AMINO IMSTC 2021 Vol 1 (Scientific Paper) by AMSA-Indonesia

AMINO AMSA-Indonesia Competition Archive

Academic Competition IMSTC 2021: Vol 1

All the works publicized here are the works of AMSA-Indonesia’s member who participated in Indonesian Medical Students’ Training and Competition 2021

AMINO | IMSTC 2021

TABLE OF CONTENTS Scientific Paper ● First Winner Larvicidal Activity Against Anopheles sp. and Ecotoxicological Evaluation of Green-synthesized Silver Nanoparticles as A Promising Vector Control Agent to Halt Mosquito-borne Disease in Rural Countries: A Systematic Review ● Second Winner Comparing Different Medications in Combating Strongyloides stercoralis Infection : A Systematic Review and Meta-Analysis

● Third Winner The Curative Innovation of Novel Triple-Drug Compared to Double-Drug Regimen in 39 Lymphatic Filariasis: A Systematic Review ● Finalists ■ The Correlation between School’s Hygiene Level, Environmental Sanitation, and Soil Contamination towards Intestinal Worm Infection Prevalence in Public Elementary School Students at Kedungkandang, Malang ■ Assessment of The Effectiveness of the Point-Of-Care Circulating Cathodic Antigen Test as A Diagnostic Tool for Schistosomiasis Infection in Children Under the Age of Six: A Systematic Review ■ Mapping of Soil-Transmitted Helminth Infection Prevalence and Its Relationship with Students’ Knowledge, Soil Contamination at Home and School in Public Elementary School Kedungkandang, Malang ■ Association Of Leprosy-Related Burden To Mental Health Problems Of Leprosy Patients For Better Management Of Leprosy: A Systematic Review ■ Comparing the Effectiveness of Vaccine and Gene Recombination of Anopheles sp. in Preventing Malaria: A Review of Literature ■ Proposed Mechanism for Wolbachia-mediated DENV Blocking in Ae. aegypti: A Systematic Review

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AMINO | IMSTC 2021 ● Entries ■ Determination of the Drug of Choice for Mass Drug Administration and Suppression of Growth Impairment in Children with Helminthiasis: A Systematic Review and Meta-Analysis ■ A Systematic Review of the Efficacy and Safety of Triple Drug Therapy (Diethylcarbamazine, Ivermectin, Albendazole) for Lymphatic Filariasis ■ The Efficiency and Safety of the Vaccine M72/AS01 as a Mean to Prevent Active Pulmonary Tuberculosis For M. Tuberculosis-Infected Adults That Are Tested HIV Positive and Negative: A Systematic Review ■ The Role of Molecular Quantitative PCR as An Alternative Tool to Increase Sensitivity and Prevalence in Diagnosis of Soil-Transmitted Helminthiasis Compared to Microscopy-based Kato-Katz Technique in Low Prevalence Settings in Asia-Africa Regions: A Systematic Review ■ Anaemia and Hepatomegaly Associated with Mortality Rate in Patients with Malaria : A Literature Review ■ The Assessment of The Safeness, Effectiveness, and Efficacy of Carica Papaya Leaf Extract Consumption as A Comprehensive Alternative Thrombocytopenia Therapeutic Application to Reduce Mortality Caused by Dengue Haemorrhagic Fever with Thrombocytopenia In Tropical States : A Systematic Review of Randomized Controlled Studies ■ Effectiveness of Using Recombinant Antigen for Pig Vaccination as a Potential Method for Controlling Taenia Solium Transmission to Humans in Cysticercosis: A Systematic Review ■ Effectiveness of Amikacin with Combination of Other Antibiotics as Treatment for Actinomycetoma: A Systematic Review ■ Systematic Review of the Impact of Mass Drug Administration for the Elimination of Lymphatic Filariasis in Endemic Areas ■ Assessment of the Bacillus Calmette Guerin (BCG) Vaccine Effectiveness in Mycobacterium Leprae Infection As Consideration for Leprosy Immunoprophylaxis Targeted to Close Contacts of Leprosy Patients: A Systematic Review ■ The Use Of Calamansi As A Spray To Overcome The Dengue Fever Caused By Larva Proliferation ■ The Effectiveness of Corticosteroids as a Means of Treatment for Nerve Function Impairment in Patients Diagnosed with Leprosy: A Systematic Review ■ The Effectiveness of Chimeric Yellow Fever Dengue - Tetravalent Dengue Vaccine (CYD-TDV) as An Efficacious Prevention for Dengue Fever in Asian and American Countries: A Systematic Review of Randomized Control Trial Studies

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219 226

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248 259 269

281 292

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AMINO | IMSTC 2021 ■ The Role of T-Cell Immunoglobulin and Mucin Domain 3 (TIM3) Blockade Signalling Enhances Cell Mediated Immunity Against Malaria : Systematic Review ■ Biochemical Analysis on Mycobacterium tuberculosis Diagnosis: A Systematic Review ■ The Performance of Serological Tests of Anti-PGL1, Anti-NDO-LID, and Anti-MMP-II for Early Detection in Individuals with Household Contact with Leprosy in Indonesia: A Literature Review ■ Observation on: "One Health Approach in Tackling Tropical Diseases and Future Pandemics" ■ Thymoquine in Nigella Sativa as A Treatment in Leprosy Patients to Prevent Erythema Nodusum Leprosum (ENL) Reaction: A Literature Review ■ The Use of Digital Health in Enhancing Medical Adherence and Reducing Stigma of Leprosy Patients ■ Development of Indonesia Public Health System to Overcome Filariasis Holistically by Preventive, Curative, and Rehabilitative Ways in The Medical Field ■ mRNA Vaccine For Covid-19 With Terpenes Peptide As An Inhibitor And Nanoparticle As A Protein Delivery ■ Ways to Ameliorate Unending Leprosy Cases in Indonesia: A Literature Review ■ What is Wrong Filariasis Control and Prevention In Indonesia? A Literature Review ■ Analysis Of Indonesia Prevention And Control Program Towards Rabies, What’s Wrong In The Implementation? A Literature Review ■ Ocimum Sanctum Linn. (Holy Basil Or Tulsi) As A Potential Natural Anthelmintics Remedy For Strongyloidiasis: A Literature Review ■ Peptide-Based Non Structural Protein 1 Inhibitor Potential in Inhibiting Dengue Virus Production: A Literature Review ■ Preventive, Curative, Rehabilitative Measures, And Activities To Raise Awareness Of The Indonesian People Towards Neglected Tropical Diseases, Especially Filariasis ■ Epidemiology of Dengue Haemorrhagic Fever In Aceh in the Last 5 years : A Literature Review

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SCIENTIFIC PAPER

TESTIMONY

AMINO | IMSTC 2021

Rivaldi Ruby AMSA-Universitas Katolik Indonesia Atma Jaya 3rd Winner of Scientific Paper Category IMSTC has wide options of competitions and training for us to participate in. This annual AMSA national event also aims to provide provisions, knowledge, skills, abilities and motivation to us members to make scientific papers along with promoting certain health topics to increase society's awareness through social platforms. Some tips and tricks while making a scientific paper is to be able to know the right and efficient way to filter necessary information and to divide tasks with other teammates during the initial data screening. One experience that we've learned throughout the process of this competition is to pay close attention to the academic guidelines provided to prevent any misunderstandings on the paper requirements. Having teammates that share the same perspective is also one important factor to ensure the work goes smoothly. It is also recommended to read different types of journals to get used to skimming as well as improving our reading skills.

MASTERPIECE

Larvicidal Activity Against Anopheles sp. and Ecotoxicological Evaluation of Greensynthesized Silver Nanoparticles as A Promising Vector Control Agent to Halt Mosquitoborne Disease in Rural Countries: A Systematic Review 1

Muhammad Afif Naufal1a, Nathaniel Gilbert Dyson1, Aldithya Fakhri1 Second Year Medical Student, Faculty of Medicine, Universitas Indonesia Asian Medical Students’ Association Indonesia a afifnaufal2001@gmail.com

Abstract Introduction: Mosquitoes still represent major threat for millions of people worldwide due to their contribution as a vector of mosquito-borne diseases, namely malaria and lymphatic filariasis, which are caused by Anopheles sp. bite. Killing mosquitoes at its larval stage is the most effective way to control them. Recently, accumulating evidences have shown the high potency of green synthesized silver nanoparticles (AgNPs) as larvicidal agent against several mosquito species, including Anopheles sp. Objectives: This systematic review aims to evaluate the potency of green synthesized AgNPs as promising larvicidal agent candidate against Anopheles sp. Materials and Method: We systematically searched through PubMed, EBSCOhost, ScienceDirect, Scopus, and ProQuest for peer-reviewed studies published up to 7 December 2020. Critical appraisal of included studies was performed using the ROBINS-I to assess the quality of the studies. Results: Fourteen eligible studies are included in this systematic review, published between 2015 and 2020. The compiled studies then assessed for risk of bias by using ROBINS-I. The results shown relatively low bias throughout the studies. Discussion: Based on included literatures, AgNPs have shown high potency at eradicating Anopheles sp. larvae. The larvicidal activity is attributed to particles size and phytochemicals cap, smaller particles and more polar reduced form of phytochemicals resulted in higher larvicidal activity although no significant increase is expected, thus plant extracts serve as a good regaent at AgNPs synthesis. Plant extract-synthesized AgNPs were found safe to non-target organisms Diplonychus indicus, Anisops bouvieri, and Gambusia affinis, with respective LC50 and LC90 values ranging from 517,86 µg/ml to 32.192,8 µg/ml and from 1.006,83 µg/ml to 61.796,55 µg/ml, respectively. Conclusion: Green synthesized AgNPs is a promising vector control agent due to its strong, stable larvicidal activity and low ecotoxicological effects. However, further studies in natural environment settings are needed to confirm its potency and safety. Keywords : Silver Nanoparticles, Plant Extracts, Anopheles sp., Larvicidal activity

Larvicidal Activity Against Anopheles sp. And Ecotoxicological Evaluation of Greensynthesized Silver Nanoparticles as A Promising Vector Control Agent to Halt Mosquitoborne Disease in Rural Countries: A Systematic Review Scientific Paper

Author : Muhammad Afif Naufal Nathaniel Gilbert Dyson Aldithya Fakhri

Faculty of Medicine Universitas Indonesia Asian Medical Students’ Association Indonesia 2020

Introduction Mosquitoes represent a major threat for millions of people around the world due to their contribution as vectors of devastating parasites and pathogens, including malaria, filariasis, yellow fever, dengue, chikungunya, and zika. This leads to reduced productivity and even death.1–3 Among the others, Anopheles sp. is one of the most important species, which serves as a vector for malaria and filariasis transmission in many rural countries, including Indonesia.4 According to the World Health Organizations (WHO), malaria causes an estimated 219 million cases globally, and results in 400,000 deaths annually.5 On the other hand, 893 million people in 49 countries worldwide are at high risk of lymphatic filariasis, which can also be caused by Anopheles sp. bite. Ironically, this disease has not gained much attention and therefore called neglected tropical diseases.6 Recently, the occurrence of mosquito-borne diseases increased due to favorable environment caused by global warming, high relative humidity, uneven rainfall, and sanitation facility all over the world.7 However, development of vaccines against this vector proved to be ineffective due to its high cost and long trial process required. Killing mosquitoes at larval stages is the only effective measure for controlling this vector-borne disease.8 Chemically synthesized insecticides, which are still used until today, have many major drawbacks, as they are expensive, non-selective and harmful to other organisms in the environment.9 In addition, some studies report the increasing resistance and high operational costs.10 Thus, eco-friendly control tools are urgently needed to obtain better efficacy with much less toxicity to the environment. Nanoparticles have increasingly attracted global attention through it’s various biomedical applications these days. Noble metal nanoparticles such as gold, silver, titanium, and platinum, are widely developed to support nanomedical field.11 Contrary to the chemical insecticides, biologically synthesized nanoparticles have proved to exhibit strong larvicidal activity against various mosquito vectors, including Anopheles sp.12,13 Furthermore, among other biological materials, plants possess a broad variety of metabolites that can aid in the biosynthesis, reduction and capping of metal ions. This can be utilized to stabilize the nanoparticles in order to provide more impact on its larvicidal activity.14 On the other hand, the use of plants for the fabrication of nanoparticles is a rapid, low cost, ecofriendly and single step method for biosynthesis process.15

Recently, accumulating evidences have shown that green synthesized AgNPs as an ecofriendly, high potential candidate of larvicidal agent. However, to our knowledge, there has not been a systematic review made to evaluate and compare the utility of those different plant extracts in regards of its effectiveness and safety. Therefore, we decided to conduct a systematic review to evaluate and conclude the potency of green synthesized AgNPs as larvicidal agent. Materials and Methods Search method For this study, the authors performed a literature search based on the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA). To retrieve relevant studies, we applied the following keywords “green synthesis” OR “plant extract” OR “phytochemical”) AND “silver nanoparticle” AND “larvicidal “ AND “anopheles” AND (“toxicity” OR “non-target”). This search method was applied in 5 databases, namely PubMed, EBSCOhost, ScienceDirect, Scopus, and ProQuest, for peer-reviewed studies published up to 7 December 2020. Inclusion and exclusion criteria In creating this review, the authors applied some inclusion and exclusion criteria. The inclusion criteria were such follows: (1) study design mainly experimental studies; (2) study use AgNPs synthesized from plant extracts; (3) study outcomes consisted of LC50 and LC90 of larvae exposed to plant extract-synthesized silver nanoparticle; (4) study assessed ecotoxicological effect to another aquatic organism; (5) study using exposure time to the sample for 24 hours. The exclusion criteria that were applied are (1) unsuitable types of articles, such as commentaries, conference (2) inaccessible studies; (3) studies published in languages other than English or Bahasa Indonesia; (4) study without a control group. Study outcomes The main outcomes of interest observed in this review were larvicidal activity and ecotoxicological outcomes: (1) The larvicidal activity outcomes include lethal concentration 50 and 90 (LC50 and LC 90) of plant extract-synthesized silver nanoparticle to Anopheles sp. larva (2) The ecotoxicological effect of plant extract-synthesized AgNPs measured in LC50 and LC90 to another aquatic organisms that live where larvae usually found (3) Physicochemical characteristics of synthesized AgNPs, including particle size and colloidal stability.

Risk of bias assessment ROBINS-I (Risk Of Bias In Non-randomised Studies-of Interventions) was utilized in evaluating the risk of bias in estimates of the effectiveness or safety (benefit or harm) of intervention from studies that did not use randomization to allocate interventions. The ROBINS-I tool consists of 7 main domains. The first two domains covering confounding and selection of participants into the study address issues before starting the interventions that are to be compared. The third domain addresses classification of the interventions themselves. The other four domains address issues after the start of interventions: biases due to deviations from intended interventions, missing data, measurement of outcomes, and selection of the reported result. The assessment was performed by three independent and blinded investigators, with conflicts being resolved through all authors’ consensus. Results and Discussion Search results After conducting searches in international databases using the aforementioned keyword, we acquired 215 studies which were then screened based on its title relevancy, eliminating 122 studies. Furthermore, duplicate titles were removed and evaluated based on its abstract, yielding 28 studies. Lastly, full-text screening were conducted, a total of 14 studies which consist of 3 study with ineligible study design, 4 studies without ecotoxicological assessment, and 7 studies that measured by other than LC value. The result of the study selection process is shown in Figure 1.

Figure 1. PRISMA flow chart of search strategies

Characteristics of included studies After rigorous screening and rechecking to maintain uniformity and relevancy to inclusion and exclusion criteria, a total of 14 non-randomized controlled studies are included. The included studies are shown in Table 1.16–29 All 14 study were conducted in India, published between 2015 until 2020, and predominantly were authored by Govindarajan et al. Due to the objective of this review being assessing larvicidal activity and ecotoxicological effect of silver nanoparticles, subject of the studies include Anopheles sp. larvae (3rd and 4th instar) and various non-target aquatic animals that live in the same habitat as said larvae, namely Diplonychus indicus, Anisops bouvieri, Gambusia affinis, Daphnia magna, Oryzias latipes, Chilocorus circumdatus, and Poecilia reticulata, though the majority of studies used the first three species as the subject. The included studies were reviewed using ROBINS-I. A total of 11 of the studies are low risk of bias, while the rest are moderate. The justification of the assessment is attached as Appendix 2. Effectiveness of Silver Nanoparticle Synthesized by Plant Extract All the studies included have shown high larvicidal potency of green synthesized silver nanoparticles (AgNPs). Based on the average of LC90 values, green synthesized AgNPs can eradicate 90% of larvae (LC90) after 24 h of exposure to a concentration as little as ±24 mg/liter. The concentration is on par with the conventional larvicidal agents, namely Bacillus thuringiensis israeli, while remaining stable for at least 8 weeks before agglomerating and precipitating, thus exerting long, constant larvicidal activity while the latter depends on higher concentration to maintain an eradication rate that lasts no longer than 35 days.21,30 The larvicidal activity of AgNPs might be attributed to its physicochemical characteristics. A study conducted by Karthiga et al, suggest that the particle size is important as smaller particles can enter the larvae through the cuticle. Inside, AgNPs enter individual cells, inducing degradation of DNA, destruction of organelles, and apoptosis, leading to disturbance of normal phsyiology.17,31 Another characteristics, phytochemicals cap, are cosynthesized as a result of reduction of Ag+ ion in the process of making AgNPs. Throughout the studies, we observed no significant difference between the data, indicated by relatively small standard deviation of the AgNPs LC50 and 90. However, the smallest LC value, mentioned in Govindarajan et al29, as in contrast to the theory, it exhibit the smallest LC while having a moderate particle size of 44 nm. The study showed phytochemicals involved in the synthesis were flavones, quinones, and organic acids that are

present in C. spinarum leaf. Possible explanation of this phenomenon is that these classes of molecules have low molecular weight and high polarity due to oxygen atom inside the molecules, thus oxidation produce polar groups of carbonyl within the molecules, which then favour higher agglomeration and concentration (dipole force).32–34 This conjecture is supported by lower-thanmean LC of AgNPs synthesized using similar extract phytochemicals constituent by Govindarajan et alc-d and Azarudeen et al.23-25 This proposed mechanism appears to be validated by the largest LC value observed by Benelli et al18, as the particle depicted to have smaller size than those of previously mentioned, while having the largest LC value. The phytochemicals involved in the synthesis were non to weakly polar and rather high in molecular weight, namely tannins. Tannins which are semi polar, contains high phenol content and are relatively “bulkier” and heavier.10 The phenol then will undergo oxidation, yielding quinone which is less polar, as a result, weakly attracted to other molecules, thus leading to less concentrated phytochemical cap surrounding the AgNPs, although Govindarajan et alh, observed lower-than-mean which we speculated that Clerodendrum chinense extract contain less tannin. In conclusion, compounds with high content of reduced oxygen atoms and small molecular weight, are highly recommended to maximize the efficacy of AgNPs although no striking difference is projected to be happened, thus plant extract serve as an excellent reducing agent. Biotoxicity on non-target aquatic organisms In recent years, mosquito larval control using chemical-based synthetic pesticides is wellthought-out as a major factor in dengue and malaria control strategies. Such a control strategy causes drastic effects on human and animal health and seriously contaminates the environment. Therefore, researchers looked at natural products as effective alternatives to conventional pesticides. The plant extract-synthesized AgNPs’ environmental toxicity was tested against nontarget mosquito predators, such as Diplonychus indicus, Gambusia affinis, and Anisops bouvieri. The effects of the plant extract-synthesized AgNPs on insects and fish were assessed using a standard method described by Sivagnaname and Kalyanasundaram (2004).22,35 From 17 studies that provide a quality assessment of our inclusion and exclusion criteria, we have LC50 and LC 90 values of non-target organisms ranged from 517,86 µg/ml to 32.192,8 µg/ml and from 1.006,83 µg/ml to 61.796,55 µg/ml, respectively. These results suggested that the plant extract-synthesized

AgNPs are safe and environment friendly. We used several statistical analyses to assess the significance of plant extract-synthesized AgNPs toxicity against target and non-target organisms. The results showed that for both LC50 and LC90 of Anopheles sp. larva and non-target aquatic organisms differ significantly. Taken together, the data presented here provide evidence that LC50 and LC90 of Anopheles sp. larva and non-target aquatic organisms were higher than all of the non-target aquatic organisms. The observed low toxicity effect may be attributed to the specific interaction between silver nanoparticles and the larval extracellular lipoprotein matrix. This interaction increases the permeability of the plasma membrane of cells and finally causes the loss of cellular function and cell death.2 This mechanism cannot occur in other non-target aquatic organisms because of these specific interactions only to mosquito larvae. This review highlighted that plant extract-synthesized AgNPs could be employed at low dosages to strongly reduce populations of vector mosquitoes of medical importance without detrimental effects on predation rates of non-target aquatic organisms. Current challenges regarding mosquito control Given the availability of various chemically synthesized insecticides, to summarize, two main problems are commonly faced, namely (1) effectivity due to developed resistance, and (2) high toxicity to the environment.9 For the first issue, the use of green synthesized silver nanoparticles, as discussed previously, has been proved effective, indicated by its high toxicity (low LC50 and LC90 value) against Anopheles sp. larvae. Furthermore, for the second issue, this systematic review has compared the differences of toxicity to Anopheles sp. larvae and non-target aquatic organisms, and the results have been proved to be highly significant. Therefore, it can be concluded that green synthesized silver nanoparticles have much less toxicity to the environment, especially for other organisms found near the target’s habitat (Diplonychus indicus, Gambusia affinis, and Anisops bouvieri). Applicability of green synthesized silver nanoparticles in Indonesia Despite commendable effort by the government to speed up elimination of these diseases, especially in Indonesia, there still need to be a novel breakthrough in terminating the threat.36 Considering all the included studies in this systematic review, we then conclude that this innovation is very potential to be applied in Indonesia based on three major reasons. Firstly, the

rearing conditions of Anopheles sp. used in all of the studies relatively able to represent Indonesia’s climate (in term of temperature and humidity). Second reason is due to the quite similar species of mosquitoes circulating both in India and Indonesia, except for several species such as Anopheles sundaicus and Anopheles balabacensis which are not tested in the studies. Furthermore, the technologies and methods used to synthesize silver nanoparticles are relatively cheap and simple, as reported by all included studies. Therefore, we believe that this innovation is highly feasible to be applied in Indonesia. Strength and limitation of the review We acknowledged that this review has its own strengths and limitations. First of all, to our knowledge, this is the first systematic review regarding the potency of green synthesized AgNPs as larvicidal agent. The other strength of this review lies on its homogenity of study design and results. The uniformity allows the reviewer to easily compare relations between variables, namely LC values of AgNPs (both on target and non-target organisms), size, and

phytochemical

substituents. Moreover, all of the included studies are no later than 2015, indicating the novelty and relevance of this idea, while maintaining mostly low risk of bias evaluated by ROBINS-I assessment. On the other hand, we realize that all of the included studies were still done in laboratory settings, hence its applicability in natural environment remains unknown. In laboratory settings, all of the rearing conditions, including the temperature, humidity, and growth medium, were kept under tight supervision, while these are not likely to happen in natural environment. Conclusion and Recommendation In conclusion, green synthesized silver nanoparticles are easy to produced, stable over time, and can be employed at low dosage to strongly exhibit larvicidal activity against Anopheles sp., which acts as a vector of various mosquito-borne diseases, without any significant ecotoxicological effect, while still yielding constant results from any plant extracts used, hence indicating its high applicability in Indonesia. Nevertheless, we also recommend further studies assessing applicability of green synthesized AgNPs in natural environment settings to ensure its potency and safety.

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Meliyanie G, Andiarsa D. Program Eliminasi Lymphatic Filariasis di Indonesia. J Heal Epidemiol Commun Dis. 2019;

Appendix 1. Study characteristics Intervention characteristics

Study outcome

Phytochemical characteristics No.

Author

Subject condition (Larvae stage, temperature, humidity) rd 3 Instar Larvae, NA, NA

Species

Silver Nanoparticles Characteristics Colloidal Stability

LC50 (µg/ml)

Detected Phytochemicals

LC50 (LCLUCL) (µg/ml)

LC90 (LCLUCL) (µg/ml)

Size

Alstonia venenata

103.41 (91.65113.82)

203.61 (188.81223.06)

30-40 nm

Stable

Non-target exposure time 48 h

Larvae (LCLUCL)

Non-target (LCLUCL)

LC90 (µg/ml) Larvae (LCLUCL)

Esan et al, 202016

Govindarajan et al, 2016a[17]

3rd Instar Larvae, 28±2°C, 70-85%

Adiantum raddianum

143.22 (126.35158.04)

285.74 (264.80313.31)

9.69-13.9 nm

Stable

48 h

10.33 (9.1411.39)

Govindarajan et al,2016b[22]

3rd Instar Larvae, 28±2°C 70-85%

Quisqualis indica

185.98 (164.65204.82)

367.39 (340.67402.51)

1-30 nm

Stable

48 h

12.52 (11.1513.74)

Govindarajan et al, 2016c[23]

3rd Instar Larvae, 28±2°C, 70-85%

Nicandra physalodes

Flavones, Quinones, and Organic Acids

202.82 (178.79223.91)

404.85 (375.19443.88)

22-44 nm

Stable

48 h

12.39 (10.9913.62)

Govindarajan et al, 2016d[24]

3rd Instar Larvae, 28±2°C, 70-85%

Ormocarpum cochinchinense

Flavones, Quinones, and Organic Acids

164.72 (145.92181.35)

324.33 (300.85355.14)

18-35 nm

Stable

48 h

10.43 (9.2411.48)

D.indicus 8100.21 (7157.01-8930.85) G.affinis 10597.53 (9397.21-11660.85)

20.62 (19.1122.59)

Azarudeen et al, 201725

3rd Instar Larvae, 28±2°C, 70-85%

Naregamia alata

Flavones, Quinones, and Organic Acids

165.15 (146.72181.50)

321.56 (298.52351.71)

5-35 nm

Stable

48 h

12.40 (11.0213.63)

24.20 (22.4626.49)

Govindarajan et al, 201726

3rd Instar Larvae, 28±2°C, 70-85%

Hugonia mystax

Flavonoids and Trepenoids

162.66 (143.23179.69)

326.16 (302.17357.79)

40-90 nm

Stable

48 h

14.45 (12.8415.88)

Govindarajan et al, 2016e[27]

3rd Instar Larvae, 28±2°C, 70-85%

Zornia diphylla

Citronellol, Geraniol, and Flavones

61.23 (54.1267.49)

121.21 (112.40132.77)

30-60 nm

Stable

48 h

12.53 (11.1813.73)

A.bouvieri 629.58 (561.45-690.39) D.indicus 1058.31 (948.12-1157.48) G.affinis 2111.34 (1883.65-2314.64) G.affinis 32192.80 (28794.52-35240.89) D.indicus 14756.43 (13094.32-16230.74) A.bouvieri 12251.72 (10819.31-13512.43) C.circumdatus 613.11 (544.08-674.24) A.bouvieri 1100.73 (982.46-1206.59) G.affinis 1583.87 (1406.58-1742.00)"

12.28 (10.8613.54)

A. bouvieri 734.73 (655.27-805.69) D.indicus 1057.86 (938.29-1163.79) G.affinis 2107.7 (1850.63-2331.46) D.indicus 517.86 (460.60-568.80) G. affinis 635.98 (563.63 - 700.02) A. bouvieri 653.05 (581.17-717.15) D.indicus 860.94 (768.53-943.57) G.affinis 2181.16 (1947.40-2393.99) D.indicus 1032.81 (916.83-1135.66)

24.36 (22.5826.71)

20.51 (19.0122.48) 24.21 (22.4826.47)

24.24 (22.49 26.52)

28.11 (26.0930.76)

24.02 (22.3226.23)

Non-target (LCLUCL)

A.bouvieri 1418.27 (1316.82-1551.17) D.indicus 2089.53 (1937.41-2289.80) G.affinis 4317.84 (3991.25-4752.97) D.indicus 1006.83 (934.37-1101.83) G. affinis 1261.72 (1169.29-1383.67) A.bouvieri 1287.88 (1192.73-1413.54) D.indicus 1667.36 (1547.53-1824.82) G.affinis 4263.53 (3953.14-4673.35) D.indicus 2020.73 (1874.652212.49) D.indicus 16030.01 (14861.38-17566.47) G.affinis 20975.84 (19443.3422995.98) A.bouvieri 1214.95 (1128.14-1328.66) D.indicus 2011.14 (1869.25-2196.24) G.affinis 4073.07 (3782.26-4454.01) G.affinis 61796.55 (57392.75-67567.76) D.indicus 29116.24 (26987.41-31924.09) A.bouvieri 24358.07 (22574.93-26706.32) C.circumdatus 1195.27 (1109.48-1307.54) A.bouvieri 2147.85 (1991.91-2353.52) G.affinis 3189.47 (2945.86-3516.56)

Alyahya et al, 201828

3rd Instar Larvae, 28±2°C, 70-85%

Holostemma adakodien

185.79 (163.78205.14)

373.47 (345.78410.08)

Stable

48 h

12.18 (10.7413.45)

D. indicus 623.48 (555.55-684.03)

24.33 (22.5526.68)

10.

Govindarajan et al, 2016f[29]

3rd Instar Larvae, 24-30°C, 85%

Carissa spinarum

Flavones, Quinones, and Organic Acids

104.24 (92.62114.55)

203.55 (188.91222.74)

44 nm

Stable

48 h

8.37 (7.449.19)

16.25 (15.0917.77)

11.

Benelli et al, 201718

3rd Instar Larvae, 28±2 °C, 70-85%

Acacia caesia

Tannins, Flavonoids, Alkaloids, Steroids and Glycosides

125.09 (111.45137.25)

241.68 (224.43264.25)

20-46 nm

Stable

24 h

18.66 (16.4520.61)

12.

Aarthi, et al., 201719

3rd Instar Larvae, 25-28 °C, NA

Habenaria plantaginea

102.51 (90.72112.90)

202.16 (187.49221.45)

37.8 nm

Stable

48 h

12.23 (10.8313.46)

13.

Govindarajan, et al., 2016g[20]

3rd Instar Larvae, 28 ± 2 ◦ C, 70-85%

Ichnocarpus frutescens

Flavones, Quinones, and Organic Acids

185.83 (164.69204.52)

365.22 (338.85399.78)

37 nm

Stable

48 h

14.22 (12.5615.69)

14.

Govindarajan, et al., 2015h[21]

3rd Instar Larvae, 28 ± 2 °C, 70-85%

Clerodendrum chinense

Alkaloids, Flavonoids, Tannins, Terpenoids, Steroids, Glycosides and Benzenoids

61.74 (54.5368.07)

122.84 (113.85134.68)

25-30 nm

Stable

48 h

10.23 (9.0511.28)

D. indicus 4145.60 (3682.52-4556.55) A. bouvieri 4475.16 (4002.47-4900.26) G. affinis 6402.68 (5656.98-7060.43) D. indicus 11,063.27 (9961.10-12,062.30) A. bouvieri 9012.19 (8164.27-9789.24) G. affinis 27,277.05 (18,642.73-33,820.03) A. bouvieri, 831.82 (741.73-912.24) D. indicus, 1286.90 (1148.64-1410.52) P. reticulata, 3102.22 (2745.75-3417.22) G. affinis, 3486.10 (3133.90-3806.23) G. affinis 2098.61(1852.442315.26) D. indicus 873.25 (775.30-960.31) A. bouvieri 636.61 (567.11-698.59) G. affinis 1145.36 (1027.23-1252.13) D. indicus 647.05 (578.99-708.18) A. bouvieri 889.45 (792.20-976.30)

37.58 (34.7841.29)

24.02 (22.2826.29)

28.23 (26.1630.93)

20.23 (18.7622.16)

D. indicus 1203.33 (1117.431315.73) D. indicus 8095.36 (7511.21-8862.07) A. bouvieri 8713.45 (8077.78-9554.02) G. affinis 12883.05 (11924.53-14154.19) D. indicus 20,815.73 (19,359.76-22,716.20) A. bouvieri 16,581.63 (15,445.22-18,058.18) G. affinis 51,065.76 (42,854.16-69,001.45) A. bouvieri, 1601.37 (1487.37-1750.37) D. indicus, 2489.26 (2311.35-2722.37) P. reticulata, 6141.95 (5693.83-6731.49) G. affinis 6717.78 (6228.99-7364.49) G. affinis 4217.40 (3903.72-4633.45) D. indicus 1738.96 (1609.49-1911.22) A. bouvieri 1238.99 (1149.59-1356.59) G. affinis 2216.73 (2056.04-2428.89) D. indicus 1242.33 (1153.76-1358.38) A. bouvieri 1756.82 (1627.08-1928.99)

Titles: a. One-pot and eco-friendly synthesis of silver nanocrystals using Adiantum raddianum: Toxicity against mosquito vectors of medical and veterinary importance; b. One-pot biogenic fabrication of silver nanocrystals using Quisqualis indica: Effectiveness on malaria and Zika virus mosquito vectors, and impact on non-target aquatic organisms; c. One-pot fabrication of silver nanocrystals using Nicandra physalodes: A novel route for mosquito vector control with moderate toxicity on nontarget water bugs; d. One-pot fabrication of silver nanocrystals using Ormocarpum cochinchinense: Biophysical characterization of a potent mosquitocidal and toxicity on non-target mosquito predators; e. Single-step biosynthesis and characterization of silver nanoparticles using Zornia diphylla leaves: A potent eco-friendly tool against malaria and arbovirus vectors; f. Bio-physical Characterization of poly-dispersed Silver Nanocrystals Fabricated Using Carissa spinarum: a potent tool against mosquito vectors; g. Facile fabrication of eco-friendly nano-mosquitocides: Biophysicalcharacterization and effectiveness on neglected tropical mosquito vectors; h. Clerodendrum chinense-mediated biofabrication of silver nanoparticles: Mosquitocidal potential and acute toxicity against non-target aquatic organisms

Appendix 2. ROBINS-I Risk of Bias Assessment

Y : Yes; PY : Probably Yes; N : No; PN : Probably No; NA : Not Available; NI : Not Indicated

Comparing Different Medications in Combating Strongyloides stercoralis Infection : A Systematic Review and Meta-Analysis Aurielle Annalicia Setiawan 1a , William Wiradinata 1 , Nathanael Ibot David1 1Undergraduate

Medical Program, Faculty of Medicine, Brawijaya University 1a aurielle.annalicia@yahoo.com

ABSTRACT Introduction : Strongyloides stercoralis infection is the most neglected yet dangerous NTD, able to cause endogenous autoinfection, hyperinfection in immunosuppressed patients, malnutrition, and stunting in children. Its non-specific symptoms and lack of effective diagnostic methods leads to underestimation of case numbers. Pharmacological interventions are crucial to control infection, therefore an analysis is necessary to determine the best mass-drug therapy regimen. Materials & Methods : Data was collected from PubMed, ScienceDirect, Google Scholar, Researchgate, and Cochrane and assessed using PRISMA flow diagram, resulting in 13 studies for qualitative analysis and 8 studies for quantitative analysis. Risk of bias was assessed using Cochrane Risk of Bias tool, and meta analysis was conducted using Review Manager 5.4. Results and Discussion : Ivermectin is shown to be significantly more effective (based on cure rate (CR)) compared to other pharmacological treatments (albendazole, thiabendazole, tribendimidine, pyrvinium pamoate, moxidectin) in curing the infection of S.stercoralis (odds ratio (OR) = 3.48, 95% confidence intervals (CI) 1.79 to 6.80, P = 0.0003). Single-dose ivermectin is also shown to have higher efficacy based on cure rate (CR) compared to multiple dose ivermectin (odds ratio (OR) = 0.97, 95% confidence intervals (CI) 0.46 to 2.04, P = 0.94). Ivermectin is also shown to have the fewest adverse effects compared to other medications, and single-dose ivermectin does not significantly cause more adverse effects compared to multiple-doseaivermectin. Single-dose ivermectin is more effective than other treatments mentioned and also causes fewer adverse effects compared to other treatments. Further cost-effectiveness analysis is needed to evaluate the economical aspect of the result of this study.

Conclusion : Single-dose ivermectin is more effective than other treatments mentioned and also causes fewer adverse effects compared to other treatments. Further cost-effectiveness analysis is needed to compare the cost-effectiveness of these medications.

Keywords: Strongyloides stercoralis, strongyloidiasis, treatment, efficacy, adverse effects

INTRODUCTION Strongyloides stercoralis is the fourth most important intestinal nematode [1], with 200370 million people estimated to be infected[2]. However, strongyloidiasis is also the most neglected of the neglected tropical diseases to exist. It is considered as the most difficult NTD to diagnose, with only 50% of cases considered symptomatic[1]. Lack of sensitivity in diagnostic methods have also caused underestimation of case numbers[3]. South-East Asia, Africa, and Western Pacific Regions are reported to account for 76.1% of the global infections[4]. Infection presents with non-specific symptoms such as fever, cough, and urticaria, making it more difficult to detect. On the other hand, S. stercoralis infection can be dangerous in immunosuppressed patients, causing hyperinfection syndrome and dissemination to other internal organs[5]. Additionally, the special ability of this helminth to cause endogenous autoinfection can result in persistent infection and chronic strongyloidiasis which can last up to 75 years[6]. Other significant health problems that can occur in this infection are malnutrition and stunting which are caused by clinical manifestations in this disease such as nausea, vomiting, diarrhea, etc. S.stercoralis infection was found in Bangladesh to be the most common in children aged 7-10 year old with 18% prevalence and also infected 1-6 year olds with 10% prevalence. These age ranges represent the most vulnerable population to be affected by stunting and morbidity, even mortality caused by malnutrition[1]. S.stercoralis can be found worldwide, most prevalently in warm, underdeveloped areas with poor sanitation[2]. Infection occurs by penetration of intact skin by L3 larvae, which will then travel to the circulatory system and the respiratory system, including pharynx, where the larvae is then swallowed and travels to the small intestine where they reside to become adults and reproduce. Rhabditiform larvae is then excreted through faeces and develop to be L3 larvae, infecting another host[7]. Pharmacological means are apparently important in controlling strongyloidiasis, as reported in a study. Treatments were very effective, and control was possible with pharmacological means alone[8]. Previously, thiabendazole was the drug of choice for this disease, but unpleasant side effects have led to search for other alternatives. Albendazole is also reported to be effective[9]. Ivermectin is currently the treatment of choice for this disease, but there are only a few studies that compare different regimens for strongyloidiasis at the same time. This systematic review aims to summarize evidence on the efficacy of a number of

strongyloidiasis treatments in order to present the latest and comprehensive evidence for the best treatment of choice.

MATERIALS & METHODS This review was conducted according to PRISMA’s flow diagram. Items considered necessary for transparent reporting of a systematic review such as title, introduction, methods, result, and discussion were included in the checklist.

1. Eligibility Criteria for Human Clinical Trials a. Types of participants This review included all studies involving male and female participants aged 3-86 year old diagnosed with S. stercoralis infection. Diagnosis was established by either faecal tests or IFAT titre. b. Types of interventions Interventions included in this review were any antihelminthic drugs such as ivermectin, albendazole, thiabendazole, tribendimidine, pyrvinium pamoate, and moxidectin administered at any dose, by any route, and for any duration. c. Types of outcome measures Outcomes included the efficacy of the drugs in (1) eliminating S.stercoralis infection in participants, measured in cure rate (CR) and (2) the adverse effect of the drugs used (AE).

2. Search Strategy This research has been conducted according to the PRISMA guidelines and flowchart which is shown in. References were gathered from various sources such as PubMed, ScienceDirect, Google Scholar, Researchgate, and Cochrane. Only studies in English ranging from 1990-2020 are included in this systematic review. Keywords used were: (“Strongyloides stercoralis treatment efficacy” OR “strongyloidiasis”), AND (“Treatment”), AND (“efficacy”), AND (“ivermectin*” OR “thiabendazole*” OR “albendazole*” OR ”tribendimidine*” OR “moxidectin*” OR “pyrvinium pamoate*”) Wildcard term was used to increase sensitivity of the search. Studies included were original researches that evaluated the efficacy of various treatment on treatment of Strongyloides stercoralis infection or strongyloidiasis. Three reviewers listed above reviewed the studies and any disagreements were resolved by discussion.

3. Data extraction and analysis Studies deemed eligible were reviewed independently by the three authors listed above and the following data was extracted: author, publication year, country, study design, intervention, study population, sample characteristics, and results. The data was then analyzed and outcomes were summarized with emphasis on statistical results of the studies included. 4. Risk of Bias assessment Risk of bias assessment was done according to the Cochrane risk of bias tool which included selection bias, measurement of exposure, confounding variables, blinding of participants and personnel, incomplete outcome data, and reporting bias. Any disagreements by the authors were resolved through discussion. 5. Statistical analysis Meta analysis was conducted using Review Manager 5.4. Data across studies were evaluated based on cure rate (CR) and adverse effect (AE). Mantel-Haenszel method were utilized as the statistical method with 95% confidence intervals (CI). Random-effects models were used and P ≤ 0.05 was considered statistically significant. Bias in studies used in the metaanalysis were visually evaluated using a funnel plot.

RESULTS AND DISCUSSION

1. RESULTS 1.1. Study Identification and Selection Our search through the various databases mentioned above has resulted in a total of 5224 studies. After screening for duplicates, 275 studies were left and screening for other criteria excluded 222 records. A total of 40 studies were excluded due to limited presentations of findings and weak methodology., and finally, a total of 13 human studies were included in the qualitative analysis[9,11-22]. Eight studies were included in the quantitative analysis (metaanalysis)[9, 11-13, 15,18-19, 22] (see Figure 1).

1.2. Risk of Bias Assessment The studies acquired were examined with the Cochrane Risk of Bias tool. The risk for bias in both human and animal studies are mostly in the low and unclear risk of bias category, and some are classified as having high risk of bias (see Table 1).

1.3. Study Characteristics

Characteristics and properties of each study included were examined and listed (see Table 2).

1.4. Meta-analysis a. Cure Rate (CR) against Strongyloides stercoralis An analysis comparing the efficacy of ivermectin to other pharmacological treatment based on the cure rate (CR) of each medication on S.stercoralis infection was conducted. Data obtained from meta-analysis)[9, 11-13, 15,18-19, 22] indicate that ivermectin is significantly more effective compared to other pharmacological treatments in curing the infection of S.stercoralis (odds ratio (OR) = 3.48, 95% confidence intervals (CI) 1.79 to 6.80, P = 0.0003; see Figure 2.1). Tests for heterogeneity showed considerable heterogeneity (I2 = 83%). Qualitative observations based on the funnel plot resulted showed that the data collected has a low to moderate risk of reporting bias (see Figure 2.2). Based on the data obtained from meta-analysis, ivermectin is also shown to be significantly more effective compared to thiabendazole in curing the infection of S.stercoralis[11,13,18] (odds ratio (OR) = 1.44, 95% confidence intervals (CI) 1.05 to 1.98, P = 0.02; see Figure 3.1). Tests for heterogeneity indicated low heterogeneity (I2 = 0%). Qualitative observations based on the funnel plot resulted showed that the data collected has a low risk of reporting bias (see Figure 3.2). Data from meta-analysis also indicate that ivermectin is significantly more effective compared to albendazole in curing the infection of S.stercoralis[9,15,19,22](odds ratio (OR) = 6.76, 95% confidence intervals (CI) 4.29 to 10.66, P = <0.00001; see Figure 4.1). Heterogeneity testing showed low heterogeneity (I2 = 0%). Qualitative observations based on the funnel plot resulted showed that the data collected has a low risk of reporting bias (see Figure 4.2). Based on the data obtained from 3 studies, authors analyzed the efficacy of single dose ivermectin compared to multiple doses of ivermectin based on the cure rate (CR) of each medication on S.stercoralis infection. Data obtained from meta-analysis indicate that multiple dose of ivermectin is not significantly more effective compared to single dose ivermectin in curing the infection of S.stercoralis[9,14,18] (odds ratio (OR) = 0.97, 95% confidence intervals (CI) 0.46 to 2.04, P = 0.94; see Figure 5.1). Tests for heterogeneity showed moderate heterogeneity (I2 = 39%). Qualitative observations based on the funnel plot resulted showed that the data collected has a low risk of reporting bias (see Figure 5.2).

b. Adverse effect An analysis comparing the adverse effect of ivermectin to thiabendazole based on the number of patients experiencing any adverse effect during medication was conducted. Data obtained from meta-analysis indicate that thiabendazole significantly causes more adverse effect compared to ivermectin[11,13,18] (odds ratio (OR) = 0.17, 95% confidence intervals (CI) 0.08 to 0.37, P = <0.00001; see Figure 6.1). Tests for heterogeneity showed substantial heterogeneity (I2 = 63%). Qualitative observations based on the funnel plot resulted showed that data collected has a low risk of reporting bias (see Figure 6.2). Data obtained from meta-analysis also indicate that albendazole does not significantly cause more adverse effect compared to ivermectin[9,15,19] (odds ratio (OR) = 0.73, 95% confidence intervals (CI) 0.46 to 1.15, P = 0.17; see Figure 7.1). Tests for heterogeneity showed low heterogeneity (I2 = 0%). Qualitative observations based on the funnel plot resulted showed that data collected has a low risk of reporting bias (see Figure 7.2). It is also indicated that multiple dose ivermectin does not significantly cause more adverse effect compared to single dose ivermectin[9,14,18] (odds ratio (OR) = 1.51, 95% confidence intervals (CI) 0.14 to 15.80, P = 0.73; see Figure 8.1). Tests for heterogeneity showed substantial heterogeneity (I2 = 62%). Qualitative observations based on the funnel plot resulted showed that data collected has a low risk of reporting bias (see Figure 8.2).

2. DISCUSSION

Strongyloides stercoralis infection, as the most neglected of the NTDs, demands our attention as it poses great threat to children with its effects in malnutrition and stunting, which can lead to negative impacts in children’s learning capacity. This is a serious issue in tropical, underdeveloped countries, where S.stercoralis infection is prevalent. Therefore a drug suited for mass-therapy is needed to fight off this disease, and an analysis on the efficacy, adverse effects, and cost-effectiveness of various drugs is needed to decide on the best option. Based on the data obtained from various publication, ivermectin is currently the most popular treatment used, followed by thiabendazole and albendazole. Data obtained through meta-analysis comparing the efficacy of ivermectin to other medications including thiabendazole, albendazole, moxidectin, tribendimidine, and pyrivinium pamoate [9, 11-13, 15,1819, 22]

shows that ivermectin is significantly more effective in treating S.stercoralis infection

based on cure rate. The same result is also found when comparing ivermectin to thiabendazole and albendazole[9,11,13,15,18,19,22]. Other treatments such as moxidectin displayed favorable cure

rate (93.6%), however the difference is not statistically significant when compared to ivermectin[12] (odds ratio (OR) = 1.33, 95% confidence intervals (CI) 0.29 to 6.22, P = 0.71). As for tribendimidine[21] (CR = 54.5%) and pyrvinium pamoate[22] (CR = 23.3%), the cure rate simply is not high enough to be considered viable. The superiority of ivermectin based on aforementioned analysis poses the question for comparing single dose to multiple doses of ivermectin. Based on the data obtained from 4 studies, the difference is miniscule and is not statistically significant[9,14,18] (odds ratio (OR) = 0.97, 95% confidence intervals (CI) 0.46 to 2.04, P = 0.94; see Figure 5.1). Therefore, based on cure rate, single dose ivermectin is more effective compared to other treatments. Analysis of adverse effects cannot be left behind in examining drug effects, therefore analyses and comparison of the adverse affects of ivermectin, albendazole, thiabendazole, single-dose ivermectin and multiple dose ivermectin were conducted. Data obtained through meta-analysis shows that thiabendazole resulted in significantly more adverse effects [11,13,18] but albendazole did not show a statistically significant difference[9,15,19]. There is no statistically significant difference between single dose and multiple doses of ivermectin[9,14,18]. Therefore it is safe to state that single-dose ivermectin has the fewest adverse effect compared to other drugs in this comparison. Cost-effectiveness is also an important aspect to be considered in determining a mass therapy regimen. Compared to albendazole, ivermectin is shown to more cost-effective in treating S.stercoralis infection[10], but no information has been found on the comparison the cost-effectiveness between ivermectin and thiabendazole to treat this disease. Further studies are needed to determine the cost-effectiveness of these three medications.

CONCLUSION

Strongyloides stercoralis infection is the most neglected of the NTDs, yet it is able to cause serious complications, such as malnutrition and stunting in children[1]. Pharmacological treatment is shown to be very effective to control infection, even without any other measures[8]. Based on the analysis above, single-dose ivermectin is shown to have the highest efficacy of the other medications (albendazole, thiabendazole, tribendimidine, pyrvinium pamoate, moxidectin, multiple dose ivermectin). Single-dose ivermectin is also shown to have generally fewer adverse effects than other medications. Further studies are needed to compare the costeffectiveness of these medications.

REFERENCES 1. Stephenson LS, Latham MC, Ottesen EA. Malnutrition and parasitic helminth infections. Parasitology. 2000 Oct;121(S1):S23-38. 2. Forrer A, Khieu V, Schär F, Hattendorf J, Marti H, Neumayr A, Char MC, Hatz C, Muth S, Odermatt P. Strongyloides stercoralis is associated with significant morbidity in rural Cambodia, including stunting in children. PLoS neglected tropical diseases. 2017 Oct 23;11(10):e0005685. 3. Buonfrate D, Formenti F, Perandin F, Bisoffi Z. Novel approaches to the diagnosis of Strongyloides stercoralis infection. Clinical Microbiology and Infection. 2015 Jun 1;21(6):543-52. 4. Buonfrate D, Bisanzio D, Giorli G, Odermatt P, Fürst T, Greenaway C, French M, Reithinger R, Gobbi F, Montresor A, Bisoffi Z. The Global Prevalence of Strongyloides stercoralis Infection. Pathogens. 2020 Jun;9(6):468. 5. Olsen A, van Lieshout L, Marti H, Polderman T, Polman K, Steinmann P, Stothard R, Thybo S, Verweij JJ, Magnussen P. Strongyloidiasis–the most neglected of the neglected tropical diseases?. Transactions of the Royal Society of Tropical Medicine and Hygiene. 2009 Oct 1;103(10):967-72. 6. Prendki V, Fenaux P, Durand R, Thellier M, Bouchaud O. Strongyloidiasis in man 75 years after initial exposure. Emerging infectious diseases. 2011 May;17(5):931. 7. Schär F, Trostdorf U, Giardina F, Khieu V, Muth S, Marti H, Vounatsou P, Odermatt P. Strongyloides stercoralis: global distribution and risk factors. PLoS Negl Trop Dis. 2013 Jul 11;7(7):e2288. 8. Hays R, Esterman A, McDermott R. Control of chronic Strongyloides stercoralis infection in an endemic community may be possible by pharmacological means alone: Results of a three-year cohort study. PLoS neglected tropical diseases. 2017 Jul 31;11(7):e0005825. 9. Suputtamongkol Y, Premasathian N, Bhumimuang K, Waywa D, Nilganuwong S, Karuphong E, Anekthananon T, Wanachiwanawin D, Silpasakorn S. Efficacy and safety of single and double doses of ivermectin versus 7-day high dose albendazole for chronic strongyloidiasis. PLoS Negl Trop Dis. 2011 May 10;5(5):e1044. 10. Muennig P, Pallin D, Challah C, Khan K. The cost-effectiveness of ivermectin vs. albendazole in the presumptive treatment of strongyloidiasis in immigrants to the United States. Epidemiology & Infection. 2004 Dec;132(6):1055-63.

11. Adenusi AA, Oke AO, Adenusi AO. Comparison of ivermectin and thiabendazole in the treatment of uncomplicated human Strongyloides stercoralis infection. African Journal of Biotechnology. 2003;2(11):465-9. 12. Barda B, Sayasone S, Phongluxa K, Xayavong S, Keoduangsy K, Odermatt P, Puchkov M, Huwyler J, Hattendorf J, Keiser J. Efficacy of moxidectin versus ivermectin against Strongyloides stercoralis infections: a randomized, controlled noninferiority trial. Clinical Infectious Diseases. 2017 Jul 15;65(2):276-81. 13. Bisoffi Z, Buonfrate D, Angheben A, Boscolo M, Anselmi M, Marocco S, Monteiro G, Gobbo M, Bisoffi G, Gobbi F. Randomized clinical trial on ivermectin versus thiabendazole for the treatment of strongyloidiasis. PLoS Negl Trop Dis. 2011 Jul 26;5(7):e1254. 14. Buonfrate D, Salas-Coronas J, Muñoz J, Maruri BT, Rodari P, Castelli F, Zammarchi L, Bianchi L, Gobbi F, Cabezas-Fernández T, Requena-Mendez A. Multiple-dose versus single-dose ivermectin for Strongyloides stercoralis infection (Strong Treat 1 to 4): a multicentre, open-label, phase 3, randomised controlled superiority trial. The Lancet Infectious Diseases. 2019 Nov 1;19(11):1181-90. 15. Datry A, Hilmarsdottir I, Mayorga-Sagastume R, Lyagoubi M, Gaxotte P, Biligui S, Chodakewitz J, Neu D, Danis M, Gentilini M. Treatment of Strongyloides stercoralis infection with ivermectin compared with albendazole: results of an open study of 60 cases. Transactions of the Royal Society of Tropical medicine and Hygiene. 1994 May 1;88(3):344-5. 16. Forrer A, Khieu V, Schindler C, Schär F, Marti H, Char MC, Muth S, Odermatt P. Ivermectin treatment and sanitation effectively reduce Strongyloides stercoralis infection risk in rural communities in Cambodia. PLoS neglected tropical diseases. 2016 Aug 22;10(8):e0004909. 17. Hailu T, Nibret E, Amor A, Munshea A, Anegagrie M. Efficacy of Single Dose Ivermectin Against Strongyloides stercoralis Infection Among Primary School Children in Amhara National Regional State. Infectious Diseases: Research and Treatment. 2020 Jun;13:1178633720932544. 18. Igual-Adell R, Oltra-Alcaraz C, Soler-Company E, Sánchez-Sánchez P, Matogo-Oyana J, Rodríguez-Calabuig D. Efficacy and safety of ivermectin and thiabendazole in the treatment of strongyloidiasis. Expert opinion on pharmacotherapy. 2004 Dec 1;5(12):2615-9.

19. Marti H, Haji HJ, Savioli L, Chwaya HM, Mgeni AF, Ameir JS, Hatz C. A comparative trial of a single-dose ivermectin versus three days of albendazole for treatment of Strongyloides stercoralis and other soil-transmitted helminth infections in children. The American journal of tropical medicine and hygiene. 1996 Nov 1;55(5):477-81. 20. Singthong S, Intapan PM, Wongsaroj T, Maleewong W. Randomized comparative trial of two high-dose albendazole regimens for uncomplicated human strongyloidiasis. Southeast Asian journal of tropical medicine and public health. 2006;37:32. 21. Steinmann P, Zhou XN, Du ZW, Jiang JY, Xiao SH, Wu ZX, Zhou H, Utzinger J. Tribendimidine and albendazole for treating soil-transmitted helminths, Strongyloides stercoralis and Taenia spp.: open-label randomized trial. PLoS Negl Trop Dis. 2008 Oct 15;2(10):e322. 22. Toma H, Sato Y, Shiroma Y, Kobayashi J, Shimabukuro I, Takara M. Comparative studies on the efficacy of three anthelmintics on treatment of human strongyloidiasis in Okinawa, Japan. Southeast Asian Journal of Tropical Medicine and Public Health. 2000 Mar;31(1):147-51.

Identification Screening

Records identified through database searching (PubMed = 256, Google Scholar = 2033, ResearchGate = 599, ScienceDirect = 1568, Cochrane = 768) (n = 5224 )

Records after duplicates removed and screened on the basis of titles and abstracts (n = 275 )

Records excluded (n = 222): Non-English journal (70) Abstract only (109) Does not include human studies (43)

Full-text articles assessed for eligibility (n = 53 )

Eligibility

Screening

Identification

TABLES & FIGURES

Included

Studies included in qualitative synthesis (n = 13 )

Studies included in quantitative synthesis (meta-analysis) (n = 8)

Figure 1. Flowchart of study identification and selection based on PRISMA.

Full-text articles excluded (n= 40) Weak methodology (n = 23) Limited presentation of findings (n = 27)

Blinding of participants Selection Measurement Confounding and bias of exposure variables personnel

No Studies

Incomplete Reporting data bias

Adenusi et al., 1 2003