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Research article

Identification of prognostic hypoxia-related genes signature on the tumor microenvironment in esophageal cancer


  • Received: 11 July 2021 Accepted: 12 August 2021 Published: 07 September 2021
  • Background 

    Hypoxia is a crucial factor in the development of esophageal cancer. The relationship between hypoxia and immune status in the esophageal cancer microenvironment is becoming increasingly important in clinical practice. This study aims to clarify and investigate the possible connection between immunotherapy and hypoxia in esophageal cancer.

    Methods 

    The Cancer Genome Atlas databases are used to find two types of esophageal cancer cases. Cox regressions analyses are used to screen genes for hypoxia-related traits. After that, the genetic signature is validated by survival analysis and the construction of ROC curves. GSEA is used to compare differences in enrichment in the two groups and is followed by the CIBERSORT tool to investigate a potentially relevant correlation between immune cells and gene signatures.

    Results 

    We found that the esophageal adenocarcinoma hypoxia model contains 3 genes (PGK1, PGM1, SLC2A3), and the esophageal squamous cell carcinoma hypoxia model contains 2 genes (EGFR, ATF3). The findings demonstrated that the survival rate of patients in the high-risk group is lower than in the lower-risk group. Furthermore, we find that three kinds of immune cells (memory activated CD4+ T cells, activated mast cells, and M2 macrophages) have a marked infiltration in the tissues of patients in the high-risk group. Moreover, we find that PD-L1 and CD244 are highly expressed in high-risk groups.

    Conclusions 

    Our data demonstrate that oxygen deprivation is correlated with prognosis and the incidence of immune cell infiltration in patients with both types of esophageal cancer, which provides an immunological perspective for the development of personalized therapy.

    Citation: Linlin Tan, Dingzhuo Cheng, Jianbo Wen, Kefeng Huang, Qin Zhang. Identification of prognostic hypoxia-related genes signature on the tumor microenvironment in esophageal cancer[J]. Mathematical Biosciences and Engineering, 2021, 18(6): 7743-7758. doi: 10.3934/mbe.2021384

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  • Background 

    Hypoxia is a crucial factor in the development of esophageal cancer. The relationship between hypoxia and immune status in the esophageal cancer microenvironment is becoming increasingly important in clinical practice. This study aims to clarify and investigate the possible connection between immunotherapy and hypoxia in esophageal cancer.

    Methods 

    The Cancer Genome Atlas databases are used to find two types of esophageal cancer cases. Cox regressions analyses are used to screen genes for hypoxia-related traits. After that, the genetic signature is validated by survival analysis and the construction of ROC curves. GSEA is used to compare differences in enrichment in the two groups and is followed by the CIBERSORT tool to investigate a potentially relevant correlation between immune cells and gene signatures.

    Results 

    We found that the esophageal adenocarcinoma hypoxia model contains 3 genes (PGK1, PGM1, SLC2A3), and the esophageal squamous cell carcinoma hypoxia model contains 2 genes (EGFR, ATF3). The findings demonstrated that the survival rate of patients in the high-risk group is lower than in the lower-risk group. Furthermore, we find that three kinds of immune cells (memory activated CD4+ T cells, activated mast cells, and M2 macrophages) have a marked infiltration in the tissues of patients in the high-risk group. Moreover, we find that PD-L1 and CD244 are highly expressed in high-risk groups.

    Conclusions 

    Our data demonstrate that oxygen deprivation is correlated with prognosis and the incidence of immune cell infiltration in patients with both types of esophageal cancer, which provides an immunological perspective for the development of personalized therapy.



    Diarrhea is defined as three or more loose or watery stools per day [1]. Diarrhea is a threat everywhere, but its frequency and impact are more severe in low-resource settings [2],[3]. It occurs world-wide and causes 4% of all deaths and 5% of health loss to disability [4]. In 2016, diarrheal diseases were the eighth leading cause of death among all ages [5]. Diarrheal diseases caused an estimated 1.3 million deaths and are the fourth leading cause of years of life lost in developing countries [6]. On a global scale, of the estimated 165 million Shigella diarrheal episodes estimated to occur each year, 99% occur in developing countries [7]. The major six pathogens responsible for diarrhea are Shigella, rotavirus, adenovirus, enterotoxigenic Escherichia coli (E. coli) Cryptosporidium, and Campylobacter. However, rotavirus and E. coli are the two most common etiological agents of moderate-to-severe diarrhea in low-income countries [8].

    Diarrheal disease affects rich and poor, old and young, and those in developed and developing countries alike, yet a strong relationship exists between poverty and an unhygienic environment. Food-borne diseases pose a significant public health burden worldwide [9],[10]. Diarrheal diseases are the most common illnesses resulting from the consumption of contaminated food and water [11],[12]. In Africa, it is estimated that 92 million people fall ill from consuming contaminated foods, resulting in 137,000 deaths each year [13]. In developing countries, there have been several attempts to improve food safety and to reduce diarrheal disease [14]. However, insufficient access to adequate hygiene and sanitation are major risk factors for the heavy burden of diarrheal diseases in developing countries [15]. Biological contaminants, largely bacteria and parasites constitute the major causes of diarrheal diseases often transmitted through food, water, and nails, and fingers contaminated with faeces. Accordingly, food handlers with poor personal hygiene are potential sources of infections from these microorganisms [16]. Based on the distribution of use of the different types of water sources and the associated risks of diarrhea, 502,000 diarrheal deaths in low and middle income countries can be attributed to inadequate and unsafe drinking water. Of these deaths, 88% occur in Africa and South-East Asia [17]. Moreover, in 2016, impure water, inadequate sanitation and poor hygiene was responsible for 829,000 annual deaths from diarrhea, and 1.9% of the global burden of disease [18].

    Though the federal government of Ethiopia launched an urban health extension program including food and water safety packages at the capital city, Addis Ababa in 2009, still the city has many health problems especially recurrent food and water borne outbreaks [19]. According to the 2016 Addis Ababa health bureau report, there is high prevalence of diarrheal diseases in Addis Ababa though its sources are not well known and studied in depth. According to the 2017 Addis Ababa Food, Medicine and Health Care Administration and Control Authority (AAFMHACA) Report, food establishments located in Addis Ababa are suspected to be major sources of diarrheal diseases which might arise from poor knowledge and practice of food handlers, poor quality of drinking water, poor waste water and solid waste management, lack of wash facilities and poor water storage conditions. Due to these and other unknown factors, the city has many health problems like a high burden of typhoid fever, amoeba, acute watery diarrhea and other diarrheal diseases. Diarrheal disease is an important public health problem, causing morbidity and mortality. However, except for verbal reports, no studies have been conducted on the health status of food handlers. Because of this, a considerable number of customers of the food establishments have been exposed to different gastro-intestinal health problems. Accordingly, this study aimed at filling the research gap on the prevalence of diarrheal disease and associated behavioral factors among food handlers in Addis Ababa.

    The study was conducted in Addis Ababa city located in Upper Awash River basin, the capital of the Federal Government of Ethiopia and the seat for the African Union Headquarters. According to the 2017 AAFMHACA report, there are 1141 licensed food establishments, employing 4565 food handlers. Of the total licensed food establishments, 95 (8%) are large (hotels with one or more stars) and the remaining 1046 (92%) are small food establishments which include unranked (non-star hotels, bars, restaurants, cafes etc). The location map of Addis Ababa city is depicted below in Figure 1.

    Figure 1.  Map of Addis Ababa city administration. Source: Berhanu M, Raghuvanshi TK, Suryabhagavan K, Web-based GIS approach for tourism development in Addis Ababa city, Ethiopia [20].

    An institutional based cross sectional study was conducted among food handlers of Addis Ababa city administration from June to July 2019.

    All food handlers located in Addis Ababa city administration were the source population.

    All selected food handlers were located in Addis Ababa.

    All 18 years and above food handlers, workings for a minimum of three months were included. However, causal food handlers were excluded.

    To estimate the two week prevalence of diarrheal diseases and associated behavioral factors among food handlers in the food establishments of Addis Ababa, a sample size was calculated using a two population proportion formula (EPI INFO version 7.2.2.6) considering that:

    For hand washing before meals and after defecation:

    n = sample size for hand washing before meals and after defecation.

    ((1))

    Or EPI INFO versions 7.2, 2.6 STATCALC, 1058 sample of food handlers were included.

    The study participants were selected using a stratified, simple random sampling technique. To collect data, a listing of the 1141 licensed food establishments was obtained from AAFMHACA. These 1141 food establishments were stratified in to slum and non-slum areas based on their location. Similarly, the food handlers were stratified into two based on their work location (slum and non-slum area). Further, food handlers working in large and small food establishments were stratified into two. Based on this, sample allocation was conducted to the slum and non-slum areas in addition to the large and small food establishments. After the food handlers were stratified based on their work location and size of food establishments (large or small), one food handler from one food establishment was selected at random. Based on this, samples from 428 and 630 food handlers were taken from the food establishments located in the non-slum and slum area respectively. From the non-slum area, 59 samples from the large/big and 369 samples from the small food establishments were collected. Also, from the slum area (630), 29 samples from the large/big and 601 samples from the small food establishments were collected. Finally, using a simple random sampling technique, 1058 food handlers were selected to assess prevalence of diarrheal diseases and associated factors. A stratified random sampling technique was used in both slum and non-slum areas as well as large and small food establishments of Addis Ababa. The main purpose of stratification was to ensure representativeness for food handlers working in different areas and in various types of establishments with different educational status and work experience. In summary, the sampling procedure for this study is depicted below in Figure 2.

    Figure 2.  Systematic structure of the study sampling procedure.

    Data enumerators were identified based on professional capability and technical experience in collecting the required data. Accordingly, fifteen health professionals with a Bachelor of Science and extensive experience in similar data collection practices were employed. In addition, four Masters' degree holders were recruited for supervision of data collection. Two-day training was given to the data collectors and supervisors. After written consent was obtained from each study subjects, the data was collected from food handlers through face-to-face interview using a structured questionnaire.

    A questionnaire was prepared in English and translated in to Amharic and back to English to maintain the consistency of questions. The quality of data was ensured through training of data collectors, close supervision, prompt feedback and daily recheck of completed questionnaire. Moreover, a brief daily activity evaluation method was established to correct problems that arose during the course of data collection. The consent and the assurance of confidentiality were ensured. The principal investigator checked and reviewed the entire completed questionnaire to ensure completeness and consistency of the information.

    All data were checked for correctness of information and code. Date analyses were performed by using SPSS (Statistical Package for the Social Sciences) software version 20. Descriptive statistics such as frequency (%) for categorical and mean and standard deviation for numerical data were used to sum up the data. A binary logistic regression model was fitted to assess any association between diarrhea and independent variables. P values of 0.05 and 95% confidence interval for adjusted odds ratio (AOR) were used to report statistical significance.

    Diarrhoea Disease: Defecation frequency of three or more loose/liquid stools in a day.

    Health Status: The presence of absence of diarrheal disease in two weeks prior to the study.

    Food Establishments: Institutions that provide food and drinks for selling to customers.

    Food: A material consisting nutritious substances that people eat or drink in order to maintain life and growth

    Food Handlers: A person who is involved in the preparation and handling of food in a food establishment.

    Large/big Food Establishment: Hotels with one or more stars.

    Small Food Establishment: Small vendors, non-star hotels, bars, restaurants, cafes.

    Slum Area: Area with poorer sanitation infrastructure.

    Non-slum Area: Area with better sanitation infrastructure.

    A: Independent or explanatory variables:

    The predictor variables of this study were sex, age, marital status, religion, educational status, length of work experience of the food handlers etc.

    B: Dependent or outcome or response variables:

    Outcome of this study was diarrheal disease.

    Firstly, a letter of support was obtained from the Ethiopian Institution of Water Resources, Addis Ababa University. Then, ethical approval was obtained from the Ethiopian Public Health Institute Scientific and Ethical Review Board with reference number EPHI 613/138 in June 2019. To collect the data, written consent was obtained from each respondent after the objectives of this particular study were explained. Candidates were informed that their participation was voluntary. Confidentiality and privacy of respondents were ensured throughout the research process. The study design did not harm those taking part and it did not include any identifying information like name, or address of respondents.. They were well informed by the data collectors that the study was only for the purpose of academic and institutional research and not for any other business or illegal activities. Then, data were collected after assuring the confidential nature of responses.

    A total of 1050 food handlers participated in the study with a response rate of 99.2%. In the current study, 77% of the participants were female. Of the total participants, 43.4% and 28.7% were between the age group of 18 to 22 and 23 to 27 years old respectively. The mean age of the respondents was 25.695 years. 82.7% of the food handlers had the ability to read and write, while 17.3% were illiterate. The majority of the participants (81.2%) were single. Of the total respondents, 73% of participants were Orthodox Christians and 13.1% were Muslims. Regarding work experience, 46.3% and 35.3% of the respondents had 1 to 5 years and <1 year of work experience as food handlers respectively. Furthermore, 17.8% of the food handlers had above 5 years of work experience as food handlers. The average length of food handlers work experience was found to be 3.34 years (Table 1).

    Table 1.  Socio-demographic characteristics of the food handlers (n = 1050).
    Study variables Category Frequency Percent
    Sex of the food handlers Male 242 23.0
    Female 808 77.0
    Age group of the food handlers 18–22 years 456 43.4
    23–27 years 301 28.7
    28–32 years 127 12.1
    >32 years 166 15.8
    Mean age of the food handles 25.695 years with SD of ±7.576
    Minimum age of the food handlers 18.00 years
    Maximum age of the participants 65.00 years
    Educational status of the food handlers Illiterate 182 17.3
    At least read and write 868 82.7
    Marital status of the food handlers Single 853 81.2
    Married 180 17.1
    Divorced and others 17 1.6
    Religion of the food handlers Orthodox 766 73.0
    Muslim 138 13.1
    Others 146 13.9
    Work experience of the food handlers <1 year 371 35.3
    1 to 5 years 492 46.9
    >5 years 187 17.8
    Mean work experience of the food handlers 3.34 years with SD of ±3.37 years

     | Show Table
    DownLoad: CSV

    The study found 45.1% and 44% of the food handlers' role was cooking and serving as waiters respectively. Of the total participants, 85% and 15% of the food handlers live and sleep in their home and at the food establishments respectively. More than half (57.4%) of the food handlers had no medical checkup or health examination certificate within the past three months prior to the study. From the total respondents, 61.3% of the food handlers reported that there was a mechanism of isolation for sick food handlers from the workplace. However, a greater number of food handlers (83.1%) had no training on food and water safety at least once in the past year prior to the study (Table 2).

    Out of the 1,050 food handlers, 36 had diarrhea two weeks before the interview or a prevalence of 3.4%. Further, from the total participants, 17 (1.6%) of the food handlers had Acute Watery Diarrhea confirmed by a laboratory in the past year prior to this study. Moreover, 10.5%, 10.7% and 9% of the food handlers had a cough, infection or runny nose (influenza) and the incidence of fever within the past two weeks prior to this study respectively (Table 3).

    Table 2.  Food handlers work profile, medical checkup practice and training situation (n = 1050).
    Study variables Category Frequency Percent
    Role of food handlers in the food establishment Cook 474 45.1
    Waiter 462 44.0
    Both cooker and waiter 114 10.9
    Place of food handlers living and sleeping At the food establishment 158 15.0
    At her/his home 892 85.0
    Type of employee in the food establishment Permanent 177 16.9
    Temporary 873 83.1
    Medical checkup or health examination certificate at least within every three month Yes 447 42.6
    No 603 57.4
    Isolation of sick food handlers from the work place when food handler is ill Yes 644 61.3
    No 406 38.7
    Training of food handles on food and water safety at least once in a year Yes 177 16.9
    No 873 83.1

     | Show Table
    DownLoad: CSV
    Table 3.  Type of disease symptom and morbidity among the food handlers.
    Study variables Category Frequency Percent (%)
    Diarrheal diseases within the past two weeks prior to this study Yes 36 3.4
    No 1014 96.6
    Acute Watery Diarrhea (AWD) confirmed by laboratory for the past one year prior to this study Yes 17 1.6
    No 1033 98.4
    Cough within the past two weeks prior to this study Yes 110 10.5
    No 940 89.5
    An infection of runny nose within the past two weeks prior to this study Yes 112 10.7
    No 938 89.3
    Incidence of any fever within the past two weeks prior to this study Yes 95 9.0
    No 955 91.0

     | Show Table
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    Of the total participants, 94.5% and 93.8% washed their hands regularly after using the toilet and before meal respectively. However, 39% of the respondents used the toilet wearing protective clothes/gown. Additionally, 81.9% of the food handlers washed their hands immediately after handling raw foods. Further, 91.6% and 92% of the participants regularly closed their drinking water container to prevent contamination, and regularly washed their drinking water container and utensils with sanitizers and disinfectants. Almost all (96.7%) of the participants were washed glasses or the materials used for drinking water at every event. Also, 82.3% of the respondents put cooked foods separately from raw foods. Although 91.1% of the respondents did not use the same chopping block and knife during processing raw food and cooked food, 24.1% of the participants had habits of eating raw beef and raw vegetables. The food handlers reported that 89% of them ate a meal regularly in the food establishments. However, only 33.3% of the participants used proper waste disposal methods. Further, 62.5% of the respondents utilized unimproved or traditional toilets (Table 4).

    Table 4.  Factors that may be contribute to diarrheal diseases among the food handlers.
    Study variables Category Frequency Percent
    Regular hands washing after toilet used (defecation) Yes 992 94.5
    No 58 5.5
    Washing hands before meal regularly Yes 985 93.8
    No 65 6.2
    Used toilet while wearing protective clothes/gown Yes 409 39.0
    No 641 61.0
    Hand washing immediately after handling raw foods Yes 860 81.9
    No 190 18.1
    Take precaution/close drinking water container regularly Yes 962 91.6
    No 88 8.4
    Washing drinking water container and food service utensils with sanitizers and disinfectants regularly Yes 966 92.0
    No 84 8.0
    Washing glass or the material used for drink water every event with safe water Yes 1015 96.7
    No 35 3.3
    Put cooked foods separately from raw foods Yes 864 82.3
    No 186 17.7
    Habit of eating raw Beef and raw vegetables Yes 253 24.1
    No 797 75.9
    Used the same chopping block and knife during the time of processing raw food and cooked food Yes 93 8.9
    No 957 91.1
    Feed regularly in the food establishment Yes 935 89.0
    No 115 11.0
    Type of food establishment that the food handlers work One and above one star Hotel 86 8.2
    Non star Hotel 69 6.6
    Bar and restaurant 194 18.5
    Cafe and restaurant 76 7.2
    Restaurant 424 40.4
    Cafe and others 201 19.1
    Used proper waste disposal methods (pedal dust bin, septic tank) Yes 350 33.3
    No 700 66.7
    Type of toilet most of the time used by food handlers Unimproved or traditional toilet 656 62.5
    Improved or water flush toilet 394 37.5
    Presence of sanitary inspection by authorized bodies in the food establishment Yes 865 82.4
    No 185 17.6
    Type of the establishment in size the food handlers work Small food establishment 964 91.8
    Big food establishment 86 8.2

     | Show Table
    DownLoad: CSV

    In the binary logistic regression analysis, thirteen (13) explanatory variables like educational level of food handlers, regular hand washing after toilet used (defecation), regular hand washing before meal, used toilet with wearing protective clothes/gown, regular hand washing immediately after holding raw foods, closing drinking water container regularly, washing drinking water container with safe water and food service utensils with sanitizers and disinfectants, washing glass or the material used for drink water every event, separation of cooked foods from raw foods, habit of eaten raw beef and raw vegetables, used the same chopping block and knife during the time of processing raw food and cooked foods, type of toilet most of the time used by food handlers and presence of sanitary inspection by authorized bodies in the food establishment were significant associated (p-value < 0.028) with diarrheal disease in the past two weeks prior to this study. However, only five (5) predictor variables including: regular hand washing after toilet used (defecation), toilet use while wearing protective clothes/gown, washing glass or the material used for drink water every event, habit of eating raw beef and raw vegetables and type of toilet used by food handlers were appeared in the final condensed model of the multivariable analysis with P-value < 0.05 (Table 5).

    Table 5.  Multivariate logistic regression analysis of diarrheal disease with selected explanatory variables among the food handlers (n = 1050).
    Study variables Diarrhea
    Β Wald P Value AOR with 95%CI
    Yes No
    Regular hand washing after toilet used or defecation Yes 9 983 −2.029 5.496 0.019 0.13(0.024–0.72)
    No 27 31 Reference
    Used toilet while wearing protective clothes/gown Yes 28 381 1.684 7.283 0.007 5.39(1.59–18.32)
    No 8 633 Reference
    Washing glass or the material used for drink water every event with safe water Yes 11 1004 −4.724 15.532 0.000 0.009(0.001–0.093)
    No 25 10 Reference
    Habit of eating raw Beef and raw vegetables Yes 30 223 1.836 9.010 0.003 6.27(1.89–20.78)
    No 6 791 Reference
    Improved or water flush Toilet used by food handler Yes 7 387 1.405 4.079 0.043 Reference
    No 29 627 4.07(0.29–6.67)

     | Show Table
    DownLoad: CSV

    The aims of this study were to identify the prevalence of diarrheal disease and associated behavioral factors among food handlers. The self-reported prevalence of diarrheal disease in the two weeks before the interview was 3.4%.

    This finding was lower than studies performed in Ethiopia and Haiti [22],[23]. This could be due to difference in attention given to health status and environmental risk factors. However, this result was consistent with a similar study conducted in Ireland [24]. This could be due to presence of good awareness among the food handlers towards diarrheal diseases. Further, this result was nearly consistent with a study conducted in South India where the prevalence of diarrhea among food handlers was 5.52% [25]. The slight difference might be due to the presents of recurrent food and water borne diseases in Addis Ababa and made alerted the food handlers about diarrheal diseases.

    From the total participants, 17 (1.6%) of the food handlers had Acute Watery Diarrhea confirmed by laboratory testing in the past year prior to this study. Because we did not find information from literature on the prevalence of acute watery diarrhea among food handlers, this result needs further research because it is a major public health problem. Moreover, 10.5%, 10.7% and 9% of the food handlers had a cough, infection or runny nose (influenza) or the incidence of fever within the past two weeks prior to this study respectively. This indicates the health status of food handlers was poor though they were expected to be healthy and not transmit any infection to customers.

    This study revealed that food handlers who had washed their hands after defecation or toilet use were 13% less likely to report diarrhea than those who did not report hand washing. This finding was supported by a study from low and middle income countries [26]. As expected, this may be due to removal of pathogenic organisms during proper hand washing after toilet use. Therefore, washing hands properly at the most recommended times is the key preventive mechanism of diarrheal disease. However, food handlers who used toilet while wearing protective clothes/gown had 5.39 times higher risk of diarrheal disease (AOR = 5.39 with 95% CI; 1.59, 18.32) relative to those who had not used the toilet while wearing personal protective device. This indicates personal protective equipment can carry pathogenic organisms or might be vehicles although no study reported this. Therefore, this needs future research to obtain additional information. Moreover, our finding revealed that food handlers who utilized washed glass or the material used for drinking water had prevented risk of diarrhea by 0.9% times higher (AOR = 0.009 with 95% CI: 0.001, 0.093) than those who did not. This indicates that, using safe water-washed glass reduces the risk of diarrheal disease. The odds of having diarrheal disease was 6.27 times higher among food handlers who had the habit of eating raw beef and raw vegetables (AOR = 6.27 with 95% CI: 1.89–20.78) than those who did not. This finding was supported by a 2017 study done in Bejing, China [21]. Further, the odds of having diarrheal disease was 4.07 times higher among those food handlers who used unimproved/traditional pit toilet (AOR = 4.07 with 95%CI: 0.29–6.67) than those who used improved or water flush toilet. Although in general the presence of a sanitary facility prevents different communicable diseases [26], this result shows using a traditional pit latrine had its own health impact on a community.

    This study assessed the prevalence of diarrheal disease and identifies behavioral factors associated with diarrhea. This assessment proved to be an essential activity for reduction of community- acquired diarrheal diseases, as a significant number of food handlers had diarrhea. Good sanitation, hygiene practice and a healthy lifestyle behavior can prevent diarrhea. A strong political commitment with appropriate budgetary allocation is essential for the control of diarrheal diseases. The government should focus on a comprehensive diarrheal disease control strategy including improvement of water quality, hygiene, and sanitation. Current public health programs of the Addis Ababa city administration should develop effective approaches to promote hand washing practice and creation of awareness. Moreover, other interventions should be strengthened to reduce the occurrence of diarrhea. Improved interventions combined with formal training on food safety practice should be strengthened to reduce occurrence of diarrhea among the food handlers and to reduce health problems of their customers. Moreover, routine inspections should be conducted by authorized bodies to enhance hygiene and sanitation practices of food handlers.



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