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   2020| November  | Volume 152 | Issue 5  
    Online since March 8, 2021

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Similar biologics in India: A story of access or potential for compromise?
Ramesh Jois, Sukumar Mukherjee, S Rajeswari, PD Rath, Vishal Goyal, Disha Gupta
November 2020, 152(5):456-467
Biosimilars or similar biotherapeutic products are the biological products approved by regulatory agencies based on the demonstration of similarity in quality, safety and efficacy with reference biologics (or original biologics). Though biosimilars could be considered as interchangeable therapeutic alternatives over original biologics, there are concerns regarding their similarity in effectiveness and safety with reference product along with the level of evidence of similarity required for approval. The biosimilars, particularly, monoclonal antibodies that are developed based on the complex manufacturing processes, require stringent comparative evaluations. The Indian Regulatory Authorities in July 2012 developed the first guidelines for approval of similar biologics, which comprised requirements for the manufacturing process, quality evaluation, preclinical and clinical studies, as well as post-marketing studies. The 2016 guidelines, an update to previous guidelines, were released with the intent to provide a well-defined pathway at par with international regulations for the approval of similar biologics in India. This article highlights the key attributes of the 2016 Regulatory Guidelines and also describes the aspects such as interchangeability, nomenclature and labelling of similar biologics in India. Rigorous consideration is imperative for highly complex similar biologics of monoclonal antibodies on a case-to-case basis.
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Health technology assessment in India: Reflection & future roadmap
Shankar Prinja, Kavitha Rajsekhar, Vijay Kumar Gauba
November 2020, 152(5):444-447
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Glycaemic control in diabetes - Bridging the gap
Nishant Raizada, Rajesh Khadgawat
November 2020, 152(5):439-441
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Validation of an indigenous assay for rapid molecular detection of rifampicin resistance in presumptive multidrug-resistant pulmonary tuberculosis patients
NS Gomathi, Manjula Singh, VP Myneedu, DS Chauhan, Srikanth Tripathy, Rohit Sarin, Anant Mohan, Anuj Bhatnagar, Jiten Singh Khangembam, T Kannan, MV V. Rao, Jyoti Logani, Bindu Dey, RR Gangakhedkar, Soumya Swaminathan, Urvashi B Singh
November 2020, 152(5):482-489
Background & objectives: There is a need for an affordable, easy, high-sensitivity test usable at the peripheral health facility for diagnosis of drug-resistant (DR) tuberculosis (TB) to interrupt disease transmission. Nucleic acid amplification tests (NAATs) for early detection of DR-TB are ideal to bring testing near to the patient. TruenatTM MTB (Mycobacterium tuberculosis) and TruenatTM MTB-RIF (rifampicin) is an indigenous chip-based real-time polymerase chain reaction (PCR) based test for detection of multidrug-resistant (MDR) TB. The test involves extraction of DNA using automated, battery operated Trueprep instrument and real-time PCR performed on the Truelab analyzer. We report here multicentric validation of Truenat MTB-RIF for detection of DR-TB in suspected DR-TB patients. Methods: Consecutive patients aged 18-65 yr, with symptoms suggestive of TB and with a history of previous treatment, reporting to the National TB Elimination Programme (NTEP) clinics under four national institutes, namely AIIMS (All India Institute of Medical Sciences, New Delhi), NITRD (National Institute of Tuberculosis and Respiratory Diseases, New Delhi), NIRT (National Institute for Research in Tuberculosis, Chennai) and ICMR-National JALMA Institute for Leprosy and other Mycobacterial Diseases, Agra, were included in the study. Two sputum samples (one spot and one morning) were collected from each patient, after obtaining informed written consent. The samples were subjected to smear, GeneXpert and MGIT 960 culture (and drug susceptibility testing to RIF) (surrogate for MDR-TB) to serve as reference tests. The samples were coded to ensure blinding and subjected to Truenat MTB-RIF. Truenat MTB-RIF Version 1.5 was used for testing 1084 samples for RIF resistance, while Version 2.0 was used to test another 1201 samples. Results: Truenat MTB-RIF Version 1.5 in comparison with comprehensive laboratory reference standards yielded sensitivity and specificity of 76.2 and 94.7 per cent, respectively for the detection of RIF resistance in 1084 samples, collected across four sites. Based on the analysis of discordant samples, Version 2.0 of Truenat was developed by the manufacturer and this was further tested on additional 1201 samples, yielding a sensitivity of 87.5 per cent and specificity of 99.5 per cent. Interpretation & conclusions: Multicentric trial of TruenatTM MTB-RIF demonstrated a great potential of this point of care NAAT for detection of MDR-TB. The test would be useful in limited resource settings and inaccessible areas without need for any additional infrastructure.
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Diagnosis & management of imported malaria in pregnant women in non-endemic countries
Maria Grazia Piccioni, Valentina Del Negro, Flaminia Vena, Carmela Capone, Lucia Merlino, James Matthaus Moore, Antonella Giancotti, Maria Grazia Porpora, Roberto Brunelli
November 2020, 152(5):449-455
DOI:10.4103/ijmr.IJMR_851_18  PMID:33707386
Malaria in pregnancy is an important cause of maternal and foetal morbidity and is a potentially life-threatening infection. With ever-growing global exchanges, imported malaria in pregnancy is becoming an issue of concern in non-endemic countries where women, because of low immunity, have higher risk of severe diseases and death. Malaria in pregnancy is a dangerous condition which can be associated with important consequences for both mother and child such as stillbirth, low birth weight, maternal anaemia. In non-endemic-countries it is more frequent in its severe form which can lead to maternal death if not treated adequately. Specific anti-malarial interventions such as the use of repellents and insecticide treated bed nets in addition to chemoprophylaxis should be used by pregnant women if they are travelling to endemic areas. In cases of confirmed infection, specific treatment regimens vary according to gestational age and the presence of complications. Malaria should be considered a global health problem, increasingly involving western countries. Clinicians all over the world need to be prepared for this emerging disease both in terms of prevention and therapy.
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Nab-paclitaxel: An effective third-line chemotherapy in patients with advanced, unresectable gallbladder cancer
Vineet Talwar, Shubhra Raina, Varun Goel, Prasanta Dash, Dinesh C Doval
November 2020, 152(5):475-481
Background & objectives: Gallbladder (GBC) is an aggressive form of cancer and most patients present with advanced unresectable disease due to lack of early signs and symptoms. This retrospective study was conducted to present the treatment outcomes with three lines of chemotherapies in a subset of patients with advanced, unresectable GBC with the primary objective to determine the response rates with nab-paclitaxel as the third-line chemotherapy after failure of the first-line gemcitabine and platinum and the second-line FOLFOX-4 (oxaliplatin, leucovorin and 5-FU) therapy. Another objective was to evaluate the toxicity, progression-free survival (PFS) and overall survival (OS). Methods: Treatment-naive patients with histologically proven inoperable GBC treated with gemcitabine/platinum, FOLFOX-4 and nab-paclitaxel as the first-, second- and third-line chemotherapy were included in this study. The dose of gemcitabine and cisplatin or carboplatin was 1 g/m[2] on days 1 and 8 and 75 mg/m[2] (or target AUC of 5) on day 1, in a 21-day cycle. FOLFOX-4 was administered every two weeks and nab-paclitaxel was administered as 125 mg/m[2] on days 1, 8 and 15 in a 28-day cycle. Results: There were eight men and 13 women with a median age of 57 yr who received nab-paclitaxel therapy. The overall response rate of the first-, second- and third-line chemotherapy was 61.9, 57.1 and 52.4 per cent, respectively. The median PFS for the gemcitabine/platinum, FOLFOX-4 and nab-paclitaxel therapy was 5.5, 5.4 and 2.9 months, respectively. The median OS with three lines of therapies was 14.0 months. Common Terminology Criteria (CTC) grade 3 or 4 haematological toxicities were observed in 28.6, 38.1 and 23.8 per cent of patients on gemcitabine/platinum, FOLFOX-4 and nab-paclitaxel therapy, respectively. Interpretation & conclusions: Our study suggests the clinical benefit of nab-paclitaxel chemotherapy in prolonging OS in a selected subgroup of advanced, unresectable GBC patients after failure of the first-line gemcitabine and platinum and the second-line FOLFOX-4 therapy.
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Indian Council of Medical Research consensus document on hepatocellular carcinoma
Bhawna Sirohi, Shailesh V Shrikhande, Vinay Gaikwad, Amol Patel, Shraddha Patkar, Mahesh Goel, Munita Bal, Atul Sharma, Raj Kumar Shrimali, Vikram Bhatia, Suyash Kulkarni, Deep Narayan Srivastava, Tanvir Kaur, RS Dhaliwal, Goura Kishor Rath, for the Indian Council of Medical Research Guidelines Working Group
November 2020, 152(5):468-474
This document aims to assist oncologists in making clinical decisions encountered while managing their patients with hepatocellular carcinoma (HCC), specific to Indian practice, based on consensus among experts. Most patients are staged by Barcelona Clinic Liver Cancer (BCLC) staging system which comprises patient performance status, Child-Pugh status, number and size of nodules, portal vein invasion and metastasis. Patients should receive multidisciplinary care. Surgical resection and transplant forms the mainstay of curative treatment. Ablative techniques are used for small tumours (<3 cm) in patients who are not candidates for surgical resection (Child B and C). Patients with advanced (HCC should be assessed on an individual basis to determine whether targeted therapy, interventional radiology procedures or best supportive care should be provided. In advanced HCC, immunotherapy, newer targeted therapies and modern radiation therapy have shown promising results. Patients should be offered regular surveillance after completion of curative resection or treatment of advanced disease.
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Nab-paclitaxel - Third-line chemotherapy in advanced gallbladder cancer
Amol Patel, Bhawna Sirohi
November 2020, 152(5):442-443
  1,052 186 -
A validation study of early warning system in high-risk pregnant women
Asmita Muthal Rathore, Sunita Bai Meena, Reena Rani, Deepti Goswami, Reva Tripathi
November 2020, 152(5):519-522
High-risk obstetric patients have chances of deterioration which can be detected by any early warning score. This study was aimed to assess the suitability of the Obstetrics National Early Warning System (ONEWS) for the pregnant women. This prospective study was conducted on 500 high-risk pregnant women attending a tertiary care teaching hospital. The ONEWS charts were plotted for each of them. The primary outcome measure was composite adverse maternal outcome (CAMO) in the form of one or more among mortality, severe maternal morbidity and intensive care unit admissions. Of the 500 women who participated, 200 (40%) had a score ≥3 (triggered an intervention). The CAMO among the triggered group [59.5% (n=119)] was significantly higher compared to that in the non-triggered group [13.3% (n=40) (P=0.001)]. The area under the receiver operating characteristic curve was 0.800 (95% confidence interval 0.752-0.847). The sensitivity of the ONEWS in predicting CAMO was 74.8 per cent, specificity 76.2 per cent, positive predictive value 59.5 per cent and negative predictive value 86.7 per cent at a cut-off score of 3. ONEWS appears to be a useful tool for predicting adverse maternal outcomes in high-risk pregnant women.
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Impact of Integrated Amrita Meditation® technique on stress in type 2 diabetic patients
KS Sarika, Harish Kumar, Vandana Balakrishnan, KR Sundaram
November 2020, 152(5):508-514
Background & objectives: Several studies on mind-body relaxation techniques have demonstrated a reduction in psychological stress levels. Implementation of such cost-effective, persons suffering from chronic disorders would be beneficial for the diabetic population. This study was undertaken to understand the effect of Integrated Amrita Meditation® technique (IAM®) technique on stress and its benefit in attaining a better glycaemic control. Methods: Thirty type 2 diabetic patients aged between 30 and 65 yr were consecutively recruited for the study. They were randomly allocated to IAM® and control groups. Weight, body mass index (BMI), fasting blood glucose (FBG), glycated haemoglobin (HbA1c) and perceived stress scale (PSS) were the variables assessed pre- and post-intervention during the three-month study period. Results: The mean changes between baseline and three months in the experimental group showed statistically significant decrease in HbA1c (P=0.018) as well as psychological stress (P<0.001), whereas an increase in weight (P=0.046) and FBG (P=0.029) was observed in the control group. When the pre- and post-mean changes of the study variables were assessed between the two groups, the differences obtained were statistically significant for weight (P=0.048), BMI (P=0.055), HbA1c (P=0.034) and PSS (P≤0.001). Interpretation & conclusions: The findings suggest that stress is an important risk factor hindering the glycaemic control of diabetic patients. Through reduction of psychological stress by IAM® practice, diabetic patients can attain a better glycaemic control along with the usual treatment regimens.
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Seroprevalence of Toxoplasma gondii in newly diagnosed HIV seropositive patients
Anuja Dutta, Preeti R Mehta, Nayana Ingole
November 2020, 152(5):515-518
Background & objectives: Immunocompromised individuals mainly HIV infected patients are at a great risk for developing toxoplasmosis. The presence of toxoplasmosis among HIV-infected patients directly correlates with the prevalence of anti- Toxoplasma gondii antibodies and the degree of immunosuppression (measured by CD4 counts). The data regarding the seroprevalence of toxoplasmosis in HIV-infected patients are scarce in India. Therefore, this study was initiated to find out the seroprevalence of toxoplasmosis in treatment-naïve HIV seropositive patients and to determine its association with CD4 counts, if any. Methods: Four hundred newly diagnosed antiretroviral therapy (ART) naïve adult HIV positive patients coming for CD4 count estimation were tested for the presence of anti- Toxoplasma IgG antibodies. Risk factors for acquisition of toxoplasmosis as well as the age, gender and CD4 counts of the patient were noted down. Results: Toxoplasma IgG was positive in 292 (73%) patients, and the positivity was not related to their CD4 counts. The proportion of anti- Toxoplasma IgG positivity showed no significant association with age, gender and risk factors of the patients. Interpretation & conclusions: In the absence of any specific vaccine or prophylaxis for toxoplasmosis, it is pertinent to screen all HIV-positive patients for Toxoplasma IgG at diagnosis, irrespective of their CD4 counts, and sensitize them about the means to prevent either acquisition or activation of infection to avert the development of toxoplasmic encephalitis.
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Identification & characterization of leucine-rich repeat kinase 2 & parkin RBR E3 ubiquitin protein ligase variants in patients with Parkinson's disease
Tamali Halder, Shiv Prakash Verma, Janak Raj, Sharad Pandey, Ranjeet Kumar Singh, Vivek Sharma, Deepika Joshi, Parimal Das
November 2020, 152(5):498-507
Background & objectives: Parkinson's disease (PD) is a motor disorder that affects movement. More than 24 loci and 28 associated genes have been identified to be associated with this disease. The present study accounts for the contribution of two candidates, leucine-rich repeat kinase 2 ( LRRK2) and parkin RBR E3 ubiquitin protein ligase ( PRKN) in the PD patients, and their characterization in silico and in vitro. Methods: A total of 145 sporadic PD cases and 120 ethnically matched healthy controls were enrolled with their informed consent. Mutation screening was performed by direct DNA sequencing of the targeted exons of LRRK2 and all exons flanking introns of PRKN. The effect of the pathogenic PRKN variants on a drug (MG-132) induced loss of mitochondrial membrane potential (△ΨM) was measured by a fluorescent dye tetramethylrhodamine methyl ester (TMRM). Results: Twelve and 20 genetic variants were identified in LRRK2 and PRKN, respectively. Interestingly, five out of seven exonic LRRK2 variants were synonymous. Further assessment in controls confirmed the rarity of two such p.Y1527 and p.V1615. Among the pathogenic missense variations (as predicted in silico) in PRKN, two were selected (p.R42H and p.A82E) for their functional study in vitro, which revealed the reduced fluorescence intensity of TMRM as compared to wild type, in case of p.R42H but not the other. Interpretation & conclusions: About 6.2 per cent of the cases (9/145) in the studied patient cohort were found to carry pathogenic (as predicted in silico) missense variations in PRKN in heterozygous condition but not in case of LRRK2 which was rare. The presence of two rare synonymous variants of LRRK2 (p.Y1527 and p.V1615) may support the phenomenon of codon bias. Functional characterization of selected PRKN variations revealed p.R42H to cause disruption of mitochondrial membrane potential (△ΨM) rendering cells more susceptible to cellular stress.
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Upsurge of chikungunya cases in Uttar Pradesh, India
Ahmad Ozair, Danish N Khan, Shantanu Prakash, Amit Bhagat, Anil Verma, Suruchi Shukla, Amita Jain
November 2020, 152(5):527-530
Background & objectives: Chikungunya (CHIK) re-emerged in India in 2006 after a gap of three decades. In Uttar Pradesh (UP), <100 confirmed cases per million were reported during this outbreak. Based on an upsurge of CHIK cases at UP, this retrospective study was conducted to investigate clinical and serological profile of CHIK cases in UP. Methods: A retrospective study was done on all clinically suspected CHIK cases that had been tested by ELISA for anti-CHIK virus IgM antibodies from September 2012 to December 2017. Based on clinical features, a subset of patients had earlier been tested serologically for dengue and Japanese encephalitis (JE). Results: Of the 3240 cases enrolled, 771 (23.8%) were seropositive. Patients had a range of clinical manifestations with seropositivity highest in those exhibiting arthralgia with fever (40%), followed by fever of unknown origin (FUO) (22%), encephalitis (13%) and fever with rash (12%). Cases (total, seropositive) increased over 20-fold in 2016 (1389, 412) and 2017 (1619, 341), compared to 2012-2015. Nearly a third of dengue serology-positive cases and a fifth of JE serology-positive cases were co-positive for CHIKV. Interpretation & conclusions: Archival data from 2006-2011 and data from this study (2012-2017) indicated that UP experienced first CHIK outbreak in the decade in 2016, as part of a large-scale upsurge across northern India. CHIK should be considered as a differential diagnosis in patients presenting with fever of unknown origin or fever with rash or acute encephalitis, in addition to classical arthralgia.
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Cost analysis of dengue from a State in south India
Zinia T Nujum, M Saboora Beegum, V Meenakshy, K Vijayakumar
November 2020, 152(5):490-497
Background & objectives: Improved dengue cost estimates offer the potential to provide a baseline measure to determine the cost-effectiveness of interventions. The objective of this study was to estimate the cost of dengue prevention, treatment and fatalities in Kerala, India, over a period of one year. Methods: The study was done in Kerala, a southern State in India. Costing of treatment was done from a family perspective. It was found by primary data collection in a sample of 83 dengue patients from Thiruvananthapuram district and estimated for Kerala using the reported number of cases in 2016. Costing of prevention was done from the government perspective for the entire State. In-depth interviews with State programme officers and experts in the field were conducted. The present value of lifetime earnings was used to value lives. Results: The cost of treatment of dengue in the State was ₹137 milion (2.16 million US$). The cost of prevention in the State was ₹535 million (8.3 million US$). The cost of fatalities was the highest among costs at ₹1760 million (27.7 million US$). US$ 38 million was the least possible estimate of total cost of dengue. The total out-of-pocket spending (OOPS) of >60 yr was significantly (P<0.05) higher than other age groups. The total OOPS was significantly (P<0.001) higher in private sector compared to public. Interpretation & conclusions: Although deaths due to dengue were few, the cost of fatalities was 12 times more than the cost of treatment and three times the cost of prevention. Focusing on mortality reduction and disease prevention in elderly would be beneficial.
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Hypermetabolic pseudotumour of the chest wall
Yasser Ali Kamal, Mohamed ElAdel
November 2020, 152(5):531-532
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Risk stratification for venous thrombosis in post-partum women in a tertiary care setup in south India
Dripta Ramya Sahoo, Gowri Dorairajan, C Palanivel
November 2020, 152(5):523-526
Background & objectives: The Royal College of Obstetricians and Gynaecologists (RCOG) guidelines for thromboprophylaxis among post-partum women are recommended across Asia. This study was aimed to find the proportion of post-partum women eligible for thromboprophylaxis based on the RCOG guidelines and how many actually received it in a tertiary care health facility in south India. Methods: This cross-sectional study was carried out on 1652 consecutive women who delivered in the setup of tertiary care. Risk stratification for venous thrombosis was done as per the RCOG guidelines. The number of women who received thromboprophylaxis was also noted. Results: Among the 1652 women studied, three [0.18%; 95% confidence interval (CI): 0.06-0.53] were in the high-risk, 598 (36.2%; 95% CI: 33.9-38.6) in the intermediate and 254 (15.4%; 95% CI: 13.7-17.2) in the low-risk category for thrombosis. All the three women in the high-risk and only two women in the intermediate-risk category actually received thromboprophylaxis with heparin. Interpretation & conclusions: It was seen that the number of women needing prophylaxis in our setup, as per the RCOG guidelines, was as high as 601 (36.4%), but only five (0.8%) received it.
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