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   Table of Contents - Current issue
Coverpage
April 2020
Volume 151 | Issue 4
Page Nos. 263-385

Online since Tuesday, May 12, 2020

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EDITORIALS  

The future of autism: Global & local achievements & challenges Highly accessed article p. 263
Catherine Lord
DOI:10.4103/ijmr.IJMR_874_20  
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Accelerating progress towards ending tuberculosis in India p. 266
Kuldeep Singh Sachdeva
DOI:10.4103/ijmr.IJMR_407_20  
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Thinking globally about cancer research on World Cancer Day p. 269
Satish Gopal, Sudha Sivaram, Preetha Rajaraman, Edward L Trimble
DOI:10.4103/ijmr.IJMR_198_20  
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COMMENTARY Top

Desmin dysregulation in gall bladder cancer p. 273
Balraj Mittal
DOI:10.4103/ijmr.IJMR_1540_19  
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PERSPECTIVE Top

Attack on statistical significance: A balanced approach for medical research p. 275
Abhaya Indrayan
DOI:10.4103/ijmr.IJMR_980_19  
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REVIEW ARTICLES Top

A juggernaut of innate & adaptive immune cells in chronic hepatitis C p. 279
Shallu Tomer, Sunil K Arora
DOI:10.4103/ijmr.IJMR_1387_17  
Hepatitis C virus (HCV) is a small positive-sense, single-stranded RNA virus, the causal organism for chronic hepatitis. Chronic hepatitis leads to inflammation of liver, causing cirrhosis, fibrosis and steatosis, which may ultimately lead to liver cancer in a few cases. Innate and adaptive immune responses play an important role in the pathogenesis of HCV infection, thus acting as an important component in deciding the fate of the disease. Numerous studies have indicated that the derangement of these immune responses results in the persistence of infection leading to chronic state of the disease. Interactions between virus and host immune system generally result in the elimination of virus, but as the virus evolves with different evading mechanisms, it makes environment favourable for its survival and replication. It has been reported that HCV impairs the immune system by functional modulation of the cells of innate as well as adaptive immune responses, resulting in chronic state of the disease, influencing the response to antiviral therapy in these patients. These defects in the immune system lead to suboptimal immune responses and therefore, impaired effector functions. This review highlights the involvement or association of different immune cells such as natural killer cells, B cells, dendritic cells and T cells in HCV infection and how the virus plays a role in manipulating certain regulatory mechanisms to make these cells dysfunctional for its own persistence and survival.
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Community-acquired bacterial pneumonia in adults: An update p. 287
Vandana Kalwaje Eshwara, Chiranjay Mukhopadhyay, Jordi Rello
DOI:10.4103/ijmr.IJMR_1678_19  
Community-acquired pneumonia (CAP) is the prominent cause of mortality and morbidity with important clinical impact across the globe. India accounts for 23 per cent of global pneumonia burden with case fatality rates between 14 and 30 per cent, and Streptococcus pneumoniae is considered a major bacterial aetiology. Emerging pathogens like Burkholderia pseudomallei is increasingly recognized as an important cause of CAP in Southeast Asian countries. Initial management in the primary care depends on clinical assessment while the hospitalized patients require combinations of clinical scores, chest radiography and various microbiological and biomarker assays. This comprehensive diagnostic approach together with additional sampling and molecular tests in selected high-risk patients should be practiced. Inappropriate therapy in CAP in hospitalized patients lengthens hospital stay and increases cost and mortality. In addition, emergence of multidrug-resistant organisms poses tough challenges in deciding empirical as well as definitive therapy. Developing local evidence on the cause and management should be a priority to improve health outcomes in CAP.
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POLICY DOCUMENT Top

ICMR Consensus Guidelines on ‘Do Not Attempt Resuscitation’ Highly accessed article p. 303
Roli Mathur
DOI:10.4103/ijmr.IJMR_395_20  
Cardiopulmonary resuscitation (CPR) is widely practised by healthcare professionals to revive heart beat and breathing in a patient suffering from cardiac/ respiratory arrest. It is increasingly being recognized that in some patients with specific medical conditions, CPR does not alter the overall outcome of illness, and is likely to increase suffering and further deteriorate the quality of life. Do Not Attempt Resuscitation (DNAR) as an option has been practised in many countries for such cases to avoid futile CPR and maintain dignity of the patient. The decision of DNAR should be taken by the treating physician who is well versed with the patient's medical condition, with information to the patient or her/his surrogate. While ordering DNAR on the patient's medical case record, every effort should be made to treat the underlying disease and continue optimal medical care with compassion. This policy document describes the principles for DNAR, offers an algorithm and format for its implementation, and guidance on frequently asked questions.
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ORIGINAL ARTICLES Top

Epigenetic downregulation of desmin in gall bladder cancer reveals its potential role in disease progression p. 311
Shushruta Bhunia, Mustafa Ahmed Barbhuiya, Sanjiv Gupta, Braj Raj Shrivastava, Pramod Kumar Tiwari
DOI:10.4103/ijmr.IJMR_501_18  
Background & objectives: Gall bladder cancer (GBC) is a fatal neoplasm, with a globally variable incidence rates. To improve the survival rate of patients, a newer set of biomarkers needs to be discovered for its early detection and better prognosis. Our earlier studies on GBC proteomics and whole-genome methylome data revealed expression of desmin to be significantly downregulated with correlated promoter hypermethylation during gall bladder carcinogenesis. Thus, to evaluate desmin as a potential biomarker for GBC, we carried out a detailed follow up study. Methods: Methylation-specific polymerase chain reaction (MS-PCR) (n=17, GBC and n=23, non-tumour control), real-time quantitative reverse transcription-polymerase chain reaction (qRT-PCR) [n=14, GBC and n=14, adjacent non-tumour (ANT)], immunohistochemistry (n=27, GBC and n=14, non-tumour) and immunoblotting (n=13, GBC and n=13, ANT) were performed in surgically removed gall bladder tissue samples. Results: MS-PCR analysis showed methylation of desmin in 88.23 per cent (15/17) gall bladder tumour samples as compared to non-tumour tissues (39.13%, 9/23). Real-time qRT-PCR analysis revealed a significant downregulation of desmin expression in GBC as compared to ANT tissue. This was further confirmed by western blot, showing reduced expression of desmin protein in GBC, as compared to non-tumour tissue. Immunohistochemical analysis also showed a decreased level of desmin i.e., more than 95 per cent (26/27) in tumour cells compared to non-tumours (35.71%, 5/14). Interpretation & conclusions: The increased frequency of desmin promoter methylation which could be responsible for its significant downregulation, indicates its potential as a candidate biomarker for GBC. This requires further validation in a large group of patients to evaluate its clinical utility.
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Club cell protein 16 as a biomarker for early detection of silicosis p. 319
Nibedita Naha, Jaseer C.J. Muhamed, Avinash Pagdhune, Bidisa Sarkar, Kamalesh Sarkar
DOI:10.4103/ijmr.IJMR_1799_18  
Background & objectives: Clinically silicosis is diagnosed by chest X-ray showing specific opacities along with history of silica dust exposure. Diagnosis is invariably made at an advanced or end stage when it is irreversible. Moreover, silicosis patients are susceptible to develop tuberculosis. Therefore, a suitable biomarker for early detection of silicosis is needed. This study evaluated the suitability of club cell protein (CC16) as a biomarker for early detection of silicosis. Methods: This pilot study included 121 individuals from X-ray-confirmed/advanced silicosis, moderate silica dust-exposed workers and healthy controls from western India. CC16 levels were quantified in serum samples through ELISA. Sensitivity and specificity of CC16 values at different cut-off points were calculated in both non-smokers and smokers. Results: Serum CC16 level was significantly (P <0.01) decreased in X-ray confirmed advanced silicosis patients (4.7±3.07 ng/ml) followed by moderately exposed workers (10.2±1.77 ng/ml) as compared to healthy non-exposed individuals (16.7±3.81 ng/ml). Tobacco smoking also caused a significant decrease of serum CC16 concentration in both healthy (10.2±1.12 ng/ml) and advanced silicosis workers (2.6±2.28 ng/ml) compared to non-smokers. Sensitivity and specificity of CC16 values were also found to be ≥83 per cent for screening all categories of individuals. Interpretation & conclusions: Because of high sensitivity and specificity, serum CC16 could be used as predictive biomarker for suspicion and early detection of silicosis, which would help in reducing/delaying premature deaths caused by silicosis. It would also control silicotuberculosis additionally.
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Homozygous sickle cell disease in Central India & Jamaica: A comparison of newborn cohorts p. 326
Dipty Jain, Rajini Tokalwar, Dipti Upadhye, Roshan Colah, Graham Roger Serjeant
DOI:10.4103/ijmr.IJMR_1946_18  
Background & objectives: Homozygous sickle cell (SS) disease in Central India runs a more severe clinical course than reports from other areas of India. The current study was undertaken to compare the disease in Central India (Nagpur) with that in Jamaica, both populations defined by newborn screening. Methods: The Nagpur cohort included infants born to sickling-positive mothers from May 2008 to 2012, examined by high-pressure liquid chromatography and DNA analysis. The Jamaican cohort screened 100,000 consecutive non-operative deliveries between June 1973 and December 1981, analyzed by haemoglobin (Hb) electrophoresis and confirmed by family studies and compatible HbA2levels. Results: In Nagpur, 103 SS patients were detected, but only 78 (76%) were followed up. In Jamaica, 311 cases were followed from birth and compliance with follow up remained 100 per cent up to 45 years. In the Nagpur cohort all had the Asian haplotype, and 82 per cent of Jamaicans had at least one Benin chromosome; none had the Asian haplotype. Compared to Jamaica, Nagpur patients had higher foetal Hb, less alpha-thalassaemia, later development of splenomegaly and less dactylitis. There were also high admission rates for febrile illness and marked anaemia. Invasive pneumococcal disease occurred in 10 per cent of Jamaicans but was not seen in Nagpur. Interpretation & conclusions: There were many differences between the disease in Nagpur, Central India and the African form observed in Jamaica. The causes of severe anaemia in Nagpur require further study, and reticulocyte counts may be recommended as a routine parameter in the management of SS disease. The role of pneumococcal prophylaxis needs to be determined in Nagpur patients. Future studies in India must avoid high default rates.
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Fibroscan as a non-invasive predictor of hepatic steatosis in women with polycystic ovary syndrome p. 333
Semanti Chakraborty, Mohd Ashraf Ganie, Ibrahim Masoodi, Manisha Jana, Shalimar, Nandita Gupta, Nighat Yaseen Sofi
DOI:10.4103/ijmr.IJMR_610_18  
Background & objectives: There is limited data on non-alcoholic fatty liver disease (NAFLD) among Indian women with polycystic ovary syndrome (PCOS), and there are no data on the utility of fibroscan in its assessment. The objective of this study was thus to investigate the frequency of hepatic steatosis in young women with PCOS and evaluate the utility of transient elastography (TE) in its assessment. Methods: Seventy women diagnosed with PCOS and 60 apparently healthy women (controls) were enrolled in this pilot study. These women were evaluated for clinical, biochemical and hormonal parameters, transabdominal ultrasonography, dual-energy X-ray absorptiometry and fibroscan assessing liver stiffness measure (LSM) and controlled attenuation parameter (CAP). Other indices such as liver fat score (LFS), lipid accumulation product (LAP), fibrosis-4 (FIB-4) and aspartate aminotransferase to platelet ratio index, hepatic steatosis index (HIS) scores were also calculated. The main outcome measures were the presence of NAFLD in women with PCOS and its correlation with CAP and LSM on TE. Results: Women with PCOS had higher frequency (38.57 vs. 6.67%) of hepatic steatosis than control women as determined by abdominal sonography. The aminotransferases were higher in PCOS group (14.28 vs. 1.7%, P=0.03) even after adjusting for body mass index implying higher non-alcoholic steatohepatitis among young PCOS patients. PCOS women had significantly higher CAP on TE compared to controls (210 vs. 196). CAP had a significant correlation with LFS, LAP and HIS. Interpretation & conclusions: NAFLD is common in young women with PCOS, and fibroscan using TE may be considered as a promising non-invasive diagnostic modality in its early detection.
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Serum procalcitonin as a biomarker of bloodstream infection & focal bacterial infection in febrile patients p. 342
Janjam Harikrishna, Alladi Mohan, DP Kalyana Chakravarthi, Abhijit Chaudhury, B Siddhartha Kumar, K.V.S. Sarma
DOI:10.4103/ijmr.IJMR_324_18  
Background & objectives: Bacteraemia is a serious form of infection in patients presenting with fever, thus, there is a necessity for a biomarker for rapid diagnosis of bacteraemia in such patients to make better therapeutic decisions. This study was conducted to measure the serum procalcitonin (PCT) levels at the time of initial presentation as a biomarker for identifying bacteraemia and as a predictor of mortality in patients admitted with acute fever. Methods: Four hundred and eighty patients, who presented with acute fever requiring admission to a tertiary care teaching hospital in south India, were prospectively studied. All patients were evaluated with a detailed history, physical examination, laboratory and imaging studies. Baseline serum PCT was measured for each patient within six hours of admission. Results: Among patients with single infectious cause (n=275), significantly higher median serum PCT levels were evident in bacteraemia compared to leptospirosis (P=0.002), dengue (P <0.001), scrub typhus (P <0.001) and evident focus of infection without bacteraemia (P=0.036). By receiver-operator characteristic curve analysis, at a cut-off value of >3.2 ng/ml, the sensitivity and specificity of serum PCT levels in predicting bacteraemia were 81.1 and 63.3 per cent, respectively. As per the worst-case scenario analysis, 91 (18.9%) patients had a poor outcome and these had significantly higher median serum PCT levels compared to survivors (n=389) [9.46 (2.03-44.4) vs. 1.23 (0.34-7.645); P <0.001]. At a cut-off value of >3.74 ng/ml, serum PCT levels at initial presentation predicted in-hospital mortality with a sensitivity and specificity of 67 and 67.5 per cent, respectively. Interpretation & conclusions: Our observations suggest that serum PCT level may be a useful biomarker for identifying bacteraemia as well as predicting mortality in patients with acute fever requiring admission to hospital.
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Seroprevalence & seroincidence of Orientia tsutsugamushi infection in Gorakhpur, Uttar Pradesh, India: A community-based serosurvey during lean (April-May) & epidemic (October-November) periods for acute encephalitis syndrome p. 350
Suchit Kamble, Arati Mane, Suvarna Sane, Suvarna Sonavale, Pallavi Vidhate, Manish Kumar Singh, Raman Gangakhedkar, Mohan Gupte
DOI:10.4103/ijmr.IJMR_1330_18  
Background & objectives: In India, acute encephalitis syndrome (AES) cases are frequently reported from Gorakhpur district in Uttar Pradesh. Scrub typhus is one of the predominant aetiological agents for these cases. In order to delineate the extent of the background of scrub typhus seroprevalence and the associated risk factors at community level, serosurveys during both lean and epidemic periods (phase 1 and phase 2, respectively) of AES outbreaks were conducted in this region. Methods: Two community-based serosurveys were conducted during lean (April-May 2016) and epidemic AES (October-November 2016) periods. A total of 1085 and 906 individuals were enrolled during lean and epidemic AES periods, respectively, from different villages reporting recent AES cases. Scrub typhus-seronegative individuals (n=254) during the lean period were tested again during the epidemic period to estimate the incidence of scrub typhus. Results: The seroprevalence of Orientia tsutsugamushi during AES epidemic period [immunoglobulin (Ig) IgG: 70.8%, IgM: 4.4%] was high as compared to that of lean AES period (IgG: 50.6%, P <0.001; IgM: 3.4%). The factors independently associated with O. tsutsugamushi positivity during lean AES period were female gender, illiteracy, not wearing footwear, not taking bath after work whereas increasing age, close contact with animals, source of drinking water and open-air defecation emerged as additional risk factors during the epidemic AES season. IgM positivity was significantly higher among febrile individuals compared to those without fever (7.7 vs. 3.5%, P=0.006). The seroincidence for O. tsutsugamushi was 19.7 per cent, and the subclinical infection rate was 54 per cent. Interpretation & conclusions: The community-based surveys identified endemicity of O. tsutsugamushi and the associated risk factors in Gorakhpur region. The findings will be helpful for planning appropriate interventional strategies to control scrub typhus.
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Genotype analysis of ofloxacin-resistant multidrug-resistant Mycobacterium tuberculosis isolates in a multicentered study from India p. 361
Anamika Gupta, Pallavi Sinha, Sunita Rathod, Siva Kumar Shanmugam, KR Uma Devi, Shampa Anupurba, Vijay Nema
DOI:10.4103/ijmr.IJMR_493_18  
Background & objectives: Drug resistance surveillance offers useful information on trends of drug resistance and the efficacy of control measures. Studies and reports of drug-resistant mutations and phenotypic assays thus become important. This study was conducted to investigate the molecular characteristics of ofloxacin (OFX)-resistant, multidrug-resistant tuberculosis (MDR-TB) isolates from different geographical regions of India and their association with strains of different genotypes. Further, the nitrate reductase assay (NRA) was tested against Mycobacteria Growth Indicator Tube (MGIT) for the determination of OFX resistance as an alternative and cost-effective method. Methods: A total of 116 Mycobacterium tuberculosis isolates were used to assess the mutations in the gyrA, gyrB genes and resistance levels to OFX. Mutational analysis in gyrA and gyrB genes and genotype analysis of M. tuberculosis isolates was done by gene-specific polymerase chain reaction (PCR) followed by DNA sequencing and spoligotyping, respectively. Results: Three (6.25%), 12 (44.44%) and 12 (29.27%) MDR-TB isolates from western, northern and southern India, respectively, were found to be OFX-resistant MDR-TB isolates. OFX resistance was observed to be significantly higher in MDR-TB cases for all study regions. Beijing genotypes from northern India were observed to be associated with OFX-resistant MDR-TB cases (P <0.05). Among 35 (30.15%) phenotypically OFX-resistant isolates, 22 (62.86%) had mutations in the gyrA gene and two (5.71%) isolates had mutations in the gyrB gene. Interpretation & conclusions: These results caution against the PCR-based prediction of OFX resistance patterns and highlight the need for searching other genetic loci for the detection of mutations conferring resistance to OFX in M. tuberculosis. Our study also showed the usefulness of NRA as an alternative method to detect OFX resistance.
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Fractional iron absorption from enteric-coated ferrous sulphate tablet p. 371
Prashanth Thankachan, Beena Bose, Rajarajan Subramanian, Raju Koneri, Anura V Kurpad
DOI:10.4103/ijmr.IJMR_1464_18  
Background & objectives: Iron supplementation is widely used public health measure to manage iron deficiency anaemia. In India, enteric-coated iron tablets are administered to adolescent boys and girls to avoid adverse effects such as gastritis, which reduces compliance, but this may result in poor iron absorption. Data on the absorption of iron from enteric-coated ferrous sulphate tablets are lacking. The present study using stable isotopic approach was aimed to measure iron absorption in iron deficient women. Methods: Iron absorption was measured from stable isotope-labelled enteric-coated ferrous sulphate ([57]Fe, ECFS) and uncoated ferrous sulphate ([58]Fe, UCFS) tablets in iron-deficient (n=9) women, aged 18-40 yr with no infection or inflammation. The two types of tablets (ECFS and UCFS) were administered on consecutive days, 60 min after breakfast, and the sequence being random. Blood samples were collected before dosing, and on day 15, to measure iron absorption from the shift in iron isotopic ratios in haemoglobin. Results: Eight women completed the iron absorption study. Iron absorption was found to be significantly lower in ECFS compared to UCFS (3.5 vs. 12%, P <0.05) consumption. Interpretation & conclusions: Our study showed poor iron bioavailability from ECFS, and supplementation programmes may consider UCFS tablets for better haematological outcomes.
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Molecular characterization of hepatitis A virus circulating in Uttar Pradesh, India: A hospital-based study p. 375
Shantanu Prakash, Suruchi Shukla, Ratnam Shukla, Amit Bhagat, Shakti S Srivastava, Amita Jain
DOI:10.4103/ijmr.IJMR_429_18  
Background & objectives: Hepatitis A is prevalent worldwide and is among the leading cause of acute viral hepatitis in India. Major geographical differences in endemicity of hepatitis A are closely related to hygienic and sanitary conditions and other indicators of the level of socio-economic development. The present study was aimed to know the seropositivity prevalence and predominant circulating strain of HAV in a north India. Methods: Patients with acute viral hepatitis were enrolled. Blood samples were collected over a period of one year from June 2016 to May 2017. Serum samples were tested for anti-immunoglobulin M (IgM) HAV antibodies. The seropositive samples were analyzed for HAV-RNA by real-time reverse transcription-polymerase chain reaction (RT-PCR). Samples detected on molecular assay were subjected to conventional semi-nested RT-PCR for VP1 gene. Further sequencing of amplified RT-PCR products was done, and data were analyzed. Results: A total of 1615 patients were enrolled, and serum samples were collected and tested. The male:female ratio was 1.3:1 with a mean age of 24.31±17.02 yr (range 0-83 yr). Among these, 128 (7.93%) were positive for anti-HAV IgM antibodies; 41.63 per cent of seropositive patients were in their childhood or early adolescent age group. Of all seropositive samples, 59 (46.09%) were positive for HAV RNA. Genotyping sequencing of 10 representative strains was carried out, and the circulating genotype was found to be IIIA. The nucleotide sequences showed homology among the strains. Interpretation & conclusions: Our results showed that hepatitis A was a common disease in children with IIIA as a circulating genotype in this region. In approximately 50 per cent of cases, HAV RNA could be detected. Higher number of HAV IgM-seropositive cases was observed during monsoon period.
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CLINICAL IMAGE Top

Limb gangrene: The first sign of essential thrombocythemia p. 380
Ali Zahit Bolaman, İrfan Yavaşoǧlu
DOI:10.4103/ijmr.IJMR_8_19  
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BOOK REVIEWS Top

Resistance to ibritumomab in lymphoma p. 382
Lalit Kumar
DOI:10.4103/ijmr.IJMR_1301_19  
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Therapeutic application of nitric oxide in cancer & inflammatory disorders p. 383
Priya Srinivas, Madhavan Radhakrishna Pillai
DOI:10.4103/ijmr.IJMR_2534_19  
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