Adverse drug effects among students following mass de-worming exercise involving administration of Praziquantel and Albendazole in KEEA Municipality, Ghana.

BACKGROUND: To manage the deleterious effects of parasitic infections such as lymphatic filariasis (LF) and schistosomiasis among school children, most countries including Ghana make use of mass drug administration (MDA). Although MDA has proven effective in reducing worm burden, unfortunately adverse drug effects (ADEs) post-MDA are derailing the gains and also remain poorly monitored. The study assessed incidence and factors associated with ADEs among students following a school-based mass de-worming exercise involving administration of Praziquantel (PZQT) and Albendazole (ADZ) against LF and SCH at Komenda-Edina-Eguafo-Abirem (KEEA) Municipal.
METHODOLOGY: After fulfilling all ethical obligations, a total of 598 students aged 5-20 years who received PZQT or ADZ monotherapy or a combination of the two (PZQT + ADZ) as part of the mass de-worming exercise were recruited through quota and random sampling. Bodyweight and height of students were measured and body mass index (BMI) calculated. Students were orally interviewed to obtain information such as age, sex, intake of diet before taking drugs. Subsequently, students were monitored over 24 hours post-MDA for cases of ADEs. Descriptive statistics and logistic regression analysis using SPSS version 26 was used to describe data collected and to determine associations between incidence of ADEs and predictor variables. PRINCIPAL
FINDINGS: Out of the 598 students, 243 (40.64%) represented by 124 males (51.03%) and 119 females (48.97%) with mean (SD) age of 13.43 (2.74) years experienced one or more forms of ADE. In decreasing order, the detected ADEs included headache (64.6%), Abdominal pain (48.6%), fever (30.0%), diarrhea (21.4%) and itching (12.8%). Multivariable statistical analysis showed that age 5-9 years (OR: 2.01, p = 0.041) and underweight (OR: 2.02, p = 0.038) were associated with incidence of ADEs. Compared with students who received combination therapy, students who received ADZ only (OR: 0.05, p < 0.001) and PZQT only (OR: 0.26, p < 0.001) had low cases of ADEs. Gender and diet intake before MDA were not associated with ADE incidence.
CONCLUSION: ADE incidence was common among students in the KEEA municipality. Age, underweight, and double dosing were associated with increase in ADE incidence, while gender and food intake were not associated with increase in ADE incidence. The Disease Control Unit of the Ghana Health Service should incorporate stringent ADE monitoring in post-MDA surveillance in the National MDA program in order to be able to detect, manage and report ADEs to inform planning for future MDA programs. Such initiatives will help not only in improving effectiveness of MDA programs but also identify high risk groups and exact strategies to reduce negative influence of ADE on MDA coverage and anthelminthic drug compliance.

Introduction

Helminth infections in humans are dominated by schistosomiasis, lymphatic filariasis and soil-transmitted helminthiasis and they afflict vulnerable populations although mortality is rare [1]. It is estimated that more than 200 million people are afflicted with schistosomiasis worldwide, with 85% of those cases in Sub-Saharan Africa [2,3]. Also, it is reported that over 1.2 billion people live in lymphatic filariasis endemic regions with approximately 25% suspected to be suffering from the infection [4,5]. Helminth infections have devastating health consequences for the infected populations, mostly children. For example, helminthic infections negatively affect physical and intellectual development of children. Also, helminth infections may affect population, particularly health bills of individuals and even quality of work [4]. Most affected countries use MDA programs to treat and manage helminthic infections among highly susceptible populations such as school-going children. Although helminthic infections afflict all age groups, but children are more susceptible not only due to their developing immune system but also due to their natural tendency to play which mostly expose them to infective stages of helminths, particularly, soil transmitted helminths. Year in year out, the clock is ticking for the completion of the Sustainable Development Goal 3 (SDG 3), target 3.3 (which aims to sustainably end the epidemics of AIDS, tuberculosis, malaria and neglected tropical diseases [NTDs] and combat hepatitis, water-borne diseases and other communicable diseases by year 2030) [6,7], which has necessitated the need to increase both MDA and coverage of highly co-endemic communities.

In the year 2000, the World Health Organization (WHO) launched the Global Programme to Eliminate Lymphatic Filariasis (GPELF) and the core aim was to disrupt the transmission cycle of W. bancrofti and Brugia spp. through annual MDA to the most at-risk populations for a period of 5–6 years. Eighty-one countries were found to be endemic from year 2000. By the year 2012, 73 countries were endemic, with 120 million people infected, over 1.4 billion people at risk, and 40 million people affected by LF-related morbidity [8]. Among the first countries to implement MDA was Ghana. For instance, the Ghana Filariasis Elimination Programme was birthed in 2000 [6,8] and the annual MDA was strictly based on the WHO guidelines for countries that are co-endemic for lymphatic filariasis and other helminthic infections [8]. Central to the strategy was the recommendation for the use of ivermectin (IVM) and ADZ treatments to be undertaken every year for identified endemic populations with antigen prevalence above 1% [8]. In Ghana implementation of these guidelines have suffered many challenges that necessitated review.

Conventionally, schistosomiasis, lymphatic filariasis and onchocerciasis are treated by using ADZ, PZQT, IVM, and mebendazole [9]. MDA has proven useful in many countries that prioritize its use. In helminth-endemic countries, mass de-worming among school children is mostly used as a cost-effective strategy to enhance school attendance [10,11]. In a study to assess the impact of seven years of MDA against Schistosoma haematobium infection in Zanzibar, a significant decline in prevalence was observed from 3.9% in 2011 to 0.4% in 2020 among adults and a decline from 6.6% in 2012 to 1.2% in 2019 among school children [12]. Similarly, MDA compliance was attributed to decrease in the prevalence of lymphatic filariasis in Nepal [13], Egypt [14] and Tanzania [15]. In view of these gains, mass de-worming among school children remains a major treatment/management program to contain helminthic infections in many developing countries including Ghana.

Anthelminthic drugs used in MDA programs are without side effects. For instance, school going children sometimes suffer choking [3] and other ADEs such as headache, itching, abdominal pain, body weakness and dizziness from administration of ADZ and PZQT [16,17]. Fear for ADEs associated with MDA is considered a major factor that contribute to low MDA participation [6,18,19]. These drawbacks impact negatively on MDA effectiveness with respect to compliance with anthelminthic drug ingestion especially when school children or their guardians does the administration [20]. Advanced countries and some emerging economies that subscribe to MDA to manage helminthic infections do have post-MDA surveillance programs to monitor ADEs associated with MDA in order to effectively manage them to ensure patient safety [21]. Most developing countries in Sub-Saharan Africa including Ghana are commonly faced with inadequate expertise, financial and technical resources needed to undertake comprehensive MDA exercise to halt transmission of helminthic parasites in disease (schistosomiasis and lymphatic filariasis)-endemic communities. As a result, post-MDA surveillance in these countries are often limited to efficacy assessment of the anthelminthic drugs used in the MDA exercise [22]. An unintended consequence is that rare or common ADEs that are highly probable with the use of anthelminthic drugs during MDA exercise go unmonitored despite the fact that ADEs contribute to low MDA coverage [18,23,24]. Therefore, there is the need to assess the nature and incidence of ADEs as well as factors that contribute to ADE incidence in disease-endemic communities.

This study assessed ADEs associated with mass administration of ADZ and PZQT either as monotherapy or combination therapy among school children in KEEA Municipality, Ghana. The present study has the potential to add to accumulating evidence that support the need for policy makers to review the current annual MDA program to include post-MDA ADE monitoring at least for the first 24 hours post-MDA.

Methods

Ethics statement

The study was approved by the Disease Control Unit of the Ghana Health Service who were undertaking MDA exercise at the schools and the Ghana Education Service, Central Region. The school authorities gave verbal consent for the study to be undertaken after having been informed of the purpose and importance of the study. All students were invited to participate after verbal informed consent from their parents and guardians had been obtained. Confidentiality, and anonymity were guaranteed during and after the study.

Study design and population

Under the National Disease Control Programme, children in primary and junior high schools in endemic Districts and Municipalities receive oral administration of ADZ and PZQT as treatment against lymphatic filariasis and schistosomiasis annually. This study was conducted in November 2016 alongside the annual MDA exercise at the KEEA Municipality in an effort to monitor incidence of ADEs and possible factors that contribute to ADEs. Four public schools (Islamic junior high school and primary, Anglican junior high school and primary, Elmina M/A junior high school and primary, and Catholic Boys junior high school and primary) which were part of the MDA program were randomly selected. From the four schools, students aged 5–20 years in both Primary and junior high schools, permanently residing in communities in the KEEA Municipality with parent/guardian consent to participate were recruited into the study. Students with existing medical conditions or known allergy to the ADZ and PZQT were excluded from the study. The protocol for the drug administration program and the study were based on WHO guidelines for community-based implementation of schistosomiasis and soil transmitted helminths control programs [25].

Sample size calculation

The study adopted quota and random sampling methods to select participants for the study. To undertake the quota sampling technique, the number of students in each school was obtained from school managements. The total population of students in the 4 selected schools, according to the school’s records was 3,815. The sample size was calculated as described previously [26,27]. Briefly, a sample size of 498 was determined based on an estimate of incidence of ADEs of 39.2% from a previous study [28], a population size of 3,819, an acceptable margin of error of 4% and a confidence interval of 95%, using the StatCalc function of Epi Info software, Version 7.2.4.0 (Center for Diseases Control, Atlanta, Georgia, USA, and World Health Organization, Geneva, Switzerland). To make up for sampling errors, nonparticipation and missing information, a final sample size of 598 students were recruited for the study. Based on the relative number of students in each school, a proportion of participants was calculated for each of the schools as follows: Islamic junior high school and primary 128, Anglican junior high school and primary 160, Elmina M/A junior high school and primary 178, and Catholic Boys junior high school and primary 132. The respective students were then randomly sampled from each of the schools for the study.

Study area

This study was conducted in the KEEA municipal (Fig 1) in the Central Region of Ghana. KEEA municipality covers an area of 452 km2 and is located between longitude 1° 20′ West and 1° 40′ West and latitude 5° 05′ North and 5° 15′ North. There are five sub-districts namely Kissi, Elmina, Komenda, Ankaful and Agona sub-districts. The municipality has an estimated population of 144,705, with 69,665 (48.1%) being males and 75,040 (51.9%) females. It is estimated that 35,225 children in the municipality are in primary and junior high school. The majority of the people (70%) in the municipality reside in the rural areas with poor road and transport network. Poor access to safe water coupled with lack of proper sanitation, bathing and toilet facilities in this area contributes to a high prevalence of soil-transmitted helminthiasis especially in infants and pre-school children [29].

Fig 1

Map of Komenda Edina Eguaafo Abirem (KEEA) Municipality.

(The map was created by the authors).

Drug administration

Doses of ADZ and PZQT were administered according to WHO-dose pole format in which dosing is required to be based on height. Although the WHO-dose pole has been used for the past 20 years and validated in multiple populations, recent reports have questioned its accuracy especially when used in groups whose height and bodyweight do not correlate [30]. The present study used the updated format [30,31]. After measurement of bodyweight and height of students by health professionals from the Disease Preventive Unit, Ghana Health Service, Central Region, students were subsequently given doses of ADZ and PZQT (donated by Merck KGaA, Darmstadt, Germany) based on bodyweight and height. Weight and heights of students were measured prior to administration of drugs. Drugs were administered to students at their schools during first (10 am– 11 am in the morning) and second (1 pm– 2 pm) break periods. Each student was given one tablet of ADZ (400 mg). PZQT (40 mg/kg) dose was determined by using the height of students according to WHO-dose pole format [30] and the District Health Directorate’s guidelines as follows: 94–109 cm received 1 tablet (40 mg/kg); 110–124 cm received 1½ tablets (60 mg/kg); 125–137 cm received 2 tablets (80 mg/kg); 138–149 cm received 2½ tablets (100 mg/kg); 150–159 cm received 3 tablets (120 mg/kg); 160–177 cm received 4 tablets (160 mg/kg) and ≥ 178 cm received 5 tablets (200 mg/kg). Some students were given a combination of both drugs. The original plan for the drug administration was to co-administer ADZ and PZQT against lymphatic filariasis and schistosomiasis one drug after the other 3 hours apart in line with WHO guidelines [25]. However, some students experienced immediate adverse effects after taking the first dose of ADZ. For such students, the second drug was not given. Co-administration of PZQT and ADZ has been reported to be efficacious and safe for the control of schistosomiasis and soil-transmitted helminthiasis in areas where both infections are endemic [25,32].

Interview and measurements

Students were randomly selected after MDA and interviewed. Under our guidance and that of their teachers, students were made to answer few questions including: age, sex, intake of diet before taking drugs and whether they experienced any adverse effects such as headache, fever, cough, dizziness, diarrhea, abdominal pains, or vomiting/nausea within 24 hours of drug intake. Additionally, body weight and height were measured and body mass index (BMI) calculated. BMI of students were classified as follows: underweight (< 18.5 kg/m2), normal weight (18.5–24.9 kg/m2), overweight (25–29.9 kg/m2), or obesity (> 30 kg/m2) [33]. Any adverse events experienced by the students immediately after taking the drugs up to 24 hours after drug intake were observed and recorded by the researchers with the assistance of the health personnel involved in the administration of the drugs.

Safety monitoring and ADEs management

Health personnel at health facilities in the study area were trained in handling possible adverse events as a result of drug administration. The documented self-reported and observed adverse effects of the two drugs were discussed during the training. A physician was available at the district hospital to attend to emergencies. Fortunately, the immediate ADEs experienced by students were mild and transient, and did not require any medical intervention.

Statistical analysis

Categorical variables were described as numbers and percentages (%) and continuous variables were described as the mean and standard deviation (SD). The Shapiro–Wilk test was used to verify normality. Differences between groups were assessed by a 2-sample t test for normally distributed continuous variables, the Mann–Whitney U test for non-normally distributed continuous variables, and the Chi-square or Fisher exact test for categorical variables. Bivariable analysis and Logistic regression models were used to examine the significant risk factors associated with ADEs. Data was first collected into Microsoft Excel and analysed using SPSS version 26.0 (Statistical Package for the Social Sciences, Chicago, IL USA) with GraphPad Prism 8 (GraphPad Software, San Diego, CA, USA) being used to generate figures. All tests were 2-tailed with p-values < 0.05 considered statistically significant in all analysis.

Results

General characteristics of study participants

A total of 598 students (mean age: 13.56 ± 2.57 years) who took part in the MDA program at the study area and satisfied the inclusion criteria were involved in the study. Out of this number, 306 (51.2%) were males, 231 (38.6%) were in primary school with 367 (61.4%) in junior high school. The average height, weight and BMI of students recruited into the study were 144 ± 16.55 cm, 44.88 ± 11.60 kg and 22.16 ± 7.21 Kg/m2 respectively with females being significantly taller (145.60 ± 15.55 vs 142.47 ± 17.34, p = 0.021) and heavier (45.94 ± 11.23 vs 43.87 ± 11.86, p = 0.029) than males. Based on gender, no significant difference in terms of age, class and BMI was observed among the students. Majority 527/598 (88.1%) of the students ate before the MDA (Table 1).

Table 1

General characteristics of study participants.

Characteristics	Total (n = 598)	Male (n = 306)	Female (n = 292)	P-value
Mean age (years)	13.56 ± 2.57	13.58 ± 2.63	13.54 ± 2.51	0.834
Age group n (%)				0.609
5–9	41 (6.9)	23 (56.1)	18 (43.9)
10–14	300 (50.2)	148 (49.3)	152 (50.7)
15–20	257 (43.0)	135 (52.5)	122 (47.5)
Class				0.480
Primary	231 (38.6)	114 (49.4)	117 (50.6)
Junior high school	367 (61.4)	192 (52.3)	175 (47.7)
Height (cm)	144.00 ± 16.55	142.47 ± 17.34	145.60 ± 15.55	0.021
Bodyweight (Kg)	44.88 ± 11.60	43.87 ± 11.86	45.94 ± 11.23	0.029
BMI (Kg/m 2 )	22.16 ± 7.21	22.19 ± 7.45	22.13 ± 6.95	0.929
BMI groups n (%)				0.126
Underweight	50 (8.4)	23 (46.0)	27 (54.0)
Normal weight	342 (57.2)	173 (50.6)	169 (49.4)
Overweight	72 (12.0)	31 (43.1)	41 (56.9)
Obese	134 (22.4)	79 (59.0)	55 (41.0)
Eaten prior to drug intake				0.673
Yes	527 (88.1)	268 (50.9)	259 (49.1)
No	71 (11.9)	38 (53.5)	33 (46.5)

BMI—body mass index (calculated as weight in kilograms divided by height in meters squared).

Administration of drugs was based on students’ height in accordance with WHO dose-pole guidelines. Table 2 summarizes distribution of students with respect to treatment with ADZ and PZQT either as monotherapy or combination therapy. Almost half the total number of students 291/598 with slight female bias received combination therapy. Most of the students received PZQT monotherapy compared to ADZ monotherapy.

Table 2

Drug administration for participants at the selected schools.

Drug dose	Schools				Total (N = 598)
	Islamic school (N = 128)	Anglican school (N = 160)	Elmina M/A (N = 178)	Catholic boys (N = 132)
ADZ only
1 tablet	24 (18.8)	9 (5.6)	12 (6.7)	23 (17.4)	68 (11.4)
PZQT only
1 tablet	0 (0.0)	0 (0.0)	6 (3.4)	1 (0.8)	7 (1.2)
1.5 tablets	0 (0.0)	2 (1.3)	13 (7.3)	0 (0.0)	15 (2.5)
2 tablets	3 (2.3)	3 (1.9)	25 (14.0)	17 (12.9)	48 (8.0)
2.5 tablets	5 (3.9)	19 (11.9)	33 (18.5)	20 (15.2)	77 (12.9)
3 tablets	4 (3.1)	4 (2.5)	20 (11.2)	19 (14.4)	47 (7.9)
4 tablets	5 (3.9)	1 (0.6)	20 (11.2)	16 (12.1)	42 (7.0)
5 tablets	0 (0.0)	0 (0.0)	3 (1.7)	0 (0.0)	3 (0.5)
ADZ and PZQT Combination therapy
(1)(1)	1 (0.8)	9 (5.6)	3 (1.7)	0 (0.0)	13 (2.2)
(1.5)(1)	2 (1.6)	16 (10.0)	4 (2.2)	0 (0.0)	22 (3.7)
(2)(1)	10 (7.8)	28 (17.5)	9 (5.1)	7 (5.3)	54 (9.0)
(2.5)(1)	12 (9.4)	36 (22.5)	21 (11.8)	12 (9.1)	81 (13.5)
(3)(1)	30 (23.4)	15 (9.4)	5 (2.8)	12 (9.1)	62 (10.4)
(4)(1)	30 (23.4)	15 (9.4)	4 (2.2)	5 (3.8)	54 (9.0)
(5)(1)	2 (1.6)	3 (1.9)	0 (0.0)	0 (0.0)	5 (0.8)

(1) (1): (One tablet of PZQT) (One tablet of ADZ)

(1.5) (1): (One and a half tablet of PZQT) (One tablet of ADZ)

(2) (1): (two tablets of PZQT) (One tablet of ADZ)

(2.5) (1): (Two and a half tablets of PZQT) (One tablet of ADZ)

(3) (1): (Three tablets of PZQT) (One tablet of ADZ)

(3.5) (1): (Three and a half tablets of PZQT) (One tablet of ADZ)

(4) (1): (Four tablets of PZQT) (One tablet of ADZ)

(4.5) (1): (Four and a half tablets of PZQT) (One tablet of ADZ)

(5) (1): (Five tablets of PZQT) (One tablet of ADZ)

ADZ–Albendazole; PZQT–Praziquantel

ADE incidence

Of 598 students observed, 243 (40.64%; 124 males [51.03%]; 119 females [48.97%]; mean [SD] age, 13.43 [2.74] years) experienced one or more forms of ADE. The 243 students experienced 431 individual ADEs, an average of 1.8 ADEs per student. Of those who experienced ADEs, headache was the most reported 157 (64.6%) while itching 31 (12.8%) was the least reported among students (Fig 2A). None of the ADEs reported was fatal. Of the students who experienced ADEs, 172 (70.78%) complained of multiple ADEs with majority of students reporting abdominal pain and headache 44 (25.58%) but few reports for headache and itching 30 (17.44%) (Fig 2B).

Fig 2

ADEs reported by the students.

(A) kinds of ADEs commonly reported by students. (B) Multiple post-treatment ADEs reported by students. A—abdominal pains; D—diarrhea; F—fever; H—headache; I–itching.

Factors that contribute to ADE incidence during MDA

A number of factors were identified to be significant risk factors for the incidence of ADEs among students when data was subjected to bivariate and logistic regression analysis. As summarized in Table 3, ADE incidence was significantly common among students aged 6–10 years 24/41 (58.5%), attending Islamic primary and junior high school 79/128 (61.7%), underweight 24/50 (48.0%) and those who were given a combination therapy 173/291 (59.5%), and 2.5 tablets of PZQT 27/77 (35.1%). In a multivariable logistic regression, risk of ADE remained significantly associated with students aged 6–10 year (OR: 2.01, p = 0.041); and highest among students attending Islamic junior high school (OR: 4.65, p < 0.001) or Anglican primary and junior high school (OR: 3.44, p < 0.001). The risk of ADE was 2.02 times likely to occur among students who were underweight compared to obese students. Students who received combination therapy (ADZ and PZQT) were more likely to experience an ADE than those who received monotherapy (either ADZ only or PZQT only). Food consumption before MDA was not associated with ADE incidence.

Table 3

Relationship between Students’-related factors and the risk of adverse drug events based on bivariable and multivariable logistic analysis.

Variable	Total	No. (%) with ADEs	Chi square p-value	OR (95% CI)	P-Value
Age Category			0.037
5–9	41	24 (58.5)		2.01 (1.03–3.93)	0.041
10–14	300	113 (37.7)		0.86 (0.61–1.21)	0.389
15–20	257	106 (41.2)		1
Gender			0.954
Male	306	124 (40.5)		0.99 (0.72–1.37)	0.954
Female	292	119 (40.8)		1
School			<0.001
Islamic primary and JHS	128	79 (61.7)		4.65 (2.74–7.88)	<0.001
Anglican primary and	160	87 (54.4)		3.44 (2.09–5.66)	<0.001
Elmina M/A primary and JHS	178	43 (24.2)		0.92 (0.55–1.54)	0.747
Catholic Boys Primary and JHS	132	34 (25.8)		1
Class			0.164
Primary	231	102 (44.2)		1.27 (0.91–1.77)	0.165
JHS	367	141 (38.4)		1
BMI Classification			0.012
Underweight	50	24 (48.0)		2.02 (1.04–3.93)	0.038
Normal weight	342	154 (45.0)		1.79 (1.18–2.74)	0.007
Overweight	72	23 (31.9)		1.03 (0.56–1.90)	0.929
Obese	134	42 (31.3)		1
Drug Intake			<0.001
ADZ only	68	5 (7.4)		0.05 (0.02–0.14)	<0.001
PZQT only	239	65 (27.2)		0.26 (0.18–0.37)	<0.001
ADZ and PZQT combination therapy	291	173 (59.5)		1
ADZ Only
1 tablet	68	5 (7.4)
PZQT Only			0.009
1 tablet	7	0 (0.0)		-	-
1.5 tablets	15	4 (26.7)		-	-
2 tablets	48	14 (29.2)		-	-
2.5 tablets	77	27 (35.1)		-	-
3 tablets	47	11 (23.4)		-	-
4 tablets	42	6 (14.3)		-	-
5 tablets	3	3 (100)		-	-
ADZ and PZQT combination therapy			0.237
(1)(1)	13	6 (46.2)		1
(1.5)(1)	22	11 (50.0)		1.17 (0.30–4.61)	0.826
(2)(1)	54	28 (51.9)		1.26 (0.37–4.23)	0.713
(2.5)(1)	81	45 (55.6)		1.46 (0.45–4.72)	0.529
(3)(1)	62	42 (67.7)		2.45 (0.73–8.25)	0.148
(4)(1)	54	38 (70.4)		2.77 (0.80–9.55)	0.106
(5)(1)	5	3 (60.0)		1.75 (0.22–14.22)	0.601
Eaten prior to drug intake			0.113
No	71	35 (49.3)		1
Yes	527	208 (39.5)		0.67 (0.41–1.10)	0.115

- = not calculable. ADEs–Adverse drug effects; BMI—body mass index (calculated as weight in kilograms divided by height in meters squared); OR—odds ratio; CI–Confidence interval; JHS—Junior high school; ADZ–Albendazole; PZQT—Praziquantel

(1) (1): (One tablet of PZQT) (One tablet of ADZ)

(1.5) (1): (One and a half tablet of PZQT) (One tablet of ADZ)

(2) (1): (Two tablets of PZQT) (One tablet of ADZ)

(2.5) (1): (Two and a half tablets of PZQT) (One tablet of ADZ)

(3) (1): (Three tablets of PZQT) (One tablet of ADZ)

(3.5) (1): (Three and a half tablets of PZQT) (One tablet of ADZ)

(4) (1): (Four tablets of PZQT) (One tablet of ADZ)

(4.5) (1): (Four and a half tablets of PZQT) (One tablet of ADZ)

(5) (1): (Five tablets of PZQT) (One tablet of ADZ)

Discussion

This study assessed the incidence of ADEs among students after mass administration of ADZ and PZQT either as monotherapy or combination therapy in randomly selected schools in the KEEA Municipal, Central Ghana. An ADE incidence of 40.6% (243/598) post-MDA was recorded, most of which were multiple and occurred within the first few hours after drug administration. Headache and abdominal pain were the most reported ADEs. Age, underweight and double dosing (administration of two or more drugs at the same time or combination therapy) were associated with ADE incidence, whiles eating before MDA and gender were not associated with ADE incidence. These observations from the present study perhaps indicate that ADE incidence is a common phenomenon experienced by students in the study area and could be the case for other MDA exercises where ADE monitoring does not form part of post-MDA surveillance. Comparatively, observations made from the present study somewhat corroborate other studies conducted in similar settings whiles at the same time appear to contrast with others.

For instance, the recorded ADE incidence of 40.6% and was found to be higher compared to ADE incidence reported from other countries with similar disease-endemicity and population characteristics. Example, in Kenya, 186 pupils from schools in Ndia community who were orally dosed with ADZ (400 mg) and PZQT (40 mg/kg) reported ADE incidence of 39.2% [28]. Similarly, two separate studies from Sri Lanka reported 7.5% and 12.6% (estimated from 160 and 2,319 dosed study subjects respectively) ADE incidences after study subjects were administered diethylcarbamazine and ADZ [34,35]. In Recife, a Brazilian community, an ADE incidence of 23.6% was reported [36]. Also, an ADE incidence of 25% was reported when Wucheraria bancrofti infected individuals were administered triple dose of IVM, diethylcarbamazine and ADZ [37]. In India, a triple (IVM, diethylcarbamazine and ADZ) and double (diethylcarbamazine and ADZ) dosed study subjects (4,758 and 4,160 respectively) reported 8.3% and 6.4% ADE incidences [38]. In Papua New Guinea, triple dosed (IVM, diethylcarbamazine and ADZ) study subjects reported ADE incidence of 20% whiles those who received double (diethylcarbamazine and ADZ) dose reported an ADE incidence of 18% [39].

In another development the estimated ADE incidence was relatively lower compared to ADE incidence of 83% recorded among students from two Kenyan communities [40,41]. Also, a study that systematically reviewed 55 studies on ADEs post-MDA reported a median ADE incidence > 60% among microfilariae infected individuals [42]. Clearly, there exist variation in ADE incidence even from studies conducted in communities with similar disease and population characteristics. Such disparities in ADE incidence from one study to the other is generally expected given the high heterogeneity in study characteristics such as sample size, sampling method, type of anthelminthic drug, anthelminthic drug combinations (double or triple therapy), anthelminthic dose, expertise level of the investigators, intensity of infection, infection stage, timing of post-MDA surveillance as well as other unspecified host factors. For instance, whiles ADE incidence was common in 5–9 year groups in the present study, a similar study among students identified 7–16 year groups as having more immediate and delayed ADEs when they were dosed orally with ADZ and PZQT [43].

Increase in MDA coverage is one of the main objectives of every succesful MDA excercise in lymphatic filariasis and schistosomiasis co-endemic communities [44]. However, increase in MDA coverage in disease-endemic communities has not reflected in a proportionate increase in anthelminthic drug compliance. This gap between MDA coverage and anthelminthic drug compliance has been attributed largely to negative perceptions about ADEs associated with MDAs, particularly fear of ADEs [44-47]. Therefore, monitoring of ADEs post-MDA and proper eductation of community members on common ADEs associated with MDA prior to MDA exercise may improve anthelminthic drug compliance for effective treatment/management of lymphatic filariasis and schistosomiasis. In the present study, headache, abdominal pain, itching, fever and vomiting were the main ADEs reported by students who received ADZ and PZQT simultaneously. It is interesting to note that the observed ADEs were not much different from those reported in previous studies across disease-endemic countries. For instance, in 2011, Anto and colleagues had reported in a study from northern Ghana that headache was the most reported ADE when study subjects ingested a triple dose of ADZ, PZQT and IVM [48], indicating that mild ADEs such as headache may be commonly associated with multiple anthelminthic drug therapy. The spectrum of ADEs observed in the present study mirrors that of a previous study which reported abdominal pain, headache, itching, fever, vomiting, nausea and diarrhea when patients suffering from hydatid infection were administered with ADZ and PZQT [49], perhaps indicating that these spectrum of ADEs may be associated with PZQT and ADZ co-administration. The spectrum of ADEs was high among students who ingested PZQT only than those who ingested ADZ only, and this observation agrees with a number of reports. Example, Jaoko and colleagues had reported abdominal pain, headache, nausea, dizziness and fever in a study in Southeastern Kenya involving school pupils who ingested PZQT [43]. Similarly, Berhe and colleagues had reported abdominal cramps, bloody diarrhoea, dizziness and vomiting in a study in Ethiopia, when school children were given oral PZQT [50]. In Haiti, headache, dizziness and abdominal pain were the 3 most reported ADEs whiles in India, fever, headache and dizziness were the commonly reported ADEs following ingestion of PZQT [38,51]. Also, a report from Kenya indicate that ADEs are common with PZQT ingestion than ADZ ingestion [28]. Further, ADE bias to PZQT ingestion as observed in the present study corroborates observations made by Olds and colleagues who had reported that ingestion of PZQT by school children produced abdominal pain and bloody diarrhoea few hours after administration [41]. As a result, Olds and colleagues speculated that those ADEs could be directly linked with PZQT due to its bioavailability [41]. This assertion had been supported by an earlier report showing that ingestion of crushed PZQT tablets (40 mg/Kg) by pre-school children produced moderately severe ADEs, mostly body and face inflammation [52], suggesting that crushing of PZQT tablets perhaps increased its absorption and bioavailability. Most students reported two or more ADEs and this observation agrees with an earlier report that showed that most individuals reported multiple ADEs during post-MDA survellance [40] and this observation is expected because of systemic exposure of anthelminthic drugs which may exert many off-target effects. It should be pointed out that ADEs reported in the present study were general in nature unlike that of a study which reported that ADEs were limited to the gastrointestinal system when students ingested PZQT and ADZ [53]. Clearly, ADEs reported in the present study and that of other studies in Africa indicate that ADEs are treatment-related, drug-related, dose-dependent and also common with all MDA exercises irrespective of the geographical location of the communities, suggesting that health policy makers should review MDAs to include pre-MDA education of communities on ADEs as well as tailored treatment for ADEs during and after MDA execercises.

Age, underweight, and double dosing were associated with ADE incidence while gender and food intake were not associated with increase in ADE incidence. It was observed that students aged between 5–9 years had more ADEs compared to other age groups suggesting that perhaps younger students are more likely to experience ADE, an observation which contrasts with an earlier report which indicated that ADE incidence increases with age [54]. In view of this, perhaps more studies should be done to ascertain the relationship between age of children and ADE incidence post-MDA. Gender was not associated with ADE incidence in sharp contrast with a study which reported that gender differences were related to ADE incidence [54]. It is established that intake of food before or concurrently with drugs may have a significant effect on the pharmacokinetics of the drugs particularly their absorption, distribution, bioavailability, metabolism and elimination [55]. For instance, bioavailability of ADZ and PZQT is shown to be influenced by intake of high-fat foods prior to drug administration [56] which means that the net effect of these two drugs which depends on their bioavailability could be influenced by food intake. Students who ate before oral administration of ADZ and PZQT reported comparatively a lower ADE incidence relative to those who did not eat before drug administration (Table 3). It is possible that poor absorption due to lack of food in the stomach as the case may be among those students who did not eat prior to drug administration contributed to more ADEs that were related to gastrointestinal tract including abdominal pain and vomiting. Although there was a difference with respect to ADE incidence for those students who ate and those who did not before drug administration, however, this difference was statistically insignificant. Nonetheless, as long as those who ate recorded a lower ADE incidence suggest that perhaps food intake may decrease ADE incidence among students and therefore food intake may be considered as a mandatory pre-condition for anthelminthic drug administration during MDA exercise.

Limitations of the study

The findings of the present study should be considered in the light of these limitations. First, the study focused on ADEs 24 hours post-MDA, therefore ADEs that occurred beyond 24 hours post-MDA could not be tracked, which could be a possible source of underestimation of the ADE incidence. Secondly, despite attempts to standardize the coding and recording of ADEs, some side effects may have been misclassified or gone unnoticed, especially in the occasional chaotic settings in which children were de-wormed. Thirdly, selection of study sites was determined by drug distribution schedules, and awareness of the routine of ongoing de-worming activity at the municipality, therefore, it is unclear the degree to which our findings are representative of other sites, even within KEEA municipality. Lastly, sample size for the study may be inadequate to assess factors for certain ADEs, and there may be confounding variables that were not accurately removed. Nonetheless the present study has shown that ADEs are associated with PZQT and ADZ use in mass treatment of lymphatic filariasis and schistosomiasis in the study area which needs to be addressed.

Conclusion

ADE incidence post-MDA was high among students in the KEEA Municipality. Age, underweight, and double dosing were associated with ADE incidence, while gender and food intake were not associated with increase in ADE incidence. Given that fear for ADEs associated with MDA is considered a major factor that contribute to low MDA coverage, it is suggested that the Disease Control Unit of the Ghana Health Service incorporate measures including feeding of students prior to MDA, ensure ADE monitoring post-MDA for the first 72 hours, manage and report ADEs among high risk groups. More importantly monitoring of ADEs post-MDA should be done in time blocks (preferably 6 hours intervals over three days post-MDA) in order to identify rare, common, immediate and delayed ADEs. Finally, health policy makers should review MDAs to include pre-MDA education of communities on ADEs as well as tailored treatment for ADEs that may arise during and after MDA execercises.

11 Sep 2021

Dear Dr Boye,

Thank you very much for submitting your manuscript "Adverse drug effects among school pupils following mass de-worming exercise involving administration of praziquantel and albendazole in KEEA Municipal, Ghana" for consideration at PLOS Neglected Tropical Diseases. As with all papers reviewed by the journal, your manuscript was reviewed by members of the editorial board and by several independent reviewers. They found manuscript interesting but raised various concerns in methodology (study instrument validation, sampling technique, analysis) and interpretation of results. Please also refer to the attached files.In light of the reviews (below this email), we would like to invite the resubmission of a significantly-revised version that takes into account the reviewers' comments. We cannot make any decision about publication until we have seen the revised manuscript and your response to the reviewers' comments. Your revised manuscript is also likely to be sent to reviewers for further evaluation.

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Associate Editor

PLOS Neglected Tropical Diseases

Jennifer Keiser

Deputy Editor

PLOS Neglected Tropical Diseases

***********************

Dear Authors, thank you for submitting in PLOS NTD. Your manuscript has been assessed by relevant experts from the field. They found manuscript interesting but raised various concerns in methodology (study instrument validation, sampling technique, analysis) and interpretation of results. It is requested to please consider the comments of reviewers.

Reviewer's Responses to Questions

Key Review Criteria Required for Acceptance?

As you describe the new analyses required for acceptance, please consider the following:

Methods

-Are the objectives of the study clearly articulated with a clear testable hypothesis stated?

-Is the study design appropriate to address the stated objectives?

-Is the population clearly described and appropriate for the hypothesis being tested?

-Is the sample size sufficient to ensure adequate power to address the hypothesis being tested?

-Were correct statistical analysis used to support conclusions?

-Are there concerns about ethical or regulatory requirements being met?

Reviewer #1: Methods

Excellent methodology; however, authors should include the study protocol if there any use for the data collection, how the interview conducted and what are the questions asked? However, it is only a suggestion that authors include a supplementary file or an appendix.

2.1. Ethical Consideration

“The study was approved by the Diseases Control Unit of Ghana Health Service who were 106 undertaking the mass drug administration exercise at the schools and Ghana Education Service 107 (Central Region)”

Please mentioned ethical approval number with year

All school pupils were invited to participate….please update people to students throughout the manuscript.

Reviewer #2: Somewhat

Reviewer #3: The points below are the main comments (but not limited to):

‎1. Lines 117-118 (Study area):‎ ‎The number of primary students ‎‎(25,299) is more than two times higher than pupils at ‎junior high school (9,926). However, in the present study, the proportion of Juniors is ‎higher (61.4%). So, the sample size is not representative for the population.‎

‎2. Lines 122-129 (Study Population):‎ The authors stated that the total study number taken was 598 school pupils, and they ‎were ‎randomly selected. Also, in the abstract authors reported using a multi-stage ‎stratified sampling technique. The design and sample strategy process were not clear, authors did not ‎mention how did they choose the schools from the 4 communities? How did they choose ‎the primary students ‎and junior students from each school and each community?‎

‎3. The authors did not provide any information about the sample size calculation?‎

‎4. It is not known when the study was conducted, no date? ‎

‎5. Since it is a mass-deworming activity (no diagnosis needed), the authors did not clarify why ‎some school pupils received a combination ‎of both drugs while others did not?‎

‎6. Line 123 (study population): age included 5-19 years. However, in table 3, there is a group for ‎ages 16-20 years.‎

Reviewer #4: Are the objectives of the study clearly articulated with a clear testable hypothesis stated?

Yes.

Is the study design appropriate to address the stated objectives? Is the population clearly described and appropriate for the hypothesis being tested?

The study design and duration of the study are missing. how the four primary and junior high schools residing in the 4 communities were selected and how the 598 samples were proportionally allocated to these four primary and junior high schools is not clear. Clarification required on these statements.

Is the sample size sufficient to ensure adequate power to address the hypothesis being tested?

Yes.

How the reported adverse drug events were classified as mild, moderate and severe is missing in the manuscript. Needs definition under the method section.

Are there concerns about ethical or regulatory requirements being met?

Yes. All requirements met.

Reviewer #5: • Your methods section although was almost complete, it was not organized and needs to be reorganized and completed to simplify the understanding of this section:

�  Start your methods section with the first paragraph which could be titled “Study design and population” where you indicate the design for the study and restating the purpose of the study. In this paragraph you will briefly indicate the site or location where the study was conducted, how the data were collected, your targeted population (by age and level in school), the medication that were administered, and how did you do the monitoring. This paragraph will help you introduce the reader to your following sections of the methods. Then, your “Ethical Consideration” section will be kept as is. The following two sections should be the “Study Area” and “Study Population”. The following sections should be “Drug Administration”, “Interview and Measurements”, “Safety Monitoring and Adverse Drug Events Management”, and “Statistical Analysis”.

�  In page 5, in the “Study Population” section: Reorganize this section to start with the justification why these studies were selected (currently the last sentence in the paragraph). Then, indicate the actual number of primary and junior high schools where data were collected before listing these schools’ names. Also, the number of students should not be mentioned in here as this should part of your results.

�  In page 5, in the “Drug Administration” section: I didn’t understand if all pupils should receive both medications or either one and why there would be discrepancy among the pupils in receiving the medication from the same MDA program. I saw that in the results as well, some pupil received both medications and others didn’t, you need to describe this in your methods. Also, this needs to be described in more details on how these medications were administered by the MDA program? Administered at home or in school, both tablets at the same time or a tablet on each day or ….? This would make a difference in the interpretation of your results. This should be adjusted then this adjustment should be reflected on the rest of the manuscript.

�  In page 5, in the “Interview and Measurements” section: you need to indicate when the actual data collection was conducted as it relates to the day of MDA in the school.

�  In page 5, your “Statistical Analysis” section needs major revision and reorganization. You may start with the descriptive data analysis, followed by the inferential statistics and try to make it more specific. Then you need to provide your sample size calculation. Then, the level of significance for the study can be listed. Finally, you may end up by the statistical software that were used in your analysis.

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Results

-Does the analysis presented match the analysis plan?

-Are the results clearly and completely presented?

-Are the figures (Tables, Images) of sufficient quality for clarity?

Reviewer #1: Results: I do not have any comments for this section.

Reviewer #2: Yes

Reviewer #3: ‎7. Table 1:‎

A. In the combination therapy cells, (4tablets) (1 tablet), row number 6, the total number ‎‎of students who received it is 54, however, the number of males 28, and females 38 ‎giving a different number of 66.

‎

B. The percentages for all rows equal 100% but for (4tablets) (1 tablet), row number six, ‎for males 51.9% and females 61.3% (114.2%). Not to say that Chi-square test results ‎‎(percentages) are not adequately presented. More elaboration on this point next.‎

‎8. The name of tests performed in the headnotes or footnotes of tables are not available.‎

The major contradictions presented in the study:‎

‎1.‎ For tables 2, 3, 4, the percentages for chi-square results are presented incorrectly and ‎‎therefore there are major flaws in its presentation. To clarify this point please see table 4, ‎the ‎association between food intake and side effects. In the table, the total number for ‎those who eat ‎and experience side effects is “74 (72.5%)” and those who do not eat and ‎experienced side ‎effects is “28 (27.5%)”. However, going back to table 1, the total ‎number of those who do not ‎eat is 71 and those who do not eat and experienced side ‎effects is 28 (table 4) so 28/71 ‎equals 39%, meaning 39% of those who did not eat have ‎experienced side effects. On the other ‎hand, the total number of those who eat is 527 (table 1), ‎and those who eat and experience side ‎effects are only 74 (table 4), so that means that 74/527 ‎‎(14% ) of those who eat experience side effects. ‎This is a different and contradicting ‎conclusion to the authors' results’ presentation where they stated ‎in lines 210-211 that ‎‎“Majority (72.5%) 74/102 of those who reported adverse effects were pupils ‎who ate ‎prior to drug intake”. Also, in the abstract line 28-29 “it was quite common among 10 -‎‎14 ‎years age group and higher among pupils who ate before taking the drugs”.‎

‎2.‎ Also the same thing for age groups. line 28-29 “it was quite common among 10 -14 years ‎age ‎group”. However, when we do proper calculation we find that side effects were more ‎common ‎among the age category 5-9. Because the total number of students at this age as ‎shown in table 1 ‎is 41, the number of side effects among this age group as shown in table ‎‎2 is 24 so 24/41 equals ‎‎58%. On the other hand, the total number of students at 10-14 ‎years old in table 1 is 300. The total side effects for ‎the 10-15 age category among ‎primary school and junior high school in table 2 and 3 is 156. So ‎the percentage will be ‎‎156/300 equals 52%. It is worth mentioning that when authors reported ‎side effects ‎among primary and junior students they use different classifications of age and I ‎included ‎the students aged 15 years and their experience side effects. This means that if we ‎remove ‎students who experience side effects and were aged 15 to match 10-14 age category in table 1 we will get even a lower ‎percentage than 52%.‎‎‎

‎3.‎ Lines 24-25 “Over one-third (243/598) of pupils who received the drugs complained of ‎at least ‎one form of an adverse drug effect” and Lines 216-217 “Among 243 pupils ‎who experienced ‎adverse effects; majority reported headache (64.6%) while a few ‎reported itching (12.8%) ‎‎(Figure 2)”. According to the authors 243 pupils “complained of ‎at least one form of an adverse drug ‎effect”. However. In figure 2 A, 118 students ‎experience abdominal pain, 157 experience ‎headaches, 52 diarrhea, 73 increase in ‎temperature, 31 itchings. So the total number of students ‎who experience at least one ‎form of side effects is 431 (73% of all students), which is a totally different number. Not only this, but in ‎figure 2B also, ‎the total number of students who experience more than one side effect equal 261, ‎higher than 243 number.‎

‎4.‎ Similarly, another contradicting result. For example, in figure 2A those who ‎experience at least ‎diarrhea was 52 (they experience it alone or together with ‎other side effects). However, in figure 2B, for those who experience diarrhea + other ‎‎side effects, the total is 106 students. How come that the number of those who ‎‎experience at least diarrhea in figure 2A is lower than than the number of students ‎who experience ‎diarrhea+other side effects in figure 2B !!!!!

‎5.‎ Table 5: Drug-specific post-treatment adverse effects among pupils.

In this table, the ‎total number ‎of adverse effects for all medications for both males and females is 178 ‎which is different from the total number reported in the results’ text, and different ‎from the figures, a ‎new number!!!‎

Reviewer #4: Are the results clearly and completely presented?

The information like, how many of the pupils develop mild, moderate and severe adverse drug events is missing and how long the adverse drug events lasted is not known. Any intervention measures to manage those undesired events are missing. Clarification is required on the above statements.

Reviewer #5: • The results section:

�  In page 6, line 160: the sentence needs revision “A total of 598 Basic school pupils were recruited into the MDA program” this cannot be true. If you included all patients that received the medication and they total only 598 pupils then this is not an MDA. You need to revise this statement.

�  In the results section, you don’t restate the numbers from the tables you rather need to focus on the important number only.

�  Whenever you conduct inferential statistics, you need to interpret the results from these tests and report it whenever its significant. Otherwise, don’t conduct the analysis that you can not interpret its meaning. This was true for the results of the “Praziquantel only (Tablet)” in table 1, if you don’t know the interpretation of this analysis then just remove the p-values from the table as this has minimal to no value in your study and it is not your objective.

�  In page 8, line 188-189: the use of “post drug administration” give the reader a false sense that there were pupils that had ADE before drug administration or that you have monitored a control group who didn’t receive medication.

�  The comparison between male and female was not the purpose of the study but you kept comparing between them with no much value for the reader.

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Conclusions

-Are the conclusions supported by the data presented?

-Are the limitations of analysis clearly described?

-Do the authors discuss how these data can be helpful to advance our understanding of the topic under study?

-Is public health relevance addressed?

Reviewer #1: Yes, conclusion supported by the data presented

Reviewer #2: Yes

Reviewer #3: The conclusion and discussion was based on incorrect data presentation. So, need to be re-written.

Reviewer #4: The conclusion of the study should be supported by the results reported in the manuscript.

Reviewer #5: �  Due to the flaws in the analyses and presentation of the results, the authors were not able to construct informative discussion and conclusion section for the reader.

�  The limitation section should address all the actual limitations in the study. The efficacy of the medication was not your objective so it is not a limitation in your study.

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Editorial and Data Presentation Modifications?

Use this section for editorial suggestions as well as relatively minor modifications of existing data that would enhance clarity. If the only modifications needed are minor and/or editorial, you may wish to recommend “Minor Revision” or “Accept”.

Reviewer #1: (No Response)

Reviewer #2: (No Response)

Reviewer #3: (No Response)

Reviewer #4: Thank you for the opportunity to review this paper. The team are required to do a major revision.

Reviewer #5: (No Response)

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Summary and General Comments

Use this section to provide overall comments, discuss strengths/weaknesses of the study, novelty, significance, general execution and scholarship. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. If requesting major revision, please articulate the new experiments that are needed.

Reviewer #1: Thank you for giving me the opportunity to review this manuscript. This is a very well written and easy to follow manuscript. I really liked the study findings and how they are reported. I would like to congratulate the authors on conducting this study in one of our key school going students in Low and middle income countries (LMIC) such as Ghana and raising much-needed voice.

I have some suggestions and queries that will help improve the quality of the manuscript. I am sure you will not be disappointed by the end product once these changes have been made.

Abstract: The abstract is a little bit confusing. Please clearly state what do you want your readers to know and what is the key message in your abstract. For example, what do you want Disease Control Unit of the Ghana Health Service institute monitoring ADRs?

Also needs to be change, school pupils can be changed into school going students?

Introduction: Is it appropriate to discuss the significance of the study? What is the study's rationale? Previous literature from Ghana and school going students from other countries, if such data is available. Please highlight in the introduction part.

Please utilise current references; for example, references 3, 5, and 7 were published in 1997 and should be updated.

3. R. J. Stoltzfus, M. Albonico, J. M. Tielsch, H. M. Chwaya and L. Savioli, "School-based 335 deworming program yields small improvement in growth of zanzibari school children after one 336 year," The Journal of Nutrition, vol. 127, no. 11, pp. 2187-2193, 1997.

5. P. K. Das, K. D. Ramaiah, D. J. Augustin and A. Kumar, "Towards elimination of lymphatic 342 filariasis in india," Trends in parasitology, vol. 17, no. 10, pp. 457-460, 2001.

7. N. De Silva, H. Guyatt and D. Bundy, "Morbidity and mortality due to ascaris-induced 346 intestinal obstruction," Transactions of the Royal Society of Tropical Medicine and Hygiene, vol. 347 91, no. 1, pp. 31-36, 1997.

Methods

Excellent methodology; however, authors should include the study protocol if there any use for the data collection, how the interview conducted and what are the questions asked? However, it is only a suggestion that authors include a supplementary file or an appendix.

2.1. Ethical Consideration

“The study was approved by the Diseases Control Unit of Ghana Health Service who were 106 undertaking the mass drug administration exercise at the schools and Ghana Education Service 107 (Central Region)”

Please mentioned ethical approval number with year

All school pupils were invited to participate….please update people to students throughout the manuscript.

Results: I do not have any comments for this section.

Discussion:

Where is the study strength? as the limitations shows separately, make it as separate heading.

References: Please review formatting of references - again particularly for consistency with Journal title.

Please ensure that someone independent and highly proficient in written English has thoroughly checked/edited your revised submission.

Reviewer #2: PLOS neglected tropical disease,

Reviewer comments

The research by Wisdom Akrasi and colleagues is an interesting piece of work on adverse effects of the commonly used de-worming drugs considered to be safe for ages.

The conclusion supports the objective of the paper.

I have some questions and suggestions that might help improve the publication.

Title: long, may you revise to make it concise

Introduction:

well narrated

The authors in the last paragraph said “In Ghana and most African countries, adverse events following mass drug administration are rarely monitored and recorded.” This statement is expected to reflect the intention of the study. Given that the drugs are widely used for deworming for ages in one hand due to their established safety profile, why you carried the current study. Is there any published study that alerts the need for monitoring? Especially in African children? In your introduction i did not found a clear argument for such important questions to be answered. Please enrich your quest for the study. In line, please also check your statement at line 90 “major set-back in using these drug……”

Methods

Ethical consent issued should be clarified further.

Study area: you better narrate the type and prevalence of NTDs in the municipality preferably in this section, or other appropriate section.

I did not find the study period.

What is the study design? The sample estimation methods were not clear as well. How about the sampling technique? How and what type of randomization applied? Why multistage? How about the inclusion and exclusion criteria? For instance, Line 145 says “….immediately after taking the medication up to the following two days.” How about before taking the medications.

Line 150 you said “A study physician was available at the district hospital to attend to emergencies.” Why? How many emergency admissions encountered? What was the role of the study physician? Hoping this is not a planning phase, these and related questions are expected to be answered with your statement. Please clarify your purpose and the occurrences. For instance your statement at the conclusion section stated here can be complimented with such clarifications “Although these adverse effects were transient and mild, they should not be overlooked during future…..”

Result:

What does this statement mean “A total of 598 Basic school pupils were recruited into the MDA program” Are you the one who recruited the MDA targets? Were the 598 children the MDA targets or the samples for safety study? If the MDA recruits, where is your sampling?

You said those receiving 2.5 gm of PZQT had shown more side effects than the other doses administered. Why do you think this happened? I did not see major explanations. This should better be discussed well in your next submission.

Discussion:

Line 267: You said “Even though the efficacy of both drugs against intestinal worms was not ascertained in this study, their adverse effects give a vivid evidence of the extent of their bioavailability” Since your stud is not a pharmacokinetic study, I did not agree with this statement.

I believe, the limitation of the study has to be addressed beyond the efficacy assessment. Please consider all possible limitations of your work to enable future researches in the area.

Reviewer #3: Generally, results presentation, interpretation, and conclusion need to be re-done. The same thing for discussion as many of ‎the major contradicting results have been discussed inadequately. I give here one example in lines ‎‎236-237 (but not limited to). Authors reported that “the highest frequency was observed in the 10–14 age group similar ‎to reports from Ethiopia [23]”. However, in the present study age 5-9 has more side effects ‎rate than 10-14 years and that the incorrect data presentation and interpretation lead to incorrect conclusion and discussion‎.

Reviewer #4: In general, the problem statement is not well stated (the need to monitor and document these adverse effects). The method section should be revised rigorously: study design employed, when and for how long the study conducted, how the samples were allocated proportionally to the selected schools and appropriateness of the statistical analysis used to determine association between variables (e.g., incidence of adverse drug events and food intake). It is not clear how the authors handle the reported adverse effects, including any medication used to manage these adverse effects.

Reviewer #5: (No Response)

--------------------

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Reviewer #1: No

Reviewer #2: Yes: Getachew Alemkere

Reviewer #3: No

Reviewer #4: No

Reviewer #5: No

Figure Files:

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. 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.

Data Requirements:

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Reproducibility:

To enhance the reproducibility of your results, we recommend that 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. Additionally, PLOS ONE offers an option to publish peer-reviewed clinical study protocols. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols

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Submitted filename: Comments to the author for PNTD-D-21-01133.pdf

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10 Jan 2022

Submitted filename: RESPONSE LETTER.docx

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20 Mar 2022

Dear Dr Boye,

Thank you very much for submitting your manuscript "Adverse Drug Events Among Students Following Mass De-Worming Exercise Involving Administration Of Praziquantel And Albendazole In KEEA Municipality, Ghana" for consideration at PLOS Neglected Tropical Diseases. As with all papers reviewed by the journal, your manuscript was reviewed by members of the editorial board and by several independent reviewers. In light of the reviews (below this email), we would like to invite the resubmission of a significantly-revised version that takes into account the reviewers' comments.

We cannot make any decision about publication until we have seen the revised manuscript and your response to the reviewers' comments. Your revised manuscript is also likely to be sent to reviewers for further evaluation.

When you are ready to resubmit, please upload the following:

[1] A letter containing a detailed list of your responses to the review comments and a description of the changes you have made in the 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.

[2] Two versions of the revised manuscript: one with either highlights or tracked changes denoting where the text has been changed; the other a clean version (uploaded as the manuscript file).

Important additional instructions are given below your reviewer comments.

Please prepare and submit your revised manuscript within 60 days. If you anticipate any delay, please let us know the expected resubmission date by replying to this email. Please note that revised manuscripts received after the 60-day due date may require evaluation and peer review similar to newly submitted manuscripts.

Thank you again for your submission. We hope that our editorial process has been constructive so far, and we welcome your feedback at any time. Please don't hesitate to contact us if you have any questions or comments.

Sincerely,

Tauqeer Hussain Mallhi, Ph.D

Associate Editor

PLOS Neglected Tropical Diseases

Jennifer Keiser

Deputy Editor

PLOS Neglected Tropical Diseases

***********************

Reviewer's Responses to Questions

Key Review Criteria Required for Acceptance?

As you describe the new analyses required for acceptance, please consider the following:

Methods

-Are the objectives of the study clearly articulated with a clear testable hypothesis stated?

-Is the study design appropriate to address the stated objectives?

-Is the population clearly described and appropriate for the hypothesis being tested?

-Is the sample size sufficient to ensure adequate power to address the hypothesis being tested?

-Were correct statistical analysis used to support conclusions?

-Are there concerns about ethical or regulatory requirements being met?

Reviewer #4: (No Response)

Reviewer #5: Very much improved in term of clarity and organization.

--------------------

Results

-Does the analysis presented match the analysis plan?

-Are the results clearly and completely presented?

-Are the figures (Tables, Images) of sufficient quality for clarity?

Reviewer #4: (No Response)

Reviewer #5: Your results section is much improved and became more meaningful.

Note: avoid saying “students used for the study ….” You can say “students included in the study …” or “students participated in the study…”.

--------------------

Conclusions

-Are the conclusions supported by the data presented?

-Are the limitations of analysis clearly described?

-Do the authors discuss how these data can be helpful to advance our understanding of the topic under study?

-Is public health relevance addressed?

Reviewer #4: (No Response)

Reviewer #5: The conclusion in the text is limited compared to the conclusion in the abstract.

The limitations is clearly described.

The implication of the findings and the public health relevance is not fully addressed and can be improved.

--------------------

Editorial and Data Presentation Modifications?

Use this section for editorial suggestions as well as relatively minor modifications of existing data that would enhance clarity. If the only modifications needed are minor and/or editorial, you may wish to recommend “Minor Revision” or “Accept”.

Reviewer #4: (No Response)

Reviewer #5: Most of these general points were previously indicated but was not addressed by the authors:

In page 6, line 163: the word “Majority” and “Municipality” should be with small letter.

In page 7, lines 177-183: in the sentence “Each student was given one (1) tablet of albendazole …” we know that one is (1), you don’t have to restate it into parenthesis. Just keep “one” in this case and the same is true in the following sentences.

In page 7, lines 180-183: the word “Tablet” or “Tablets” should be with small letter.

In page 6 lines 162-163: the words “primary”, “junior high”, and “school” does not have to be started with capital letters. Only the name of the school should be started with Capital letter. This was the case in the result section as well, so you need to adjust it everywhere in your manuscript.

In page 9, line 224: “Body Mass Index (BMI)” this should be body mass index (BMI) but since it was mentioned in the methods then you should use the abbreviation directly.

In page 15, line 305: “Neglected Tropical Diseases (NTDs)” was defined twice in the same paragraph.

In page 15, line 306: What do you mean by basic schools? I think schools should be fine.

The manuscript may benefit from a revision by language editing service to improve the writing and flow of the paragraphs.

In page 16, line 346: “increase in body temperature (fever)” you don’t have to define fever. Everyone knows what fever means.

--------------------

Summary and General Comments

Use this section to provide overall comments, discuss strengths/weaknesses of the study, novelty, significance, general execution and scholarship. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. If requesting major revision, please articulate the new experiments that are needed.

Reviewer #4: The comments were corrected thoroughly.

Thank you all in advance.

Reviewer #5: The paper explored the incidence and type of adverse drug effects or events (ADE) among school pupils in KEEA Municipality of Ghana after mass drug administration in an effort to fight lymphatic filariasis and schistosomiasis. The study presented significant findings about the incidence of ADE. Although the authors’ revision has improved the manuscript, I think this still need to be revised to make this manuscript good for readers.

--------------------

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Reviewer #4: No

Reviewer #5: No

Figure Files:

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. 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.

Data Requirements:

Please note that, as a condition of publication, PLOS' data policy requires that you make available all data used to draw the conclusions outlined in your manuscript. Data must be deposited in an appropriate repository, included within the body of the manuscript, or uploaded as supporting information. This includes all numerical values that were used to generate graphs, histograms etc.. For an example see here: http://www.plosbiology.org/article/info%3Adoi%2F10.1371%2Fjournal.pbio.1001908#s5.

Reproducibility:

To enhance the reproducibility of your results, we recommend that 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. Additionally, PLOS ONE offers an option to publish peer-reviewed clinical study protocols. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols

Submitted filename: Comments to the Editor and the author for PNTD-D-21-01133 R1 to authors.docx

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6 May 2022

Submitted filename: RESPONSE LETER.docx

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29 May 2022

Dear Dr Boye,

Thank you very much for submitting your manuscript "Adverse Drug Events Among Students Following Mass De-Worming Exercise Involving Administration Of Praziquantel And Albendazole In KEEA Municipality, Ghana" for consideration at PLOS Neglected Tropical Diseases. As with all papers reviewed by the journal, your manuscript was reviewed by members of the editorial board and by several independent reviewers. In light of the reviews (below this email), we would like to invite the resubmission of a significantly-revised version that takes into account the reviewers' comments.

Dear authors, thank you for revising the draft. There are still some concerns raised by the reviewers in the manuscript. Please refer to the attached files too. The referees are suggesting to improve the writing as well as methodological shortcomings in this manuscript.

We cannot make any decision about publication until we have seen the revised manuscript and your response to the reviewers' comments. Your revised manuscript is also likely to be sent to reviewers for further evaluation.

When you are ready to resubmit, please upload the following:

[1] A letter containing a detailed list of your responses to the review comments and a description of the changes you have made in the 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.

[2] Two versions of the revised manuscript: one with either highlights or tracked changes denoting where the text has been changed; the other a clean version (uploaded as the manuscript file).

Important additional instructions are given below your reviewer comments.

Please prepare and submit your revised manuscript within 60 days. If you anticipate any delay, please let us know the expected resubmission date by replying to this email. Please note that revised manuscripts received after the 60-day due date may require evaluation and peer review similar to newly submitted manuscripts.

Thank you again for your submission. We hope that our editorial process has been constructive so far, and we welcome your feedback at any time. Please don't hesitate to contact us if you have any questions or comments.

Sincerely,

Tauqeer Hussain Mallhi, Ph.D

Associate Editor

PLOS Neglected Tropical Diseases

Jennifer Keiser

Deputy Editor

PLOS Neglected Tropical Diseases

***********************

Dear authors, thank you for revising the draft. There are still some concerns raised by the reviewers in the manuscript. Please refer to the attached files too. The referees are suggesting to improve the writing as well as methodological shortcomings in this manuscript.

Reviewer's Responses to Questions

Key Review Criteria Required for Acceptance?

As you describe the new analyses required for acceptance, please consider the following:

Methods

-Are the objectives of the study clearly articulated with a clear testable hypothesis stated?

-Is the study design appropriate to address the stated objectives?

-Is the population clearly described and appropriate for the hypothesis being tested?

-Is the sample size sufficient to ensure adequate power to address the hypothesis being tested?

-Were correct statistical analysis used to support conclusions?

-Are there concerns about ethical or regulatory requirements being met?

Reviewer #5: (No Response)

Reviewer #6: (No Response)

Reviewer #7: No

Reviewer #8: The method section clearly stated the objectives, the study design was appropriate to address the stated objectives. The population clearly stated and appropriated and sample size sufficient to ensure adequate power to address the hypotheses . Correct statistical analysis were used and no concerns about ethical or regulatory requirements.

Reviewer #9: -Are the objectives of the study clearly articulated with a clear testable hypothesis stated? : Yes, the study objectives are clearly stated although I have my reservations about the 'testability' of the hypothesis. Just because an individual experiences any effect after a drug is administered, does not mean that the effect was caused by the drug, especially for several of the very non-specific signs and symptoms usually reported in pharmacovigilance studies like the ones reported by this study's authors. Hence the need for something known as 'causality assessments' (e.g. the WHO-UMC system) which is a whole different ballgame, but which can help to produce really good quality evidence. The other thing is I think what the authors refer to as adverse drug events are actually just side effects (these words are used interchangeably but are not the same)

-Is the study design appropriate to address the stated objectives?: I am not sure especially as the authors did not provide in depth details as to exactly how the students were monitored for 24 hours after the MDA and how the 'ADEs' were defined. This study was conducted in school aged children who would have needed to go home after school hours, so how exactly were they monitored and data collected? Were the ADEs self reported by the participants or directly observed by the data collectors? How were the ADES defined, was 'fever' objectively measured with a thermometer or self reported? the same thing for 'diarrhea', how many loose stools did participants need to report before they were classed as having 'diarrhea' etc. Were the students asked to report any symptoms they experienced or shown a list of expected symptoms and asked whether they experienced any on the list (which could be a source of bias) etc. All these details need to be added in the 'interviews and measurements' subsection of the manuscript

-Is the population clearly described and appropriate for the hypothesis being tested?: Yes.

-Is the sample size sufficient to ensure adequate power to address the hypothesis being tested? Yes, I think so. Although I'm not sure why the authors used 4% as their margin of error instead of 5%, and why they used 3819 in their sample size calculation when the total number of students in the selected schools was 3815.

-Were correct statistical analysis used to support conclusions?. Yes.

-Are there concerns about ethical or regulatory requirements being met?: No. Although, the authors should include the actual approval numbers in their manuscript.

--------------------

Results

-Does the analysis presented match the analysis plan?

-Are the results clearly and completely presented?

-Are the figures (Tables, Images) of sufficient quality for clarity?

Reviewer #5: (No Response)

Reviewer #6: (No Response)

Reviewer #7: Yes

Reviewer #8: The results are clear and well presented, analysis presented matches the plan

Reviewer #9: Does the analysis presented match the analysis plan?: Yes

-Are the results clearly and completely presented?: Yes

-Are the figures (Tables, Images) of sufficient quality for clarity?: Yes.

--------------------

Conclusions

-Are the conclusions supported by the data presented?

-Are the limitations of analysis clearly described?

-Do the authors discuss how these data can be helpful to advance our understanding of the topic under study?

-Is public health relevance addressed?

Reviewer #5: (No Response)

Reviewer #6: (No Response)

Reviewer #7: No

Reviewer #8: The conclusions support the data presented, limitations clearly described and authors discussed how these data can be helpful. Public health is relevance and has been addressed.

Reviewer #9: -Are the conclusions supported by the data presented?: Yes

-Are the limitations of analysis clearly described?: Yes.

-Do the authors discuss how these data can be helpful to advance our understanding of the topic under study?: Yes

-Is public health relevance addressed?: Yes

--------------------

Editorial and Data Presentation Modifications?

Use this section for editorial suggestions as well as relatively minor modifications of existing data that would enhance clarity. If the only modifications needed are minor and/or editorial, you may wish to recommend “Minor Revision” or “Accept”.

Reviewer #5: (No Response)

Reviewer #6: (No Response)

Reviewer #7: No

Reviewer #8: A few grammar error and omission such as line 101," it should read not without side effects"

Reviewer #9: (No Response)

--------------------

Summary and General Comments

Use this section to provide overall comments, discuss strengths/weaknesses of the study, novelty, significance, general execution and scholarship. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. If requesting major revision, please articulate the new experiments that are needed.

Reviewer #5: (No Response)

Reviewer #6: This manuscript is titled " Adverse Drug Events Among Students Following Mass De-Worming Exercise Involving Administration Of Praziquantel And Albendazole In KEEA Municipality, Ghana" At KEEA Municipality, Ghana, the authors examined the ADEs associated with mass administration of ADZ and PZQT either as monotherapy or in combination therapy among school students. Results showed that Students in the KEEA Municipality's designated schools had an unusually high number of ADEs after their MDA.

Overall, this is a well-written manuscript. However, the authors make any contribution to the research literature in this area of investigation.

Specific comments/inquiries are below:

No additional comments at this stage

Reviewer #7: No

Reviewer #8: A well written manuscript, that addresses a relevant and important issue.

Reviewer #9: 1. Why is the abstract in the manuscript submission system different from the one currently attached to the body of the manuscript? Did the authors forget to update the abstract in the manuscript submission system after the initial review?

2. Minor English language editing may also be necessary for some portions of the manuscript E.g. Line 12: Use ‘Many’ instead of ‘Most’, Line 101: 'not' is missing, Tables 1 and 3: 'ate' instead of eaten and so on.

3. Please note that there is no need to refer again to your results in the discussion section. Therefore all references to tables 1 and 3 etc. in the discussion section can be taken out. Similarly, percentages and/ proportions already reported in the results section e.g. lines 307 and 317 can also be taken out.

4. The paragraph starting from line 354 can be edited for clarity. How exactly does the pharmacokinetics of albendazole explain its ADE profile?

--------------------

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 #5: No

Reviewer #6: No

Reviewer #7: No

Reviewer #8: No

Reviewer #9: No

Figure Files:

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. 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.

Data Requirements:

Please note that, as a condition of publication, PLOS' data policy requires that you make available all data used to draw the conclusions outlined in your manuscript. Data must be deposited in an appropriate repository, included within the body of the manuscript, or uploaded as supporting information. This includes all numerical values that were used to generate graphs, histograms etc.. For an example see here: http://www.plosbiology.org/article/info%3Adoi%2F10.1371%2Fjournal.pbio.1001908#s5.

Reproducibility:

To enhance the reproducibility of your results, we recommend that 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. Additionally, PLOS ONE offers an option to publish peer-reviewed clinical study protocols. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols

Submitted filename: Reviewer Comments 24 5 22.docx

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Submitted filename: Comments to the author for PNTD-D-21-01133 R2 to authors.docx

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22 Jun 2022

Submitted filename: RESPONSE LETTER.docx

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20 Jul 2022

Dear Dr Boye,

We are pleased to inform you that your manuscript 'Adverse Drug Effects Among Students Following Mass De-Worming Exercise Involving Administration Of Praziquantel And Albendazole In KEEA Municipality, Ghana' has been provisionally accepted for publication in PLOS Neglected Tropical Diseases.

Before your manuscript can be formally accepted you will need to complete some formatting changes, which you will receive in a follow up email. A member of our team will be in touch with a set of requests.

Please note that your manuscript will not be scheduled for publication until you have made the required changes, so a swift response is appreciated.

IMPORTANT: The editorial review process is now complete. PLOS will only permit corrections to spelling, formatting or significant scientific errors from this point onwards. Requests for major changes, or any which affect the scientific understanding of your work, will cause delays to the publication date of your manuscript.

Should you, your institution's press office or the journal office choose to press release your paper, you will automatically be opted out of early publication. We ask that you notify us now if you or your institution is planning to press release the article. All press must be co-ordinated with PLOS.

Thank you again for supporting Open Access publishing; we are looking forward to publishing your work in PLOS Neglected Tropical Diseases.

Best regards,

Tauqeer Hussain Mallhi, Ph.D

Academic Editor

PLOS Neglected Tropical Diseases

Jennifer Keiser

Section Editor

PLOS Neglected Tropical Diseases

***********************************************************

Reviewer's Responses to Questions

Key Review Criteria Required for Acceptance?

As you describe the new analyses required for acceptance, please consider the following:

Methods

-Are the objectives of the study clearly articulated with a clear testable hypothesis stated?

-Is the study design appropriate to address the stated objectives?

-Is the population clearly described and appropriate for the hypothesis being tested?

-Is the sample size sufficient to ensure adequate power to address the hypothesis being tested?

-Were correct statistical analysis used to support conclusions?

-Are there concerns about ethical or regulatory requirements being met?

Reviewer #5: (No Response)

Reviewer #8: The methods addresses the objectives, study design, population, sample size and the analysis appropriately

Reviewer #9: Please see my comments to the editor below

**********

Results

-Does the analysis presented match the analysis plan?

-Are the results clearly and completely presented?

-Are the figures (Tables, Images) of sufficient quality for clarity?

Reviewer #5: (No Response)

Reviewer #8: The analysis presented matched the plan, results were clearly and completely presented and figures and tables were of sufficient quality and clarity

Reviewer #9: Please see my comments to the editor below

**********

Conclusions

-Are the conclusions supported by the data presented?

-Are the limitations of analysis clearly described?

-Do the authors discuss how these data can be helpful to advance our understanding of the topic under study?

-Is public health relevance addressed?

Reviewer #5: (No Response)

Reviewer #8: The conclusions were supported by the data presented, limitations of analysis were clearly described and authors described how data can be helpful to advance understanding of the topic. Public health relevance was addressed.

Reviewer #9: Please see my comments to the editor below

**********

Editorial and Data Presentation Modifications?

Use this section for editorial suggestions as well as relatively minor modifications of existing data that would enhance clarity. If the only modifications needed are minor and/or editorial, you may wish to recommend “Minor Revision” or “Accept”.

Reviewer #5: The paper now is much better than than the last three versions. However, this needs language revision as the writing of many part of this can be improved and benefit from language revision.

Reviewer #8: None

Reviewer #9: (No Response)

**********

Summary and General Comments

Use this section to provide overall comments, discuss strengths/weaknesses of the study, novelty, significance, general execution and scholarship. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. If requesting major revision, please articulate the new experiments that are needed.

Reviewer #5: (No Response)

Reviewer #8: This is a much improved manuscript, findings worth publishing

Reviewer #9: (No Response)

**********

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 #5: No

Reviewer #8: No

Reviewer #9: No

8 Sep 2022

Dear Dr Boye,

We are delighted to inform you that your manuscript, " Adverse Drug Effects Among Students Following Mass De-Worming Exercise Involving Administration Of Praziquantel And Albendazole In KEEA Municipality, Ghana ," has been formally accepted for publication in PLOS Neglected Tropical Diseases.

We have now passed your article onto the PLOS Production Department who will complete the rest of the publication process. All authors will receive a confirmation email upon publication.

The corresponding author will soon be receiving a typeset proof for review, to ensure errors have not been introduced during production. Please review the PDF proof of your manuscript carefully, as this is the last chance to correct any scientific or type-setting errors. Please note that major changes, or those which affect the scientific understanding of the work, will likely cause delays to the publication date of your manuscript. Note: Proofs for Front Matter articles (Editorial, Viewpoint, Symposium, Review, etc...) are generated on a different schedule and may not be made available as quickly.

Soon after your final files are uploaded, the early version of your manuscript will be published online unless you opted out of this process. The date of the early version will be your article's publication date. The final article will be published to the same URL, and all versions of the paper will be accessible to readers.

Thank you again for supporting open-access publishing; we are looking forward to publishing your work in PLOS Neglected Tropical Diseases.

Best regards,

Shaden Kamhawi

co-Editor-in-Chief

PLOS Neglected Tropical Diseases

Paul Brindley

co-Editor-in-Chief

PLOS Neglected Tropical Diseases