15; Graham RC, Smith NM, White CM. The reliability and validity of the physiological cost index in healthy subjects while walking on 2 different tracks. Arch Phys Med Rehabil. 2005 Oct;86(10):2041-6. doi: 10.1016/j.apmr.2005.04.022. PMID: 16213251). In this case we need to calculate the walk speed by dividing the 6MWD by 6.
            .Since we have previously published our protocol without reporting our intention to evaluate the PCI (see: Bergaoui J, Latiri I, Ben Saad H. Deficiency, incapacity and social disadvantage of patients with chronic hepatitis B: a case-control study. Tunis Med. 2021 Juillet;99(7):682-692. PMID: 35260999; PMCID: PMC8796680. ), at this stage we cannot add this interesting variable. However, in the revised version, we have recommended to evaluate the PCI in future studies. The following sentence was added: “In future research, it would be valuable to assess the physiological cost index. ^{97, 98} The latter (expressed as heartbeats per meter), determined by dividing the difference between ending and resting HRs by walking speed, represents the additional HR demand during walking. ^{97, 98} Studies have shown that healthy adults typically exhibit mean physiological cost index values ranging from 0.23 to 0.42. ^{97, 98}”

COMMENT 15.
In the Discussion : You justified the use of 6MWW by the fact that it has strong correlations with peak VO2 and this is very interesting in the absence of a technical platform allowing the measurement of peak VO2. However, the strong and significant correlations between DM6 and SpO2 are still known and validated in the literature, thus, the use of the multiplication of 6MWD by the SpO2End is useless in this work especially since you have not shown in this work correlations between this parameter and other measured parameters, which could justify its usefulness.
In the Discussion :The same remarks for the “6MWDxBMI”, “6MWDxmuscle-mass” and “6MWDxbody-fat” especially given the lack of references and scientific validity for these parameters even in your study.

RESPONSE
            .Thank you for your remark. We understand your point of view concerning the indices “6MWD x SpO_2End”, “6MWD x BMI”, “6MWD x MM” and “6MWD x BF”.
            .In order to shorten our paper, we have deleted all these indices.
            .Thank you for this interesting remark.

COMMENT 17.
The English version of this work leaves something to be desired.
RESPONSE
            .Thank you for your pertinent remark.
            .We have revised the English version. We have used a generative AI tool for that reason.
.Inside the paper, we have made the following declaration related to the use of AI chatbots: “In preparing this paper, the authors used ChatGPT ephemeral, to revise some passages of the manuscript, to double-check for any grammar mistakes or improve academic English only. After using this tool, the authors have reviewed and edited the content as necessary and take full responsibility for the content of the publication.”

COMMENT 18.
The conclusion: The conclusion should be better structured, it should respond to the objectives of the study in a clear and precise manner and not contain references.
RESPONSE
            .Thank you for your valuable feedback and insightful comments. We appreciate your suggestion regarding the conclusion.
.We have revised the conclusion to ensure a clearer and more structured response to the study’s objectives, while also removing any references. Your input is highly valuable in strengthening the clarity and impact of the manuscript.
.Here is the new conclusion: “Our study reveals that NC-CHB impairs sub-maximal aerobic capacity, with patients showing reduced 6MWD and 6MWW compared to controls. Chronotropic insufficiency and accelerated cardiorespiratory-muscular aging suggest systemic dysfunction beyond liver disease. Our study contributes to the limited literature on CHB-related functional impairment and calls for integrated management strategies addressing both hepatic and extrahepatic manifestations of the disease. Future research should explore mechanisms and interventions to address these impairments.”
COMMENT 19.
Is the work clearly and accurately presented and does it cite the current literature?
Yes
Is the study design appropriate and is the work technically sound?
Yes
Are sufficient details of methods and analysis provided to allow replication by others?
Yes
If applicable, is the statistical analysis and its interpretation appropriate?
I cannot comment. A qualified statistician is required.
Are all the source data underlying the results available to ensure full reproducibility?
Partly
Are the conclusions drawn adequately supported by the results?
No
RESPONSE
.Thank you for your thorough review and valuable feedback.
.We appreciate your positive assessment of the clarity, study design, and methodology.
.Regarding your comment on statistical analysis, we confirm that all our statistics are correct.
.Additionally, we have addressed the issue of data availability to enhance reproducibility by uploading an Excel data of the 54 participants (26 patients and 28 controls) included in the pilot case-control study titled. Please see (reference 100): https://doi.org/10.5281/zenodo.14542662.
.Finally, we have revised the conclusion to ensure that it is fully supported by the results.
.Your insights are greatly appreciated and helped improve the quality of the manuscript.
.We have added this sentence in the ACKNOWLEDGMENTS subsection: “The authors would like to express their sincere gratitude to the two reviewers for their excellent feedback, which has substantially improved the quality of this work. Their insightful comments and constructive suggestions were invaluable in refining our manuscript. ¹⁰⁴”
The authors sincerely thank the reviewer for her thorough and insightful feedback on our manuscript. We have carefully considered each comment and made the necessary revisions to address her concerns. We believe these changes have significantly improved the manuscript. Below are our specific responses to the reviewer positive comments/suggestions.

COMMENT 1.
This is a rare and original study, focusing on the assessment of sub-maximal aerobic capacity in North African patients with chronic hepatitis B (CHB) through a case-control study. This is a study that could provide a great benefit to the management of chronic diseases, but also to the importance of integrating adapted physical activity as an effective and promising therapeutic means in these diseases.
RESPONSE
            Thank you so much for your kind and thoughtful comments. We are grateful for your recognition of the originality and potential impact of our study. We fully agree that integrating adapted physical activity can offer significant therapeutic benefits for patients with chronic diseases like chronic hepatitis B, and we hope our work contributes meaningfully to the ongoing discussions in this field. Your encouragement is highly appreciated.

COMMENT 2.
In the introduction: Page 2 : Some studies have reported the harmful impacts of CHB on the main elements of the chain involved during adaptation to both maximal (eg; oxygen consumption ( _VO2)) and sub-maximal (eg; 6-min walk test (6MWT)) aerobic exercise…..
This example is not suitable, it is the maximal oxygen consumption (V'O2 max) which rather evaluates the tolerance to maximum effort
RESPONSE
            .We agree with the reviewer.
            .The sentence was changed as: “Some studies have reported the harmful impacts of CHB on the main elements of the chain involved during adaptation to both maximal effort ( eg ; maximal oxygen consumption ( V̇O2max)) ^{9, 10} and sub-maximal aerobic exercise ( eg ; 6-min walk test (6MWT)) ^{10, 11}^”

COMMENT 3
In the introduction: Page 3: Exercise tolerance is commonly quantified through the measurement of _VO2 during a cardiorespiratory test (à cardiopulmonary exercise testing CPET)
RESPONSE
            .We agree with the reviewer.
            .The sentence was changed as: “Exercise tolerance is commonly quantified through the measurement of oxygen consumption (V̇O2) during a cardiopulmonary exercise testing,”

COMMENT 4
In the introduction: Page 3: (On the one hand, _VO2 at peak of exercise ( _VO2peak) was a predictor of mortality, as patients with a low _VO2peak (ie; < 17 ml/kg) had a survival rate of 55%,10 and it is significantly correlated with maximal inspiratory pressure (r = 0.64) and with the Model for End-Stage Liver Disease (r = 0.91).9 On the other hand, the authors of the Saudi study reported that compared to healthy participants (n=45), patients with CHB (n=49) had a significantly lower 6-min walk distance (6MWD) by 31 m.11 The Saudi study had some methodological weaknesses that can “slightly” modify the findings.11 First, the inclusion of patients with diverse liver diseases (eg; non-cirrhotic chronic hepatitis B (NC-CHB) or C, cirrhotic), is a source of ‘perplexity’ since the clinical outcomes are different.6 Second, the absence of sample size determination is a statistical flaw.21 Third, the expression of the main outcome (ie; 6MWD) only in absolute value, and the lack of its standardization according to participants’ characteristics (eg; sex and anthropometric data), could lead to misinterpretation.8,10,11 The standardized 6MWD allows a more objective comparison between the diverse groups.22 Fourth, the use on the quantitative significance approach with a “p value” < 0.05 is criticized, and the qualitative significance approach is recommended in medical exercise research.23)
This whole part should be mentioned in the discussion and not in the introduction
RESPONSE
.Thank you for your valuable feedback. We understand your suggestion to move the long paragraph from the introduction to the discussion.
.However, we believe that this would complicate the comprehension of the introduction, as this paragraph represents the core of our introduction. In this part of the introduction, we addressed certain methodological weaknesses observed in a Saudi study (eg; inclusion of patients with diverse liver diseases, absence of sample size determination, expression of the 6MWD only in absolute value, and the lack of its standardization according to participants’ characteristics, use on the quantitative significance approach with a “p value” < 0.05), which were important, and can modify the Saudi authors’ findings. By numbering these limitations, we aim to highlight the originality and unique aspects of our study and inform readers that we have avoided some confusion factors noted in the Saudi study.
.We hope that this explanation clarifies our reasoning, and we appreciate your understanding.

COMMENT 5.
In the methods: Page 4: To the finest of the authors’ knowledge, no previous study has explored the incapacity (aerobic capacity) via the 6MWT in a homogeneous group of NC-CHB patients….
RESPONSE
.We agree with the reviewer.
            .The sentence was changed as: “To the finest of the authors’ knowledge, no previous study has explored the aerobic incapacity via the 6MWT in a homogeneous group of NC-CHB patients compared to a control-group (CG) of “apparently” healthy participants. The main aim of this case-control study was to compare the 6MWT data of the CHB-group and CG. The null hypothesis was that the two groups would have a comparable 6MWD ( ie ; the main outcome).”

COMMENT 6.
In the methods Page 5: co-morbidities such as respiratory or cardiovascular diseases, systemic conditions that could influence blood test results like diabetes mellitus or renal failure, consumption of alcohol….
Why did you exclude diabetics from this study knowing that diabetes does not contraindicate 6MWT?
RESPONSE
.Thank you for this remark.
.A previous Tunisian study (Latiri I, et al.: Six-minute walk test in non-insulin-dependent diabetes mellitus patients living in Northwest Africa. Diabetes Metab. Syndr. Obes. 2012;5:227–245) concluded that diabetes mellitus seems to accelerate the decline of the submaximal aerobic capacity evaluated through the 6MWD. For that reason, we have excluded diabetics from our study.
.We have added the aforementioned reference inside the text after diabetes mellitus (diabetes mellitus ²⁵)

COMMENT 7.
In the methods Page 6: (non-smoker: <5 pack-years; smoker3: 5 pack-years or over )
RESPONSE
.Thank you for this remark.
.Correction done inside the paper: ³5 pack-years

COMMENT 8.
There is a mistake in the formula for the predicted value of the 6-minute walking distance for subjects under 40 years old
For patients under 40 years of age, you used the following formula:
6MWD (m) = 800.05-64.71 x Sex (0: Man; 1: Woman) - 10.23 x BMI (kg/m2) - 1.63 x Age (years) + 2.05 x Weight (kg)
But, according to reference 43 The formula which allows the theoretical DM6 to be calculated is as follows:
6MWD (m) = 800.05 + 64.71 x Sex (men:1/women:0) - 10.23 x BMI (kg/m2) - 1.63 x Age (years) + 2.05 x Weight (kg).
So you need to correct your formula and precise coefficient for gender.
RESPONSE
.Thank you for your remark.
.Sorry to let you know that there is no mistake in the formula for the predicted value of the 6MWD for subjects under 40 years old. We have simply have simply inverted codes for sex [ie; (0: Man; 1: Woman) by (men:1/women:0)] and therefore we have changed “-64.71 x Sex” by “+ 64.71 x Sex”. We have changed the signs in order to make the formulas of subjects aged more and less than 40 years homogenized.
.Therefore, our 6MWD results are correct. Thank you for your comprehension.

COMMENT 9.
In the methods Page 7: For the ECRMC, reference 45 only contains the formula for calculating this parameter in patients over 40 years old, so it is necessary to specify the reference of the other formula which allows the calculation of the ECRMC for patients under 40 years old.
RESPONSE
.Thank you for this remark.
.Correction done inside the paper.

COMMENT 10.
In the Statistical analysis:
In this study, it was necessary to calculate the Odds ratio to confirm the risk of hepatitis on aerobic capacity and the acceleration of aging of the cardiorespiratory and muscular chain.
RESPONSE
            .Thank you for your remark.
            .We have calculated the odds ratio (OR) to confirm the risk of hepatitis on aerobic capacity and the acceleration of aging of the cardiorespiratory and muscular chain. Mainly we have calculated the OR for the following two data: abnormal 6MWD and Low HR (we do not calculated the OR for Desaturation and High dyspnea_End since no participant from both groups exhibited Desaturation or High dyspnea_End (see Table 4).
.We have added the following sentences inside the paper:
*Abstract:
“The CHB-group was 8.1 and 14.3 times more likely to have chronotropic insufficiency and abnormal 6MWD than the CG, respectively”
*Manuscript:
“Moreover, to confirm the risk of CHB on aerobic capacity, odds ratios were calculated for abnormal 6MWD and chronotropic insufficiency”.
“The CHB-group was 8.1 times more likely to have chronotropic insufficiency than the CG.”
“The CHB-group was 14.3 times more likely to have an abnormal 6MWD than the CG.”

COMMENT 11.
”Results Page 7: Out of the 128 participants assessed, data from 54 participants [26 cases (15 m/11w) and 28 controls (15m/13w)] were retained for the final dataset…
RESPONSE
.Thank you for this remark.
.Correction done inside the paper: “Out of the 128 participants assessed, data from 54 participants [26 cases (15 men/11 women) and 28 controls (15 men/13 women)] were retained for the final dataset.”

COMMENT 12.
”Results Page 7: Table 1, 2, 3 and 4 : mean change should be mentioned for each group and the change in the measured value should be expressed as a percentage change from the baseline value (mean % change CHB Group and mean % change CG) and in this case the significance of the difference between the percentage change of the parameter for each group should be sought. Then, the comparison between the percentages of change will allow to evaluate the effect of the groups in the statistical analysis.
RESPONSE
            .We failed to correctly understand your comment.
            .Inside the statistical analysis subsection, we have added the following sentence: For quantitative data, mean percentage changes (%) between the two groups were calculated [mean percentage change = 100 x (CHB-group mean value minus CG mean value)/CHB-group mean]. For each group, percentage delta changes (∆) between data determined at _Restand _End walk were calculated for HR, SpO₂, SBP, DBP, and dyspnea VAS [ ie ; ∆HR (%) = 100 x (HR_End – HR_Rest)/HR_Rest, ∆SpO₂ (%) = 100 x (SpO_2End - SpO_2Rest)/ SpO_2Rest, ∆SBP (%) = 100 x (SBP_End – SBP_Rest)/SBP_Rest, and ∆DBP (%) = 100 x (DBP_End – DBP_Rest)/DBP_Rest].
            .We have not calculated percentage delta changes (∆) for Dyspnea VAS, since all _Restvalues were equal to zero.
.In tables 1, 2, and 3, mean changes were calculated between the two groups for quantitative data. We cannot calculate mean percentage changes for each group because there is no baseline and after intervention data. We have applied all needed changes in Table 1.
            .In tables 3 and 4, we have calculated, for each group, the change (∆) in HR, SBP, DBP, and VAS. Then we have compared the changes between the two groups.
            .Please consult all changes inside the abstract, text and tables.

COMMENT 13.
In the Discussion: Discussion of methodology should come before discussion of results
RESPONSE
            .Thank you for your suggestion. We understand that there is two approaches related to the subjects you raised: should we begin with the discussion of results or methods?
.In an original medical article, it is generally recommended to begin the Discussion section by interpreting and discussing the key results of the study. This approach helps maintain a logical flow, as readers are usually most interested in understanding the study’s findings before delving into methodological considerations.
.Thank you for your comprehension.

COMMENT 14.
In the Discussion: Why you did not evaluate the physiological cost index of walking (ICP). This index is defined by the difference in heart rate at the end of the 6MWT and that at rest reported to the walking speed during the 6MWT. It is an index that was created and validated by J. MacGregor and which evaluates the cost of cardiac work deployed in walking and which could have interesting correlations with the ECRMC.
RESPONSE
            .Thank you for your remark concerning the physiological cost index (PCI).
.We have consulted the paper by MacGregor J ‘The evaluation of patient performance using long-term ambulatory monitoring technique in the domiciliary environment. Physiotherapy. 1981 Feb 10;67(2):30-3. PMID: 7312961”.
            .The PCI, created and validated by J. MacGregor, is a metric used to quantify the energy cost or efficiency of walking, particularly in individuals with mobility impairments or disabilities. It is designed to provide a standardized way to assess walking performance by considering factors such as speed, energy expenditure, and physiological effort. The PCI is often used in clinical and rehabilitation settings to evaluate the effectiveness of interventions, such as prosthetics, orthotics, or physical therapy, on walking ability. This was not the aim of our study.
.The PCI i) measures the energy cost of walking, typically expressed as the amount of energy expended per unit distance walked (e.g., oxygen consumption per meter); ii) often normalizes energy expenditure to body weight or other physiological parameters to allow for comparisons across individuals, iii) is useful for identifying inefficiencies in walking patterns and guiding interventions to improve mobility. Again, this was not the main aim of our study.
            .The PCI is calculated using data from walking tests, often involving measures of: i) Oxygen consumption during walking, ii) Walking speed (distance over time), and iii) Body weight or other anthropometric data. Its formula typically involves dividing the energy expenditure (e.g., oxygen consumption) by the product of walking speed and body weight, though the exact formula may vary depending on the study or application. In our study, we cannot calculate the PCI, since we have not all needed data.
            .In practice, the PCI can be calculated as PCI (bpm*min/m) = (HR_End (bpm) minus HR_Rest) (bpm)/walk speed (m/min). Mean PCI values for healthy adults have been reported to be between 0.23 and 0.42 (MacGregor J. The evaluation of patient performance using long-term ambulatory monitoring technique in the domiciliary environment. Physiotherapy. 1981 Feb 10;67(2):30-3. PMID: 7312961. 13-15; Graham RC, Smith NM, White CM. The reliability and validity of the physiological cost index in healthy subjects while walking on 2 different tracks. Arch Phys Med Rehabil. 2005 Oct;86(10):2041-6. doi: 10.1016/j.apmr.2005.04.022. PMID: 16213251). In this case we need to calculate the walk speed by dividing the 6MWD by 6.
            .Since we have previously published our protocol without reporting our intention to evaluate the PCI (see: Bergaoui J, Latiri I, Ben Saad H. Deficiency, incapacity and social disadvantage of patients with chronic hepatitis B: a case-control study. Tunis Med. 2021 Juillet;99(7):682-692. PMID: 35260999; PMCID: PMC8796680. ), at this stage we cannot add this interesting variable. However, in the revised version, we have recommended to evaluate the PCI in future studies. The following sentence was added: “In future research, it would be valuable to assess the physiological cost index. ^{97, 98} The latter (expressed as heartbeats per meter), determined by dividing the difference between ending and resting HRs by walking speed, represents the additional HR demand during walking. ^{97, 98} Studies have shown that healthy adults typically exhibit mean physiological cost index values ranging from 0.23 to 0.42. ^{97, 98}”

COMMENT 15.
In the Discussion : You justified the use of 6MWW by the fact that it has strong correlations with peak VO2 and this is very interesting in the absence of a technical platform allowing the measurement of peak VO2. However, the strong and significant correlations between DM6 and SpO2 are still known and validated in the literature, thus, the use of the multiplication of 6MWD by the SpO2End is useless in this work especially since you have not shown in this work correlations between this parameter and other measured parameters, which could justify its usefulness.
In the Discussion :The same remarks for the “6MWDxBMI”, “6MWDxmuscle-mass” and “6MWDxbody-fat” especially given the lack of references and scientific validity for these parameters even in your study.

RESPONSE
            .Thank you for your remark. We understand your point of view concerning the indices “6MWD x SpO_2End”, “6MWD x BMI”, “6MWD x MM” and “6MWD x BF”.
            .In order to shorten our paper, we have deleted all these indices.
            .Thank you for this interesting remark.

COMMENT 17.
The English version of this work leaves something to be desired.
RESPONSE
            .Thank you for your pertinent remark.
            .We have revised the English version. We have used a generative AI tool for that reason.
.Inside the paper, we have made the following declaration related to the use of AI chatbots: “In preparing this paper, the authors used ChatGPT ephemeral, to revise some passages of the manuscript, to double-check for any grammar mistakes or improve academic English only. After using this tool, the authors have reviewed and edited the content as necessary and take full responsibility for the content of the publication.”

COMMENT 18.
The conclusion: The conclusion should be better structured, it should respond to the objectives of the study in a clear and precise manner and not contain references.
RESPONSE
            .Thank you for your valuable feedback and insightful comments. We appreciate your suggestion regarding the conclusion.
.We have revised the conclusion to ensure a clearer and more structured response to the study’s objectives, while also removing any references. Your input is highly valuable in strengthening the clarity and impact of the manuscript.
.Here is the new conclusion: “Our study reveals that NC-CHB impairs sub-maximal aerobic capacity, with patients showing reduced 6MWD and 6MWW compared to controls. Chronotropic insufficiency and accelerated cardiorespiratory-muscular aging suggest systemic dysfunction beyond liver disease. Our study contributes to the limited literature on CHB-related functional impairment and calls for integrated management strategies addressing both hepatic and extrahepatic manifestations of the disease. Future research should explore mechanisms and interventions to address these impairments.”
COMMENT 19.
Is the work clearly and accurately presented and does it cite the current literature?
Yes
Is the study design appropriate and is the work technically sound?
Yes
Are sufficient details of methods and analysis provided to allow replication by others?
Yes
If applicable, is the statistical analysis and its interpretation appropriate?
I cannot comment. A qualified statistician is required.
Are all the source data underlying the results available to ensure full reproducibility?
Partly
Are the conclusions drawn adequately supported by the results?
No
RESPONSE
.Thank you for your thorough review and valuable feedback.
.We appreciate your positive assessment of the clarity, study design, and methodology.
.Regarding your comment on statistical analysis, we confirm that all our statistics are correct.
.Additionally, we have addressed the issue of data availability to enhance reproducibility by uploading an Excel data of the 54 participants (26 patients and 28 controls) included in the pilot case-control study titled. Please see (reference 100): https://doi.org/10.5281/zenodo.14542662.
.Finally, we have revised the conclusion to ensure that it is fully supported by the results.
.Your insights are greatly appreciated and helped improve the quality of the manuscript.
.We have added this sentence in the ACKNOWLEDGMENTS subsection: “The authors would like to express their sincere gratitude to the two reviewers for their excellent feedback, which has substantially improved the quality of this work. Their insightful comments and constructive suggestions were invaluable in refining our manuscript. ¹⁰⁴”
Competing Interests: No competing interests Close
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COMMENTS ON THIS REPORT

Author Response 08 Apr 2025

Helmi BEN SAAD, Hospital Farhat HACHED, Research laboratory “Heart Failure, LR12SP09, Universite de Sousse Faculte de Medecine de Sousse, Sousse, 4000, Tunisia

08 Apr 2025

Author Response

The authors sincerely thank the reviewer for her thorough and insightful feedback on our manuscript. We have carefully considered each comment and made the necessary revisions to address her concerns. ... Continue reading The authors sincerely thank the reviewer for her thorough and insightful feedback on our manuscript. We have carefully considered each comment and made the necessary revisions to address her concerns. We believe these changes have significantly improved the manuscript. Below are our specific responses to the reviewer positive comments/suggestions.

COMMENT 1.
This is a rare and original study, focusing on the assessment of sub-maximal aerobic capacity in North African patients with chronic hepatitis B (CHB) through a case-control study. This is a study that could provide a great benefit to the management of chronic diseases, but also to the importance of integrating adapted physical activity as an effective and promising therapeutic means in these diseases.
RESPONSE
            Thank you so much for your kind and thoughtful comments. We are grateful for your recognition of the originality and potential impact of our study. We fully agree that integrating adapted physical activity can offer significant therapeutic benefits for patients with chronic diseases like chronic hepatitis B, and we hope our work contributes meaningfully to the ongoing discussions in this field. Your encouragement is highly appreciated.

COMMENT 2.
In the introduction: Page 2 : Some studies have reported the harmful impacts of CHB on the main elements of the chain involved during adaptation to both maximal (eg; oxygen consumption ( _VO2)) and sub-maximal (eg; 6-min walk test (6MWT)) aerobic exercise…..
This example is not suitable, it is the maximal oxygen consumption (V'O2 max) which rather evaluates the tolerance to maximum effort
RESPONSE
            .We agree with the reviewer.
            .The sentence was changed as: “Some studies have reported the harmful impacts of CHB on the main elements of the chain involved during adaptation to both maximal effort ( eg ; maximal oxygen consumption ( V̇O2max)) ^{9, 10} and sub-maximal aerobic exercise ( eg ; 6-min walk test (6MWT)) ^{10, 11}^”

COMMENT 3
In the introduction: Page 3: Exercise tolerance is commonly quantified through the measurement of _VO2 during a cardiorespiratory test (à cardiopulmonary exercise testing CPET)
RESPONSE
            .We agree with the reviewer.
            .The sentence was changed as: “Exercise tolerance is commonly quantified through the measurement of oxygen consumption (V̇O2) during a cardiopulmonary exercise testing,”

COMMENT 4
In the introduction: Page 3: (On the one hand, _VO2 at peak of exercise ( _VO2peak) was a predictor of mortality, as patients with a low _VO2peak (ie; < 17 ml/kg) had a survival rate of 55%,10 and it is significantly correlated with maximal inspiratory pressure (r = 0.64) and with the Model for End-Stage Liver Disease (r = 0.91).9 On the other hand, the authors of the Saudi study reported that compared to healthy participants (n=45), patients with CHB (n=49) had a significantly lower 6-min walk distance (6MWD) by 31 m.11 The Saudi study had some methodological weaknesses that can “slightly” modify the findings.11 First, the inclusion of patients with diverse liver diseases (eg; non-cirrhotic chronic hepatitis B (NC-CHB) or C, cirrhotic), is a source of ‘perplexity’ since the clinical outcomes are different.6 Second, the absence of sample size determination is a statistical flaw.21 Third, the expression of the main outcome (ie; 6MWD) only in absolute value, and the lack of its standardization according to participants’ characteristics (eg; sex and anthropometric data), could lead to misinterpretation.8,10,11 The standardized 6MWD allows a more objective comparison between the diverse groups.22 Fourth, the use on the quantitative significance approach with a “p value” < 0.05 is criticized, and the qualitative significance approach is recommended in medical exercise research.23)
This whole part should be mentioned in the discussion and not in the introduction
RESPONSE
.Thank you for your valuable feedback. We understand your suggestion to move the long paragraph from the introduction to the discussion.
.However, we believe that this would complicate the comprehension of the introduction, as this paragraph represents the core of our introduction. In this part of the introduction, we addressed certain methodological weaknesses observed in a Saudi study (eg; inclusion of patients with diverse liver diseases, absence of sample size determination, expression of the 6MWD only in absolute value, and the lack of its standardization according to participants’ characteristics, use on the quantitative significance approach with a “p value” < 0.05), which were important, and can modify the Saudi authors’ findings. By numbering these limitations, we aim to highlight the originality and unique aspects of our study and inform readers that we have avoided some confusion factors noted in the Saudi study.
.We hope that this explanation clarifies our reasoning, and we appreciate your understanding.

COMMENT 5.
In the methods: Page 4: To the finest of the authors’ knowledge, no previous study has explored the incapacity (aerobic capacity) via the 6MWT in a homogeneous group of NC-CHB patients….
RESPONSE
.We agree with the reviewer.
            .The sentence was changed as: “To the finest of the authors’ knowledge, no previous study has explored the aerobic incapacity via the 6MWT in a homogeneous group of NC-CHB patients compared to a control-group (CG) of “apparently” healthy participants. The main aim of this case-control study was to compare the 6MWT data of the CHB-group and CG. The null hypothesis was that the two groups would have a comparable 6MWD ( ie ; the main outcome).”

COMMENT 6.
In the methods Page 5: co-morbidities such as respiratory or cardiovascular diseases, systemic conditions that could influence blood test results like diabetes mellitus or renal failure, consumption of alcohol….
Why did you exclude diabetics from this study knowing that diabetes does not contraindicate 6MWT?
RESPONSE
.Thank you for this remark.
.A previous Tunisian study (Latiri I, et al.: Six-minute walk test in non-insulin-dependent diabetes mellitus patients living in Northwest Africa. Diabetes Metab. Syndr. Obes. 2012;5:227–245) concluded that diabetes mellitus seems to accelerate the decline of the submaximal aerobic capacity evaluated through the 6MWD. For that reason, we have excluded diabetics from our study.
.We have added the aforementioned reference inside the text after diabetes mellitus (diabetes mellitus ²⁵)

COMMENT 7.
In the methods Page 6: (non-smoker: <5 pack-years; smoker3: 5 pack-years or over )
RESPONSE
.Thank you for this remark.
.Correction done inside the paper: ³5 pack-years

COMMENT 8.
There is a mistake in the formula for the predicted value of the 6-minute walking distance for subjects under 40 years old
For patients under 40 years of age, you used the following formula:
6MWD (m) = 800.05-64.71 x Sex (0: Man; 1: Woman) - 10.23 x BMI (kg/m2) - 1.63 x Age (years) + 2.05 x Weight (kg)
But, according to reference 43 The formula which allows the theoretical DM6 to be calculated is as follows:
6MWD (m) = 800.05 + 64.71 x Sex (men:1/women:0) - 10.23 x BMI (kg/m2) - 1.63 x Age (years) + 2.05 x Weight (kg).
So you need to correct your formula and precise coefficient for gender.
RESPONSE
.Thank you for your remark.
.Sorry to let you know that there is no mistake in the formula for the predicted value of the 6MWD for subjects under 40 years old. We have simply have simply inverted codes for sex [ie; (0: Man; 1: Woman) by (men:1/women:0)] and therefore we have changed “-64.71 x Sex” by “+ 64.71 x Sex”. We have changed the signs in order to make the formulas of subjects aged more and less than 40 years homogenized.
.Therefore, our 6MWD results are correct. Thank you for your comprehension.

COMMENT 9.
In the methods Page 7: For the ECRMC, reference 45 only contains the formula for calculating this parameter in patients over 40 years old, so it is necessary to specify the reference of the other formula which allows the calculation of the ECRMC for patients under 40 years old.
RESPONSE
.Thank you for this remark.
.Correction done inside the paper.

COMMENT 10.
In the Statistical analysis:
In this study, it was necessary to calculate the Odds ratio to confirm the risk of hepatitis on aerobic capacity and the acceleration of aging of the cardiorespiratory and muscular chain.
RESPONSE
            .Thank you for your remark.
            .We have calculated the odds ratio (OR) to confirm the risk of hepatitis on aerobic capacity and the acceleration of aging of the cardiorespiratory and muscular chain. Mainly we have calculated the OR for the following two data: abnormal 6MWD and Low HR (we do not calculated the OR for Desaturation and High dyspnea_End since no participant from both groups exhibited Desaturation or High dyspnea_End (see Table 4).
.We have added the following sentences inside the paper:
*Abstract:
“The CHB-group was 8.1 and 14.3 times more likely to have chronotropic insufficiency and abnormal 6MWD than the CG, respectively”
*Manuscript:
“Moreover, to confirm the risk of CHB on aerobic capacity, odds ratios were calculated for abnormal 6MWD and chronotropic insufficiency”.
“The CHB-group was 8.1 times more likely to have chronotropic insufficiency than the CG.”
“The CHB-group was 14.3 times more likely to have an abnormal 6MWD than the CG.”

COMMENT 11.
”Results Page 7: Out of the 128 participants assessed, data from 54 participants [26 cases (15 m/11w) and 28 controls (15m/13w)] were retained for the final dataset…
RESPONSE
.Thank you for this remark.
.Correction done inside the paper: “Out of the 128 participants assessed, data from 54 participants [26 cases (15 men/11 women) and 28 controls (15 men/13 women)] were retained for the final dataset.”

COMMENT 12.
”Results Page 7: Table 1, 2, 3 and 4 : mean change should be mentioned for each group and the change in the measured value should be expressed as a percentage change from the baseline value (mean % change CHB Group and mean % change CG) and in this case the significance of the difference between the percentage change of the parameter for each group should be sought. Then, the comparison between the percentages of change will allow to evaluate the effect of the groups in the statistical analysis.
RESPONSE
            .We failed to correctly understand your comment.
            .Inside the statistical analysis subsection, we have added the following sentence: For quantitative data, mean percentage changes (%) between the two groups were calculated [mean percentage change = 100 x (CHB-group mean value minus CG mean value)/CHB-group mean]. For each group, percentage delta changes (∆) between data determined at _Restand _End walk were calculated for HR, SpO₂, SBP, DBP, and dyspnea VAS [ ie ; ∆HR (%) = 100 x (HR_End – HR_Rest)/HR_Rest, ∆SpO₂ (%) = 100 x (SpO_2End - SpO_2Rest)/ SpO_2Rest, ∆SBP (%) = 100 x (SBP_End – SBP_Rest)/SBP_Rest, and ∆DBP (%) = 100 x (DBP_End – DBP_Rest)/DBP_Rest].
            .We have not calculated percentage delta changes (∆) for Dyspnea VAS, since all _Restvalues were equal to zero.
.In tables 1, 2, and 3, mean changes were calculated between the two groups for quantitative data. We cannot calculate mean percentage changes for each group because there is no baseline and after intervention data. We have applied all needed changes in Table 1.
            .In tables 3 and 4, we have calculated, for each group, the change (∆) in HR, SBP, DBP, and VAS. Then we have compared the changes between the two groups.
            .Please consult all changes inside the abstract, text and tables.

COMMENT 13.
In the Discussion: Discussion of methodology should come before discussion of results
RESPONSE
            .Thank you for your suggestion. We understand that there is two approaches related to the subjects you raised: should we begin with the discussion of results or methods?
.In an original medical article, it is generally recommended to begin the Discussion section by interpreting and discussing the key results of the study. This approach helps maintain a logical flow, as readers are usually most interested in understanding the study’s findings before delving into methodological considerations.
.Thank you for your comprehension.

COMMENT 14.
In the Discussion: Why you did not evaluate the physiological cost index of walking (ICP). This index is defined by the difference in heart rate at the end of the 6MWT and that at rest reported to the walking speed during the 6MWT. It is an index that was created and validated by J. MacGregor and which evaluates the cost of cardiac work deployed in walking and which could have interesting correlations with the ECRMC.
RESPONSE
            .Thank you for your remark concerning the physiological cost index (PCI).
.We have consulted the paper by MacGregor J ‘The evaluation of patient performance using long-term ambulatory monitoring technique in the domiciliary environment. Physiotherapy. 1981 Feb 10;67(2):30-3. PMID: 7312961”.
            .The PCI, created and validated by J. MacGregor, is a metric used to quantify the energy cost or efficiency of walking, particularly in individuals with mobility impairments or disabilities. It is designed to provide a standardized way to assess walking performance by considering factors such as speed, energy expenditure, and physiological effort. The PCI is often used in clinical and rehabilitation settings to evaluate the effectiveness of interventions, such as prosthetics, orthotics, or physical therapy, on walking ability. This was not the aim of our study.
.The PCI i) measures the energy cost of walking, typically expressed as the amount of energy expended per unit distance walked (e.g., oxygen consumption per meter); ii) often normalizes energy expenditure to body weight or other physiological parameters to allow for comparisons across individuals, iii) is useful for identifying inefficiencies in walking patterns and guiding interventions to improve mobility. Again, this was not the main aim of our study.
            .The PCI is calculated using data from walking tests, often involving measures of: i) Oxygen consumption during walking, ii) Walking speed (distance over time), and iii) Body weight or other anthropometric data. Its formula typically involves dividing the energy expenditure (e.g., oxygen consumption) by the product of walking speed and body weight, though the exact formula may vary depending on the study or application. In our study, we cannot calculate the PCI, since we have not all needed data.
            .In practice, the PCI can be calculated as PCI (bpm*min/m) = (HR_End (bpm) minus HR_Rest) (bpm)/walk speed (m/min). Mean PCI values for healthy adults have been reported to be between 0.23 and 0.42 (MacGregor J. The evaluation of patient performance using long-term ambulatory monitoring technique in the domiciliary environment. Physiotherapy. 1981 Feb 10;67(2):30-3. PMID: 7312961. 13-15; Graham RC, Smith NM, White CM. The reliability and validity of the physiological cost index in healthy subjects while walking on 2 different tracks. Arch Phys Med Rehabil. 2005 Oct;86(10):2041-6. doi: 10.1016/j.apmr.2005.04.022. PMID: 16213251). In this case we need to calculate the walk speed by dividing the 6MWD by 6.
            .Since we have previously published our protocol without reporting our intention to evaluate the PCI (see: Bergaoui J, Latiri I, Ben Saad H. Deficiency, incapacity and social disadvantage of patients with chronic hepatitis B: a case-control study. Tunis Med. 2021 Juillet;99(7):682-692. PMID: 35260999; PMCID: PMC8796680. ), at this stage we cannot add this interesting variable. However, in the revised version, we have recommended to evaluate the PCI in future studies. The following sentence was added: “In future research, it would be valuable to assess the physiological cost index. ^{97, 98} The latter (expressed as heartbeats per meter), determined by dividing the difference between ending and resting HRs by walking speed, represents the additional HR demand during walking. ^{97, 98} Studies have shown that healthy adults typically exhibit mean physiological cost index values ranging from 0.23 to 0.42. ^{97, 98}”

COMMENT 15.
In the Discussion : You justified the use of 6MWW by the fact that it has strong correlations with peak VO2 and this is very interesting in the absence of a technical platform allowing the measurement of peak VO2. However, the strong and significant correlations between DM6 and SpO2 are still known and validated in the literature, thus, the use of the multiplication of 6MWD by the SpO2End is useless in this work especially since you have not shown in this work correlations between this parameter and other measured parameters, which could justify its usefulness.
In the Discussion :The same remarks for the “6MWDxBMI”, “6MWDxmuscle-mass” and “6MWDxbody-fat” especially given the lack of references and scientific validity for these parameters even in your study.

RESPONSE
            .Thank you for your remark. We understand your point of view concerning the indices “6MWD x SpO_2End”, “6MWD x BMI”, “6MWD x MM” and “6MWD x BF”.
            .In order to shorten our paper, we have deleted all these indices.
            .Thank you for this interesting remark.

COMMENT 17.
The English version of this work leaves something to be desired.
RESPONSE
            .Thank you for your pertinent remark.
            .We have revised the English version. We have used a generative AI tool for that reason.
.Inside the paper, we have made the following declaration related to the use of AI chatbots: “In preparing this paper, the authors used ChatGPT ephemeral, to revise some passages of the manuscript, to double-check for any grammar mistakes or improve academic English only. After using this tool, the authors have reviewed and edited the content as necessary and take full responsibility for the content of the publication.”

COMMENT 18.
The conclusion: The conclusion should be better structured, it should respond to the objectives of the study in a clear and precise manner and not contain references.
RESPONSE
            .Thank you for your valuable feedback and insightful comments. We appreciate your suggestion regarding the conclusion.
.We have revised the conclusion to ensure a clearer and more structured response to the study’s objectives, while also removing any references. Your input is highly valuable in strengthening the clarity and impact of the manuscript.
.Here is the new conclusion: “Our study reveals that NC-CHB impairs sub-maximal aerobic capacity, with patients showing reduced 6MWD and 6MWW compared to controls. Chronotropic insufficiency and accelerated cardiorespiratory-muscular aging suggest systemic dysfunction beyond liver disease. Our study contributes to the limited literature on CHB-related functional impairment and calls for integrated management strategies addressing both hepatic and extrahepatic manifestations of the disease. Future research should explore mechanisms and interventions to address these impairments.”
COMMENT 19.
Is the work clearly and accurately presented and does it cite the current literature?
Yes
Is the study design appropriate and is the work technically sound?
Yes
Are sufficient details of methods and analysis provided to allow replication by others?
Yes
If applicable, is the statistical analysis and its interpretation appropriate?
I cannot comment. A qualified statistician is required.
Are all the source data underlying the results available to ensure full reproducibility?
Partly
Are the conclusions drawn adequately supported by the results?
No
RESPONSE
.Thank you for your thorough review and valuable feedback.
.We appreciate your positive assessment of the clarity, study design, and methodology.
.Regarding your comment on statistical analysis, we confirm that all our statistics are correct.
.Additionally, we have addressed the issue of data availability to enhance reproducibility by uploading an Excel data of the 54 participants (26 patients and 28 controls) included in the pilot case-control study titled. Please see (reference 100): https://doi.org/10.5281/zenodo.14542662.
.Finally, we have revised the conclusion to ensure that it is fully supported by the results.
.Your insights are greatly appreciated and helped improve the quality of the manuscript.
.We have added this sentence in the ACKNOWLEDGMENTS subsection: “The authors would like to express their sincere gratitude to the two reviewers for their excellent feedback, which has substantially improved the quality of this work. Their insightful comments and constructive suggestions were invaluable in refining our manuscript. ¹⁰⁴”
The authors sincerely thank the reviewer for her thorough and insightful feedback on our manuscript. We have carefully considered each comment and made the necessary revisions to address her concerns. We believe these changes have significantly improved the manuscript. Below are our specific responses to the reviewer positive comments/suggestions.

COMMENT 1.
This is a rare and original study, focusing on the assessment of sub-maximal aerobic capacity in North African patients with chronic hepatitis B (CHB) through a case-control study. This is a study that could provide a great benefit to the management of chronic diseases, but also to the importance of integrating adapted physical activity as an effective and promising therapeutic means in these diseases.
RESPONSE
            Thank you so much for your kind and thoughtful comments. We are grateful for your recognition of the originality and potential impact of our study. We fully agree that integrating adapted physical activity can offer significant therapeutic benefits for patients with chronic diseases like chronic hepatitis B, and we hope our work contributes meaningfully to the ongoing discussions in this field. Your encouragement is highly appreciated.

COMMENT 2.
In the introduction: Page 2 : Some studies have reported the harmful impacts of CHB on the main elements of the chain involved during adaptation to both maximal (eg; oxygen consumption ( _VO2)) and sub-maximal (eg; 6-min walk test (6MWT)) aerobic exercise…..
This example is not suitable, it is the maximal oxygen consumption (V'O2 max) which rather evaluates the tolerance to maximum effort
RESPONSE
            .We agree with the reviewer.
            .The sentence was changed as: “Some studies have reported the harmful impacts of CHB on the main elements of the chain involved during adaptation to both maximal effort ( eg ; maximal oxygen consumption ( V̇O2max)) ^{9, 10} and sub-maximal aerobic exercise ( eg ; 6-min walk test (6MWT)) ^{10, 11}^”

COMMENT 3
In the introduction: Page 3: Exercise tolerance is commonly quantified through the measurement of _VO2 during a cardiorespiratory test (à cardiopulmonary exercise testing CPET)
RESPONSE
            .We agree with the reviewer.
            .The sentence was changed as: “Exercise tolerance is commonly quantified through the measurement of oxygen consumption (V̇O2) during a cardiopulmonary exercise testing,”

COMMENT 4
In the introduction: Page 3: (On the one hand, _VO2 at peak of exercise ( _VO2peak) was a predictor of mortality, as patients with a low _VO2peak (ie; < 17 ml/kg) had a survival rate of 55%,10 and it is significantly correlated with maximal inspiratory pressure (r = 0.64) and with the Model for End-Stage Liver Disease (r = 0.91).9 On the other hand, the authors of the Saudi study reported that compared to healthy participants (n=45), patients with CHB (n=49) had a significantly lower 6-min walk distance (6MWD) by 31 m.11 The Saudi study had some methodological weaknesses that can “slightly” modify the findings.11 First, the inclusion of patients with diverse liver diseases (eg; non-cirrhotic chronic hepatitis B (NC-CHB) or C, cirrhotic), is a source of ‘perplexity’ since the clinical outcomes are different.6 Second, the absence of sample size determination is a statistical flaw.21 Third, the expression of the main outcome (ie; 6MWD) only in absolute value, and the lack of its standardization according to participants’ characteristics (eg; sex and anthropometric data), could lead to misinterpretation.8,10,11 The standardized 6MWD allows a more objective comparison between the diverse groups.22 Fourth, the use on the quantitative significance approach with a “p value” < 0.05 is criticized, and the qualitative significance approach is recommended in medical exercise research.23)
This whole part should be mentioned in the discussion and not in the introduction
RESPONSE
.Thank you for your valuable feedback. We understand your suggestion to move the long paragraph from the introduction to the discussion.
.However, we believe that this would complicate the comprehension of the introduction, as this paragraph represents the core of our introduction. In this part of the introduction, we addressed certain methodological weaknesses observed in a Saudi study (eg; inclusion of patients with diverse liver diseases, absence of sample size determination, expression of the 6MWD only in absolute value, and the lack of its standardization according to participants’ characteristics, use on the quantitative significance approach with a “p value” < 0.05), which were important, and can modify the Saudi authors’ findings. By numbering these limitations, we aim to highlight the originality and unique aspects of our study and inform readers that we have avoided some confusion factors noted in the Saudi study.
.We hope that this explanation clarifies our reasoning, and we appreciate your understanding.

COMMENT 5.
In the methods: Page 4: To the finest of the authors’ knowledge, no previous study has explored the incapacity (aerobic capacity) via the 6MWT in a homogeneous group of NC-CHB patients….
RESPONSE
.We agree with the reviewer.
            .The sentence was changed as: “To the finest of the authors’ knowledge, no previous study has explored the aerobic incapacity via the 6MWT in a homogeneous group of NC-CHB patients compared to a control-group (CG) of “apparently” healthy participants. The main aim of this case-control study was to compare the 6MWT data of the CHB-group and CG. The null hypothesis was that the two groups would have a comparable 6MWD ( ie ; the main outcome).”

COMMENT 6.
In the methods Page 5: co-morbidities such as respiratory or cardiovascular diseases, systemic conditions that could influence blood test results like diabetes mellitus or renal failure, consumption of alcohol….
Why did you exclude diabetics from this study knowing that diabetes does not contraindicate 6MWT?
RESPONSE
.Thank you for this remark.
.A previous Tunisian study (Latiri I, et al.: Six-minute walk test in non-insulin-dependent diabetes mellitus patients living in Northwest Africa. Diabetes Metab. Syndr. Obes. 2012;5:227–245) concluded that diabetes mellitus seems to accelerate the decline of the submaximal aerobic capacity evaluated through the 6MWD. For that reason, we have excluded diabetics from our study.
.We have added the aforementioned reference inside the text after diabetes mellitus (diabetes mellitus ²⁵)

COMMENT 7.
In the methods Page 6: (non-smoker: <5 pack-years; smoker3: 5 pack-years or over )
RESPONSE
.Thank you for this remark.
.Correction done inside the paper: ³5 pack-years

COMMENT 8.
There is a mistake in the formula for the predicted value of the 6-minute walking distance for subjects under 40 years old
For patients under 40 years of age, you used the following formula:
6MWD (m) = 800.05-64.71 x Sex (0: Man; 1: Woman) - 10.23 x BMI (kg/m2) - 1.63 x Age (years) + 2.05 x Weight (kg)
But, according to reference 43 The formula which allows the theoretical DM6 to be calculated is as follows:
6MWD (m) = 800.05 + 64.71 x Sex (men:1/women:0) - 10.23 x BMI (kg/m2) - 1.63 x Age (years) + 2.05 x Weight (kg).
So you need to correct your formula and precise coefficient for gender.
RESPONSE
.Thank you for your remark.
.Sorry to let you know that there is no mistake in the formula for the predicted value of the 6MWD for subjects under 40 years old. We have simply have simply inverted codes for sex [ie; (0: Man; 1: Woman) by (men:1/women:0)] and therefore we have changed “-64.71 x Sex” by “+ 64.71 x Sex”. We have changed the signs in order to make the formulas of subjects aged more and less than 40 years homogenized.
.Therefore, our 6MWD results are correct. Thank you for your comprehension.

COMMENT 9.
In the methods Page 7: For the ECRMC, reference 45 only contains the formula for calculating this parameter in patients over 40 years old, so it is necessary to specify the reference of the other formula which allows the calculation of the ECRMC for patients under 40 years old.
RESPONSE
.Thank you for this remark.
.Correction done inside the paper.

COMMENT 10.
In the Statistical analysis:
In this study, it was necessary to calculate the Odds ratio to confirm the risk of hepatitis on aerobic capacity and the acceleration of aging of the cardiorespiratory and muscular chain.
RESPONSE
            .Thank you for your remark.
            .We have calculated the odds ratio (OR) to confirm the risk of hepatitis on aerobic capacity and the acceleration of aging of the cardiorespiratory and muscular chain. Mainly we have calculated the OR for the following two data: abnormal 6MWD and Low HR (we do not calculated the OR for Desaturation and High dyspnea_End since no participant from both groups exhibited Desaturation or High dyspnea_End (see Table 4).
.We have added the following sentences inside the paper:
*Abstract:
“The CHB-group was 8.1 and 14.3 times more likely to have chronotropic insufficiency and abnormal 6MWD than the CG, respectively”
*Manuscript:
“Moreover, to confirm the risk of CHB on aerobic capacity, odds ratios were calculated for abnormal 6MWD and chronotropic insufficiency”.
“The CHB-group was 8.1 times more likely to have chronotropic insufficiency than the CG.”
“The CHB-group was 14.3 times more likely to have an abnormal 6MWD than the CG.”

COMMENT 11.
”Results Page 7: Out of the 128 participants assessed, data from 54 participants [26 cases (15 m/11w) and 28 controls (15m/13w)] were retained for the final dataset…
RESPONSE
.Thank you for this remark.
.Correction done inside the paper: “Out of the 128 participants assessed, data from 54 participants [26 cases (15 men/11 women) and 28 controls (15 men/13 women)] were retained for the final dataset.”

COMMENT 12.
”Results Page 7: Table 1, 2, 3 and 4 : mean change should be mentioned for each group and the change in the measured value should be expressed as a percentage change from the baseline value (mean % change CHB Group and mean % change CG) and in this case the significance of the difference between the percentage change of the parameter for each group should be sought. Then, the comparison between the percentages of change will allow to evaluate the effect of the groups in the statistical analysis.
RESPONSE
            .We failed to correctly understand your comment.
            .Inside the statistical analysis subsection, we have added the following sentence: For quantitative data, mean percentage changes (%) between the two groups were calculated [mean percentage change = 100 x (CHB-group mean value minus CG mean value)/CHB-group mean]. For each group, percentage delta changes (∆) between data determined at _Restand _End walk were calculated for HR, SpO₂, SBP, DBP, and dyspnea VAS [ ie ; ∆HR (%) = 100 x (HR_End – HR_Rest)/HR_Rest, ∆SpO₂ (%) = 100 x (SpO_2End - SpO_2Rest)/ SpO_2Rest, ∆SBP (%) = 100 x (SBP_End – SBP_Rest)/SBP_Rest, and ∆DBP (%) = 100 x (DBP_End – DBP_Rest)/DBP_Rest].
            .We have not calculated percentage delta changes (∆) for Dyspnea VAS, since all _Restvalues were equal to zero.
.In tables 1, 2, and 3, mean changes were calculated between the two groups for quantitative data. We cannot calculate mean percentage changes for each group because there is no baseline and after intervention data. We have applied all needed changes in Table 1.
            .In tables 3 and 4, we have calculated, for each group, the change (∆) in HR, SBP, DBP, and VAS. Then we have compared the changes between the two groups.
            .Please consult all changes inside the abstract, text and tables.

COMMENT 13.
In the Discussion: Discussion of methodology should come before discussion of results
RESPONSE
            .Thank you for your suggestion. We understand that there is two approaches related to the subjects you raised: should we begin with the discussion of results or methods?
.In an original medical article, it is generally recommended to begin the Discussion section by interpreting and discussing the key results of the study. This approach helps maintain a logical flow, as readers are usually most interested in understanding the study’s findings before delving into methodological considerations.
.Thank you for your comprehension.

COMMENT 14.
In the Discussion: Why you did not evaluate the physiological cost index of walking (ICP). This index is defined by the difference in heart rate at the end of the 6MWT and that at rest reported to the walking speed during the 6MWT. It is an index that was created and validated by J. MacGregor and which evaluates the cost of cardiac work deployed in walking and which could have interesting correlations with the ECRMC.
RESPONSE
            .Thank you for your remark concerning the physiological cost index (PCI).
.We have consulted the paper by MacGregor J ‘The evaluation of patient performance using long-term ambulatory monitoring technique in the domiciliary environment. Physiotherapy. 1981 Feb 10;67(2):30-3. PMID: 7312961”.
            .The PCI, created and validated by J. MacGregor, is a metric used to quantify the energy cost or efficiency of walking, particularly in individuals with mobility impairments or disabilities. It is designed to provide a standardized way to assess walking performance by considering factors such as speed, energy expenditure, and physiological effort. The PCI is often used in clinical and rehabilitation settings to evaluate the effectiveness of interventions, such as prosthetics, orthotics, or physical therapy, on walking ability. This was not the aim of our study.
.The PCI i) measures the energy cost of walking, typically expressed as the amount of energy expended per unit distance walked (e.g., oxygen consumption per meter); ii) often normalizes energy expenditure to body weight or other physiological parameters to allow for comparisons across individuals, iii) is useful for identifying inefficiencies in walking patterns and guiding interventions to improve mobility. Again, this was not the main aim of our study.
            .The PCI is calculated using data from walking tests, often involving measures of: i) Oxygen consumption during walking, ii) Walking speed (distance over time), and iii) Body weight or other anthropometric data. Its formula typically involves dividing the energy expenditure (e.g., oxygen consumption) by the product of walking speed and body weight, though the exact formula may vary depending on the study or application. In our study, we cannot calculate the PCI, since we have not all needed data.
            .In practice, the PCI can be calculated as PCI (bpm*min/m) = (HR_End (bpm) minus HR_Rest) (bpm)/walk speed (m/min). Mean PCI values for healthy adults have been reported to be between 0.23 and 0.42 (MacGregor J. The evaluation of patient performance using long-term ambulatory monitoring technique in the domiciliary environment. Physiotherapy. 1981 Feb 10;67(2):30-3. PMID: 7312961. 13-15; Graham RC, Smith NM, White CM. The reliability and validity of the physiological cost index in healthy subjects while walking on 2 different tracks. Arch Phys Med Rehabil. 2005 Oct;86(10):2041-6. doi: 10.1016/j.apmr.2005.04.022. PMID: 16213251). In this case we need to calculate the walk speed by dividing the 6MWD by 6.
            .Since we have previously published our protocol without reporting our intention to evaluate the PCI (see: Bergaoui J, Latiri I, Ben Saad H. Deficiency, incapacity and social disadvantage of patients with chronic hepatitis B: a case-control study. Tunis Med. 2021 Juillet;99(7):682-692. PMID: 35260999; PMCID: PMC8796680. ), at this stage we cannot add this interesting variable. However, in the revised version, we have recommended to evaluate the PCI in future studies. The following sentence was added: “In future research, it would be valuable to assess the physiological cost index. ^{97, 98} The latter (expressed as heartbeats per meter), determined by dividing the difference between ending and resting HRs by walking speed, represents the additional HR demand during walking. ^{97, 98} Studies have shown that healthy adults typically exhibit mean physiological cost index values ranging from 0.23 to 0.42. ^{97, 98}”

COMMENT 15.
In the Discussion : You justified the use of 6MWW by the fact that it has strong correlations with peak VO2 and this is very interesting in the absence of a technical platform allowing the measurement of peak VO2. However, the strong and significant correlations between DM6 and SpO2 are still known and validated in the literature, thus, the use of the multiplication of 6MWD by the SpO2End is useless in this work especially since you have not shown in this work correlations between this parameter and other measured parameters, which could justify its usefulness.
In the Discussion :The same remarks for the “6MWDxBMI”, “6MWDxmuscle-mass” and “6MWDxbody-fat” especially given the lack of references and scientific validity for these parameters even in your study.

RESPONSE
            .Thank you for your remark. We understand your point of view concerning the indices “6MWD x SpO_2End”, “6MWD x BMI”, “6MWD x MM” and “6MWD x BF”.
            .In order to shorten our paper, we have deleted all these indices.
            .Thank you for this interesting remark.

COMMENT 17.
The English version of this work leaves something to be desired.
RESPONSE
            .Thank you for your pertinent remark.
            .We have revised the English version. We have used a generative AI tool for that reason.
.Inside the paper, we have made the following declaration related to the use of AI chatbots: “In preparing this paper, the authors used ChatGPT ephemeral, to revise some passages of the manuscript, to double-check for any grammar mistakes or improve academic English only. After using this tool, the authors have reviewed and edited the content as necessary and take full responsibility for the content of the publication.”

COMMENT 18.
The conclusion: The conclusion should be better structured, it should respond to the objectives of the study in a clear and precise manner and not contain references.
RESPONSE
            .Thank you for your valuable feedback and insightful comments. We appreciate your suggestion regarding the conclusion.
.We have revised the conclusion to ensure a clearer and more structured response to the study’s objectives, while also removing any references. Your input is highly valuable in strengthening the clarity and impact of the manuscript.
.Here is the new conclusion: “Our study reveals that NC-CHB impairs sub-maximal aerobic capacity, with patients showing reduced 6MWD and 6MWW compared to controls. Chronotropic insufficiency and accelerated cardiorespiratory-muscular aging suggest systemic dysfunction beyond liver disease. Our study contributes to the limited literature on CHB-related functional impairment and calls for integrated management strategies addressing both hepatic and extrahepatic manifestations of the disease. Future research should explore mechanisms and interventions to address these impairments.”
COMMENT 19.
Is the work clearly and accurately presented and does it cite the current literature?
Yes
Is the study design appropriate and is the work technically sound?
Yes
Are sufficient details of methods and analysis provided to allow replication by others?
Yes
If applicable, is the statistical analysis and its interpretation appropriate?
I cannot comment. A qualified statistician is required.
Are all the source data underlying the results available to ensure full reproducibility?
Partly
Are the conclusions drawn adequately supported by the results?
No
RESPONSE
.Thank you for your thorough review and valuable feedback.
.We appreciate your positive assessment of the clarity, study design, and methodology.
.Regarding your comment on statistical analysis, we confirm that all our statistics are correct.
.Additionally, we have addressed the issue of data availability to enhance reproducibility by uploading an Excel data of the 54 participants (26 patients and 28 controls) included in the pilot case-control study titled. Please see (reference 100): https://doi.org/10.5281/zenodo.14542662.
.Finally, we have revised the conclusion to ensure that it is fully supported by the results.
.Your insights are greatly appreciated and helped improve the quality of the manuscript.
.We have added this sentence in the ACKNOWLEDGMENTS subsection: “The authors would like to express their sincere gratitude to the two reviewers for their excellent feedback, which has substantially improved the quality of this work. Their insightful comments and constructive suggestions were invaluable in refining our manuscript. ¹⁰⁴”
Competing Interests: No competing interests Close
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Khadija Ayed, Faculty of medicine of Tunis, Tunis, Tunisia; Center of expertise in aeronautical medicine, Tunis, Tunisia; National Center for Sports Medicine and Science, Tunis, Tunisia
Kaouther MASMOUDI, University of Sfax, Sfax, Tunisia

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Kaouther MASMOUDI, University of Sfax, Sfax, Tunisia

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respiratory functional exploration

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I would like to thank the authors for responding to all my comments. I also thank them for all the explanations they provided to demonstrate their excellent work.

I confirm that this is very interesting work and that it will greatly contribute to the exploration of liver disease, particularly viral hepatitis, during exercise.

I confirm that this revised version of this manuscript meets the recommendations of the scientific editors and deserves to be accepted.

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exercise physiology and pulomonary functionnal testing

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26 Apr 2025

Helmi BEN SAAD, Hospital Farhat HACHED, Research laboratory “Heart Failure, LR12SP09, Universite de Sousse Faculte de Medecine de Sousse, Sousse, 4000, Tunisia

Dear Reviewer,
On behalf of all the authors, I would like to sincerely thank you for your kind words and your positive assessment of our work. We are truly grateful for your thoughtful comments and constructive feedback throughout the review process, which have greatly contributed to improving the quality and clarity of our manuscript. Your recognition of the potential contribution of our study to the understanding of liver disease, particularly viral hepatitis during exercise, is deeply appreciated. Thank you once again for your valuable input and for supporting the acceptance of our revised manuscript. With kind regards,
Pr. Helmi Ben Saad

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Kaouther MASMOUDI, University of Sfax, Sfax, Tunisia

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Is the work clearly and accurately presented and does it cite the current literature?

Yes
Is the study design appropriate and is the work technically sound?

Partly
Are sufficient details of methods and analysis provided to allow replication by others?

Yes
If applicable, is the statistical analysis and its interpretation appropriate?

Yes
Are all the source data underlying the results available to ensure full reproducibility?

Yes
Are the conclusions drawn adequately supported by the results?

Yes

Competing Interests

No competing interests were disclosed.

Reviewer Expertise

respiratory functional exploration

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08 Apr 2025

Helmi BEN SAAD, Hospital Farhat HACHED, Research laboratory “Heart Failure, LR12SP09, Universite de Sousse Faculte de Medecine de Sousse, Sousse, 4000, Tunisia

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Approved With Reservations

This example is not suitable, it is the maximal oxygen consumption (V'O2 max) which rather evaluates the tolerance to maximum effort

This whole part should be mentioned in the discussion and not in the introduction

Why did you exclude diabetics from this study knowing that diabetes does not contraindicate 6MWT?

Page 6 : (non-smoker: <5 pack-years; smoker3: 5 pack-years or over )

There is a mistake in the formula for the predicted value of the 6-minute walking distance for subjects under 40 years old

Is the work clearly and accurately presented and does it cite the current literature?

Yes
Is the study design appropriate and is the work technically sound?

Yes
Are sufficient details of methods and analysis provided to allow replication by others?

Yes
If applicable, is the statistical analysis and its interpretation appropriate?

I cannot comment. A qualified statistician is required.
Are all the source data underlying the results available to ensure full reproducibility?

Partly
Are the conclusions drawn adequately supported by the results?

No

Competing Interests

No competing interests were disclosed.

Reviewer Expertise

exercise physiology and pulomonary functionnal testing

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Author Response

08 Apr 2025

Helmi BEN SAAD, Hospital Farhat HACHED, Research laboratory “Heart Failure, LR12SP09, Universite de Sousse Faculte de Medecine de Sousse, Sousse, 4000, Tunisia

The authors sincerely thank the reviewer for her thorough and insightful feedback on our manuscript. We have carefully considered each comment and made the necessary revisions to address her concerns. We believe these changes have significantly improved the manuscript. Below are our specific responses to the reviewer positive comments/suggestions.

COMMENT 1.
This is a rare and original study, focusing on the assessment of sub-maximal aerobic capacity in North African patients with chronic hepatitis B (CHB) through a case-control study. This is a study that could provide a great benefit to the management of chronic diseases, but also to the importance of integrating adapted physical activity as an effective and promising therapeutic means in these diseases.
RESPONSE
            Thank you so much for your kind and thoughtful comments. We are grateful for your recognition of the originality and potential impact of our study. We fully agree that integrating adapted physical activity can offer significant therapeutic benefits for patients with chronic diseases like chronic hepatitis B, and we hope our work contributes meaningfully to the ongoing discussions in this field. Your encouragement is highly appreciated.

COMMENT 2.
In the introduction: Page 2 : Some studies have reported the harmful impacts of CHB on the main elements of the chain involved during adaptation to both maximal (eg; oxygen consumption ( _VO2)) and sub-maximal (eg; 6-min walk test (6MWT)) aerobic exercise…..
This example is not suitable, it is the maximal oxygen consumption (V'O2 max) which rather evaluates the tolerance to maximum effort
RESPONSE
            .We agree with the reviewer.
            .The sentence was changed as: “Some studies have reported the harmful impacts of CHB on the main elements of the chain involved during adaptation to both maximal effort ( eg ; maximal oxygen consumption ( V̇O2max)) ^{9, 10} and sub-maximal aerobic exercise ( eg ; 6-min walk test (6MWT)) ^{10, 11}^”

COMMENT 3
In the introduction: Page 3: Exercise tolerance is commonly quantified through the measurement of _VO2 during a cardiorespiratory test (à cardiopulmonary exercise testing CPET)
RESPONSE
            .We agree with the reviewer.
            .The sentence was changed as: “Exercise tolerance is commonly quantified through the measurement of oxygen consumption (V̇O2) during a cardiopulmonary exercise testing,”

COMMENT 4
In the introduction: Page 3: (On the one hand, _VO2 at peak of exercise ( _VO2peak) was a predictor of mortality, as patients with a low _VO2peak (ie; < 17 ml/kg) had a survival rate of 55%,10 and it is significantly correlated with maximal inspiratory pressure (r = 0.64) and with the Model for End-Stage Liver Disease (r = 0.91).9 On the other hand, the authors of the Saudi study reported that compared to healthy participants (n=45), patients with CHB (n=49) had a significantly lower 6-min walk distance (6MWD) by 31 m.11 The Saudi study had some methodological weaknesses that can “slightly” modify the findings.11 First, the inclusion of patients with diverse liver diseases (eg; non-cirrhotic chronic hepatitis B (NC-CHB) or C, cirrhotic), is a source of ‘perplexity’ since the clinical outcomes are different.6 Second, the absence of sample size determination is a statistical flaw.21 Third, the expression of the main outcome (ie; 6MWD) only in absolute value, and the lack of its standardization according to participants’ characteristics (eg; sex and anthropometric data), could lead to misinterpretation.8,10,11 The standardized 6MWD allows a more objective comparison between the diverse groups.22 Fourth, the use on the quantitative significance approach with a “p value” < 0.05 is criticized, and the qualitative significance approach is recommended in medical exercise research.23)
This whole part should be mentioned in the discussion and not in the introduction
RESPONSE
.Thank you for your valuable feedback. We understand your suggestion to move the long paragraph from the introduction to the discussion.
.However, we believe that this would complicate the comprehension of the introduction, as this paragraph represents the core of our introduction. In this part of the introduction, we addressed certain methodological weaknesses observed in a Saudi study (eg; inclusion of patients with diverse liver diseases, absence of sample size determination, expression of the 6MWD only in absolute value, and the lack of its standardization according to participants’ characteristics, use on the quantitative significance approach with a “p value” < 0.05), which were important, and can modify the Saudi authors’ findings. By numbering these limitations, we aim to highlight the originality and unique aspects of our study and inform readers that we have avoided some confusion factors noted in the Saudi study.
.We hope that this explanation clarifies our reasoning, and we appreciate your understanding.

COMMENT 5.
In the methods: Page 4: To the finest of the authors’ knowledge, no previous study has explored the incapacity (aerobic capacity) via the 6MWT in a homogeneous group of NC-CHB patients….
RESPONSE
.We agree with the reviewer.
            .The sentence was changed as: “To the finest of the authors’ knowledge, no previous study has explored the aerobic incapacity via the 6MWT in a homogeneous group of NC-CHB patients compared to a control-group (CG) of “apparently” healthy participants. The main aim of this case-control study was to compare the 6MWT data of the CHB-group and CG. The null hypothesis was that the two groups would have a comparable 6MWD ( ie ; the main outcome).”

COMMENT 6.
In the methods Page 5: co-morbidities such as respiratory or cardiovascular diseases, systemic conditions that could influence blood test results like diabetes mellitus or renal failure, consumption of alcohol….
Why did you exclude diabetics from this study knowing that diabetes does not contraindicate 6MWT?
RESPONSE
.Thank you for this remark.
.A previous Tunisian study (Latiri I, et al.: Six-minute walk test in non-insulin-dependent diabetes mellitus patients living in Northwest Africa. Diabetes Metab. Syndr. Obes. 2012;5:227–245) concluded that diabetes mellitus seems to accelerate the decline of the submaximal aerobic capacity evaluated through the 6MWD. For that reason, we have excluded diabetics from our study.
.We have added the aforementioned reference inside the text after diabetes mellitus (diabetes mellitus ²⁵)

COMMENT 7.
In the methods Page 6: (non-smoker: <5 pack-years; smoker3: 5 pack-years or over )
RESPONSE
.Thank you for this remark.
.Correction done inside the paper: ³5 pack-years

COMMENT 8.
There is a mistake in the formula for the predicted value of the 6-minute walking distance for subjects under 40 years old
For patients under 40 years of age, you used the following formula:
6MWD (m) = 800.05-64.71 x Sex (0: Man; 1: Woman) - 10.23 x BMI (kg/m2) - 1.63 x Age (years) + 2.05 x Weight (kg)
But, according to reference 43 The formula which allows the theoretical DM6 to be calculated is as follows:
6MWD (m) = 800.05 + 64.71 x Sex (men:1/women:0) - 10.23 x BMI (kg/m2) - 1.63 x Age (years) + 2.05 x Weight (kg).
So you need to correct your formula and precise coefficient for gender.
RESPONSE
.Thank you for your remark.
.Sorry to let you know that there is no mistake in the formula for the predicted value of the 6MWD for subjects under 40 years old. We have simply have simply inverted codes for sex [ie; (0: Man; 1: Woman) by (men:1/women:0)] and therefore we have changed “-64.71 x Sex” by “+ 64.71 x Sex”. We have changed the signs in order to make the formulas of subjects aged more and less than 40 years homogenized.
.Therefore, our 6MWD results are correct. Thank you for your comprehension.

COMMENT 9.
In the methods Page 7: For the ECRMC, reference 45 only contains the formula for calculating this parameter in patients over 40 years old, so it is necessary to specify the reference of the other formula which allows the calculation of the ECRMC for patients under 40 years old.
RESPONSE
.Thank you for this remark.
.Correction done inside the paper.

COMMENT 10.
In the Statistical analysis:
In this study, it was necessary to calculate the Odds ratio to confirm the risk of hepatitis on aerobic capacity and the acceleration of aging of the cardiorespiratory and muscular chain.
RESPONSE
            .Thank you for your remark.
            .We have calculated the odds ratio (OR) to confirm the risk of hepatitis on aerobic capacity and the acceleration of aging of the cardiorespiratory and muscular chain. Mainly we have calculated the OR for the following two data: abnormal 6MWD and Low HR (we do not calculated the OR for Desaturation and High dyspnea_End since no participant from both groups exhibited Desaturation or High dyspnea_End (see Table 4).
.We have added the following sentences inside the paper:
*Abstract:
“The CHB-group was 8.1 and 14.3 times more likely to have chronotropic insufficiency and abnormal 6MWD than the CG, respectively”
*Manuscript:
“Moreover, to confirm the risk of CHB on aerobic capacity, odds ratios were calculated for abnormal 6MWD and chronotropic insufficiency”.
“The CHB-group was 8.1 times more likely to have chronotropic insufficiency than the CG.”
“The CHB-group was 14.3 times more likely to have an abnormal 6MWD than the CG.”

COMMENT 11.
”Results Page 7: Out of the 128 participants assessed, data from 54 participants [26 cases (15 m/11w) and 28 controls (15m/13w)] were retained for the final dataset…
RESPONSE
.Thank you for this remark.
.Correction done inside the paper: “Out of the 128 participants assessed, data from 54 participants [26 cases (15 men/11 women) and 28 controls (15 men/13 women)] were retained for the final dataset.”

COMMENT 12.
”Results Page 7: Table 1, 2, 3 and 4 : mean change should be mentioned for each group and the change in the measured value should be expressed as a percentage change from the baseline value (mean % change CHB Group and mean % change CG) and in this case the significance of the difference between the percentage change of the parameter for each group should be sought. Then, the comparison between the percentages of change will allow to evaluate the effect of the groups in the statistical analysis.
RESPONSE
            .We failed to correctly understand your comment.
            .Inside the statistical analysis subsection, we have added the following sentence: For quantitative data, mean percentage changes (%) between the two groups were calculated [mean percentage change = 100 x (CHB-group mean value minus CG mean value)/CHB-group mean]. For each group, percentage delta changes (∆) between data determined at _Restand _End walk were calculated for HR, SpO₂, SBP, DBP, and dyspnea VAS [ ie ; ∆HR (%) = 100 x (HR_End – HR_Rest)/HR_Rest, ∆SpO₂ (%) = 100 x (SpO_2End - SpO_2Rest)/ SpO_2Rest, ∆SBP (%) = 100 x (SBP_End – SBP_Rest)/SBP_Rest, and ∆DBP (%) = 100 x (DBP_End – DBP_Rest)/DBP_Rest].
            .We have not calculated percentage delta changes (∆) for Dyspnea VAS, since all _Restvalues were equal to zero.
.In tables 1, 2, and 3, mean changes were calculated between the two groups for quantitative data. We cannot calculate mean percentage changes for each group because there is no baseline and after intervention data. We have applied all needed changes in Table 1.
            .In tables 3 and 4, we have calculated, for each group, the change (∆) in HR, SBP, DBP, and VAS. Then we have compared the changes between the two groups.
            .Please consult all changes inside the abstract, text and tables.

COMMENT 13.
In the Discussion: Discussion of methodology should come before discussion of results
RESPONSE
            .Thank you for your suggestion. We understand that there is two approaches related to the subjects you raised: should we begin with the discussion of results or methods?
.In an original medical article, it is generally recommended to begin the Discussion section by interpreting and discussing the key results of the study. This approach helps maintain a logical flow, as readers are usually most interested in understanding the study’s findings before delving into methodological considerations.
.Thank you for your comprehension.

COMMENT 14.
In the Discussion: Why you did not evaluate the physiological cost index of walking (ICP). This index is defined by the difference in heart rate at the end of the 6MWT and that at rest reported to the walking speed during the 6MWT. It is an index that was created and validated by J. MacGregor and which evaluates the cost of cardiac work deployed in walking and which could have interesting correlations with the ECRMC.
RESPONSE
            .Thank you for your remark concerning the physiological cost index (PCI).
.We have consulted the paper by MacGregor J ‘The evaluation of patient performance using long-term ambulatory monitoring technique in the domiciliary environment. Physiotherapy. 1981 Feb 10;67(2):30-3. PMID: 7312961”.
            .The PCI, created and validated by J. MacGregor, is a metric used to quantify the energy cost or efficiency of walking, particularly in individuals with mobility impairments or disabilities. It is designed to provide a standardized way to assess walking performance by considering factors such as speed, energy expenditure, and physiological effort. The PCI is often used in clinical and rehabilitation settings to evaluate the effectiveness of interventions, such as prosthetics, orthotics, or physical therapy, on walking ability. This was not the aim of our study.
.The PCI i) measures the energy cost of walking, typically expressed as the amount of energy expended per unit distance walked (e.g., oxygen consumption per meter); ii) often normalizes energy expenditure to body weight or other physiological parameters to allow for comparisons across individuals, iii) is useful for identifying inefficiencies in walking patterns and guiding interventions to improve mobility. Again, this was not the main aim of our study.
            .The PCI is calculated using data from walking tests, often involving measures of: i) Oxygen consumption during walking, ii) Walking speed (distance over time), and iii) Body weight or other anthropometric data. Its formula typically involves dividing the energy expenditure (e.g., oxygen consumption) by the product of walking speed and body weight, though the exact formula may vary depending on the study or application. In our study, we cannot calculate the PCI, since we have not all needed data.
            .In practice, the PCI can be calculated as PCI (bpm*min/m) = (HR_End (bpm) minus HR_Rest) (bpm)/walk speed (m/min). Mean PCI values for healthy adults have been reported to be between 0.23 and 0.42 (MacGregor J. The evaluation of patient performance using long-term ambulatory monitoring technique in the domiciliary environment. Physiotherapy. 1981 Feb 10;67(2):30-3. PMID: 7312961. 13-15; Graham RC, Smith NM, White CM. The reliability and validity of the physiological cost index in healthy subjects while walking on 2 different tracks. Arch Phys Med Rehabil. 2005 Oct;86(10):2041-6. doi: 10.1016/j.apmr.2005.04.022. PMID: 16213251). In this case we need to calculate the walk speed by dividing the 6MWD by 6.
            .Since we have previously published our protocol without reporting our intention to evaluate the PCI (see: Bergaoui J, Latiri I, Ben Saad H. Deficiency, incapacity and social disadvantage of patients with chronic hepatitis B: a case-control study. Tunis Med. 2021 Juillet;99(7):682-692. PMID: 35260999; PMCID: PMC8796680. ), at this stage we cannot add this interesting variable. However, in the revised version, we have recommended to evaluate the PCI in future studies. The following sentence was added: “In future research, it would be valuable to assess the physiological cost index. ^{97, 98} The latter (expressed as heartbeats per meter), determined by dividing the difference between ending and resting HRs by walking speed, represents the additional HR demand during walking. ^{97, 98} Studies have shown that healthy adults typically exhibit mean physiological cost index values ranging from 0.23 to 0.42. ^{97, 98}”

COMMENT 15.
In the Discussion : You justified the use of 6MWW by the fact that it has strong correlations with peak VO2 and this is very interesting in the absence of a technical platform allowing the measurement of peak VO2. However, the strong and significant correlations between DM6 and SpO2 are still known and validated in the literature, thus, the use of the multiplication of 6MWD by the SpO2End is useless in this work especially since you have not shown in this work correlations between this parameter and other measured parameters, which could justify its usefulness.
In the Discussion :The same remarks for the “6MWDxBMI”, “6MWDxmuscle-mass” and “6MWDxbody-fat” especially given the lack of references and scientific validity for these parameters even in your study.

RESPONSE
            .Thank you for your remark. We understand your point of view concerning the indices “6MWD x SpO_2End”, “6MWD x BMI”, “6MWD x MM” and “6MWD x BF”.
            .In order to shorten our paper, we have deleted all these indices.
            .Thank you for this interesting remark.

COMMENT 17.
The English version of this work leaves something to be desired.
RESPONSE
            .Thank you for your pertinent remark.
            .We have revised the English version. We have used a generative AI tool for that reason.
.Inside the paper, we have made the following declaration related to the use of AI chatbots: “In preparing this paper, the authors used ChatGPT ephemeral, to revise some passages of the manuscript, to double-check for any grammar mistakes or improve academic English only. After using this tool, the authors have reviewed and edited the content as necessary and take full responsibility for the content of the publication.”

COMMENT 18.
The conclusion: The conclusion should be better structured, it should respond to the objectives of the study in a clear and precise manner and not contain references.
RESPONSE
            .Thank you for your valuable feedback and insightful comments. We appreciate your suggestion regarding the conclusion.
.We have revised the conclusion to ensure a clearer and more structured response to the study’s objectives, while also removing any references. Your input is highly valuable in strengthening the clarity and impact of the manuscript.
.Here is the new conclusion: “Our study reveals that NC-CHB impairs sub-maximal aerobic capacity, with patients showing reduced 6MWD and 6MWW compared to controls. Chronotropic insufficiency and accelerated cardiorespiratory-muscular aging suggest systemic dysfunction beyond liver disease. Our study contributes to the limited literature on CHB-related functional impairment and calls for integrated management strategies addressing both hepatic and extrahepatic manifestations of the disease. Future research should explore mechanisms and interventions to address these impairments.”
COMMENT 19.
Is the work clearly and accurately presented and does it cite the current literature?
Yes
Is the study design appropriate and is the work technically sound?
Yes
Are sufficient details of methods and analysis provided to allow replication by others?
Yes
If applicable, is the statistical analysis and its interpretation appropriate?
I cannot comment. A qualified statistician is required.
Are all the source data underlying the results available to ensure full reproducibility?
Partly
Are the conclusions drawn adequately supported by the results?
No
RESPONSE
.Thank you for your thorough review and valuable feedback.
.We appreciate your positive assessment of the clarity, study design, and methodology.
.Regarding your comment on statistical analysis, we confirm that all our statistics are correct.
.Additionally, we have addressed the issue of data availability to enhance reproducibility by uploading an Excel data of the 54 participants (26 patients and 28 controls) included in the pilot case-control study titled. Please see (reference 100): https://doi.org/10.5281/zenodo.14542662.
.Finally, we have revised the conclusion to ensure that it is fully supported by the results.
.Your insights are greatly appreciated and helped improve the quality of the manuscript.
.We have added this sentence in the ACKNOWLEDGMENTS subsection: “The authors would like to express their sincere gratitude to the two reviewers for their excellent feedback, which has substantially improved the quality of this work. Their insightful comments and constructive suggestions were invaluable in refining our manuscript. ¹⁰⁴”

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Competing Interests

No competing interests

Alongside their report, reviewers assign a status to the article:

Approved - the paper is scientifically sound in its current form and only minor, if any, improvements are suggested

Approved with reservations - A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.

Not approved - fundamental flaws in the paper seriously undermine the findings and conclusions

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Assessment of sub-maximal aerobic capacity in North African patients with chronic hepatitis B: a pilot case-control study

Abstract

Background

Methods

Results

Conclusion

Keywords

Revised Amendments from Version 1

Introduction

Methods

Study design

Study population

Figure 1. Study flow chart.

Sample size

Study protocol

Applied questionnaires

Sex and anthropometric data

Biological data

Handgrip strength

6-min walk test

Statistical analysis

Results

Table 1. Characteristics of the chronic hepatitis B (CHB, n=26) and control (CG, n=28) groups.

Table 2. 6-min walk distance (6MWD) and 6-min walk work (6MWW) values of the chronic hepatitis B (CHB, n=26) and control (CG, n=28) groups.

Table 3. Heart rate (HR) data of the chronic hepatitis B (CHB, n=26) and control (CG, n=28) groups.

Table 4. Blood-pressure, oxy-hemoglobin saturation (SpO2), dyspnea, and exercise intolerance’ signs of the chronic hepatitis B (CHB, n=26) and control (CG, n=28) groups.

Discussion

Discussion of results

Discussion of methods

Collected data

Conclusion

Ethical approval

Informed consent

Data availability

Extended data

Reporting guidelines

Acknowledgments

References

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Table 4. Blood-pressure, oxy-hemoglobin saturation (SpO₂), dyspnea, and exercise intolerance’ signs of the chronic hepatitis B (CHB, n=26) and control (CG, n=28) groups.