Indian Journal of Dermatology
  Publication of IADVL, WB
  Official organ of AADV
Indexed with Science Citation Index (E) , Web of Science and PubMed
 
Users online: 4477  
Home About  Editorial Board  Current Issue Archives Online Early Coming Soon Guidelines Subscriptions  e-Alerts    Login  
    Small font sizeDefault font sizeIncrease font size Print this page Email this page


 
Table of Contents 
ORIGINAL ARTICLE
Year : 2022  |  Volume : 67  |  Issue : 3  |  Page : 232-238
How to predict the diagnosis of cutaneous leishmaniasis in a Non-Endemic Region


1 Department of General Surgery, University of Health Sciences, Istanbul Bagcilar and Training and Research Hospital, Istanbul, Turkey
2 Department of Dermatology and Venereology, University of Health Sciences, Istanbul Bagcilar and Training and Research Hospital, Istanbul, Turkey

Date of Submission05-Jan-2020
Date of Acceptance07-Jan-2021
Date of Web Publication23-Sep-2022

Correspondence Address:
Betul Tas
Atakoy 7-8. Kısım, Martı sitesi, 14/105, Bakirkoy, Istanbul
Turkey
Login to access the Email id

Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijd.IJD_452_20

Rights and Permissions

   Abstract 


Background: Cutaneous leishmaniasis (CL) is a parasitic infection transmitted by the female sandfly, which has limited knowledge in non-endemic areas. Aims: To predict the epidemiological and clinical characteristics of CL cases on treatment during the period of Syrian refugees' settlement. Methods and Material: The epidemiological and clinical data of 81 patients with CL who were admitted to the Istanbul Bagcilar Research and Training Hospital between March 2010 and April 2017 were conducted as a retrospective cohort study. A logistic regression analysis was performed. Results: Most detected demographics were Syrians (n = 56, 69.1%), ages <= 18 (n = 37, 45.7%), males (n = 49, 60.5%), elementary-school graduates (n = 35, 43.2%), and $500–750 income (n = 42, 51.9%). Most detected clinical characteristics were head/neck location (n = 38, 46.9%), acute-dry localized type (n = 71, 88%), crusted-papule (n = 79, 97.5%), and two lesions (n = 29, 35.8%). Means for age, family population, and session were 25.28 ± 20.90, 7.04 ± 2.03, and 11.27 ± 3.52, respectively. Majority of patients were admitted in 2014 and June. Significant factors by age were location, lesion type/number, and disease-duration. Lesion number ≥10, ages ≥41, crusted-nodule, cicatrix, and dissemination increased in session numbers, whereas crusted-nodule showed significant predictivity (P = 0.01). Conclusion: Location, lesion type/number, and disease duration may change by age in CL cases, whereas the presence of a crusted nodule may have a predictive effect on the number of treatment sessions.


Keywords: Epidemiology, leishmaniasis, refugees, treatment session


How to cite this article:
Altinel Y, Tas B. How to predict the diagnosis of cutaneous leishmaniasis in a Non-Endemic Region. Indian J Dermatol 2022;67:232-8

How to cite this URL:
Altinel Y, Tas B. How to predict the diagnosis of cutaneous leishmaniasis in a Non-Endemic Region. Indian J Dermatol [serial online] 2022 [cited 2022 Oct 6];67:232-8. Available from: https://www.e-ijd.org/text.asp?2022/67/3/232/356737





   Introduction Top


Leishmaniasis (Le) is a group of protozoan infectious diseases caused by the intracellular parasite Leishmania transmitted by phlebotomine sandflies. Although Le is rarely fatal, it is an important public health problem with gradually increasing incidence in recent years. The World Health Organization (WHO) reported that nearly 12 million people from 98 countries worldwide are currently infected with Le, 1.5–2 million new Le cases (¾ are cutaneous leishmaniasis, CL) are diagnosed and 70,000 deaths occur each year, and 350 million people are at risk of transmission of infection and disease.[1],[2],[3] Morbidity and mortality caused by Le are estimated at 2.4 million disability-adjusted life-years.[1],[2]

Epidemiologically, Le is described as New World Le, Old Word Le, and New and Old Word based on the Leishmania species, anthroponotic or zoonotic transmission origin, and main geographical distribution.

The main species of Old World Le are mainly seen in the Middle East, southwest/southeast/central Asia, north and east Africa, and southern Europe. Old and New World Le is caused by L. infantum, and it is usually seen in Europe, North Africa, and Central and South America.[4] Le is considered endemic in at least 102 tropical and subtropical countries or geographical regions.[1] Ninety percent of CL cases occur in Afghanistan, Algeria, Brazil, Pakistan, Peru, Saudi Arabia, and Syria.[2],[4],[5] Experience in managing Le is often limited in non-endemic regions, which may lead to a delay in diagnosis and unfavorable treatment outcomes.[6] In our country, nearly 50 million people are at risk of Le. The number of estimated annual new cases has been reported as 5000, and an important part of these cases have been reported from nine endemic provinces in Turkey. However, the disease has been spreading from endemic regions to non-endemic areas via increased commercial and touristic trips, an increase of temporary-seasonal and permanent-domestic migrations, and an increase of settlement of Syrian refugees.[7] Little is known about the data in non-endemic areas; this encouraged us to conduct this study. Our main aim is to predict the current challenges for epidemiological and clinical diagnostics of CL cases on therapeutical approaches during the refugee period in non-endemic regions.


   Materials and Method Top


The present study was conducted as a retrospective cohort study after the local ethics committee approval was obtained from our university.

Le is one of the infectious diseases that must be mandatorily reported to the public-health authorities in our country; thus, the medical reports of patients are regularly recorded and reported electronically by doctors for each patient.

In this process, written informed consent is obtained from each patient or his/her parent. Thus, data related to CL patients were obtained from the previously recorded and reported medical reports of our patients. Regardless of age and gender, all CL patients who were admitted to the Department of Dermatovenereology clinic of our University between March 2010 and April 2017 were included in the study. Data related to the epidemiological and clinical information of cases were evaluated and analyzed. Demographics such as nationality, gender, age, education, family income, and number of family members were studied. Patients were classified in the age groups of <18 years old, 19–40 years old, and ≥41 years old. Education level was classified as illiterate, pre-school, elementary school, high school, and university. Family income was classified as <$500, $500–750, and >$750.

The average family number of the study population was established as a classification according to the number of family members as <7 and >7.

Additionally, the presence of intrafamilial transmission and the number of previously or already infected people in the family were evaluated. The location of the lesions was classified as head/neck, upper extremity, lower extremity, and upper/lower extremity. The numbers of the lesions were classified as single, 2–9, and ≥10 (the first two found in one or more anatomical areas were considered to be “localized,” whereas the last one found in one or more anatomical areas was considered to be “diffuse”).

Based on the observed lesions, morphological types of lesions were stratified as crusted-papule, crusted-nodule, crusted-plaque, and cicatrix.

Disease duration no longer than 2 years was considered “acute,” whereas longer durations were considered “chronic.”[7]

We carefully investigated the clinical types of the lesions, extracutaneous symptoms (pain, fever, weakness, dyspnea, lymphadenopathy, hepato-splenomegaly, and mucosal findings), laboratory findings (whole blood count, CRP, and blood sedimentation rate), and abdominal ultrasonography. Thus, clinical types of the lesions were categorized according to both duration of the lesions and their dry or wet view, and also being of them localized or diffuse, as acute-dry localized, acute-dry diffuse, and chronic-dry diffuse. Disease duration was classified as 1–3 months, 3–6 months, 6–9 months, 9–12 months, 12–24 months, and higher than 24 months.

We evaluated the patients who had a sandfly-bite history, previously received antibacterial therapy, and at least two times without a response to medical therapy in their medical records.

Lesions were diagnosed with smear test positivity or clinical properties of the lesions and patients' personal and family histories for smear-negative cases. An impression smear was determined negative for leishmaniasis, which was without amastigotes, after examining the fields with an oil immersion lens (×1,000 magnification).

Microbiological diagnoses were made based on the national diagnosis and treatment manually.[7] The procedure of skin biopsy was performed by blinded general surgeons in our hospital. The lesion was cleaned with 70% ethanol, and a sterile half-inch incision extending to the upper dermis was made after the removal of crusts. Later, a dermal scraping material was taken from the edge and base of the wound perpendicular to the incision, with the blunt side of the scalpel. Obtained dermal material was applied on a glass slide parallel to the slide with circular motions, fixed with methanol, and stained with Giemsa stain. With the examination under high-power magnification with an immersion objective, observing basophilic intracellular amastigotes (Leishman–Donovan bodies) with kinetoplasts, lesions were diagnosed with Le. Because most of our foreign patients were refugees and they did not have comprehensive health insurance except for basic health support for emergency health conditions and preventive health services until the end of 2015, any other diagnostic tests such as microbiological culture, histopathological examination, or polymerase chain reaction (PCR) were not performed for these patients. Thus, the diagnosis of smear-negative lesions was made with their personal and family histories, clinical properties, and visualization of the “nail sign” of Hulusi Behçet after removing the crusts.[8],[9] Patients were treated with intralesional meglumine antimoniate or intralesional filtered-Na stibogluconate injections. For these treatments, the solutions were circularly injected into the base of lesions until the desired whitening was obtained in the whole lesion, at weekly sessions. Treatment responses of lesions were evaluated in each session of these intralesional injections until all wounds regress or close.

Statistical analysis

Descriptive statistics were reported as percentages for categorical variables, and as mean with standard deviation for continuous ones. Univariate regression analyses comparing patients with low session numbers for treatment versus those with higher session numbers were performed using a Chi-square test for categorical variables and a t test for continuous variables. A selection-based analysis was used to measure the clinical effectiveness of the session numbers among the unadjusted risk factors. Multivariable logistic regression analysis was used with the CL disease to determine variables predictive of session numbers to control for potential cofounders. P < 0.05 was considered to have significantly related patterns. All analyses were completed by R studio software, version 3.4.2.


   Results Top


Epidemiological, clinical, and laboratory properties and their responses to the given therapies of a total of 81 patients with CL were evaluated. Histopathological findings of lesions showed only granulomatous infiltration, including epithelioid histiocytes, rare Langerhans type giant cells, and necrosis. All treated lesions were healed with scarring. No mucocutaneous, visceral, or post-kala-azar dermal type was detected. Most detected demographics were Syrians (n = 56, 69.1%), ages < = 18 (n = 37, 45.7%), males (n = 49, 60.5%, elementary-school graduates (n = 35, 43.2%), and $500–750 income (n = 42, 51.9%) [Table 1] and [Table 2]. Most detected features were head/neck location (n = 38, 46.9%), acute-dry localized type (n = 71, 88%), crusted-papule (n = 79, 97.5%), and two lesions (n = 29, 35.8%). Sixty-seven (82.7%) patients were diagnosed with positivity in wound smears, whereas wound smears gave negative results in 14 (17.3%) cases. Thus, they were diagnosed with their personal and family histories, strong clinical suspicion in the appearances for CL, and detection of “nail-sign” in the lesions. Forty (59.3%) of them were treated with intralesional filtered-Na stibogluconate injections, whereas 33 (40.7%) were treated with intralesional meglumine antimoniate injections. The majority of patients were admitted to us in 2014 and in June [Figure 1]. Significant clinical factors by age are shown in [Table 3]. They were location, lesion type and number, and disease duration. Comparison of meaningful demographic and clinical characteristics of patients on session numbers of <10 and ≥10 are given in [Table 4]. The odd ratios of unadjusted confounders such as lesion number ≥10, ages ≥41, crusted nodule, cicatrix, and diffuse lesions were increased in session numbers [Table 5]. The presence of crusted nodule has a significant predictive effect on session numbers (P = 0.01) [Figure 2].
Figure 1: Distribution of admitted patients number according to years and months

Click here to view
Figure 2: Predictive effects of cofounders among session number

Click here to view
Table 1: Distribution of the general characteristics of the study population

Click here to view
Table 2: Descriptive statistics of clinical, diagnostic, and treatment properties

Click here to view
Table 3: Significant clinical factors by age groups

Click here to view
Table 4: Comparison of meaningful demographic and clinical characteristics of patients on session number of <10 and ≥10

Click here to view
Table 5: Effects of meaningful cofounders on session number

Click here to view



   Discussion Top


The majority of the worldwide reported cases of CL have been from Algeria, Brasil, Iran, Syria, and Afghanistan between the years 2003 and 2008.[3] Over the years, Old World Le has been the mainly seen type in our country which is usually caused by L. tropica,[9] and 96% of these cases are usually limited to the endemic areas of the country such as the southeastern and east-Mediterranean provinces of Turkey. The various number of cases were reported across the country as L. major L. donovani, and L.infantum.[3],[10],[11] It has been stated that the prevalence of CL usually depends on the geographic distribution of the reservoir and vectors and the ecologic climate properties of the regions. However, it has been increased by diagnosis and case notification based on the infection from endemic areas to previously non-endemic regions as a result of seasonal or permanent domestic migrations because of the economic hardships and increase of settlements of immigrated refugees after a certain period of armed conflicts in nearby countries.[3],[4],[10] Because of similar reasons, the number of cases increased in the southeast after the 1980s in our country, and the number of new refugee cases made a peak in non-endemic provinces such as Istanbul, especially in the years 1994 and 2004.[3],[12] According to a recent report by The Republic of Turkey, Ministry of Interior, Directorate General of Migration Management (published on 12.27.2018), the majority of Syrian refugees are in Istanbul.[3],[12] Most of our patients were Syrian refugees [Table 1]. Similarly, most of our patients were admitted in June and in the year 2014, which corresponds with a high influx of Syrian refugees.[3],[12] Previously, it was reported in various age groups.[1],[3],[4],[9],[10],[12],[13],[14] Consistently, it was seen more likely in the youngest age group [Table 3] and [Table 4]. Most of our patients (60.5%) were also males, consistent with previous studies.[1],[9],[10],[13],[14],[15],[16] There is no sufficient and comparative data about the educational and financial condition of Le cases.[17],[18],[19],[20],[21] Most of our patients were elementary-school graduates, persons whose monthly family income was $500–750, and crowded families [Table 1] and [Table 2]. CL is defined as skin lesions, papules that evolve into plaques, nodules, and ulcers and scars, depending on the type and stage of the disease. The lesions are usually distinct enough to suggest the clinical diagnosis in endemic areas,[1],[2],[4],[7],[22] although CL usually appears as nonspecific lesions and without naming of clinical properties of the lesions such as acute/chronic and dry/wet.[3],[7],[9],[10],[14] However, considering the importance of immunity in the spreading of the disease, misleading wetness that may be caused by coexisted secondary infections aside from Leishmania spp., and the aim of the present study, we thought that whether the lesions are localized or diffuse should be added to the previous descriptions to be able to make more detailed descriptions. Thus, we classified the clinical types according to their whole properties (acute or chronic, dry or wet, and localized or diffuse), and most of (88%) our lesions were acute-dry-localized types. Crusted papule was the most common lesion type. The number of lesions varies according to the host's immunity and the number of bites but is usually unique. They are located at the site of sandfly bite, which is usually on exposed areas of the body, and especially on the head/neck regions.[1],[3],[7],[10],[14] The lesions of our patients were also mostly located on the head/neck (46.9%) regions and mostly seen with two lesions (35.8%). Because uncomplicated CL lesions usually heal over 2–20 months, they may not require treatment. However, absolute indications for treatment are stubborn lesions (lupoid type or duration > 6 months); lesion diameter > 2 cm; location on the face and joint; number of lesions > 5; location on lips, eyelids, or mucous membranes; accompanying nodular lymphangitis; psychological affected patients; and immunodeficiency.[7] Additionally, following the evaluation of predictive factors for CL in the region of our population, eventually, we reported that older age (≥41 years), higher lesion numbers (≥10) diffuse type, crusted-nodüle, and cicatrix had an impact on the increase in the session numbers for the treatment. The required treatment (≥10 sessions) was measured as a prolonged process in our observational study that we created a new prediction model to classify the new patterns of CL. It was consistent with the literature that various diverse clinical presentations and therapeutic interventions depend on the type of lesions likely in Ethiopia or Iraq where the current classification remains insufficient in CL. Probably, the combination of clinical features and predictive markers such as crusted-nodule, higher lesion numbers, cicatrix, or diffuse-type might lead to a new assessment for classification of CL and enlighten the changeability in the sessions of treatment observed in clinical practice.[13],[14],[15],[16],[23],[24] Interestingly, based on the multivariate regression analysis, we concluded that the crusted nodule had a positive influence on the number of the processes in session numbers regardless of the literature.[2],[3],[14],[25] The limited experiences in non-endemic regions, diagnosis, and unpredictable outcomes[6] can cause to estimate less likely the risks among the cases of CL from the endemic provinces in Turkey. Moreover, the disease transferred from endemic regions to non-endemic areas by increased trips, migrations, and an increase in the number of Syrian refugees.[7] The limited knowledge of non-endemic areas enlightened us to evaluate our population in the region. It is important to report that by the change of time and geographical challenges, even clinically higher lesion numbers and crusted nodules (P < 0.05) influenced the session numbers of treatment.

Regarding the limitations of our study, the small sample size has been analyzed from the data of a dermatology group in a single center and a restricted region; this might limit the generalization. In addition, our study was limited by its retrospective analysis, including measurement, observational, and recall biases. Despite these limitations, this study is a clinically valuable diagnostic tool showing to predict primary markers for CL in clinical settings. The crusted nodule was observed as a strong predictive factor regarding the strengths of our study.

The pattern of leishmaniasis patients based on the underestimated environmental changes and the impact of refugees diagnosed in Istanbul was affected by migrants from endemic countries. Although leishmaniasis is rare in Turkey, patients were evaluated properly and treated according to guidelines regardless of its re-emerged challenges. However, larger randomized clinical trials are required for the optimization of the current therapeutics of leishmaniasis in non-endemic regions.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
   References Top

1.
Glans H, Dotevall L, Söbirk SK, Färnert A, Bradley M. Cutaneous, mucocutaneous and visceral leishmaniasis in Sweden from 1996–2016: A retrospective study of clinical characteristics, treatments and outcomes. BMC Infect Dis 2018;18:632.  Back to cited text no. 1
    
2.
World Health Organization. Control of the leishmaniases. World Health Organ Tech Rep Ser 2010;xii-xiii, 1-186.  Back to cited text no. 2
    
3.
Harman M. Cutaneous Leishmaniasis. Turk J Dermatol 2015;9:168-76.  Back to cited text no. 3
    
4.
Reithinger R, Dujardin JC, Louzir H, Pirmez C, Alexander B, Brooker S. Cutaneous leishmaniasis. Lancet Infect Dis 2007;7:581-96.  Back to cited text no. 4
    
5.
Desjeux P. Leishmaniasis. Nat Rev Mirobiol 2004;2:692.  Back to cited text no. 5
    
6.
Hodiamont CJ, Kager PA, Bart A, de Vries HJ, van Thiel PP, Leenstra T, et al. Species-directed therapy for leishmaniasis in returning travellers: A comprehensive guide. PLoS Negl Trop Dis 2014;8:e2832.  Back to cited text no. 6
    
7.
Uzun S, Gurel MS, Harman M. Kutanoz Layşmanyazis Tani ve Tedavi Rehberi. Turkderm 2017;7(Suppl 1):1-30.  Back to cited text no. 7
    
8.
World Health Organization. Leishmaniasis in high-burden countries: An epidemiological update based on data reported in 2014. Releve Epidemiol Hebd 2016;91:287-96.  Back to cited text no. 8
    
9.
Akman A, Durusoy C, Seckin D, Alpsoy E. Antalya'da Görülen Kutanöz Layflmanyazis Olgularinin Epidemiyolojik Özellikleri. Turkderm 2007;41:93-6.  Back to cited text no. 9
    
10.
Özbilgin A, Töz S, Harman M, Günaştı Topal S, Uzun S, Okudan F, et al. The current clinical and geographical situation of cutaneous leishmaniasis based on species identification in Turkey. Acta Tropica 2019;190:59-67.  Back to cited text no. 10
    
11.
Gurel MS, Yesilova Y, Olgen MK, Ozbel Y. Türkiye'de Kutanöz leishmaniasisin durumu. [Current situation of cutaneous leishmanias in Turkey]. Türkiye Parazitol Derg 2012;36:121-9.  Back to cited text no. 11
    
12.
Göç İdaresi Genel Müdürlüğü. Available from: http://www.goc.gov.tr/icerik3/gecici koruma_363_378_4713.  Back to cited text no. 12
    
13.
Al-Warid HS, Al-Saqur IM, Al-Tuwaijari SN, AL Zadawi KAM. The distribution of cutaneous leishmaniasis in Iraq: Demographic and climate aspects. Asian Biomed 2017;11:255-60.  Back to cited text no. 13
    
14.
Fikre H, Mohammed R, Atinafu S, van Griensven J, Diro E. Clinical features and treatment response of cutaneous leishmaniasis in North-West Ethiopia. Trop Med Int Health 2017;22:1293-301.  Back to cited text no. 14
    
15.
Reithinger R, Mohsen M, Aadil K, Sidiqi M, Erasmus P, Coleman PG. Anthroponotic cutaneous leishmaniasis, Kabul, Afghanistan. Emerg Infect Dis 2003;9:727-9.  Back to cited text no. 15
    
16.
Kumar R, Bumb RA, Ansari NA, Mehta RD, Salotra P. Cutaneous leishmaniasis caused by Leishmania Tropica in Bikaner, India: Parasite identification and characterization using molecular and immunologic tools. Am J Trop Med Hyg 2007;76:896-901.  Back to cited text no. 16
    
17.
Bern C, Courtenay O, Alvar J. Of cattle, sand flies and men: A systematic review of risk factor analyses for South Asian visceral leishmaniasis and implications for elimination. PLoS Negl Trop Diseases 2010;4:e599.  Back to cited text no. 17
    
18.
Boelaert M, Meheus F, Sanchez A, Singh SP, Vanlerberghe V, Picado A, et al. The poorest of the poor: A poverty appraisal of households affected by visceral leishmaniasis in Bihar, India. Trop Med Int Health 2009;14:639-44.  Back to cited text no. 18
    
19.
Herrero M, Orfanos G, Argaw D, Mulugeta A, Aparicio P, Parreño F, et al. Natural history of a visceral leishmaniasis outbreak in highland Ethiopia. Am J Trop Med Hyg 2009;81:373-7.  Back to cited text no. 19
    
20.
Malafaia G. Protein-energy malnutrition as a risk factor for visceral leishmaniasis: A review. Parasite Immunol 2009;31:587-96.  Back to cited text no. 20
    
21.
Harhay MO, Olliaro PL, Costa DL, Costa CH. Urban parasitology: Visceral leishmaniasis in Brazil. Trends Parasitol 2011;27:403-9.  Back to cited text no. 21
    
22.
Handler MZ, Patel PA, Kapila R, Al-Qubati Y, Schwartz RA. Cutaneous and mucocutaneous leishmaniasis: Differential diagnosis, diagnosis, histopathology, and management. J Am Acad Dermatol 2015;73:911-26.  Back to cited text no. 22
    
23.
Uzun S, Gürel MS, Durdu M, Akyol M, Fettahlıoğlu Karaman B, Aksoy M, et al. Clinical practice guidelines for the diagnosis and treatment of cutaneous leishmaniasis in Turkey. Int J Dermatol 2018;57:973-82.  Back to cited text no. 23
    
24.
Sergiev V, Kondrashin A, Litvinov S, Morozova L, Turbabina N, Stepanova E, et al. Epidemiology and control of leishmaniasis in the former USSR: A review article. Iran J Parasitol 2018;13:342-50.  Back to cited text no. 24
    
25.
Pigott DM, Bhatt S, Golding N, Duda KA, Battle KE, Brady OJ, et al. Global distribution maps of the leishmaniases. Elife 2014;3:e02851.  Back to cited text no. 25
    


    Figures

  [Figure 1], [Figure 2]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5]



 

Top
Print this article  Email this article
 
 
  Search
 
  
    Similar in PUBMED
   Search Pubmed for
   Search in Google Scholar for
 Related articles
    Article in PDF (590 KB)
    Citation Manager
    Access Statistics
    Reader Comments
    Email Alert *
    Add to My List *
* Registration required (free)  


    Abstract
   Introduction
   Materials and Method
   Results
   Discussion
    References
    Article Figures
    Article Tables

 Article Access Statistics
    Viewed222    
    Printed4    
    Emailed0    
    PDF Downloaded15    
    Comments [Add]    

Recommend this journal