A cross-sectional study of barriers to cervical cancer screening uptake in Ghana: An application of the health belief model.

BACKGROUND: The high incidence (32.9, age-standardized per 100,000) and mortality (23.0, age-standardized per 100,000) of cervical cancer (CC) in Ghana have been largely attributed to low screening uptake (0.8%). Although the low cost (Visual inspection with acetic acid) screening services available at various local health facilities screening uptake is meager.
OBJECTIVE: The purpose of the study is to determine the barriers influencing CC screening among women in the Ashanti Region of Ghana using the health belief model.
METHODS: A analytical cross-sectional study design was conducted between January and March 2019 at Kenyase, the Ashanti Region of Ghana. The study employed self-administered questionnaires were used to collect data from 200 women. Descriptive statistics were used to examine the differences in interest and non-interest in participating in CC screening on barriers affecting CC screening. Multivariable logistic regression was used to determine factors affecting CC screening at a significance level of p<0.05.
RESULTS: Unemployed women were less likely to have an interest in CC screening than those who were employed (adjustes odds ratio (aOR) = 0.005, 95%CI:0.001-0.041, p = 0.005). Women who were highly educated were 122 times very likely to be interested in CC screening than those with no or low formal education (aOR = 121.915 95%CI: 14.096-1054.469, p<0.001) and those who were unmarried were less likely to be interested in CC screening than those with those who were married (aOR = 0.124, 95%CI: 0.024-0.647, p = 0.013). Also, perceived threat, perceived benefits, perceived barriers and cues for action showed significant differences with interest in participating in screening with a P-values <0.003. The association was different for long waiting time, prioritizing early morning and late evening screening which showed no significant difference (P-value > 0.003).
CONCLUSIONS: Married women, unemployed and those with no formal education are less likely to participate in CC screening. The study details significant barriers to cervical cancer screening uptake in Ghana. It is recommended that the Ghana health services should develop appropriate, culturally tailored educational materials to inform individuals with no formal education through health campaigns in schools, churches and communities to enhance CC screening uptake.

Introduction

The incidence and mortality of cervical cancer in low-and lower-middle-income countries (LLMIC) continue to rise, including sub-Saharan African[1]. According to Globocan (2018), the age-standardized incidence and mortality rate per 100,000 women of cervical cancer (CC) in LLMIC countries is 28.8 and 22.1 making CC the leading cause of cancer-related mortality in these countries [1]. Ghana, one of the sub-Saharan countries, has a high age-standardized incidence and mortality rate of 32.9 and 23.0 per 100,000, respectively. These estimates make cervical cancer the most frequently diagnosed cancer after breast cancer (43.0, age-standardized per 100,000 women) and the leading cause of cancer deaths amongst women in Ghana [1].

Despite the burden of cervical cancer in sub-Saharan Africa few interventions such as mass media campaigns, special education and reminders have been used to create awareness of primary and secondary prevention of cervical cancer including screening [2]. No policies towards national screening programmes currently exist in these countries, and a similar situation is seen in Ghana. Thus if steps are not taken, it may lead to the estimated 5-year prevalence of CC (46.4, age standardized rate per 100,000) across all ages [1].

Although population-based cervical screening and guidelines have resulted in a substantial decline in the burden of CC in developed countries, the lack of screening programs contributes to the high risk of CC in sub-Saharan Africa [3-6]. In Ghana, the non-existent national screening program for CC [6], most of the time, is attributed to lack of funds, limited qualified personnel, and infrastructure for the development of widespread screening initiatives [7]. This deficit has resulted in CC screening test such as Pap smear or visual inspection with acetic acid (VIA) services being offered on local uncoordinated basis. In other words, it is considered as an opportunistic screening, where doctors request Pap smear and VIA for patients in clinics and hospitals either as part of general medical examination or for consultations related or unrelated to CC [8]. In addition to this, government and private hospitals have trained nurses and doctors who conduct CC screening, especially in various family planning units as a routine before the insertion of an intrauterine device (IUD). Furthermore, organized screening by benevolent organizations is done occasionally in various communities in Ghana. Despite the multiple avenues for CC screening, uptake for these services are very low [8-10] with participation rates lower than 3% in Ghana [11]. Therefore, the evidence regarding screening uptake in Ghana remains very scarce.

Given the evidence that CC screening has accounted for a significant decline in mortality in some countries, well-coordinated programs are vital in achieving such outcomes [12, 13]. High-income countries have seen a successful decrease in CC incidence and mortality, and this has been greatly attributed to well patronized preventive screening programs [1]. For instance, the United Kingdom has experienced a significant 70% drop in mortality over the years, with 70–73% screening uptake between [14]. Also, a 60% reduction in mortality was seen in the Netherlands; where invitations for screening are sent out annually to eligible women to increase participation [15]. Moreover, since the introduction of Papanicolaou (Pap) smear-based screening in the United States, the incidence rate of CC among white and African-American women has dramatically decreased by over 50% and 70% respectively. [16].

Previous studies conducted in Ghana have established the inadequate knowledge about cervical cancer risk factors and screening amongst women, leads to low self-perception of risk on the disease and low patronage of screening services. For instance, Ebu et al. [17] reported a high number (93.6%) and (97.7%) of women in the central region of Ghana had inadequate knowledge of the risk factors and screening of cervical cancer respectively. On the contrary, 85.6% of college students in Ghana were aware of cervical cancer. Therefore the knowledge level of the disease amongst women in Ghana remains unclear [18].

Although the high incidence of cervical cancer exists, low CC screening uptake, little knowledge on cervical cancer and various factors may contribute to the low interest in CC screening in Ghana. According to the health belief model (HBM), one of the most widely used health behavioural models due to its ability to understand health behaviour, modifying factors such as sociodemographic characteristics, knowledge of the disease, perceptions threat (susceptibility and seriousness), benefits, barriers and self-efficacy of the illness, behaviour and its cues for action are likely to influence a particular behaviour [19]. In systematic reviews across countries including sub-Saharan regions, low awareness of CC, perceived barriers like cultural beliefs, perceived fear of screening procedure and adverse outcome, societal stigmatisation, embarrassment, and lack of spousal support have been largely attributed to CC screening [20-25]. This evidence suggests that literature perceived threat, benefits and self-efficacy of cervical cancer is limited in sub-Saharan countries.

In Ghana, a qualitative study investigated only the psychological barriers affecting CC screening [26]. Although Ebu et al. [17] assessed the barriers of CC screening in the Central Region of Ghana, this study could determine the associated factors with interesting participating in CC cancer such as sociodemographic characteristics (education, marital status and occupation). Moreover, the current study can find the association between CC screening interest and barriers to screening, applying thethe health belief model. Therefore the evidence regarding barriers to CC screening remains unclear.

To best of the authors' knowledge, no empirical study has investigated women’s behaviours towards CC screening in the Kenyase, Ashanti region of Ghana given the evidence that CC incidence and mortality is more common in this area [27]. More to this evidence there exist a differential cultural belief is prevalent across regions in Ghana. This study sought to determine the 1) uptake and interest in CC screening, 2) knowledge level of CC, 3) barriers influencing interest in CC screening, 4) association between sociodemographic characteristics and CC screening uptake under the lens of the health belief model among women in Ashanti region of Ghana. The findings will provide an insights into factors affecting CC screening participation and appropriate ways of targeting educational interventions amongst women in Ghana.

Materials and methods

Study setting and population

The study was conducted at Kenyase in the Kwabre District in the Ashanti region in Ghana. Kenyase shares boundaries with Duase, Bouhban, and Bosore. Akans are the predominant ethnic group with a smaller proportion of the population originating from outside ethnic Akan. Kenyase has quite a large number of people, which is about 5000. A significant activity of the area is petty trading. The study population consisted of reproductive women in Kenyase environs, including Market places and schools.

Study design and period

The analytical cross-sectional study design was used to conduct the study between January and March 2019 in Kenyase, a suburb of the Ashanti Region of Ghana.

Sampling size and sampling procedure

A sample size of 245 was calculated using 5% error, 95% confidence interval using the formula below [28]: Where;

n = minimum sample size.

z = confidence interval at 95%, 1.96.

p = estimated proportion of CC screening uptake in Ghana, 0.2.

q = 1-p.

e = margin of error at 5%.

The sample size (n) was calculated as follows; n = 246

Convenience sampling where random shops and houses in the community under study were chosen and visited until the predetermined number of surveys were completed.

Data collection procedure

Well-structured self-administered questionnaires, which required about 20 minutes, were developed. The description of the questionnaire was as follows:

The sociodemographic characteristics consisted of age, occupation, educational background, religion, marital status and number of children, family history of cancer. The participants' beliefs about CC and screening were measured by 37 items based on constructs adapted from the HBM, as shown in Fig 1. These included four subscales of HBM: perceived threat, perceived benefits, perceived barriers and cue for action. The items were arranged as section B was for awareness of CC with 12 response items. Section C–the perceived threat of CC referred to woman’s perception about the chances of getting cervical cancer and beliefs concerning the severity of cervical cancer screening. Section D—perceived benefits of cervical cancer screening. Section E—perceived barriers to cervical cancer screening were categories into psychosocial barriers, socioeconomic barriers, and healthcare system barriers. Section G—cues for action. For each item, the respondents were asked to answer yes, no or I don’t know.

Fig 1

Health belief model components and linkages.

The pre-test was conducted among fifteen (15) women within age considered in a different community not selected for the study to ensure the contents of the questionnaire was clear. The questions were piloted using a one-on-one interview with women by the study researchers. The Cronbach alpha, which is a measure of internal consistency ranging from 0.70 to 1.00, with high coefficients indicating high levels of reliability, was used to determine the validity and the reliability of the questionnaire. The Cronbach alpha of most of the questions was 0.934. Appropriate changes were made to modify the questionnaire after the pilot study. The entire questionnaire was also available in English. The questionnaire was then personally delivered to the women in paper form by the research assistants. In situations where participants were illiterates, the researchers explained the questions to them in the local dialect (Twi).

Data analysis

The data were analyzed using the Statistical Package for the Social Sciences (SPSS, IBM Corporation, Armonk, NY, USA) version 21.0. The results are presented with tables. The dependent variables were “the interest in participating in CC screening” and “have you been screened before” measured as “Yes” or “No” and presented as frequencies (percentages). With regards to assessing participants knowledge on cervical cancer, scoring was one ‘1’ for each correct response and zero ‘0’ for the wrong answer. The analysis of awareness and knowledge score was ranked as high if the total score is 6–9, fair if the overall score is 3–5 and low if the total score is less than 2. Pearson chi-square test was used to show the differences between proportions of individuals who were interested or not interested in participating in CC screening on the HBM subscales (perceived threat, perceived benefits, perceived barriers and cue for action). The significance level was set at p< 0.003 (Bonferroni's correction was used to adjust the significance level due to multiple comparisons). The independent variables were categorized as; the educational background was classified as high formal (tertiary graduates), low formal (primary, junior and senior high school), no formal education (illiterates). Marital status was married or unmarried (single, widowed, divorced and informal union). The number of children was none or more than or equal to one. Religion was categorized as Christian or Muslim, and family history was indicated as “Yes” or “No”. Bivariate analysis was used to examine the relationship between the dependent variable (interest in participating in screening) and the explanatory variables. Variables that were not significant were dropped from the model while those found to be significant were entered in multivariable logistic regression analysis. Crude odds ratio were adjusted a priori for age, family history, religious status, and number of children to identify factors influencing CC screening. Significance was set at p-value <0.05.

Ethical approval

Approval was obtained from Garden City University College after the internal review board reviewed the proposal of the study. Also, an introductory letter was sent to the Unit Committee leader of the community and the queen mother of Kenyase. The proposal of the research was also reviewed by the committee leader of the community and consent was given to proceed with the study. Written consent of the participants was sought. Furthermore, participants had the freedom to participate or withdraw from the study at any time. Confidentiality and anonymity of respondents were ensured.

Results

Socio-demographic characteristics

There was 81% response rate since 200 questionnaires were returned. Majority of the respondents’ 115 (57.5%) were between 26–40, and 155 (77.5%) of the respondents were employed. 119 (59.5%) of the respondents had low education, and 160 (80%) of the total respondents were Christians. 105 (52.5%) of the evaluated respondents were not married, and 151 (75.5.5%) of the respondents had more than or equal to one child or children while 78% had no family history of CC (see Table 1).

Table 1

Respondents’ sociodemographic characteristics amongst women in Kenyase, Ghana, N = 200.

Variable	Frequency N = 200	Percentage (%)
Age
15–25	54	27
26–40	115	57.5
41–50	31	15.5
Occupation
employed	155	77.5
unemployed	45	22.5
Educational background
High formal education	31	15.5
Low formal education	119	59.5
No formal education	50	25
Religion
Christian	160	80
Muslim	40	20
Marital status
unmarried	105	52.5
married	95	47.5
Number of children
More than or equal to one	151	75.5
None	49	24.5
Family history
Yes	44	22
No	156	78

Interest and uptake in cervical cancer screening

Table 2 shows the interest and uptake CC screening amongst the respondents. More than half 163 (81.5%) had heard of CC screening. However, an overwhelming majority of 194 (97%) reported they had not been screened before. Out of the 6 (3%) who had been screened before, 4 (2%) had screened one year ago while 2 (1%) said they were screened not more than five years ago. 198 (99%) did not know how often they should go for screening. Interestingly, more than half 174 (87%) of the women evaluated said they were interested in participating in CC screening.

Table 2

Interest and uptake cervical cancer screening amongst women in Kenyase, Ghana, N = 200.

Variable	Frequency N = 200	Percentage (%)
Have you heard of cervical cancer screening?
Yes	163	81.5
No	37	18.5
Have you been screened with cervical cancer before?
Yes	6	3
No	194	97
If Yes, Last time Screened
No answer	194	97
A year ago	4	2
Not more than five years ago	2	1
How often do you go for cervical cancer screening?
Once a year	2	1
Don’t know	198	99
Are you interested in participating in screening?	Yes: 174	87
	No: 26	13
TOTAL	200	100

Knowledge of cervical cancer

Table 3 presents knowledge of CC amongst respondents. Overall, 164 (82%) had scores below 5 for their level of knowledge of CC denoting inadequate understanding of cervical cancer. Only 36 (18%) of the respondents had adequate knowledge of cervical cancer. Almost all 190 (95%) of the women surveyed responded that CC was not a sexually transmitted disease and a little more than half 112 (56%) of the women surveyed indicated that CC could not be prevented. Also, majority 189 (94.5%) of the respondents mentioned it could not be prevented through vaccination of young girls.

Table 3

Knowledge of cervical cancer amongst women in Kenyase, Ghana, N = 200.

Variable	Frequency N = 200	Percentage (%)
Cervical cancer is a sexually transmitted disease
Yes	10	5
No	190	95
Cervical cancer is preventable
Yes	88	44
No	112	56
Cervical cancer is curable through vaccination
Yes	11	5.5
No	189	94.5
Cervical cancer is curable in hospitals when diagnosed early
Yes	143			71.5
No	57	28.5
Risk Factors of cervical cancer
Early-onset of sexual activity	8	4
Infection with sexually transmitted infection	60	30
HPV	6	3
Multiple male sexual partners	78	39
Smoking cigarettes/tobacco	12	6
Grand multiparity	17	8.5
All the above	19	9.5
Don’t know	10	5
Signs and symptoms of cervical cancer
Intermenstrual vaginal bleeding	10	5
Post-menopausal bleeding	12	6
Vaginal bleeding	25	12.5
Post-coital vaginal bleeding	18	9
Excessive vaginal discharge	12	6
Lower abdominal pain	71	35.5
Pain in the genital during sexual intercourse	11	5.5
All the above	25	12.5
Don’t know	16	8
Knowledge level on cervical cancer
High	Fair	Low
9–6	5–3	Less than 2
36 (18%) of the respondents scored high.	74 (37%) of the respondents had a fair score.	90 (45%) of the respondents had a low score.

Additionally, the majority of 143 (71.5%) of the respondents knew CC is curable in hospitals when diagnosed early. Most of the respondents had inadequate knowledge of the risk factors of cervical cancer. 60 (39%) of the respondents knew that multiple male sexual partners, while 78 (30%) knew a sexually transmitted virus caused CC. Surprisingly only 6 (3%) of them indicated HPV as a risk factor of CC, while 8 (4%) knew early sexual activity could lead to cervical cancer. Most of the respondent could not identify the signs and symptoms of CC. Less than half 71 (35.5%) of the respondents knew lower abdominal pains were part of the signs and symptoms of CC while few 25(12.5%), 11 (5.5%), 10 (5%) reported vaginal bleeding, pain in the genital during sexual intercourse and intermenstrual vaginal bleeding respectively as part of the signs and symptoms of CC.

Barriers to cervical cancer screening

Table 4 shows the responses to barriers that may affect CC screening among respondents. The main barriers identified by the respondents were individual beliefs and attitudes to screening, socioeconomic and healthcare system barriers. Majority of the respondents affirmed the fact that certain individual beliefs and attitudes may prevent them from participating in screening. For instance, a considerable number of the respondents 160 (80%) thought the screening was scary while about two thirds 149 (74.5%) of the respondents mentioned they were not susceptible to CC and thus will not screen. In addition to this, socioeconomic barriers such as lack of affordability and time may prevent respondents’ likelihood of undergoing screening procedures. For instance, more than half of the respondents, 139 (69.5%) indicated screening was expensive, and 46(23%) could only afford between USD 2–10. Again, some aspects of the healthcare system are likely to pose as barriers to CC screening. For example, almost all the respondents 157 (78.5%) mentioned they did not like male health personnel offering screening services and 172 (86%) and 133 (66.5%) alluded that long waiting time at the health facility and communication respectively may prevent them from seeking CC screening services.

Table 4

Barriers to cervical cancer screening amongst women in Kenyase, Ghana, N = 200.

Variable	Yes, N (%)	No, N (%)	Don’t know, N (%)
Perceived threat
Are you afraid of bad diagnosis?	147 (73.5)	33 (16.5)	20 (10)
Do you feel susceptible to cervical cancer?	16 (8)	149 (74.5)	35(17.5)
Does the thought of cancer scare you?	160 (80)	27 (13.5)	13(6.5)
Perceived benefits
Is cervical cancer screening important?	186 (93)	0 (0)	14 (7)
Do you believe cervical cancer can be cured?	37 (18.5)	87 (43.5)	76 (38)
Perceived barriers
Psychosocial barriers
Does respondent’s culture forbid cervical screening?	0 (0)	185 (92.5)	15(7.5)
Is CC screening embarrassing?	153 (76.5)	35 (17.5)	12(6)
Is cervical cancer screening painful?	8 (4)	27 (13.5)	165 (82.5)
Does respondent’s religion have anything against CC screening?	11 (5.5)	173 (86.5)	16(8)
Is CC a curse from the gods?	3 (1.5)	182 (91)	15 (7.5)
Socioeconomic barriers
Is CC screening test affordable?	47(23.5)	14 (7)	139 (69.5)
Can afford USD 2–10	46 (23)	0 (0)	154 (77)
Is the transport system in the facility good?	139 (69.5)	29 (14.5)	32 (16)
Do you have time for screening?	23 (11.5)	177 (88.5)	0 (0)
Healthcare system barriers
Are there long waiting time at health facility?	172 (86)	28 (14)	0(0)
Does the respondent feel comfortable with male health personnel offering to screen?	8 (4)	157 (78.5)	35 (17.5)
Does the respondent know any health facility offering CC screening?	83 (41.5)	110 (55)	7(3.5)
Is it difficult to communicate with health personnel?	133 (66.5)	38 (19)	29(14.5)
Cues for action
Prioritizing early morning and late evening increase screening	165 (78)	7(3.5)	37 (18.5)
Ensuring awareness of facility improve behavior for screening	163 (81.5)	14 (7)	23 (11.5)
Will preferring female health personnel increase screening uptake?	178 (89%)	15 (7.5)	7 (3.5)

The difference between respondents’ interest in participating in screening and HBM constructs

Table 5 describes the difference between respondents’ interest in participating in screening and HBM constructs. There was a significant difference between all the constructs and the respondents' interest in screening except long waiting time, CC can be cured and prioritizing early morning and late evening screening which showed no significant difference (P-value > 0.003).

Table 5

Chi-square analysis of respondents’ interest in participating in screening on the perceived threat, perceived benefits, perceived barriers and cues of action amongst women in Kenyase, Ghana, N = 200.

Variable	Pearson chi-square	P-value
Perceived threat of Cervical Cancer
Thought of cancer is scary	230.500	<0.001*
Susceptibility to cervical cancer	149.730	<0.001*
Afraid of bad diagnosis	20.123	<0.001*
Perceived benefits of cervical cancer screening
Importance of cervical cancer screening	185.663	<0.001*
Cervical cancer be cured	3.300	0.192
Perceived barriers of cervical cancer screening
Psychosocial barriers
Cervical cancer screening is embarrassing	14.874	0.005
Culture forbid cervical screening	92.529	<0.001*
Religion against CC screening	100.366	<0.001*
CC is a curse from the gods	94.472	<0.001*
Cervical cancer screening painful	16.580	<0.001*
Socioeconomic barriers
Cervical cancer is screening expensive	162.551	<0.001*
Transport system	130.575	<0.001*
Have time for screening	21.901	<0.001*
Healthcare system barriers
Knowledge of health facility offering screening	15.985	0.003*
Comfortable with male personnel	17.594	<0.001*
Long waiting time	3.835	0.429
Difficulties in communication	121.585	<0.001*
Cues for action for cervical cancer screening
Prioritizing early morning and late evening screening	0.916	0.619
Ensuring awareness of facility improve behavior for screening	85.043	<0.001*
Prefer female health personnel for screening	95.667	<0.001*

*p-value statistically significant.

The relationship between respondents’ sociodemographic characteristics and interest in participating in screening

Table 6 describes the sociodemographic predictors and interest in participating in CC screening using multivariate logistic regression analysis. Occupation (unemployed), educational background (high and no formal education) and marital status (married) were independent predictors of interest in participating in CC screening. Unemployed women were less likely to have an interest in CC screening than those who were employed (aOR = 0.005, 95%CI:0.001–0.041, p = 0.005). Women who were highly educated were 122 times very likely to be interested in CC screening than those with no or low formal education (aOR = 121.915 95%CI: 14.096–1054.469, p<0.001) and those who were unmarried were less likely to be interested in CC screening than those with those who were married (aOR = 0.124, 95%CI: 0.024–0.647, p = 0.013).

Table 6

Sociodemographic factors predicting interest in participating in cervical cancer screening amongst women in Kenyase, Ghana, N = 200.

Variable	N	P-value	aOR (95% CI) a
Occupation
Employed	155	Ref
Unemployed	45	0.005*	0.005 (0.001–0.041)
Educational background
High formal education	31	<0.001*	121.9 (14.095–1054.469)
Low formal education	119	Ref
No formal education	50	0.208	2.573 (0.591–11.211)
Marital status
Unmarried	105	Ref
Married	95	0.013*	0.124 (0.024–0.647)

*p-value statistically significant.

Adjusted for age, family history, religious status, and number of children.

aOR = adjusted odds ratio.

Discussion

Although CC screening reduces the incidence and mortality rates of cervical cancer, women in developing countries have reported low screening uptake, especially in Ghana. The current study revealed that only 3% of the respondents had ever patronized a CC screening test (either VIA or Pap test) even though there is high interest in participating in CC screening. This finding is consistent with a study conducted in which only 0.8% of the women and 8% of college students in the central region of Ghana had been screened before [17, 18]. Two systematic reviews reported similar findings of low screening uptake of 10%, 11%-19.9% and 14% in Tanzania, Ethiopia and Kenya, respectively [26, 29]. An explanation for these findings could be attributed to inadequate information about CC screening techniques and the unavailability of stimulating factors to enhance screening uptake. Thus national screening programs or routine screening during hospital visits could be adopted to improve screening rates.

Even though the study reported that majority of the respondents 194 (97%) had not been screened of CC before, a considerable number 163 (81.5%) had heard of screening, and more than 174 (87%) were interested in participating in screening. These findings were consistent with a study conducted in the capital of Ghana, Accra in 2009 amongst college students in which the majority of the respondents had heard of CC screening [30]. On the contrary, a study conducted in 2015 in the Central Region of Ghana found that a greater proportion (68.4%) of the participants had never heard of screening [17]. Likewise, studies in other developing countries like Zimbabwe, Ethiopia, and Nigeria [31-33]. A possible explanation for these differences in results could be attributed to improved CC education in Ghana across the years. Also, the fact that most of the women were interested in CC screening means that a national screening programme with intensive education and awareness is likely to see improved uptake.

Despite the high proportion of respondents knowing about CC screening, there was a low level of awareness of risk factors, signs and symptoms and preventive strategies. For instance, a notable finding is a fact that only 3% and 4% of the respondents could recognize HPV and first sexual intercourse as part of the risk factors of CC respectively [1, 34]. Previous studies in Ghana, Ethiopia, Nigeria, Kenya had similar findings [30, 33, 35–39]. Therefore, it was not surprising that majority of the respondents were not aware that CC ould be prevented through vaccination, which may result in low patronage of vaccination services. Hence, education on CC should be intensified since HPV has been highly associated with CC [1].

The key to effective screening programs depends primarimainly on an in-depth understanding of women and following clarification of beliefs and myths, which may lead to a reduction in barriers to screening despite high interest. The perceived threat, benefit, barriers and cues for action may influence interest in participating in CC screening except for long waiting time, which showed no statistically significant difference in interest in participating in screening in the current study. However, a notable finding in the current study is the fact that psychosocial barriers, such as cultural taboos and beliefs and were not indicated to affect CC screening. In detail, the study revealed that fear of pain and the outcome of diagnosis influenced respondents’ interest in screening. Studies conducted in Ghana and other sub-Saharan countries like Nigeria, Kenya have provided similar insights [17, 32, 40–43]. Also, the study indicated perceived lack of susceptibility and the importance of CC screening were significantly associated with interest in screening as well as high cost, transportation to the health facility and busy work schedules could affect interest in screening.

Another finding that prevented women from participating in screening is lack of knowledge on facilities offering screening services, male caregiver and difficulty in communication with the healthcare workers. These findings were affirmed in other studies conducted in Ghana and other sub-Saharan countries [32, 42–44]. Possible explanations to these outcomes could be because most women feel they do not experience signs and symptoms of the disease and thus may not find screening very important. Hence might result in a lack of time to attend or even seek locations where screening is ongoing or takes place.

The last HBM constructs, cues for action denotes a readiness to take action to improve interest in screening were found to include promoting awareness of screening facilities and using female screeners. The authors recommend that CC screening services should be incorporated into the national health insurance scheme as well as initiating a national screening program to improve coverage of CC screening services. Also, mobile screening sites could be set up in the communities, especially during market days, to enhance screening uptake.

The evidence concerning the likelihood of employment influencing the intention to screen is unclear. The current findings revealed that unemployed women were less likely than those employed to be interested in participating in CC screening, which is in line with studies conducted in Ghana and Nigeria. These studies reported a statistically significant association between employment and participating in CC screening services [45, 46]. Similarly, a study in Ethiopia said that women who were employed were four times more likely to utilize CC screening services [47]. However, amongst HIV patients, a study conducted in Ghana indicated that employment was not expected to affect the intention to have CC screening [48]. A possible explanation to this finding could be attributed to the fact that women who are employed have the financial ability to afford the cost of screening or perhaps they are keen on their health to be able to continue their work. Because CC services continue to be paid for, the occupation of women will play a significant role in seeking screening services as low socioeconomic status, including unemployed and part-time workers are less likely to patronise screening services.

The present finding revealed that women with high to no formal of education were more likely to show interest in CC screening. However, no formal education showed a statistically insignificant relationship with an interest in CC screening. This finding affirmed a study conducted in Ghana, in which respondents with a high level of education were more likely to screen [17]. Individuals with a higher level of education are more than 100 times likely to have an interest in CC screening. Thus, education could play a significant role in enhancing participation of CC screening activities. According to Ebu [48], educated women are placed in a position to understand health risk and so are more likely to engage in screening test. Education tends to change beliefs and unfavourable behaviours towards interventions put in place to enhance knowledge of health and illness [49]. Hence it is not surprising they have better chances of using maternal health services [50].

Furthermore, the finding of the current study suggests that married women are less likely to be interested in screening. Contrary to this finding, married women are two times more likely to accept CC screening than those who are single in Tanzania [49]. An outcome which was not consistent with the current study. However, a study conducted in Ghana showed that marital status is not a statistically significant determinant of women’ intention to have CC screening [48]. Thus the influence of marital status on CC screening appears to be inconsistent across studies. A possible explanation could be due to the concept of the different measurement across the studies as those who were in an informal union, or cohabiting were regarded as unmarried in the present study and other studies may classify them as married. Furthermore, the domineering power of men in African societies could prevent their partners from seeking CC services. This is because their partners influence health-seeking behaviours of women, and an example of this has been reported in situations whereby partners set up appointments with a physician [51].

Even though the current study has shown low screening uptake exists, and has provided insights into the factors affecting CC screening participation in Ghana, it’s limitation cannot be overlooked. The major limitation is the less rigorous and biased sampling technique, convenience sampling, which makes generalizations impossible. Therefore, the likelihood of selecting more women who were interested in screening may be biased the findings. Thus future studies should use robust methods. This study has also contributed to the application of the health belief model to understand human behaviour by guiding the authors to identify various factors and barriers affecting cervical cancer screening Ghana.

Conclusions

The study has documented that married women, unemployed and those with no formal education are less likely to participate in CC screening. Also, essential barriers relating to perceived lack of susceptibility, feeling of embarrassment, fear of wrong diagnosis and pains, feeling afraid, high cost, busy work schedule, lack of knowledge on screening facilities, the gender of screener and communication barriers affects women’s interest in participating in screening. Hence the Ghana health services should develop appropriate, culturally tailored educational materials on CC screening to inform women particularly those with no formal education through social media, television, radio and community information systems to enhance uptake. Also, in the short term, the government of Ghana should make policies to incorporate cervical cancer screening to maternal health services such as family planning. In the long run, a national screening program should be instituted to enhance cervical screening uptake. Future studies should use larger sample sizes to make generalizations to improve policy decisions. Also, even though the current research identified various barriers that may affect interest in participating in CC screening using the HBM, the constructs of this model can be used in future studies to predict interest in CC screening among women in Ghana.

(DOCX)

Click here for additional data file.

10 Oct 2019

PONE-D-19-23516

A Cross-Sectional Study of Barriers to Cervical Cancer Screening Uptake in Ghana: An application of the Health Belief Model

PLOS ONE

Dear Miss Ampofo,

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.

We would appreciate receiving your revised manuscript by Nov 24 2019 11:59PM. When you are 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.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter.

To enhance the reproducibility of your results, we recommend that if applicable you deposit your laboratory protocols in protocols.io, where a protocol can be assigned its own identifier (DOI) such that it can be cited independently in the future. For instructions see: http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols

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). This letter should be uploaded as separate file and labeled 'Response to Reviewers'.

A marked-up copy of your manuscript that highlights changes made to the original version. This file should be uploaded as separate file and labeled 'Revised Manuscript with Track Changes'.

An unmarked version of your revised paper without tracked changes. This file should be uploaded as separate file and labeled 'Manuscript'.

Please note while forming your response, if your article is accepted, you may have the opportunity to make the peer review history publicly available. The record will include editor decision letters (with reviews) and your responses to reviewer comments. If eligible, we will contact you to opt in or out.

We look forward to receiving your revised manuscript.

Kind regards,

Michael Johnson Mahande, PhD

Academic Editor

PLOS ONE

Journal Requirements:

When submitting your revision, we need you to address these additional requirements.

1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at http://www.journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf and http://www.journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf

2. Please include captions for your Supporting Information files at the end of your manuscript, and update any in-text citations to match accordingly. Please see our Supporting Information guidelines for more information: http://journals.plos.org/plosone/s/supporting-information.

Additional Editor Comments (if provided):

Section Comment, question, suggestion.

Abstract 1. On the introduction report high incidence and high mortality of Cervical Cancer with low screening uptake (needs to quantify)

2. Study period is missing in methods section

3. Reports descriptive Cross-sectional study design while multivariable logistic regression was done ( needs to change to analytical cross-sectional study design)

4. Missed recommendations and policy implications on Conclusion.

Introduction

Background 1. What is the burden of Cervical Cancer in Ghana (Incidence & mortality of Cervical Cancer)?

2. What are the interventions have been done in SA in recognition of the burden of cervical cancer? Are there any Strategic plans? Policies? (This will highlight any efforts which have been attempted to address the problem under study and outcomes of this effort)

3. Missed the gap (Why is the study being conducted?)

Literature review 4. Did not follow specific objectives (literature review should be reorganized to capture what is currently known about the proposed study outcomes/objectives, and it should provide available evidence about the topic under study from a global perspective to local)

a. Missed literature on Cervical Cancer Uptake

b. Missed literature on barriers to Cervical Cancer uptake

c. Factors influencing Cervical Cancer uptake applying the health belief model

Problem Statement 5. Problem under study is not stated clearly

6. Missed the knowledge gap (what information is lacking in the literature and what cannot be done because that information is not available?

Justification 7. Missed the benefits of study findings (to whom, why and how will the study findings benefit the beneficiaries)

8. Who are the beneficiaries of these findings?

Objectives 9. Objective number 2 is not clear “the study determines the association between sociodemographic characteristics and constructs under the lens of the health belief model”- misses the element of cervical cancer screening uptake.

Methodology 1. Missed the study duration (only mentions study was conducted on “March 2019”- it is not clear if this is the beginning or the end of the study).

2. What was the reason of doing convenience sampling technique?

3. How the Health Belief Model was introduced during data collection is not clear.

4. What was the criteria to conduct questionnaire pre-test among 15 women in the pilot study?

5. Prevalence of Cervical Cancer Screening uptake is >10%, were the alternative to logistic regression considered?

6. In the data analysis section SPSS is not cited correctly

7. Study design should be changed to analytical cross-sectional design as logistic regression was done

8. Why was classical analysis (chi-square) done after the regression analysis and what was the reason to do chi-square and logistic regression as per the objectives? It is not clear what method answers what objective

9. Were the priori confounders considered? And how were they controlled for?

10. Overall data analysis section should be revised and reorganized and should state clearly which method answers what objectives.

Results 1. It is important to mention the total sample size while reporting the results.

2. “N” showing total sample size should appear at the title of the table.

3. Results did not follow the specific objectives, makes it difficult to follow up.

4. What was being controlled for in the multivariable logistic regression analysis? Missed the bivariate analysis results

5. Overall results section should be re-organized per the specific objectives to enable the reader to follow through

Discussion 1. Discussion is also per the specific objectives; we do not discuss the background characteristics of study participants (Objective 0)

2. When mentioning study similarities and differences it is worth mentioning study areas and the study populations for clarity

3. Discussion did not follow specific objectives, missed the link between the study findings and the possible explanations basing on policies and interventions in place regarding Cervical Cancer screening.

Strengths and limitations 4. How is the current study able to improve Cervical Cancer screening uptake in Ghana? Please elaborate

5. How did the sampling design affect your study findings? Please elaborate more

6. What is the contribution of the current study to the scientific community?

Conclusion 7. Recommendations are not clearly stated (to whom, and what actions should be done, with what resources and under what timeframe)

8. What is the way forward basing on the study findings?

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

Reviewers' comments:

[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 to be viewed.]

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 us at figures@plos.org. Please note that Supporting Information files do not need this step.

Submitted filename: summary of the report- Cervical Cancer.docx

Click here for additional data file.

23 Oct 2019

Section Comment, question, suggestion. Response

Abstract 1. On the introduction report high incidence and high mortality of Cervical Cancer with low screening uptake (needs to quantify)

The high incidence (32.9, age-standardized per 100,000) and mortality (23.0, age-standardized per 100,000)

2. Study period is missing in methods section

Study period included (January and March 2019)

3. Reports descriptive Cross-sectional study design while multivariable logistic regression was done ( needs to change to analytical cross-sectional study design)

Descriptive cross-sectional study design changed to analytical cross-sectional study design

4. Missed recommendations and policy implications on Conclusion.

Hence, the Ghana health services should develop appropriate, culturally tailored educational materials to inform individuals with no formal education through health campaigns in schools, churches and communities to enhance CC screening uptake.

Introduction

Background 1. What is the burden of Cervical Cancer in Ghana (Incidence & mortality of Cervical Cancer)?

Ghana, one of the sub-Saharan countries, has a high age-standardized incidence and mortality rate of 32.9 and 23.0 per 100,000 respectively. These estimates make cervical cancer the most frequently diagnosed cancer after breast cancer (43.0, age-standardized per 100,000 women) and the leading cause of cancer deaths amongst women in Ghana.

2. What are the interventions have been done in SA in recognition of the burden of cervical cancer? Are there any Strategic plans? Policies? (This will highlight any efforts which have been attempted to address the problem under study and outcomes of this effort)

No policies towards national screening programmes currently exists in these countries and a similar situation is seen in Ghana and thus if steps are not taken, it may lead to the estimated 5-year prevalence of CC (46.4, age standardized rate per 100,000) across all ages.

3. Missed the gap (Why is the study being conducted?) Although population-based cervical screening and guidelines have resulted in a substantial decline in the burden of CC in developed countries, the lack of screening programs contributes to the high risk of CC in sub-Saharan Africa [3-6]. In Ghana, the non-existent national screening program for CC [6] have been mainly attributed to lack of funds, limited qualified personnel, and infrastructure for the development of widespread screening initiatives [7]. This has resulted in CC screening test such as, Pap smear or visual inspection with acetic acid (VIA) services being offered on local uncoordinated basis or as opportunistic screening, where doctors request Pap smear and VIA for patients in clinics and hospitals either as part of general medical examination or for consultations related or unrelated to CC [8]. Ina addition to this, government and private hospitals have trained nurses and doctors who conduct CC screening, especially in various family planning units as a routine before the insertion of an intrauterine device (IUD). Furthermore, organized screening by benevolent organizations is done occasionally in various communities in Ghana. In spite of the various avenues for CC screening, uptake for these services are very low [8-10] with participation rates lower than 3% in Ghana [11]. Therefore, the evidence regarding screening uptake in Ghana remains very scarce.

Literature review 1. Did not follow specific objectives (literature review should be reorganized to capture what is currently known about the proposed study outcomes/objectives, and it should provide available evidence about the topic under study from a global perspective to local)

a. Missed literature on Cervical Cancer Uptake

b. Missed literature on barriers to Cervical Cancer uptake

c. Factors influencing Cervical Cancer uptake applying the health belief model The literature review has been reorganized and it follows the study objective, and it provides global perspective now.

Problem Statement 1. Problem under study is not stated clearly

Problem statement has been clearly stated

2. Missed the knowledge gap (what information is lacking in the literature and what cannot be done because that information is not available? To best of the authors knowledge no empricial study has investigated the women’s behaviors towards CC screening in the Kenyase, Ashanti region of Ghana given the evidence that CC incidence and mortality is more common in this area [27], and the fact that differential cultural beliefs is prevalent across regions in Ghana.

Justification 1. Missed the benefits of study findings (to whom, why and how will the study findings benefit the beneficiaries)

The findings of the provided good insights into factors affecting CC screening participation and appropriate ways of targeting educational interventions amongst women in Ghana.

2. Who are the beneficiaries of these findings? Women in Ghana

Objectives 1. Objective number 2 is not clear “the study determines the association between sociodemographic characteristics and constructs under the lens of the health belief model”- misses the element of cervical cancer screening uptake. The objectives have been clearly stated now: This study sought to determine the 1) uptake and interest in CC screening, 2) knowledge level of CC, 3) barriers influencing interest in CC screening , 4) association between sociodemographic characteristics and CC screening uptake under the lens of the health belief model among women in Ashanti region of Ghana.

Methodology 1. Missed the study duration (only mentions study was conducted on “March 2019”- it is not clear if this is the beginning or the end of the study). January and March 2019

2. What was the reason of doing convenience sampling technique? The sample was chosen as follows: random shops and houses in the community under study were chosen and visited until predetermined number of surveys were completed. The term convenience sampling was used because a structured sampling frame was not done due to the unstructured nature of the community, time and resource constraints.

3. How the Health Belief Model was introduced during data collection is not clear. It was used in the questionnaire development and data analysis

4. What was the criteria to conduct questionnaire pre-test among 15 women in the pilot study? The criteria for the pilot test was amongst women with the age considered in a different community not selected for the study.

5. Prevalence of Cervical Cancer Screening uptake is >10%, were the alternative to logistic regression considered? Prevalence of cervical cancer screening uptake <10% and not used in logistic regression.

6. In the data analysis section SPSS is not cited correctly Statistical Package for the Social Sciences (SPSS, IBM Corporation, Armonk, NY, USA) version 21.0.

7. Study design should be changed to analytical cross-sectional design as logistic regression was done The analytical cross-sectional study design was used to conduct the study between January and March 2019 in Kenyase, a suburb of the Ashanti Region of Ghana.

8. Why was classical analysis (chi-square) done after the regression analysis and what was the reason to do chi-square and logistic regression as per the objectives? It is not clear what method answers what objective Pearson chi-square test was used to show the differences between proportions of individuals who were interested or not interested in participating in CC screening in relation to the HBM constructs as subscales. This has been clearly stated now

9. Were the priori confounders considered? And how were they controlled for? Yes, age, family history, religious status, and number of children were controlled for. However after controlling for each variable in the logistic regression model, those that were not significant at p<0.05.

10. Overall data analysis section should be revised and reorganized and should state clearly which method answers what objectives. The data analysis has been reorganised as suggested.

Results 1. It is important to mention the total sample size while reporting the results. The total results have been reported in each part of the results

2. “N” showing total sample size should appear at the title of the table. N on the title has been stated

3. Results did not follow the specific objectives, makes it difficult to follow up. Results have been reorganised according to specific objectives

4. What was being controlled for in the multivariable logistic regression analysis? Missed the bivariate analysis results Age, family history, religious status, and number of children were controlled for. However after bivariate analysis these variables were dropped because they were not significant.

5. Overall results section should be re-organized per the specific objectives to enable the reader to follow through The results section has been reorganised.

Discussion 1. Discussion is also per the specific objectives; we do not discuss the background characteristics of study participants (Objective 0) Background characteristics have been removed.

2. When mentioning study similarities and differences it is worth mentioning study areas and the study populations for clarity Study areas and population has been stated

3. Discussion did not follow specific objectives, missed the link between the study findings and the possible explanations basing on policies and interventions in place regarding Cervical Cancer screening. Discussion follow objectives and has been reorganised

Strengths and limitations 4. How is the current study able to improve Cervical Cancer screening uptake in Ghana? Please elaborate The current study has shown low screening uptake exists, and has provided insights into the factors affecting CC screening participation in Ghana.

5. How did the sampling design affect your study findings? Please elaborate more The major limitation is the less rigorous and biased sampling technique, convenience sampling, which makes generalizations impossible. Therefore the likelihood of selecting more women who were interested in screening may be have biased the findings. Thus future studies should use robust methods

6. What is the contribution of the current study to the scientific community? This study has also contributed to application of the health belief model to understand human behavior by guiding the authors to identify various factors and barriers affecting cervical cancer screening Ghana.

7. How is the current study able to improve Cervical Cancer screening uptake in Ghana? Please elaborate The current study has shown low screening uptake exists, and has provided insights into the factors affecting CC screening participation in Ghana.

Conclusion 8. Recommendations are not clearly stated (to whom, and what actions should be done, with what resources and under what timeframe) The Ghana health services should develop appropriate, culturally tailored educational materials on CC screening to inform women particularly those with no formal education through social media, television, radio and community information systems to enhance uptake. Also, in the short term the government of Ghana should make policies to incorporate cervical cancer screening to maternal health services such as family planning. In the long term a national screening program should be instituted to enhance cervical screening uptake.

9. What is the way forward basing on the study findings Future studies should use larger sample sizes to make generalizations to enhance policy decisions. Also, even though the current study identified various barriers that may affect interest in participating in CC screening using the HBM, the constructs of this model can used in future studies to predict interest in CC screening among women in Ghana.

Submitted filename: Response to reviewers.docx

Click here for additional data file.

25 Mar 2020

A Cross-Sectional Study of Barriers to Cervical Cancer Screening Uptake in Ghana: An application of the Health Belief Model

PONE-D-19-23516R1

Dear Dr. Ampofo,

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

Within one week, you will receive an e-mail containing information on the amendments required prior to publication. When all required modifications have been addressed, you will receive a formal acceptance letter and your manuscript will proceed to our production department and be scheduled for publication.

Shortly after the formal acceptance letter is sent, an invoice for payment will follow. To ensure an efficient production and billing process, please log into Editorial Manager at https://www.editorialmanager.com/pone/, click the "Update My Information" link at the top of the page, and update your user information. 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 enable them to help maximize its impact. If they will be preparing press materials for this manuscript, you must inform our press team as soon as possible and 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.

With kind regards,

Ali Montazeri

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: 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: The authors have appropriately addressed reviewer comments.

Please correct few typographical and grammatical errors along the manuscript, pay attention to the abstract.

**********

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

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

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

Reviewer #1: No

21 Apr 2020

PONE-D-19-23516R1

A Cross-Sectional Study of Barriers to Cervical Cancer Screening Uptake in Ghana: An application of the Health Belief Model

Dear Dr. Ampofo:

I am 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 notify them about your upcoming paper at this point, to enable them to help maximize its impact. If they will be preparing press materials for this manuscript, 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.

For any other questions or concerns, please email plosone@plos.org.

Thank you for submitting your work to PLOS ONE.

With kind regards,

PLOS ONE Editorial Office Staff

on behalf of

Professor Ali Montazeri

Academic Editor

PLOS ONE