Heavy khat (Catha edulis) chewing and dyslipidemia as modifiable hypertensive risk factors among patients in Southwest, Ethiopia: Unmatched case-control study.

BACKGROUND: The burden of hypertension is more devastating in low-and middle-income countries, including sub-Saharan Africa than in high-income countries. Among the modifiable risk factors, dyslipidemia and khat chewing were expanding at an alarming rate in Ethiopia but were still underestimated. Thus, this study aimed to assess heavy khat (Catha edulis) chewing and dyslipidemia as modifiable hypertensive risk factors among patients in the southwest, Ethiopia.
METHODS: A facility-based case-control study was conducted among 136 cases and 270 controls from May 15 to July 30, 2017. A consecutive sampling technique was used in this study. Epi data version 3.1.1 and SPSS version 21 were used for data entry and analysis. Descriptive statistics and bivariate and multivariate logistic regression analyses were performed. Both crude and adjusted odds ratios and 95% confidence intervals were reported.
RESULTS: The majority of the cases had a total cholesterol to high-density lipoprotein ratio of >5 (72.1%). The odds of hypertension increased among participants who had attended no formal education [AOR = 2.25, 95% CI: (1.05-4.82)], history of alcohol consumption [AOR = 5.93,95% CI:(3.11-11.30)], moderate khat chewing [AOR = 3.68, 95% CI:(1.69,8.01)], heavy khat chewing [AOR = 18.18, 95% CI: (3.56-92.89)], mild intensity physical activity [AOR = 3.01, 95% CI: (1.66-5.47)], type of oil used for food preparation [AOR = 2.81, 95% CI: (1.49-5.28)], and dyslipidemia [AOR = 6.68, 95% CI: (2.93-15.23)].
CONCLUSION: The study showed that modifiable risk factors were the major factors associated with the development of hypertension. The findings of this study highlighted that health education is needed to focus on physical exercise, quitting excess alcohol consumption, quitting khat chewing by giving special emphasis to those who had no formal education. In addition, consideration should be given to a healthy diet free of cholesterol and unhealthy behavior.

Introduction

Elevated blood pressure (BP) is the leading cause of mortality and morbidity related to cardiovascular disorders worldwide [1]. Globally, it is estimated that one billion adults live with hypertension; this figure is predicted to be more than a 1.5billion by the year 2025 [2]. Currently, the burden of hypertension has become more devastating in low- and middle-income countries, including sub-Saharan Africa (SSA), than in high-income countries [3]. The prevalence of hypertension in SSA is estimated to be approximately 30% [4]. As treatment and control of hypertension are low in this area, the high burden of hypertension in these nations is likely to have an increased risk of more morbidity and mortality from potentially preventable complications such as stroke, myocardial infarction, and renal failure [5]. Worldwide, over 50% of the 17.4 million annual deaths were caused by cardiovascular diseases that attributed to hypertension. Moreover, at least 45% of deaths due to heart disease and 51% of deaths due to stroke were related to hypertension [2]. Africa, including the rural population, needs more consideration of cardiovascular health by responsible authorities [6].

Hypertension is one of the most common public health burdens in Ethiopia. A meta-analysis conducted in Ethiopia reported the prevalence of hypertension to be 19.4% [7]. These may be related to the changing lifestyle of the Ethiopian population due to urbanization and demographic transition [8]. Empirical findings in this country revealed that various risk factors were associated with hypertension. These risk factors were age, obesity, family history of hypertension, smoking, diabetes, alcohol consumption, inadequate intake of fruit and vegetable, excess salt use, and not continuous walking for at least 10 minutes per day [9-12].

Among the modifiable risk factors of hypertension, khat chewing is the one. Khat (Qat, Kat and Miraa, Catha edulis) is a dicotyledonous evergreen flowering tree. It is a member of Celastraceae that grows in equatorial climates, mainly in the horn of Africa and the Arabian Peninsula [13]. Approximately, 20 million people worldwide are believed to be khat chewers, which were previously localized in East Africa and the Arabian peninsula [14]. Chewing is the fundamental mechanism by which the fresh leaves of khat were chewed slowly for several hours [6]. A study in Yemen reported a rise in blood pressure with the duration of khat chewing [7] but another study failed to associate [15]. When we compare khat chewers to non-chewers, the prevalence of hypertension and diastolic blood pressure is high among chewers [10].

Ethiopia is one of the five countries that cultivate khat. In Ethiopia, though efforts have been made to identify the risk factors for hypertension and to overcome its effect, the prevalence of HTN and its risk factors have not decreased [16]. Despite some studies uncovering chewing khat repeatedly and frequently results in increased blood pressure and development of myocardial infarction [17-20], most of the previous studies in Ethiopia neglected to investigate the association between khat chewing, dyslipidemia, and hypertension.

Since there is growing evidence on the prevalence of hypertension and khat chewing [20], there is a need to investigate their association for better intervention. Most previous studies did not investigate the amount of khat chewed, dyslipidemia, and hypertension in a case-control association. Moreover, it was hard to reach more studies that included dyslipidemia and khat chewing as risk factors for hypertension. Thus, this study aimed to assess modifiable risk factors for hypertension among patients in Southwest Ethiopia, including the most dominant factors (khat chewing and dyslipidemia), applying unmatched case-control study. A clear understanding of such factors is crucial for building responsive interventions by the responsible bodies.

Materials and methods

Study setting, study period and study design

A facility-based unmatched case-control study was conducted from May 15th to July 30th, 2017, at Jimma University medical center (JUMC), found in Jimma, southwest Ethiopia. Jimma zone is located 600 km southwest of Addis Ababa, Ethiopia’s capital. As the information gained from the JUMC website (http://www.ju.edu.et), JUMC is the only referral hospital in the Zone, providing services for approximately 15,000 inpatients and 160,000 outpatients per year with a catchment population of about 15 million people.

Ascertainment of cases and controls

The source population comprised all adults (aged 18 years and above) who attended outpatient departments in JUMC. Cases were patients already diagnosed with hypertension by a physician or those taking anti-hypertensive drugs during the study period. Controls were patients attending JUMC with no history of hypertension and whose blood pressure was <140 mmHg/<90 mmHg during the study period.

Inclusion criteria for cases

patients who are known hypertensive patients diagnosed by a physician (diagnosed with (BP ≥ 140/90)) and on anti-hypertensive treatment and attended services during the study period which were selected consecutively from the follow-up clinic where all patients with chronic illness attend this clinic. Two hospital-based controls were selected from the same medical ward that sought other services and proved to be free from hypertension (diagnosed as normal BP and confirmed by three re-measurement of BP).

Exclusion criteria for cases and controls

Pregnant women, a client with renal disease, mentally unstable or critically ill, and unable to respond were excluded from both groups.

Measurement variables

Outcome variable

The outcome variable for the study was hypertension. Patients were categorized as cases if they were diagnosed with hypertension by a physician or those taking anti-hypertensive drugs during the study period.

Arterial blood pressure

blood pressure was measured three times according to a standardized protocol using an automatic oscillometric method (dynamap). It was obtained from the left arm in a seated position using a standard mercury sphygmomanometer BP cuff. Participants were asked if they had hot drinks, smoke cigarettes, stressed or had vigorous-intensity physical activity before measurement and then waited for 30min. Finally, the average of the readings was considered as the final BP of each participant. The same blood pressure recorder was used for the overall study population. Hypertension was defined as systolic BP>140 mmHg and/or diastolic BP>90 mmHg or reported use of regular anti-hypertensive medication(s). As the 6th Joint National Committee categorized hypertension as stage one and stage two, it also classified those patients taking the anti-hypertensive drug in stage two [21].

Independent variables

The independent variables were conceptualized based on the WHO standard questionnaire [18] and previous similar studies [8–11, 19] and then clustered into four sets of factor characteristics. The independent variables were socio-demographic factors such as educational, occupational, religion, income, and oral contraceptive use history. Non-modifiable factors such as age, sex, family history of hypertension and modifiable lifestyle determinants such as smoking status, history of alcohol consumption, khat chewing, intensity of physical activity, dyslipidemia and anthropometric measurements such as BMI. Heavy khat chewers where those who had a history of khat chewing of two or more bundles of khat in one chewing session, moderate chewers were those who chew almost a bundle of khat and those mild chewers were those who chew less than one bundle of khat for one chewing session at least for more than six months. Since Ethiopian drinks such as “Tella, Areki, Teji, and borde “are the main types of alcoholic drinks in the study area; alcohol consumption was defined as the use of these alcohols in addition to the standard ones. In this study packed (palm) oil was packed in the jar “Chef, Hayat, Viking”. Physical activity is considered to be at least 150–300 minutes of moderate-intensity aerobic physical activity; or at least 75–150 minutes of vigorous-intensity aerobic physical activity or an equivalent combination of moderate and vigorous-intensity activity throughout the week [22, 23]. Lipid profiles (Total cholesterol, HDL, LDL, and triglyceride) were determined and dyslipidemia was classified according to the American heart association, and the TC/HDL ratio was >5 [18].

Sample size determination and sampling technique

The sample size was calculated using Epi info version 3.1 with the following assumptions; 20.9% proportion of exposure (history of cigarette smoking) among control groups with an odds ratio of 2.06 [12], 95% confidence interval, 80% power, and 2:1 control to case ratio. After adding a non-response rate of 10% total sample size was 406 (136 cases and 270 controls). A consecutive sampling technique was used to recruit the required sample sizes for the cases. The control groups were also selected consecutively after case selection had been completed until the calculated sample size was achieved. Selected study participants were interviewed upon their exit from the chronic illness clinic and to avoid overlapping we put a mark on the patient’s card.

Data collection procedure and quality management

Data were collected using pre-tested interviewer-administered structured questionnaires, adapted with modifications from the WHO standard questionnaire [24] and previous studies [11, 12, 17] according to the study objective and local context. Doctors in internship facilitated data collection, six BSc nurses, and two laboratory technicians with extensive experience in data collection collected the data and analyzed it, respectively. The final questionnaire has four sub-parts; socio-demographic characteristics, behavioral characteristics, biochemical characteristics, and nutritional characteristics. Item questions were checked for reliability and internal consistency using Cronbach’s alpha coefficients. The tool was translated into the local language (Amharic & Afaan Oromoo) and subsequently translated back to English by different language experts to check the consistency and quality of the translation. (S1 Questionnaire) Study participants were interviewed on their exit from the chronic illness clinic in a private setting after a deep discussion that removed their doubts and cleared their confusion. Before administration of the questionnaire, it was reviewed by two senior experts and pre-tested on 5% of the sample size in the nearby Shenen Gibe hospital. All required revisions were made to the study tool based on the pre-test and expert comments. Before the actual data collection day, two-day intensive training on the aim of the study and sampling procedures was provided to the enumerators. The supervisors (PI and co-author) underwent routine checkups for completeness and scientific soundness. To minimize measurement error anthropometric measurements were taken after prerequisites to avoid error that is, weight was measured after the scale pointer was checked at zero, and subjects wore light clothes and stood straight and unassisted in the center of a balance platform. Height was also measured after participants were requested to remove their shoes, stood erect, a position at the plane with feet together and knee straight. The heels, buttocks, and shoulder blades were made straight against the stadiometer’s vertical stand. Instrument calibration and random auditing were performed; measurements were taken twice, and finally, height to the nearest 0.1cm and weight to the nearest 0.1kg was taken. Anthropometric measurements were translated according to the WHO Steps guidelines. Participants with a BMI lower than 18.5 kg/m2 were considered as underweight; between 18.5 and 24.9 kg/m2 as normal; between 25.0 and 29.9 kg/m2 as overweight and 30.0 kg/m2 and above as obese [25]. Medical records and consultation with the person in charge of the patient were the gold standards for identifying cases and controls.

Sample collection and biochemical analysis

After overnight fasting, participants conducted the interviews and anthropometric measurements and provided 5 ml of venous blood. Then, the sample was centrifuged for 5 minutes at 4000 revolutions per minute and stored at-80°C for subsequent biochemical tests. Around 2.5 ml of pure serum sample was separated into a Nunc tube. The samples were analyzed using a Mindray BS-200 chemistry analyzer (Shenzen Mindray Bio-Medical Electronics Co. Ltd) according to the manufacturer’s instructions. Before sample analysis, the machine was checked using controls and blank daily. The sample was analyzed to determine the lipid profile of the four parameters (triglyceride, high-density lipoprotein, low-density lipoprotein, and total cholesterol); and dichotomized the parameters and found that there was a risk factor for dyslipidemia (total cholesterol to high-density lipoprotein ratio >5 [26].

Data processing and analysis

The data were entered into Epi-data version 3.1 and exported to SPSS version 21 for analysis. It was explored to check for outliers, missing data, and assumptions. A chi-square test was used to assess each independent variable’s association with the outcome variable. Descriptive statistics and cross-tabulation were calculated. Bivariate and multivariate logistic regression analyses were also performed. Significant variables with a p-value of ≤0.25, in bivariate analysis, were retained for further consideration in multivariate logistic regression to control for confounders. This is basically to compensate for the power of the test because negative findings (i.e. p > 0.05) may be due to inadequate power [27, 28]. Finally, multivariable logistic regression was performed to control for possible confounding effects of variables such as (BMI, behavioral factors and dyslipidemia). Odds ratios and 95% confidence intervals were computed, and a p-value of less than 0.05 was used to determine the cut-off points for statistical significance.

Ethical approval and consent to participate

Jimma University institute of health science and the ethical review committee approved the study. All the study participants were informed about the purpose of the study, their right to refuse, and ensured confidentiality and verbal and written consent was obtained before the interview. No personal details were recorded or produced on any documentation related to the study and privacy was assured. At the end of each interview and measurement procedure, we created awareness of risk factors of hypertension and aggravating factors for the cases.

Results

Socio-demographic characteristics of study participants

A total of 406 participants (136 hypertensive cases and 270 non-hypertensive controls) were participated making, a response rate of 100%. Almost half of the cases 70(51.5%), and 143 (53.0%) controls were male. A large proportion (42.6%) of both the cases and controls fell within the age group of above 55 years. The mean ± SD age for the cases and controls were (52.65±13.09) years and (50.95±13.55), respectively. More than half of the cases and almost half of controls did not attend any formal education (p<0.001) and had low monthly income p = 0.25 Table 1.

Table 1

Socio-demographic characteristics of study participants, Southwest Ethiopia, 2019.

Variable		Case No (%)	Control No (%)	Total No (%)	X 2	p-value
Sex	Male	70(51.5%)	143(53.0%)	213(52.5%)	0.08	0.78
	Female	66(48.5%)	127(47.0%)	193(47.5%)
Age category (years)	<35	28(20.6%)	61(22.6%)	89(21.9%)	0.26	0.88
	35–55	50(36.8%)	94(34.8%)	144(35.5%)
	>55	58(42.6%)	115(42.6%)	173(42.6%)
Place of residence	Urban	82(60.3%)	156(57.8%)	238(58.6%)	0.24	0.63
	Rural	54(39.7%)	114(42.2%)	168(41.4%)
Ethnicity	Oromo	96(70.6%)	184(68.1%)	280(69.0%)	11.23	0.47
	Amhara	17(12.5%)	34(12.6%)	51(12.6%)
	Dawuro, Kafa, Yem	23(16.9%)	52(19.26%)	75(18.47%)
Marital status	Married	106(77.9%)	217(80.4%)	323(79.6%)	0.33	0.57
	Single/divorced/ widowed	30(22.1%)	53(19.6%)	83(20.4%)
Religion	Orthodox	31(22.8%)	77(28.5%)	108(26.6%)	3.44	0.33
	Muslim	85(62.5%)	156(57.8%)	241(59.4%)
	Other**	20(14.7%)	37(13.7%)	57(14.03%
Educational status	No formal education	78(57.4%)	113(41.9%)	191(47.0%)	14.66	0.001*
	Primary education	34(25.0%)	61(22.6%)	95(23.4%)
	Secondary and above	24(17.6%)	96(35.6%)	120(29.6%)
Occupation	Farmer	48(35.3%)	74(27.4%)	122(30.0%)	3.11	0.37
	Government employee	25(18.4%)	49(18.1%)	74(18.2%)
	House wife	34(25.0%)	76(28.1%)	110(27.1%)
	Other***	29(21.3%)	71(26.3%)	100(24.6%)
Income (1dollar = 40birr)	Low	77(56.6%)	132(48.9%)	210(51.5%)	2.80	0.25*
	Middle	32(23.5%)	66(24.4%)	98(24.1%)
	High	27(19.9%)	72(26.7%)	99(24.4%)
OCP use	Yes	43(65.2%)	62(48.8%)	105(54.4%)	4.67	0.03*
	No	23(34.8%)	65(51.2%)	88(45.6%)
Family hx of HPN	Yes	30(22.1%)	53(19.6%)	83(20.4%)	0.33	0.57
	No	106(77.9%)	217(80.4%)	323(79.6%)

Note: Other

*p≤0.25

** protestant, Catholic, Adventis

***Student, merchant, Self-Employed, hx; history, ocp; oral contraceptive; HPN; hypertension.

Behavioral, biochemical and nutritional characteristics

Ninety-six (70.6%) cases and one hundred eight (43.7%) controls had a history of khat chewing during their lifetime (p<0.001). A large proportion of cases chew one bundle of khat during one chewing session compared to controls (39.0% vs. 13.3%, (p<0.001)) of which (38.5%) of cases and 36.4% chew khat daily. Most of the reasons for chewing were religious prayers, to increase social interaction, addiction, and to stay awake. More cases 56.6% than controls 26.3% drank alcohol (p<0.001). Among alcohol users, 36.4% of cases and 46.5% of controls drank “Tella”, “Tejj”, “areki” and beer three times a week. More than half (57.3%) of the cases and (63.0%) of the controls drank alcohol for over ten years. Only 38(27.9%) cases and 40(14.8%) controls had a previous history of smoking cigarettes (p = 0.002), and only 5.3% of cases and 2.5% of controls were smokers during the time of data collection. Moreover, 93(68.4%) of cases and 102(37.8%) controls had moderate and vigorous physical activity, p<0.001). More than half of the cases used oral contraceptives compared to controls (65.2% vs. 48.8%, p = 0.03).

As shown in Table 2, the total cholesterol levels above 200mg/dl among the two groups were significantly different (58.1% vs. 33.7%, p<0.001). Among the cases, nearly three out of four (72.1%) had dyslipidemia (TC/HDL ratio >5) and (23.7%) of controls. In most of the cases, 77.2% and 63.7% of controls used packed (palm) oil for food preparation. Regarding anthropometric measurements, most of the study participants had a normal body mass index range (18.5–24.9, p = 0.12) Table 2.

Table 2

Behavioral, nutritional and biochemical hypertensive risk factors among patients in southwest, Ethiopia, 2020.

Variable	Categories	Cases No (%)	Controls No (%)	Total No (%)	X 2	p-value
History of Smoking	Yes	38(27.9%)	40(14.8%)	78(19.2%)	10.04	0.002
	No	98(72.1%)	230(85.2%)	328(80.8%)
Frequency of smoking	Daily	16(41.0%)	13(32.5%	29(36.7%)	1.66	0.65
	Three times a week	15(38.5%)	16(40.0%)	31(39.2%)
	Once a week	6(15.4%)	10(25.0%)	16(20.3%)
	One a month	2(5.1%)	1(2.5%)	3(3.8%)
Current smoking status	Still smoking	2(5.3%)	1(2.5%)	3(3.8%)	0.62	0.74
	Reduced	8(21.1%)	7(17.5%)	15(19.2%)
	Ceased	28(73.7%)	32(80.0%)	60(76.9%)
History of alcohol consumption	Yes	77(56.6%)	71(26.3%)	148(36.5%)	35.89	<0.001
	No	59(43.4%)	199(73.7%)	258(63.5%)
Frequency of Alcohol consumption	Daily	8(10.4%)	5(7.0%)	13(8.8%)	2.58	0.46
	Three times a week	28(36.4%)	33(46.5%)	61(41.2%)
	Once a week	18(23.4%)	11(15.5%)	29(19.6%)
	One a month	23(29.9%)	22(31.0%)	45(30.4%)
Current alcohol status	Still drinking	25(32.5)	27(38.0)	52(35.1%)	0.50	0.78
	Reduced	18(23.4%)	15(21.1%)	33(22.3%)
	Ceased	34(44.2%)	29(40.8%)	63(42.6%)
History of Khat Chewing	Yes	96(70.6%)	118(43.7%)	214(52.7%)	26.23	<0.001
	No	40(29.4%)	152(56.3%)	192(47.3%)
Frequency of khat chewing	Daily	37(38.5%)	43(36.4%)	80(37.4%)	1.41	0.70
	Three times a week	26(27.1%)	40(33.9%)	66(30.8%)
	Once a week	25(26.0%)	28(23.7%)	53(24.8%)
	Once a month	8(8.3%)	7(5.9%)	15(7.0%0
Amount of khat chewed per session	Mild chewer	30(22.1%)	79(29.3%)	109(26.8%)	59.01	<0.001
	Moderate chewing	53(39.0%)	36(13.3%)	89(21.9%)
	Heavy chewing	13(9.6%)	3(1.1%)	16(3.9%)
	Non-chewers	40(29.4%)	152(56.3%)	192(47.3%)
Intensity of Physical activity	Mild	43(31.6%)	168(62.2%)	211(52.0%)	33.94	<0.001
	Moderate & vigorous-	93(68.4%)	102(37.8%)	195(48.0%)
Fruit and vegetable intake	<3times/week	76(55.9%)	137(51.1%)	213(52.7%)	0.82	0.37
	>3times/week	60(44.1%)	131(48.9%)	191(47.3%)
Type of oil for food preparation	Packed(Palm) oil	105(77.2%)	172(63.7%)	277(68.2%)	7.61	0.006
	Sun-flower oil	31(22.8%)	98(36.3%)	129(31.8%)
Salt you consumption	Optimal	83(61.0%)	187(69.3%)	270(66.5%)
	High	53(39.0%)	83(30.7%)	136(33.5%)	2.75	0.09
Total Cholesterol	>200mg/dl	79(58.1%)	91(33.7%)	170(41.9%)	22.09	<0.001
	<200mg/dl	57(41.9%)	179(66.3%)	236(58.1%)
HDL level	<40mg/dl	53(39.0%)	151(55.9%)	204(50.2%)	10.40	0.001
	>40mg/dl	83(61.0%)	119(44.1%)	202(49.8%)
LDL level	>100mg/dl	103(75.7%)	147(54.4%)	250(61.6%)	17.33	<0.001
	<100mg/dl	33(24.3%)	123(45.6%)	156(38.4%)
Triglycerides	>150mg/dl	73(53.7%)	91(33.7%)	164(40.4%)	14.99	<0.001
	<150mg/dl	63(46.3%)	179(66.3%)	242(59.6%)
TC/HDL ratio	>5	98(72.1%)	64(23.7%)	162(39.9%)	88.19	<0.001
	<5	38(27.9%)	206(76.3%)	244(60.1%)
BMI	Underweight	37(27.2%)	48(17.8%)	85(20.9%)	5.75	0.12
	Normal	75(55.1%)	158(58.5%)	233(57.4%)
	Over weight	18(13.2%)	51(18.9%)	69(17.0%)
	Obese	6(4.4%)	13(4.8%)	19(4.7%)

Note: x2, Chi square; BMI, Body mass index.

Risk factors for hypertension

Binary logistic regression was performed to determine the association between the dependent and independent variables. Variables that were transferred from the bivariate analysis to the multi-variable analysis were; educational status, income, history of smoking, history of alcohol consumption, history of khat chewing, amount of khat (bundle) chewed per session, the intensity of physical activity, type of oil used for food preparation, salt consumption, TC, HDL level, LDL level, TG level, dyslipidemia, and BMI. After adjusting for confounders; educational status (no formal education), history of alcohol consumption, amount of khat chewed per session, the intensity of physical activity, type of oil used for food preparation and dyslipidemia were significantly associated with hypertension.

Having no formal education increases the odds of developing hypertension by 2.25 times (AOR = 2.25(1.05–4.82) as compared to controls with primary or secondary and above educational status. Similarly, those with a history of excess alcohol consumption had five times (AOR = 5.93(3.11–11.30)) higher odds of developing hypertension than those with no history of alcohol consumption. Considering that the amount of khat chewed per session, moderate khat chewers (1 bundle during one chewing session) were shown to be at high risk (AOR = 3.68(1.69–8.01)) and heavy khat chewers had even higher risk (AOR = 18.18(3.56–92.89)) of developing the disease. The odds of developing the disease in those who had no or mild intensity of physical activity were three times higher than in the control group (AOR = 3.01(1.66–5.47)). In those study, participants who used solidified palm oil for food preparation had two time increased odds of developing the diseases (AOR = 2.81(1.49–5.28)) as compared to controls. Also, having dyslipidemia (total cholesterol to HDL ratio >5) increased the chance by six times (AOR = 6.68(2.93–15.23)) as compared to controls Table 3.

Table 3

Bivariate and multivariate logistic regression of heavy khat (Catha edulis) chewing and dyslipidemia as modifiable risk factors among patients in Southwest, Ethiopia, 2020.

Variable		Case No (%)	Control No (%)	COR (95%CI)	AOR (95% CI)
Educational status	No formal education	34(25.0%)	61(22.6%)	2.76(1.62–4.70)	2.25(1.05–4.82)*
	Primary education	78(57.4%)	113(41.9%)	2.23(1.21–4.12)	1.45(0.61–3.47)
	Secondary and above	24(17.6%)	96(35.6%)	1	1
Income (1dollar = 40birr)	Low	78(57.4%)	132(48.9%)	1.56(0.92–2.63)	2.19(0.89–5.42)
	Middle	32(23.5%)	66(24.4%)	1.29(0.70–2.38)	1.74(0.54–5.63)
	High	26(19.1%)	72(26.7%)	1	1
History of Smoking	Yes	38(27.9%)	40(14.8%)	2.23(1.35–3.69)	1.27(0.56–2.88)
	No	98(72.1%)	230(85.2%)	1	1
History of alcohol consumption	Yes	77(56.6%)	71(26.3%)	3.66(2.37–5.65)	5.93(3.11–11.30)*
	No	59(43.4%)	199(73.7%)	1	1
History of Khat Chewing	Yes	96(70.6%)	118(43.7%)	3.09(1.99–4.80)	1.55(0.74–3.24)
	No	40(29.4%)	152(56.3%)	1	1
Amount of khat chewed per session	Mild chewer	29(21.3%)	79(29.3%)	1	1
	Moderate chewing	51(37.5%)	36(13.3%)	3.88(2.14–7.04)	3.68(1.69–8.01)*
	Heavy chewing	16(11.8%)	3(1.1%)	11.41(3.04–42.88)	18.18(3.56–92.89)*
	Non-chewers	40(29.4%)	152(56.3%)	0.69(0.40–1.19)	-
Intensity of Physical activity	Mild	43(31.6%)	168(62.2%)	3.56(2.30–5.52)	3.01(1.66–5.47)*
	Moderate/vigorous	93(68.4%)	102(37.8%)	1	1
Type of oil for food preparation	Packed(Palm) oil	105(77.2%)	172(63.7%)	1.93(1.21–3.09)	2.81(1.49–5.28)*
	Sun-flower oil	31(22.8%)	98(36.3%)	1	1
Salt you consumption	Optimal	83(61.0%)	187(69.3%)	1	1
	High	53(39.0%)	83(30.7%)	1.44(0.94–2.21)	1.30(0.77–2.21)
Total Cholesterol	>200mg/dl	79(58.1%)	91(33.7%)	2.73(1.78–4.17)	1.55(0.47–5.12)
	<200mg/dl	57(41.9%)	179(66.3%)	1	1
HDL level	<40mg/dl	53(39.0%)	151(55.9%)	1.98(1.31–3.03)	1.32(0.74–2.34)
	>40mg/dl	83(61.0%)	119(44.1%)	1	1
LDL level	>100mg/dl	103(75.7%)	147(54.4%)	2.61(1.65–4.14)	1.26(0.61–2.59)
	<100mg/dl	33(24.3%)	123(45.6%)	1
Triglycerides	>150mg/dl	73(53.7%)	91(33.7%)	2.28(1.49–3.47)	1.59(0.51–4.96)
	<150mg/dl	63(46.3%)	179(66.3%)	1
TC/HDL ratio	>5	98(72.1%)	64(23.7%)	8.30(5.19–13.25)	6.68(2.93–15.23)*
	<5	38(27.9%)	206(76.3%)	1

Note: *, p<0.05.

Discussion

The study aimed to assess heavy khat chewing and dyslipidemia as a modifiable risk factor among hypertensive patients in Southwest Ethiopia. This study found educational status (no formal education), excess alcohol consumption, the amount of bundles of khat chewed per session; the intensity of physical activity, type of oil used for food preparation, and dyslipidemia as the risk factors for the development of the disease.

Educational status affects the development of hypertension. Those who had no formal education were 2.25 times more likely to be exposed to hypertension. This was in line with a study in Gaza Governorates where the risk of developing hypertension was five times higher among low educational level [19]. In contrast to this study, a study in Bale, Nekemte Ethiopia, and Korea showed, having a secondary and above educational level increases the chance of the development of hypertension [12, 20, 29]. The variation observed may be explained by the differences in methodological approach, socio-economic status of the study population, cultural, dietary and lifestyle differences of the areas and countries.

Moderate khat chewers (1 bundle during one chewing session) and heavy khat chewers (>2 bundles during one chewing session) had a higher risk of developing a disease. This was consistent with a study in Bahirdar, Ethiopia that associates khat chewing with elevated systolic blood pressure [28]. A study in Butajira, Ethiopia showed regular khat chewing increased diastolic blood pressure [10]. Another observational study in Yemeni khat chewers who had acute coronary syndrome showed that khat chewers had worse outcomes than non-chewers [14]. But in contrast, another study in Ethiopia found there is no association [12]. This may support the fact that khat chewing is a powerful chronic illness determinant and reducing or cessation is the single most effective lifestyle measure to prevent numerous deaths and disabilities related to hypertension. A study on healthy volunteers investigated that khat chewing leads to a significant and progressive rise in systolic and diastolic blood pressure and heart rate [30]. And for the difference, there needs to be a more experimental study that should be carried on for the future.

In this study, community obesity is not a problem; there is no association between anthropometric measurements and being hypertensive. This might be due to the high consumption of khat in the study population and the community because khat chewing results in anorexia, which suppresses appetite [6].

Several researchers reported sedentary lifestyle is related to hypertension [31, 32]. Also in this study, those who participate in mild intensity physical activity had three times increased odds of developing the disease as compared to moderate and vigorous-intensity physical activity. This study is in line with different studies [2, 33, 34]. Many epidemiological studies showed that repeated physical activity results in significant BP and weight reduction. Sedentary life, which is a predictor of obesity, is one of the main risk factors of high blood pressure [35, 36]. But another study in Tigray, north Ethiopia related vigorous work-related activity as a risk factor [17]. This might be because of stressful activities increasing stress in everyday life activity and the release of stress hormones. But to compare to those who have a sedentary lifestyle, moderate physical activity is protective but different studies were against this [19, 28].

The odd of developing hypertension in those with history of excess alcohol consumption was 5.93 times more likely than the control groups. Because alcohol consumption increases the odds of hypertension due to its sympathetic effect and in line with other studies [37-39].

In our finding, using a solidified palm oil is another risk factor where the odds of having hypertension were increased by two times than the control groups. A study in Assosa Ethiopia showed that the level of total saturated fatty acid ranged from 14.3% for sunflower oil to 69.97% for chief palm oil, with the predominant presence of palmitic acid and stearic acid. Especially total saturated fatty acid in Chief palm oil accounted for more than 2/3 of the total fatty acid. The high saturated fatty acid content of Chief palm oil differed from other reports [40]. Another study in Gonder, Ethiopia which studied a risk factor for metabolic syndrome supported this [41-43].

Our finding showed a significant association between hypertension and abnormal lipid profile where the odds of developing hypertension were increased by 6.68 times compared to control group. Dyslipidemia appeared to be the strongest predictor in determining the probability of having hypertension [44-46]. A study in north Ethiopia showed that abnormal lipid profile especially having low HDL-c being the most commonly encountered abnormality [47]. Another study among Japanese men showed that elevated serum levels of TC/HDL ratio increased the risk of hypertension [48]. This is because dyslipidemia causes endothelial damage and the loss of physiological vasomotor activity those results from endothelial damage which is manifested as increased blood pressure (BP).

Though institution based cases were selected to minimize selection bias, as a result of the nature of case-control study the temporal relationships of events between explanatory variables and hypertension cannot be determined. And also cases were selected consecutively as soon as they were identified, selection bias might be introduced. Recall bias and social desirability bias were also limitations that might have affected the accuracy of information as the respondents were asked questions about some of their previous health-related events. Moreover, the findings of the current research cannot be generalized to the whole community, because of its institution-based nature.

Conclusion

The study showed that modifiable risk factors were the main risk factor for the development of hypertension. The findings of this study highlighted that health education is needed to focus on physical exercise, quitting excess alcohol consumption, quitting khat chewing by giving special emphasis to those who had no formal education and also focusing on a healthy diet free of cholesterol. We recommend that the policymakers need to focus on community-level intervention through integration to health extension programs. It is also better to give special emphasis to health education regarding a healthy diet.

English version questionnaires.

(DOCX)

Click here for additional data file.

Amharic version questionnaires.

(DOCX)

Click here for additional data file.

Afaan Oromoo version questionnaires.

(DOCX)

Click here for additional data file.

The SPSS data.

(SAV)

Click here for additional data file.

10 Mar 2021

PONE-D-20-40692

Heavy khat (Catha edulis) chewing and dyslipidemia as a cardiovascular risk factor among hypertensive patients in Jimma, Ethiopia: Unmatched case control study

PLOS ONE

Dear Dr. Gebremedhin,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process. The reviewers have raised critical concerns on the sample size estimation, measurement of key variables and data analysis that you need to be address. Further, the organization and write up of the manuscript have to be improved.

Please submit your revised manuscript by Apr 17 2021 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

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We look forward to receiving your revised manuscript.

Kind regards,

Samson Gebremedhin, PhD

Academic Editor

PLOS ONE

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

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

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: No

Reviewer #2: Partly

**********

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

Reviewer #1: Yes

Reviewer #2: No

**********

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

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

Reviewer #1: No

Reviewer #2: No

**********

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Reviewer #1: No

Reviewer #2: No

**********

5. Review Comments to the Author

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

Reviewer #1: Dear editor,

Thank you for inviting me to review this manuscript. I read the manuscript with much interest, especially given that khat is purported to be a risk factor for cardiovascular disorders and has been less subjected to epidemiological studies in Ethiopia. The present study has shown, using a case-control study, that hypertension is associated with khat chewing and other factors such as dyslipidemia. The paper is potentially publishable; however, as it stands now it doesn’t seem suitable for publication. The author needs to do a very good job of revising the manuscript if it is to be acceptable for publication.

I have provided my comments on the manuscript section by section next.

Language:

The manuscript needs to be extensively revised for language (grammar and mechanics) starting from the title. As it currently stands, it is unsuitable for publication.

Title:

The study is not about cardiovascular risk factors among hypertensive patients. It is about risk factors for hypertension. Hence, the title needs to be accordingly revised.

Abstract:

Make sure that the findings presented in the results part of the abstract make sense. For example, is the finding that work-related vigorous physical activity increases the odds of hypertension plausible and logical? The author needs to re-check the analysis. Also, to what level of education does “educational status” refer to? The author should also accompany abbreviations with their expanded form when they first appear in the abstract.

Furthermore, the author should conclude only based on the findings. This study has nothing about whether minimizing khat cultivation by farmers would have an effect in reducing khat consumption and thereby the risk of hypertension. In countries where khat is not cultivated, it may be imported from other countries. Reducing cultivation may not necessarily reduce khat consumption. That conclusion is off-topic. The recommendation about increasing educational attainment also does not seem to be feasible and may not have an effect in the short term. The recommendations about stress and type of food oil are also not supported by the findings of the present study.

Introduction:

The arguments in the introduction lack coherence. Make sure that you coherently address one main idea in a paragraph. As the introduction currently stands, each paragraph seems to entertain multiple unrelated ideas and hence makes reading through it difficult.

Accompany all abbreviations with their full form when they appear first in the body of the manuscript.

In the last paragraph of the introduction, the argument about the objectives of the present study is confusing. Is the aim of the study to investigate the association between khat chewing and dyslipidemia or the association of khat chewing and dyslipidemia with hypertension? You should clearly re-write this argument.

Methods and Materials:

Reference #20 does not seem a proper reference for the information presented about the study setting. For one thing, it is out-of-date. Besides, it is not an original source for such information.

Description of the study population should be revised. It doesn't sound right. On the one hand, all hypertensive patients do not seem to be in the study population. They were recruited through a sampling procedure based on a sample size calculated a-priori. On the other hand, the study is not limited solely to hypertensive patients.

While defining cases on page 5, the author should clarify based on how many occasions of blood pressure measurement hypertension was defined.

When describing the methodology, do not do it in the first person singular. Eg., "I selected two controls for each case." (Page 5, last line.)

Description of the inclusion criteria for both the cases and the controls on page 6 must be properly revised. For one thing, the description is unnecessarily long. Besides, the criteria should be clear and properly justified. For example, once you stated that the population studied was comprised of adults > 18 years, then no need of stating that persons under 18 years were excluded.

The description of the sample size calculation on page 6 is unclear. The language is awkward and the assumptions are not clearly stated. For example, what was the exposure variable? You also need to cite reference for the assumptions about the magnitude of exposure among the cases and the controls. Further, what do you mean by the "standard sample size formula"? If you used software to calculate the sample size, better to omit the description about the formula.

Merge the description of the sampling procedure with the description of the sample size. Further, the description of the sampling procedure is too brief and too vague. Clear and sufficient description of the sampling procedure both for the cases and the controls should be provided.

In the data collection section (page 7), write the proper name of the local language - Afaan Oromoo. Besides, the description about the definition of hypertension is unclear. Also the description of hypertensive patients on medication is confusing. Should be re-written.

Remove the operational definitions section (pages 8 & 9) and provide a description of how the different variables were measured and operationalized under the variables of the study section (page 8). Further, the main independent variables, namely heavy khat use and dyslipidemia need explicit elaboration. As the description stands now, it is difficult to properly understand how the IDVs were measured and operationalized. As necessary, sources for the given definitions need to be provided by way of reference citation.

Assimilate the data quality management section into the data collection procedure section.

Results:

Under the sociodemographic characteristics section, describe only the salient sociodemographic features in text. The rest can be seen from the table. Also clearly indicate in terms of which characteristics the cases and controls significantly differ.

In Table 1, do a statistical comparison of the cases and controls to show whether or not they were balanced in terms of basic characteristics. You may use chi-square test.

The descriptive results about the biochemical, behavioural and nutritional characteristics of the study participants (pages 13-14) are unclear and confusing. Just provide a brief description of the salient aspects of these findings under one sub-heading titled "biochemical, behavioural and nutritional characteristics". Like in Table 1, here also provide in a table the statistical comparison of the cases and the controls in terms of characteristics provided. Replace Table 2 with a table similar to the one I suggested for Table 1.

The study is specifically about risk factors for hypertension. Hence you should modify the sub-heading "Cardiovascular risk factors" on page 19 with a more descriptive sub-heading such as "Risk factors for hypertension".

Avoid discussion from the results section. For example, the arguments about choice of analytical methods provided on page 19 may be justified in the methods section, not in the results. Further, such arguments must be substantiated by appropriate reference citations to convince readers about the trustworthiness of the claims.

In the methods section, nothing was described about the use of unconditional logistic regression but in the results (page 19) there is a claim of the use of such method. If unconditional logistic regression was used, then in the methods section the use of this method should be clearly described.

As heavy khat use has not been clearly defined in the methods section, it is difficult to understand the result pertaining to the association of heavy khat use and hypertension on page 19.

Further, as already commented in the abstract, the finding that vigorous work-related activity increases the odds of hypertension is not plausible. The authors should re-do the analysis using an appropriate reference category and check the findings.

In Table 3, the columns for AOR and COR should be transposed. Also better to omit the p-value columns.

In Table 3, is the number of bundles chewed per day or per session or per what?

Discussion:

The author should revise the discussion to make it more mature and scholarly.

Remove the introductory statement about khat from the first paragraph of the discussion. In the first paragraph, just summarize the main findings and discuss those findings in subsequent paragraphs.

Do not sensationalize the discussion of the findings (e.g., “But to surprise”, line 310, page 23).

Your study did not investigate the association of khat chewing with dyslipidemia and HDL. Your argument on page 23 (line 310-311) is not supported by your data and is misleading.

Further, the result pertaining to the association between dyslipidemia and hypertension needs to be sufficiently discussed.

As already commented above, the claim on the last paragraph of page 23 that work-related vigorous physical activity increases the odds of hypertension is counterfactual and not plausible. You need to re-check your analysis and update the discussion accordingly.

The first sentence in the last paragraph of the discussion (page 24) that the present study is the first study in the study setting seems an exaggeration of the findings. There may already be a study which the author failed to find. At least, it is already known that dyslipidemia is a risk factor for hypertension. Revise or avoid such claim.

Clearly discuss the limitations of this study.

Conclusion:

The conclusion seems to stray away from the objective of the study and from what the data shows. For example, the first sentence of the conclusion section is wrong and not in line with the objective of the study. The second sentence is also unclear and not in line with the study's objective. Generally, the author should revise the conclusion to be in line with the objective of the study and suggest a pertinent recommendation about what should be done.

Reviewer #2: The study is relevant as it tries to assess the factors associated with hypertension in Ethiopia. Knowing these factors will contribute to the implementation of policies and adoption of lifestyle aimed at combating hypertension. However, there are several major concerns or issues that must be addressed to make the manuscript suitable for publication.

Major issues:

1. The title is not correct. I should read “Heavy khat (Catha edulis) chewing and dyslipidemia as cardiovascular risk factors among hypertensive patients in Jimma, Ethiopia: Unmatched case3 control study”

2. On page 8, under biochemical analysis you did describe the quality control processes that were undertaken to ensure the reliability of the results. How did you measure these results? Did you use an automated analyzer and what was the name of the analyzer and the country or company of manufacture?

3. You have not stated how your independent variables were collected or have not defined them.

4. In your data analysis on page 9, you did not state which variables were controlled for. Similarly, on page 19, line 256, you stated that possible confounders were adjusted for. What were these confounders?

5. On page 19, line 257, you mentioned that excess alcohol consumption was associated with hypertension. The bivariate analysis in the table did not mention excess alcohol consumption. The category there is “still drinking” and this is different from excess alcohol consumption.

6. If after adjusting for confounders excess alcohol consumption, educational status, vigorous work-related activity etc. in addition to Khat chewing were each independently associated with hypertension why is your focus only on Khat chewing? If your interest ids on Khat chewing then you need to adjust for all other variables (confounders) that are associated hypertension before you determine whether Khat chewing is independently associated with hypertension.

7. Again, in your conclusion you stated other factors that are associated with hypertension. Why should Khat chewing be given particular attention.

Minor issues:

1. On page 7, state the reference/source for the cut off value for hypertension using the National Committee Categorization of Hypertension.

2. Define OCP in both tables 1 and 2 and COR in table 2.

3. The statement from lines 73 to 75 under the introduction is not correct. Check this “…..and the association of the two variables and other factors to the study area and our

75 country, Ethiopia”

4. The statement in line 46 and 47 is quite ambiguous. Which percentage is for which condition?

**********

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Reviewer #1: Yes: Ayalew Astatkie

Reviewer #2: No

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Submitted filename: PONE-D-20-40692_reviewer [Khat_&_Hypertension].pdf

Click here for additional data file.

18 Jun 2021

Dear editor and reviewers, I have included a response for all the points raised, please see the attached document as "response to reviewers".

Submitted filename: response to reviewers.docx

Click here for additional data file.

11 Jul 2021

PONE-D-20-40692R1

Heavy khat (Catha edulis) chewing and dyslipidemia as modifiable hypertensive risk factors among patients in Southwest, Ethiopia: Unmatched case-control study

PLOS ONE

Dear Dr. Gebremedhin,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process. Please address all the concerns raised by the reviewer regards measurement of key variables, data analysis and write of the manuscript. Further, please provide justification why you added new authors and why it was not possible to include them in the first submission.

Please submit your revised manuscript by Aug 25 2021 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.

A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.

An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

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

We look forward to receiving your revised manuscript.

Kind regards,

Samson Gebremedhin, PhD

Academic Editor

PLOS ONE

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

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

Reviewer #1: (No Response)

**********

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

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Partly

**********

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

Reviewer #1: No

**********

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

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

Reviewer #1: Yes

**********

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

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

Reviewer #1: No

**********

6. Review Comments to the Author

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

Reviewer #1: Dear editor,

Thank you for inviting me to review the revised version (Revision 1) of this manuscript. I would like to witness that the manuscript has been substantially improved relative to the initial submission. However, the authors still need to do some more work in order to make the manuscript suitable for publication.

I have provided my comments and suggestions below.

The initial submission had only a single author. However the present submission has two additional authors (totally three). The submitting author should justify if these newly included authors really deserve being listed as authors.

The entire manuscript still needs careful language revision. As it stands now, the language is not suitable for publication.

The description in the third paragraph of the introduction (lines 65-70) is confusing and not coherent. It needs to be re-written.

The fourth paragraph of the introduction (lines 71-79) doesn't connect smoothly to the preceding and succeeding paragraphs. Must be revised.

In the description of the study setting, line 97, provide the URL of JUMC.

The main exposure variables of interest in the present study were "heavy khat use" and "dyslipidemia". So why was "past history of cigarette smoking" used as an exposure variable in the sample size calculation? It is not in line with the objective of the study.

The sampling procedure still needs a clearer description.

In the initial submission, it was stated that the tool was translated to the local language in Oromia (i.e., Afaan Oromoo). In the revised submission, the authors claim that the tool was translated to Amharic, and there is no mention of the language stated in the initial submission. This casts doubt on the trustworthiness of the authors’ claims.

The reason for back-translation should be revised. The reason stated as “to check for internal consistency” is not sound and convincing.

On page 9, the authors have provided a detailed procedure for arterial blood pressure measurement. However, earlier in the manuscript, they have stated that "Cases were patients who were already diagnosed with hypertension by a physician or those taking antihypertensive drugs during the study period." If that is how cases were ascertained, how did the authors make sure that the BP measurement for cases was done as per the procedure described there? Clearly, measurement of blood pressure for cases was not under the control of the authors.

The reference cited in relation to the use of a p-value of 0.25 for selection of variables for the multivariable model (reference #21, page 11) does not seem to be the appropriate reference for the argument provided. The cited reference (#21) is a book about clinical examination and has nothing to do with statistical data analysis. The appropriate reference must be cited. Also check the appropriateness of all other citations.

Better to describe the results pertaining to physical activity in terms of the intensity of the physical activity. The “active/inactive” dichotomy doesn’t seem to make much sense.

One of the independent variables used in the multivariable analysis was oral contraceptive use. However, oral contraceptive use applies only to females. Such a variable which applies to only a sub-set of the sample should not be used in multivariable analysis as it will significantly diminish the total sample used in the multivariable analysis. In the present manuscript, including OC use will preclude all males from the analysis.

Further, the analysis of "amount of khat chewed per session" should include “non-chewers” in the analysis so that the analysis will apply to the entire sample, not to a sub-set of the sample (khat chewers) only. Hence, recode the "amount of khat chewed per session" as "non-chewer, mild khat chewer, moderate khat chewer, and heavy khat chewer" and re-do the analysis.

Do not state odds ratios with 95% CIs in the discussion section.

The results in the present study pertaining to the association of level of education with hypertension are contrary to several previous studies. The authors tried to justify this simply as “…because of the difference in the socio-economic status of the study population, cultural, dietary and lifestyle differences of the areas and countries,” (lines 287-289). What if it is due to methodological problem with the present study? The authors should re-check the analysis. Even if the re-analysis may not change the results, the argument the authors come up with must be very critical and convincing.

In lines 299-300, the authors recommend an experimental study to further investigate the association of khat chewing with hypertension-related morbidity and mortality. Is that practicable and ethically sound?

Discussion of the effect of physical activity on hypertension risk (lines 304-310) must be done carefully and critically taking account of the whole body of evidence on the topic. The authors' arguments in their present form lack a critical analysis of the state-of-the-art evidence.

In the last paragraph of the discussion, the authors need to provide careful and critical discussion of the limitations of the present study. What has been provided is very superficial and not convincing.

Check the authors' guideline of PLoS ONE for the appropriate placement of tables within the manuscript.

In Tables 1 & 2, include a p-value column to show whether the differences were significant or not.

Better to remove the p-values from Table 3 as it is unclear whether they were based on the crude analysis or the adjusted analysis. Besides, ORs with 95% CIs can tell both about the magnitude and significance of the association. Hence, the use of a p-value is superfluous. Also, include columns which provide the cross-tabulation of each independent variable with the dependent variable in Table 3.

**********

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

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

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

Reviewer #1: Yes: Ayalew Astatkie

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

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8 Sep 2021

Manuscript Title: Heavy khat (Catha edulis) chewing and dyslipidemia as modifiable hypertensive risk factors among patients in Southwest, Ethiopia: Unmatched case-control study

Dear editor and reviewers

We would like to extend our heartfelt gratitude and appreciation for your valuable comments and priceless time. Thank you, your comments have helped us a lot to improve the manuscript and focus on important points and also a base for our future performance. We are very happy with all the points raised because this is not only a comment rather we learnt a lot. We tried to address all comments point by point in this paper.

Responses for the editor

1. Dear editor, we tried to include all concerns raised by the reviewer in the response to the reviewer section below including measurement of key variables, data analysis, and write of the manuscript and justification for adding new authors.

Response to reviewer 1

1. The initial submission had only a single author. However the present submission has two additional authors (totally three). The submitting author should justify if these newly included authors really deserve being listed as authors.

Response: Thanks for the comment and sorry for not including them in the initial submission. Of course this authors participated in the work and there specific role has been listed in the “author contribution”. A vast study had been carried out on some chronic illness and some of the data is under write up and this paper concerning hypertension is taken from it.

2. The entire manuscript still needs careful language revision. As it stands now, the language is not suitable for publication.

Response: Comment accepted and we tried to make changes.

3. The description in the third paragraph of the introduction (lines 65-70) is confusing and not coherent. It needs to be re-written.

Response: Comment accepted and amendments have been done. Please see the highlighted manuscript from line (62-85).

4. The fourth paragraph of the introduction (lines 71-79) doesn't connect smoothly to the preceding and succeeding paragraphs. Must be revised.

Response: Comment accepted and changes have been made. Please see the highlighted manuscript again from line (62-85).

5. In the description of the study setting, line 97, provide the URL of JUMC.

Response: Comment accepted and the URL of JUMC was provided. Please see the highlighted manuscript from line (94).

6. The main exposure variables of interest in the present study were "heavy khat use" and "dyslipidemia". So why was "past history of cigarette smoking" used as an exposure variable in the sample size calculation? It is not in line with the objective of the study.

Response: The sample size was calculated and fixed during the development of proposal. And the title was modified after analysis because heavy khat chewing and dyslipidemia have a higher odds ratio. Any further recommendation on the title can be accepted.

7. The sampling procedure still needs a clearer description.

Response: Comment accepted and changes have been made. Please see the highlighted manuscript from line (136-140).

8. In the initial submission, it was stated that the tool was translated to the local language in Oromia (i.e., Afaan Oromoo). In the revised submission, the authors claim that the tool was translated to Amharic, and there is no mention of the language stated in the initial submission. This casts doubt on the trustworthiness of the authors’ claims.

Response: Comment accepted and changes have been made and we will attach questionnaires with local languages.

9. The reason for back-translation should be revised. The reason stated as “to check for internal consistency” is not sound and convincing.

Response: Comment accepted and changes have been made. Please see the highlighted manuscript from line (149-151).

10. When On page 9, the authors have provided a detailed procedure for arterial blood pressure measurement. However, earlier in the manuscript, they have stated that "Cases were patients who were already diagnosed with hypertension by a physician or those taking antihypertensive drugs during the study period." If that is how cases were ascertained, how did the authors make sure that the BP measurement for cases was done as per the procedure described there? Clearly, measurement of blood pressure for cases was not under the control of the authors.

Response: Comment accepted and data collectors were taken from the chronic illness clinic where the same procedure was carried out. And the procedure was used for the control groups, too.

11. The reference cited in relation to the use of a p-value of 0.25 for selection of variables for the multivariable model (reference #21, page 11) does not seem to be the appropriate reference for the argument provided. The cited reference (#21) is a book 1about clinical examination and has nothing to do with statistical data analysis. The appropriate reference must be cited. Also check the appropriateness of all other citations.

Response: Comment accepted and changes have been made. Please see the highlighted manuscript from line (204).

12. Better to describe the results pertaining to physical activity in terms of the intensity of the physical activity. The “active/inactive” dichotomy doesn’t seem to make much sense.

Response: Comment accepted and modifications have been made. Please see the highlighted manuscript from line (235-236) and Table 2 and 3.

13. One of the independent variables used in the multivariable analysis was oral contraceptive use. However, oral contraceptive use applies only to females. Such a variable which applies to only a sub-set of the sample should not be used in multivariable analysis as it will significantly diminish the total sample used in the multivariable analysis. In the present manuscript, including OC use will preclude all males from the analysis.

Response: Comment accepted and amendment has been done. We tried to screen starting from Epi data and coding in SPSS. There was of course some gap with the analysis and even coding. But we did rigorous analysis to include all raised concerns. Please see the Table 2 and Table 3.

14. Further, the analysis of "amount of khat chewed per session" should include “non-chewers” in the analysis so that the analysis will apply to the entire sample, not to a sub-set of the sample (khat chewers) only. Hence, recode the "amount of khat chewed per session" as "non-chewer, mild khat chewer, moderate khat chewer, and heavy khat chewer" and re-do the analysis.

Response: Thanks for the comment and “non-chewer” has been included. Please see Table 2 & Table 3).

15. Do not state odds ratios with 95% CIs in the discussion section.

Response: Comment accepted and amendment has been done.

16. The results in the present study pertaining to the association of level of education with hypertension are contrary to several previous studies. The authors tried to justify this simply as “…because of the difference in the socio-economic status of the study population, cultural, dietary and lifestyle differences of the areas and countries,” (lines 287-289). What if it is due to methodological problem with the present study? The authors should re-check the analysis. Even if the re-analysis may not change the results, the argument the authors come up with must be very critical and convincing.

Response: Comment accepted and amendment has been done. Please see from line (280-282).

17. In lines 299-300, the authors recommend an experimental study to further investigate the association of khat chewing with hypertension-related morbidity and mortality. Is that practicable and ethically sound?

Response: Thanks for the comment. Though old we had included some literatures regarding the effect of khat on myocardial function and effect on blood vessels. So, further clinical trials involving animal studies can be carried out to strengthen the result (292-295).

18. Discussion of the effect of physical activity on hypertension risk (lines 304-310) must be done carefully and critically taking account of the whole body of evidence on the topic. The authors' arguments in their present form lack a critical analysis of the state-of-the-art evidence.

Response: Comment accepted and amendment has been done. Please see the highlighted manuscript from line (300-309).

19. In the last paragraph of the discussion, the authors need to provide careful and critical discussion of the limitations of the present study. What has been provided is very superficial and not convincing.

Response: Comment accepted and amendment has been done. Please see the highlighted manuscript from line (330-336).

20. Check the authors' guideline of PLoS ONE for the appropriate placement of tables within the manuscript.

Response: Comment accepted and changes have been made. Please see Table1-3.

21. In Tables 1 & 2, include a p-value column to show whether the differences were significant or not.

Response: Comment accepted and change has been made. Please see Table1&2.

22. Better to remove the p-values from Table 3 as it is unclear whether they were based on the crude analysis or the adjusted analysis. Besides, ORs with 95% CIs can tell both about the magnitude and significance of the association. Hence, the use of a p-value is superfluous. Also, include columns which provide the cross-tabulation of each independent variable with the dependent variable in Table 3.

Response: Comment accepted and changes have been made. Please see Table 3.

Submitted filename: response to reviewers.docx

Click here for additional data file.

27 Sep 2021

PONE-D-20-40692R2Heavy khat (Catha edulis) chewing and dyslipidemia as modifiable hypertensive risk factors among patients in Southwest, Ethiopia: Unmatched case-control studyPLOS ONE

Dear Dr. Gebremedhin,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process. Specifically please address the comments raised by the reviewer including those on selection of variables for the multivariable model and formatting, structuring and writeup of the manuscript.

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

Please include the following items when submitting your revised manuscript:

A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.

A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.

An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

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

We look forward to receiving your revised manuscript.

Kind regards,

Samson Gebremedhin, PhD

Academic Editor

PLOS ONE

Additional Editor Comments (if provided):

Please address comments of the reviewers including those related to selection of variables for the multivariable model, structuring and writeup of the manuscript.

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

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

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

Reviewer #1: (No Response)

**********

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

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Partly

**********

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

Reviewer #1: No

**********

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

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

Reviewer #1: Yes

**********

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

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

Reviewer #1: Yes

**********

6. Review Comments to the Author

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

Reviewer #1: Many of my previous concerns have been addressed. However, there are still concerns remaining to be addressed. My major concern is the use of OCP use in the multivariable model (see comment 8 below). The authors should give careful attention to that comment.

Hereunder are my remaining concerns.

1. The language still needs careful revision.

2. The term "physical inactivity" in the abstract must be revised.

3. One of the justifications the authors provided for doing the present study in lines 78-80 is "Because previous studies conducted in Ethiopia were cross-sectional in nature which lacked a cause-and-effect relationship." The case-control design used by the present study also has the same limitation. Therefore, that argument is not convincing. It should be omitted or re-phrased.

4. Better to indicate the URL of JUMC in the text describing the study setting instead of giving it a reference number and citing it as a formal reference. If it has to be cited formally, the reference information should comprise of all important information for a Web page used as a reference.

5. In the data collection section, the authors should state into what local languages the questionnaire was translated.

6. The information provided under "Arterial blood pressure measurement" (pages 9-10) should be part of the "Measurement of variables" section (page 7). Hence, merge it with the description of the "Outcome variable". Also avoid bulleted listing. Provide your arguments using complete sentences.

7. The response the authors provided for my earlier comment regarding measurement of blood pressure for cases is not convincing. Merely taking data collectors from the chronic illness clinic does not make the blood pressure measurement for cases similar to the blood pressure measurement of the controls.

8. The authors have still retained OCP use in the multivariable analysis. As I commented in my previous review, OCP use applies only to females and as such should not be used as an independent variable in the multivariable model because its inclusion automatically excludes all males from the multivariable model. As it is seen from the cross tabulation in Table 3, the sample size for USP use is only 193, which is the sample size for female study participants. What the authors should clearly recognize is, in the multivariable model if the sample size for OCP use is 193, then the sample size for all other variables in the model is automatically diminished to 193. That is, 213 study participants (all males) are excluded from the analysis for all independent variables in the model. Therefore, the authors should re-do the analysis by excluding OCP use if the results of the present study are to be valid.

9. The authors should still check the authors' guideline of PLoS ONE for the appropriate placement of tables within the manuscript.

10. The discussion still needs to be more critical.

11. The authors should make sure that all references are properly written.

12. The data availability statement should be in line with PLoS ONE’s data availability policy.

**********

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

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

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

Reviewer #1: Yes: Ayalew Astatkie

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

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

3 Oct 2021

Response to reviewer 1

1. The language still needs careful revision.

Response: Comment accepted and changes had been done.

2. The term "physical inactivity" in the abstract must be revised.

Response: Comment accepted and amendment has been done. Please see the highlighted manuscript line (32).

3. One of the justifications the authors provided for doing the present study in lines 78-80 is "Because previous studies conducted in Ethiopia were cross-sectional in nature which lacked a cause-and-effect relationship." The case-control design used by the present study also has the same limitation. Therefore, that argument is not convincing. It should be omitted or re-phrased.

Response: Comment accepted and changes have been made. Please see the highlighted manuscript again from line (78-82).

4. Better to indicate the URL of JUMC in the text describing the study setting instead of giving it a reference number and citing it as a formal reference. If it has to be cited formally, the reference information should comprise of all important information for a Web page used as a reference.

Response: Comment accepted and the URL of JUMC was included in the manuscript. Please see the highlighted manuscript line (91).

5. In the data collection section, the authors should state into what local languages the questionnaire was translated.

Response: Comment accepted and changes have been made. Please see the highlighted manuscript from line (158-159).

6. The information provided under "Arterial blood pressure measurement" (pages 9-10) should be part of the "Measurement of variables" section (page 7). Hence, merge it with the description of the "Outcome variable". Also avoid bulleted listing. Provide your arguments using complete sentences.

Response: Comment accepted and changes have been made. Please see the highlighted manuscript from line (112-121).

7. The response the authors provided for my earlier comment regarding measurement of blood pressure for cases is not convincing. Merely taking data collectors from the chronic illness clinic does not make the blood pressure measurement for cases similar to the blood pressure measurement of the controls.

Response: Cases were already selected because they were confirmed hypertensive patients OR on anti-hypertensive treatment and controls were confirmed to be free from hypertension by following the same procedure followed in the chronic illness clinics.

8. The authors have still retained OCP use in the multivariable analysis. As I commented in my previous review, OCP use applies only to females and as such should not be used as an independent variable in the multivariable model because its inclusion automatically excludes all males from the multivariable model. As it is seen from the cross tabulation in Table 3, the sample size for USP use is only 193, which is the sample size for female study participants. What the authors should clearly recognize is, in the multivariable model if the sample size for OCP use is 193, then the sample size for all other variables in the model is automatically diminished to 193. That is, 213 study participants (all males) are excluded from the analysis for all independent variables in the model. Therefore, the authors should re-do the analysis by excluding OCP use if the results of the present study are to be valid.

Response: We feel very sorry for not deleting the variable OCP use from “Table 3”. It was included by mistake. As per the previous comment we already removed OCP use from multivariable analysis and done the analysis again in the previous submission.

9. The authors should still check the authors' guideline of PLoS ONE for the appropriate placement of tables within the manuscript.

Response: Comment accepted and changes have been made. Please see “Table 1”, “Table 2” and “Table 3”.

10. The discussion still needs to be more critical.

Response: Comment accepted and changes have been made.

11. The authors should make sure that all references are properly written.

Response: Comment accepted and modifications have been made.

12. The data availability statement should be in line with PLoS ONE’s data availability policy.

Response: Comment accepted and changes have been made. Please see the highlighted manuscript line (358).

Submitted filename: response to reviewers.docx

Click here for additional data file.

13 Oct 2021

Heavy khat (Catha edulis) chewing and dyslipidemia as modifiable hypertensive risk factors among patients in Southwest, Ethiopia: Unmatched case-control study

PONE-D-20-40692R3

Dear Dr. Gebremedhin,

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

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

An invoice for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org.

If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org.

Kind regards,

Samson Gebremedhin, PhD

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

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

Reviewer #1: All comments have been addressed

**********

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

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

**********

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

Reviewer #1: Yes

**********

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

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

Reviewer #1: Yes

**********

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

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

Reviewer #1: Yes

**********

6. Review Comments to the Author

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

Reviewer #1: (No Response)

**********

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

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

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

Reviewer #1: Yes: Ayalew Astatkie

18 Oct 2021

PONE-D-20-40692R3

Heavy khat (Catha edulis) chewing and dyslipidemia as modifiable hypertensive risk factors among patients in Southwest, Ethiopia: Unmatched case-control study

Dear Dr. Gebremedhin:

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org.

If we can help with anything else, please email us at plosone@plos.org.

Thank you for submitting your work to PLOS ONE and supporting open access.

Kind regards,

PLOS ONE Editorial Office Staff

on behalf of

Dr. Samson Gebremedhin

Academic Editor

PLOS ONE