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Human Immunodeficiency Virus (HIV) infection is a global pandemic, with cases reported from virtually every country. World Health Organization (WHO) has estimated 34.0 million (31.4-35.9) global people living with HIV in 2011. Based on HIV Sentinel Surveillance 2008-09, it is estimated that India has 23.9 lakh people infected with HIV. Human Immunodeficiency Virus infection was first reported in India in the state of Tamil Nadu in 1986, since then the cases of Cryptococcal Meningitis (CM) have also increased. [1] Morbidity and mortality in HIV patients is mostly caused by opportunistic infections (OI) that occur due to lowered immune defences of the patients associated with decreased CD4 counts. Among these, meningitis with HIV has an important impact causing considerable morbidity and mortality. Meningitis associated with HIV infection can be classified according to aetiologic agents as fungal, tubercular, syphilitic and pyogenic. The most common OI in HIV patients in India is either tubercular or fungal. [2] Cryptococcosis is a fungal disease caused by Cryptococcus neoformans (CN), which begins as droplet infection in the respiratory tract and eventually spreads to central nervous

system to produce meningitis (CM).

Cryptococcal meningitis (CM) is one of the presenting manifestations of Acquired Immune Deficiency Syndrome (AIDS). [3] Cryptococcal meningitis is one of the most common OI among HIV-infected individuals, with an estimated 10 lakh cases of HIV associated CM and 6 lakh deaths every year or more than 1700 deaths everyday. [4] Despite cryptococcal disease accounting for 13-44% of deaths in HIV-infected patients, cryptococcal diseases continue to be grossly under-diagnosed. [5] Recent data indicates that the incidence of cryptococcal infection is high in India. [6] It is the leading infectious cause of meningitis in patients with AIDS and is the initial AIDS defining diagnosis in approximately 2% of patients, mostly occurring in those with CD4 counts less than 100 cells/[mm.sup.3]. [7]

Cryptococcal antigen (CRAG), a biological marker for Cryptococcal infection, is detectable in sera a median of 3 weeks (range 5-234 days) before symptoms of meningitis appear. [8] Positive Cryptococcal antigenaemia is an independent predictor of CM and death in patients with severe immunosuppression. [9] This asymptomatic period before development of symptomatic meningitis provides a window of opportunity to treat patients and potentially prevent fatal Cryptococcal disease. CRAG detection is highly sensitive as compared with microscopy and culture. [10] The best prophylaxis to prevent OI is an immune reconstitution with anti-retro viral therapy (ART). In areas of high prevalence, the CM screening prior to ART is necessary for potential early diagnosis and treatment. This could decrease the risk of Immune Reconstitution Inflammatory Syndrome (IRIS). The WHO has recently released "Rapid Advice" guidelines for Cryptococcal disease among persons living with HIV. Early diagnosis is key to reduce mortality due to Cryptococcal disease. A major WHO recommendation is implementation of SCRAG screening and presumptive antifungal therapy (typically oral fluconazole) in those with a positive diagnostic test among ART naive adults with a CD4 count less than 100 cell/[mm.sup.3] in areas with a high prevalence of Cryptococcal disease (> 3%).

One limitation to implementing the WHO guidelines is that currently very less data exists on the extent of Cryptococcal infection in India. Hence, this prompted the study which aims at finding occurrence of and risk factors associated with Cryptococcal antigenaemia in ART naive patients with HIV. The purpose of our study was to determine the prevalence of and risk factors for Cryptococcal antigenaemia among HIV-infected adults attending ART clinic and medical emergency at SCB Medical College and Hospital, Cuttack.


Study Design: Cross-sectional observational study with asking research questionnaire developed for this purpose.

Study Location

This study was undertaken among newly diagnosed antiretroviral therapy naive HIV/AIDS infected patients at the Postgraduate Department of Medicine, SCB Medical College, Cuttack after taking written informed consent. Hundred patients admitted in the medical wards and visiting ART clinic were considered for this study from May 2016 to Apr 2017. The screening test was done for serum cryptococcal antigen (SCRAG).

Inclusion Criteria

ART naive patients [greater than or equal to] 18 years documented for HIV infection and confirmed by a series of 3 tests as per NACO Guidelines (First by dot immunoassay followed by two different immunochromatographic tests).

Exclusion Criteria

Previously diagnosed Cryptococcosis patients on fluconazole therapy and satisfying the above criteria.

Ethical Issues

This study confirms to the ethical principles of medical research developed by the World Medical Association Declaration of Helsinki. Ethical clearance was given by the Institutional Ethics Committee of SCB Medical College, Cuttack.

Data Analysis: All data obtained with questionnaire and microbiological culture analysis were analysed using the statistical software SSPS 16.0. The Chi-square test was used to compare between two groups. Statistical significance was accepted when P value is [less than or equal to] 0.05 and the Univariate and multivariate logistic regression analyses were done to assess risk factors for a positive cryptococcal antigenaemia. Risk factors with possible significance and known to be associated with cryptococcal disease were included in the present study.


The mean age of the study population was being 36.14 [+ or -] 10.42 years (ranges 18-67 years) and median was being 35 years. The mean body mass index (BMI) of our study population was 20.54 kg/[m.sup.2] [+ or -] 2.72 (ranges 15.1 to 26.48 kg/[m.sup.2]). The present study population had mean cluster differentiation (CD4) count of 233 cells/[mm.sup.3] [+ or -] 176 (ranges 6 to 780 cells/[mm.sup.3]) (Table 1).

The maximum number of patients were from age group of 30-39 years (42%) followed by 18-30 years (24%), 40-50 years (20%) and >50 years (14%). There were 65% males (65 out of 100) and 35% (35 out of 100) females in our study and the male to female ratio was being 1.86. Maximum patients had BMI in between 18.5 to 25 kg/[m.sup.2] followed by 20% with < 18.5 kg/[m.sup.2] and 6% with >25 kg/[m.sup.2]. In the present study, 31% of individuals had CD4 count <100 cells/[mm.sup.3] and 69% >100 cells/[mm.sup.3] were observed. Signs and symptoms of meningitis were found in 17% and others were asymptomatic (Table 2).

The mean age among patients with serum cryptococcal antigen positive (SCRAG +) was 43.71 years as compared to 35.57% in cryptococcal antigen negative (SCRAG-) and this difference was statistically significant (p-0.046). The mean BMI of SCRAG+ patients and SCRAG- were 20.22 [+ or -] 2.64 kg/[m.sup.2] and 20.56 [+ or -] 2.74 respectively, which is statistically insignificant. The mean CD4 count of SCRAG- patients (246 [+ or -] 175.0) cells/[mm.sup.3] was higher than SCRAG+ patients (56.57 [+ or -] 56.0). The median CD4 count was being forty one (41 cells/[mm.sup.3]) in SCRAG+ and 203 cells/[mm.sup.3] in SCRAG- patients. The difference was statistically significant (p=0.001) (Table 3).

Out of 65 males, 5 (7.7%) were positive for SCRAG and 2 (5.7%) were positive among 35 female patients. Majority of the study population were literate (77%) and doing unskilled work (63%). Maximum cases (88, 88%) of the study population were married. The sexual transmission route for HIV infection was found to be 99% where the duration of illness is longer. The majority of SCRAG+ (6 out of 7) patients had BMI between 18.5 to 25 kg/[m.sup.2] as compared to the other groups, but the difference was not statistically significant. Out of 33 patients who had CD4 count <100 cells/[mm.sup.3], 6 (19.35%) were positive for SCRAG and significant statistically (p< 0.003). Of sixty-nine patients who had CD4 count >100 cells/[mm.sup.3], 1 (1.45%) was positive for SCRAG having statistically significance (p<0.012). Patients with cryptococcal antigenaemia were more prone to have CD4 count <100 cells/[mm.sup.3] (Table 4).

Univariate analysis showed fever (p<0.005, OR 23.368, CI 2.652-205.398), headache (p<0.010, OR 8.205, CI 1.644-40.950), vomiting (p<0.004, OR 13.200, CI 2.300-75.750), neck rigidity (p<0.014, OR 7.969, CI 1.510-42.044) and CD4 count <100 cells/[mm.sup.3] (p<0.012, OR 16.320, CI 1.871-142.374) were significantly associated with Cryptococcal antigenaemia. However, age, sex, socioeconomic status, marital status, altered mental status, duration of HIV infection, BMI and CD4 count <200 cells/[mm.sup.3] were not significantly associated with cryptococcal antigenaemia (Table 5).

In multivariate analysis, CD4 count <50 cells/[mm.sup.3] was acting as independent risk factor for cryptococcal antigenaemia (p <0.019, OR 17.769, CI 1.594-198.042) (Table 6). However, the other factors did not contribute to independent risk factors in the present study.


In the present study, overall prevalence of Cryptococcal antigenaemia is found to be 7%, which is comparable to the studies in Uganda (5-10%), [11] South Africa (7%) [12] and Kenya (7%), [13] which confirms that India has high rates of cryptococcal disease in HIV-infected patients in comparison to tuberculosis. The prevalence of patients with CD4 count less than 100 cells/[mm.sup.3] is 19.35% in the present study, which coincides with the study of Otella et al [13] in Uganda. Out of 17 meningitis cases, 4 (23.52%) cases are having cryptococcal meningitis as compared with Gomerep et al. [14] We observed the overall mean age being 36 years (range 18-67 years) and 43 years in SCRAG positive group as compared to 35 years in SCRAG negative group (p<0.046). On univariate analysis, we did not find advanced age as a risk factor. [15] There are 65 males and 35 females and the M: F ratio being 1.86:1 as compared with earlier studies. [15] Most of the study population has average income and literate doing unskilled work but they do not have any significant difference with positivity of SCRAG (p>0.05).

In the present study, all patients with SCRAG+ are recently diagnosed for HIV and 14 (19.71%) out of 71 have advanced disease and 25 (35.21%) patients have CD4 count less than 100 cells/[mm.sup.3], which may be due to lack of IEC (information, education and communication) activities to reach all section of population of our country.

There are 17 symptomatic patients out of which 4 (23.5%) are SCRAG+ and out of 83 asymptomatic patients 3 (3.6) are SCRAG+, which is statistically significant (p<0.015). [10] The symptoms of fever, headache, vomiting and neck rigidity are significantly associated with Cryptococcal antigenaemia (p<0.05). [16]

The mean BMI of the study population is 20.54 kg/[m.sup.2]. The SCRAG + has showed BMI 20.22 kg/[m.sup.2] whereas SCRAG-cases 20.56 kg/[m.sup.2], which is definitely higher than the previous researchers (<15.4 kg/[m.sup.2]) Oyella et. al and Micol et al.13,17 They have included patients with more advanced disease and lesser CD4 counts.

The median CD4 count of SCRAG+ individuals is 41 cells/[mm.sup.3] (mean 56, range 6-168, IQR 19.000-78.250) as compared to 203 cells/[mm.sup.3] (mean 246, range 15-780, IQR 91-370) in SCRAG- individuals (p<0.001) in Andama et al study.18 The CD4 count <100 cells/[mm.sup.3] is found in 31 patients out of which 6 (19.35%) are SCRAG+ in comparison to CD4 count >100 cells/[mm.sup.3] in which 1.45% are SCRAG+. On univariate analysis, CD4 count <100 cells/[mm.sup.3] is significantly associated with positive SCRAG (p< 0.012, OR- 16.320, 95% CI 1.871-142.374) as studied by Tenna et al, [11] but 67 cases in multivariate analysis do act as independent risk factor for Cryptococcal antigenaemia in Oyella et al study. [13] We observed high prevalence of subclinical infection 3 (3.6%) in the present study irrespective of CD4 count. Antigenaemia is not only predictive of the development of cryptococcal meningitis but also an independent predictor of mortality. [12]


There is a high prevalence of symptomatic Cryptococcal antigenaemia (7%) and asymptomatic Cryptococcal antigenaemia (3.6%) in ART naive HIV patients irrespective of CD4 count. There is a high prevalence of Cryptococcal antigenaemia (19.35%) in ART naive patients having CD4 count <100 cells/[mm.sup.3]. Symptoms like fever, headache, vomiting and neck rigidity have been observed in patients having CD4 count <100 cells/[mm.sup.3], significant association with Cryptococcal antigenaemia on univariate analysis seen. Cryptococcal antigenaemia is not only predictive of the development of cryptococcal meningitis in HIV patients but also an independent predictor of mortality. All ART naive adults having CD4 count <100 cells/[mm.sup.3] should be screened for serum Cryptococcal antigen followed by presumptive antifungal therapy if serum Cryptococcal antigen is positive. There is a need to strengthen IEC (information, education and communication) activities and increase routine counselling and testing of the patients attending ART clinics in Odisha.


SCRAG--serum cryptococcal antigenaemia, CD4--cluster differentiation, HIV--Human Immunodeficiency Virus, WHO--World Health Organization, CM--Cryptococcal meningitis, OI--opportunistic infections, AIDS--Acquired Immune Deficiency Syndrome, IQR--Interquartile range, CD4--cluster differentiation (cells/[mm.sup.3]) and BMI--body mass index and C.I-95% Confidence Intervals of Odds Ratios.


[1] Simoes EA, Babu GP, John TJ, et al. Evidence for HTLV-3 infection in prostitutes in Tamil Nadu (India). Indian J Med Res 1987;85:335-8.

[2] Sharma SK, Kadhiravan T, Banga A, et al. Spectrum of clinical disease in a series of 135 hospitalised HIV-infected patients of north India. BMC Infected Dis 2004;4:52.

[3] Lakshmi V, Sudha T, Teja VD, et al. Prevalence of central nervous system cryptococcosis in human immunodeficiency virus reactive hospitalized patients. Indian Med Microbiol 2007;25(2):146-9.

[4] Park BJ, Wannemuehler KA, Marston BJ, et al. Estimation of current global burden of cryptococcal meningitis among persons living with HIV/AIDS. AIDS 2009;23(4):525-30.

[5] Churchyard GJ, Kleinschmidt I, Corbett EL, et al. Factors associated with an increased case-fatality rate in HIV-infected and non-infected South African gold miners with pulmonary tuberculosis. Int J Tuberc Lung Dis 2000;4(8):705-12.

[6] Manoharan G, Padmavathy BK, Vasanthi S, et al. Cryptococcal meningitis among HIV-infected patients. Indian J Med Microbiol 2001;19(3):157-8.

[7] Rao VK, Thomas FP. Neurological complications of HIV/AIDS. BETA 2005;17(2):37-46.

[8] French N, Gray K, Watera C, et al. Cryptococcal infection in a cohort of HIV-1-infected Ugandan adults. AIDS 2002;16(7):1031-8.

[9] Liechty CA, Solberg P, Were W, et al. Asymptomatic serum cryptococcal antigenemia and early mortality during antiretroviral therapy in rural Uganda. Trop Med Int Health 2007;12(8):929-35.

[10] Kambugu A, Meya DB, Rhein J, et al. Outcomes of cryptococcal meningitis in Uganda before and after the availability of highly active antiretroviral therapy. Clin Infect Dis 2008;46(11):1694-701.

[11] Tenna A. Screening for cryptococcal infection in HIV-infected patients visiting HIV clinics at two hospitals in Addis Ababa, Ethiopia. 3 rd Methods in International Neuro AIDS Rearch 2011.

[12] Tassie JM, Pepper L, Fogg C, et al. Systematic screening of cryptococcal antigenemia in HIV-positive adults in Uganda. J Acquir Immune Defic Syndr 2003;33(3):411-2.

[13] Oyella J, Meya D, Bajunirwe F, et al. Prevalence and factors associated with cryptococcal antigenemia among severely immunosuppressed HIV-infected adults in Uganda: a cross sectional study. J Int AIDS Soc 2012;15(1):15.

[14] Gomerep SS, Idoko JA, Ladep NG, et al. Frequency of cryptococcal meningitis in HIV-1 infected patients in north central Nigeria. Niger J Med 2010;19(4):395-9.

[15] Osazuwa F, Dirisu JO, Okuonghae PE, et al. Screening for cryptococcal antigenenemia in anti-retroviral naive AIDS patient in Benin City, Nigeria. Oman Med J 2012;27(3):228-31.

[16] Beyene T, Woldeamanuel Y, Asrat D, et al. Comparison of cryptococcal antigenemia between antiretroviral naive and antiretroviral experienced HIV positive patients at two hospitals in Ethiopia. PLoS One 2013;8(10):e75585.

[17] Micol R, Lortholary O, Sar B, et al. Prevalence, determinants of positivity, and clinical utility of cryptococcal antigenemia in Cambodian HIV-infected patients. J Acquir Immune Defic Syndr 2007;45(5):555-9.

[18] Andama AO, den Boon S, Meya D, et al. Prevalence and outcomes of cryptococcal antigenemia in HIVseropositive patients hospitalized for suspected tuberculosis in Uganda. J Acquir Immune Defic Syndr 2013;63(2):189-94.

Dibya Prasana Mohanty (1), Dharma Niranjan Mishra (2), Dillip Kumar Pradhan (3)

(1) Assistant Professor, Department of Microbiology, Utkal University, SCB Medical College, Cuttack.

(2) Assistant Professor, Department of Anatomy, Utkal University, SCB Medical College, Cuttack.

(3) Senior Resident, Department of Medicine, Utkal University, SCB Medical College, Cuttack.

'Financial or Other Competing Interest': None.

Submission 12-10-2017, Peer Review 05-11-2017, Acceptance 11-11-2017, Published 20-11-2017.

Corresponding Author:

Dharma Niranjan Mishra, Flat No. 3-B, Neelamani Enclave, Professor Pada, Post- College Square, Cuttack-753003.


DOI: 10.14260/jemds/2017/1365
Table 1. Age, BMI and CD4 Count Characteristics Distribution of
Study Population

    Characteristic        No.      Mean [+ or -] SD       Median

     Age in years         100     36.14 [+ or -] 10.42       35
   BMI(kg/[m.sup.2])      100     20.54 [+ or -] 2.72      20.271
   CD4 count cells/       100    233.06 [+ or -] 176.13     196

    Characteristic        Range Min-Max     I Q Range

     Age in years             18-67          30.0-42
   BMI(kg/[m.sup.2])        15.1-26.48     19.13-22.36
   CD4 count cells/           6-780         70.5-355.5

I. Q. R.--Interquartile range, CD4--cluster differentiation
(cells/[mm.sup.3]) and BMI--body mass index

Table 2. Demographic and Clinical Characteristics of the Study

            Age in years                Number(n)    Percentage

                18-29                       24           24%
                30-39                       42           42%
                40-49                       20           20%
    [greater than or equal to]50            14           14%
                Male                        65           65%
               Female                       35           35%
       BMI (kg/[m.sup.2])<18.5              20           20%
      BMI (kg/[m.sup.2])18.5-25             74           74%
        BMI (kg/[m.sup.2])>25               06           6%
  CD4 count <100 (cells/[mm.sup.3])         31           31%
  CD4 count >100 (cells/[mm.sup.3])         69           69%
    Signs and symptoms Meningitis           17           17%
            Asymptomatic                    83           83%

BMI--body mass index, CD-cluster differentiation

Table 3. Age, BMI and CD4 Count Characteristics Distribution of SCRAG
Positive and SCRAG Negative Patients

        Type                        SCRAG Positive(n=7)

   Characteristic           Age in years         BMI (kg/[m.sup.2])

 Mean [+ or -] S.D      43.71 [+ or -] 13.94     20.22 [+ or -] 2.64
       Median                    40                     19.1
       Range                   26-67                  16.9-23.9
     I Q Range               35.5-52.25               18.7-22.8
      P value                  0.046                    0.750

        Type            SCRAG Positive(n=7)     SCRAG Negative(n=93)

   Characteristic        CD4 count (cells/          Age in years

 Mean [+ or -] S.D      56.57 [+ or -] 56.0     35.57 [+ or -] 9.978
       Median                   41                       35
       Range                   6-168                   18-64
     I Q Range               19.0-78.3               29.75-42.0
      P value                  0.001                   0.046

        Type                         SCRAG Negative(n=93)

   Characteristic       BMI (kg/[m.sup.2])        CD4 count (cells/

 Mean [+ or -] S.D      20.56 [+ or -] 2.74     246.34 [+ or -] 175.0
       Median                  20.5                      203
       Range                 15.1-26.5                 15-780
     I Q Range               19.3-22.4                91-370.0
      P value                  0.750                    0.001

SCRAG--serum cryptococcal antigen, I Q Range--Interquartile range,
CD4 count-cluster differentiation count (cells/[mm.sup.3]), P value

Table 4. Comparison of Different Parameters in SCRAG+ and
SCRAG- Study Group

          Parameters              SCRAG+ (n=7)    SCRAG- (93)

             Male                    5 (7.7)       60 (92.3%)
            Female                  2 (5.7%)       33 (94.3%)
          Illiterate                2 (8.7%)       21 (91.3%)
   Education <10th standard         2 (4.5%)       42 (95.5%)
   Education >10th standard         3 (9.1%)       30 (90.9%)
        Skilled worker              3 (8.1%)       34 (91.9%)
       Unskilled worker             4 (6.3%)       59 (93.7%)
            Married                 6 (6.8%)       82 (93.2%)
           Unmarried                1 (8.3%)       11 (91.7%)
  Recent onset of the disease       7 (9.9%)       64 (90.1%)
  Past history of the disease        0 (0%)        29 (100%)
    BMI <18.5 kg/[m.sup.2]          1 (4.5%)       19 (95.5%)
  BMI 18.5-25.0 kg/[m.sup.2]        6 (8.2%)       68 (91.8%)
    BMI >25.1 kg/m[m.sup.2]          0 (0%)         6 (100%)
   CD4<100 cells/[mm.sup.3]        6 (19.35%)     27 (80.65%)
   CD4>100 cells/[mm.sup.3]         1 (1.45%)     68 (98.55%)
       Symptomatic Cr Ag            4 (23.5%)      13 (76.5%)
      Asymptomatic Cr Ag            3 (3.6%)       80 (96.4%)

          Parameters                 Total      P Value

             Male                  65 (100%)      1.00
            Female                 35 (100%)      1.00
          Illiterate               23 (100%)     0.660
   Education <10th standard        44 (100%)     0.660
   Education >10th standard        33 (100%)     0.660
        Skilled worker             37 (100%)     0.708
       Unskilled worker            63 (100%)     0.708
            Married                88 (100%)      1.00
           Unmarried               12 (100%)      1.00
  Recent onset of the disease      71 (100%)     0.104
  Past history of the disease      29 (100%)     0.104
    BMI <18.5 kg/[m.sup.2]         20 (100%)     0.700
  BMI 18.5-25.0 kg/[m.sup.2]       74 (100%)     0.700
    BMI >25.1 kg/m[m.sup.2]        6 (100%)      0.700
   CD4<100 cells/[mm.sup.3]        33 (100%)     0.001
   CD4>100 cells/[mm.sup.3]        69 (100%)     0.001
       Symptomatic Cr Ag          17 (76.5%)     0.015
      Asymptomatic Cr Ag          83 (96.4%)     0.015

CD--cluster differentiation, SCRAG--serum cryptococcal antigen

Table 5. Univariate Analysis of Risk Factors for Cryptococcal
Antigenaemia among HIV-infected Patients

                                   Odds     95% CI for Odds Ratio
     Risk Factor        P value    Ratio
                                              Lower        Upper

    Age in years         0.055     1.072      0.999        1.151

      Male sex           0.713     0.727      0.134        3.957

   Education < 8th       0.489     0.488      0.064        3.712

   Education > 8th       0.913     1.086      0.167        7.085

       Married           0.847     0.805      0.088        7.237

  BMI kg/[m.sup.2]       0.747     0.954      0.718        1.268

 CD4 count <50cells/     0.001     20.750     3.548       121.385

   CD4 count <100        0.012     16.320     1.871       142.374

   CD4 count <200        0.053     17.414     0.967       313.749

        Fever            0.005     23.368     2.652       205.368

      Headache           0.010     8.205      1.644       40.950

      vomiting           0.004     13.200     2.300       75.750

    Neck rigidity        0.014     7.969      1.510       42.044

   Altered mental        0.617     1.771      0.189       16.595

C.I-95% Confidence Intervals of Odds Ratios

Table 6. Multivariate Analysis of Risk Factors for Cryptococcal
Antigenaemia Among HIV-infected Patients

       Risk factor           P value    Odds Ratio

          Fever               0.074       12.736
         Headache             0.991        1.022
         vomiting             0.293        4.474
      Neck rigidity           0.568       17.761
   CD4 count <50 cells/       0.019       17.769

       Risk factor           95% C.I for Odds Ratio

          Fever                 0.780      208.014
         Headache               0.022       47.211
         vomiting               0.274       73.150
      Neck rigidity             1.594      198.042
   CD4 count <50 cells/         1.594      198.042

95% Confidence Intervals of Odds Ratios
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Title Annotation:Original Research Article
Author:Mohanty, Dibya Prasana; Mishra, Dharma Niranjan; Pradhan, Dillip Kumar
Publication:Journal of Evolution of Medical and Dental Sciences
Date:Nov 20, 2017

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