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Background: The pharmacokinetics of primaquine [PQ] have been the subject of studies in both adults and healthy participants. However, there is no study on its pharmacokinetics in a setting of undernourishment. In India, there is evidence to show considerable malnourishment in children that in turn can affect drug pharmacokinetics. Given that the country is moving towards malaria elimination, the present study was planned with the objective of comparing pharmacokinetics of the drug in undernourished children relative to normally nourished children. Materials and Methods: After Institutional Ethics Committee approval, children of either gender between the ages of 5 and 12 years and smear-positive for Plasmodium vivax malaria were included. Nourishment status was determined using the Indian Academy of Pediatrics classification of protein energy malnutrition based on Khadilkar's growth charts. Twelve children each were enrolled in the two groups. PQ was given in the dose of 0.3 mg/kg/d and blood collections were made at 0, 1, 2, 3, 4, 6, 8 and 24 hours post-dosing. Levels were estimated by high-performance liquid chromatography. Chloroquine in the dose of 25 mg/kg was given over three days along with supportive care. Results: Of the 24 children, there were 17 boys and 7 girls. There was a statistically significant difference in the body weight between the undernourished and the normally nourished children [21.5 ± 5.52 vs. 28.8 ± 8.84, P < 0.05]. PQ levels showed wide inter-individual variation in both groups. No significant difference was seen in any pharmacokinetic parameter between the two groups. Discussion: This study adds to the limited body of evidence on the pharmacokinetics of PQ in children with malaria and indicates that the dosing of primaquine could potentially be independent of the nourishment status.

Background and Objectives: School students with specific learning disabilities (SpLDs) endure academic difficulties, anxiety, and social maladaptation. The primary objective of the present study was to evaluate the emotional intelligence (EI) abilities of these afflicted students. Its secondary objective was to analyze the impact of socio-demographic variables on their EI abilities. Settings and Design: Cross-sectional single-arm questionnaire-based study was conducted in the Learning Disability clinic in a public medical college in Mumbai. Subjects and Methods: SpLD students studying in class standards VII–IX were recruited by non-probability sampling. Their EI (overall, subscales, and settings) scores were measured using the Four EsScale of Emotional Intelligence-Adolescents (FESEI-A) questionnaire; and compared with Indian norm scores by utilizing the Mann - Whitney U test. To evaluate the unadjusted impact that each of the “variables” had on the FESEI-A scores, linear regression or the Mann-Whitney U test, or the Kruskal-Wallis test, was utilized as applicable. Results: SpLD students had similar “overall” EI abilities as their regular peers. Their EI scores in school setting were significantly lower (P = 0.001), but significantly higher in social setting (P = 0.005). At univariate level, presence of co-occurring attention-deficit/hyperactivity disorder was significantly associated with a lower “school setting” score (P = 0.040). Higher socioeconomic status was significantly associated with a higher “overall” score and “family setting” score (P = 0.023 and P= 0.041, respectively). Conclusions: There is an urgent need to evaluate the EI abilities of SpLD students to identify deficits so that optimum rehabilitation can be facilitated.

To evaluate questions asked during the informed consent process by adult participants in a COVID-19 vaccine regulatory study conducted at our center in 2020.After approval by the IEC, informed consent documents and consent narratives were evaluated. We collated the total number and nature of questions. We then looked at the association between education, gender, socio-economic status, employment status, the language of consent, and number of questions. Between-group comparison (female vs male, unemployed vs employed, primary school vs secondary school vs graduate vs post-graduates, upper vs upper-middle vs middle vs lower middle vs lower) for the number of questions asked was done using univariate analysis followed by multivariate regression analysis with post hoc Tukey's test. Independent variables were gender, employment status, education and socioeconomic status and the dependent variable was the number of questions asked by the participant. All analyses were done at 5% significance. Content analysis was done in addition by creating categories after evaluation and coding them.A total of N = 129 consents from the same number of participants were evaluated. A total of N = 127/129 participants asked at least one question. Sixty-seven percent of participants asked questions related to the study procedure, followed by 44.9% of participants who asked questions related to the safety of vaccine or placebo. A total of N = 295 questions were asked by the 127 participants. In content analysis, 149/295 (50.5%) questions were on study-related procedures followed by one quarter 76/295 (25.8%) based on safety associated with Investigational Product. Very few participants [2.4%] asked about post-trial access as the regulatory trial was a placebo-controlled trial. None of the independent variables were found to be associated with the number of questions.The majority of the questions asked by the participants were about study-related procedures and vaccine safety. No association was found between any of the independent variables and the number of questions asked. However, there were differences in the demographics of the trial participants between the pandemic and pre-pandemic era.

Background Randomized controlled trials [RCTs] form the corner-stone of evidence-based medicine. RCTs published in high impact factor journals such as the New England Journal of Medicine [NEJM] are a key driver of clinical practice and policy decisions. RCTs are expected to report both efficacy and safety, however, safety reporting in many studies tends to be poor. The present audit was undertaken with the primary objective of evaluating safety reporting during a five-year period in all RCTs published in the NEJM. Methods PubMed alone was searched for RCTs published in NEJM from 2013-17. Each RCT was searched for the following outcome measures -whether the trial was sponsored by pharmaceutical industry or investigator initiated, phase of trial, nature of intervention and therapeutic area in terms of reporting of safety outcomes [with 'P values' or '95% confidence interval']. Results A total of n=623 articles reported safety outcomes of which 275/623 (44.1%) articles reported statistics for safety outcome. There was significant difference in reporting of safety statistics between investigator initiated studies and pharmaceutical industry sponsored studies, [cOR=4.0, 95% CI 2.8- 5.5 P < 0.001]; phase 3 and phase 4 trials, [cOR 0.67, 95% CI 0.5 - 0.9, P = 0.02]; trials involving drugs and surgery, [ cOR 2.07, 95% CI 1.2-3.5, P = 0.01] and in therapeutic areas, cardiovascular and oncology [cOR 0.26, 95% CI 0.1-0.4, P < 0.0001]. Conclusions Safety reporting in RCTs continues to take a back seat relative to efficacy reporting and is worse for pharmaceutical industry funded studies. Safety reporting should be emphasized in the CONSORT guidelines.

Objectives: We evaluated the extent of consent declines and consent withdrawals during the COVID-19 pandemic as seen in published randomized controlled trials (RCTs) and compared it with non-COVID-19 RCTs published at the same time and two historical controls. Methods: PubMed/Medline only was searched using key-word “COVID-19” and “RCTs” separately, and filtered for COVID-19 RCTs and non-COVID-19 RCTs respectively, published during a nine-month period (1 Feb - 1 Nov 2020). Exclusions were study protocols, observational studies, interim analysis of RCT data and RCTs with missing data. Primary outcome measures were the proportion of consent declines and consent withdrawals as percentage of total participants screened and randomized respectively in COVID-19 RCTs. We compared consent declines and consent withdrawals of COVID-19 RCTs with non-COVID-19 RCTs and two earlier studies on the same topic that served as historical controls (non-pandemic setting). Results: The search yielded a total of 111 COVID-19 RCTs and 49 non-COVID-19 RCTs. Of these, 39 (35.13%) COVID-19 RCTs and 11 (22.45%) non-COVID-19 RCTs were finally analysed. A total of 770/17759 (4.3%) consent declines and 100/7607 (1.31%) consent withdrawals were seen in 39 COVID-19 RCTs. A significant difference was observed in consent declines between COVID-19 vs non-COVID-19 RCTs [4.3% vs 11.9%, p < 0.0001] and between COVID-19 RCTs vs two historical controls [(4.3% vs 8.6%, p < 0.0001) and (4.3% vs 21.1%, p < 0.0001), respectively]. Conclusion: RCTs conducted during the COVID-19 pandemic appear to have significantly lower consent declines relative to non-COVID-19 RCTs during pandemic and RCTs conducted in non-pandemic settings.

Background and Rationale: Ensuring research participants’ autonomy is one of the core ethical obligations of researchers. This fundamental principle confers on every participant the right to refuse to take part in clinical research, and the measure of the number of consent refusals could be an important metric to evaluate the quality of the informed consent process. This audit examined consent refusals among Indian participants in clinical studies done at our center. Materials and Methods: The number of consent refusals and their reasons in 10 studies done at our center over a 5-year period were assessed. The studies were classified by the authors according to the type of participant (healthy vs patients), type of sponsor (investigator-initiated vs pharmaceutical industry), type of study (observational vs interventional), level of risk [based on the Indian Council of Medical Research (ICMR) “Ethical Guidelines for Biomedical Research on Human Participants”], available knowledge of the intervention being studied, and each patient's disease condition. Results: The overall consent refusal rate was 21%. This rate was higher among patient participants [23.8% vs. healthy people (14.9%); P = 0.002], in interventional studies [33.6% vs observational studies (7.5%); P < 0.0001], in pharmaceutical industry-sponsored studies [34.7% vs investigator-initiated studies (7.2%); P < 0.0001], and in studies with greater risk (P < 0.0001). The most common reasons for consent refusals were multiple blood collections (28%), inability to comply with the study protocol (20%), and the risks involved (20%). Conclusion: Our audit suggests the adequacy and reasonable quality of the informed consent process using consent refusals as a metric.

Background and Objective: Epilepsy, the most common neurological disorder, has treatment failure rate of 20 to 25%. Inter-individual variability in drug response can be attributed to genetic polymorphism in genes encoding different drug metabolizing enzymes, drug transporters (P-gp), and enzymes involved in sodium channel biosynthesis. The present study attempted to evaluate association of polymorphisms of CYP2C9, CYP2C19, and ABCB1, and P-gp activity with treatment response in patients with epilepsy. Materials and Methods: Patients with epilepsy on phenytoin and/or phenobarbital and/or carbamazepine were categorized into responders and non-responders as per the International League Against Epilepsy. Plasma drug concentration was estimated by high-performance liquid chromatography. P-gp activity was measured by flow cytometry using rhodamine efflux. The polymerase chain reaction (PCR-RFLP) was used to study polymorphisms of ABCB1 (C3435T), CYP2C9 (416 C > T, and 1061 A > T), and CYP2C19 (681 G > A and 636 G > A). Results: Of total 117 patients enrolled in this study, genotype data was available for 115 patients. P-gp activity was higher in non-responders (n = 68) compared to responders (n = 47) (P T and 1061 A > T in CYP2C9 or 681 G > A and 636 G > A in CYP2C19 was observed with response phenotype in genotypic analysis. Significant genotypic (odds ratio, OR = 4.5; 95% CI, 1.04 to 20.99) and allelic association (OR = 1.73; 95% CI, 1.02 to 2.95) was observed with ABCB1 C3435T and response phenotype. Conclusions: The response to antiepileptics seems to be modulated by C3435T in ABCB1 or P-gp activity. At present, role of other genetic factors in treatment responsiveness in epilepsy appears limited, warranting analysis in a larger cohort.

Aims: The primary objective of this study was to evaluate the economic burden of slow learners (students with “borderline intellectual functioning”) by estimating its direct, indirect, and intangible costs. The secondary objective was to assess the impact of variables on the economic burden. Settings and Design: Cross-sectional, single-arm descriptive study. Setting: Learning disability clinic in a public medical college in Mumbai. Materials and Methods: The study cases (age ≥5 - 18 years) were recruited by nonprobability sampling. A structured questionnaire was used to interview the parent to collect data related to direct and indirect costs. Intangible costs data were collected by documenting the willingness-to-pay value using the contingent valuation technique. Statistical Analysis Used: A quantile regression model was used to assess the impact of predictor variables on the costs. Results: The direct, indirect, and intangible costs of slow learners were INR 6,065,915, 10,298,613, and 145,172,800, respectively. Indirect costs comprised 62.9% of the total costs. Expenditure on tuitions, medications, and remedial education comprised 57.38%, 16.18%, and 10.30% of the direct costs, respectively. The average annual total costs of slow learners were INR 3,544,880. The average annual learning disability clinic costs were INR 2,250,194. The average annual total costs per student were INR 57,951. Longer duration of poor school performance was predictive of higher direct and total costs. Conclusion: The economic burden of slow learners is enormous (intangible > indirect > direct costs). Tuitions are the most costly component of direct costs. Parental loss of earnings is the most costly component of indirect costs.

Aims: The primary objective of the present study was to evaluate the economic burden of specific learning disability (SpLD) by estimating its direct, indirect, and intangible costs. A secondary objective was to assess the impact of variables on the economic burden. Settings and Design: Cross-sectional single-arm descriptive study. Setting: Learning disability clinic in a public medical college in Mumbai. Subjects and Methods: The study cases (aged ≥8 years) were recruited by non-probability sampling. A structured questionnaire was used to interview the parent/guardian to collect data related to direct and indirect costs. Intangible costs data were collected by documenting the willingness-to-pay value using the contingent valuation technique. Statistical Analysis Used: A quantile regression model was used to assess the impact of predictor variables on the costs. Results: The direct, indirect, and intangible costs due to SpLD were Indian Rupees (INR) 5,936,053, 29,261,220, and 42,295,000, respectively. Indirect costs comprised 83.1% of the total costs. Expenditure on tuitions and remedial education comprised 61.61% and 64.39% of the indirect and direct costs, respectively. The average annual learning disability clinic costs were INR 2,169,888. The average annual total costs per student were INR 90,773. Longer duration of poor school performance was predictive of higher direct, indirect, and total costs; and higher socioeconomic status was predictive of lower intangible costs. Conclusion: SpLD is a cost-intensive disability (intangible > indirect > direct costs). Tuitions, which are not the therapy for SpLD, are the most costly component of indirect costs. Remedial education is the most costly component of direct costs.

There are no published case reports of esomeprazole-induced photoallergic dermatitis. We report here a 58-year-old lady with prior history of propylthiouracil and carbimazole-induced photoallergy, who presented with heartburn and dysphagia. She was diagnosed to have erosive esophagitis and was treated with esomeprazole, following which she developed photoallergic dermatitis. It improved on cessation of the drug and did not recur on subsequent treatment with ranitidine. Naranjo score for this adverse drug event was 8, thereby making it a probable adverse drug reaction. This reaction may be due to sulphur moiety, which is common to all these drugs. Physicians must be aware of this possible side-effect, especially in patients with prior history of photoallergy to other drugs.

Background and Objectives: School students with specific learning disabilities (SpLDs) experience chronic academic underachievement and resultant stress. The present study aimed to determine if school students with newly diagnosed SpLD were more likely to have anxiety than their regular peers. Materials and Methods: The study cases (aged 8-15 years) were recruited from our institute′s learning disability clinic. The matched controls were recruited from four schools in Mumbai, Maharashtra, India. Anxiety was measured using the Spence Children′s Anxiety Scale (SCAS)-child self-report version questionnaire. Median SCAS scores and the proportion of students with an SCAS score in the "clinical anxiety" range were compared between the groups. Results: SCAS scores were significantly higher in 8-11-year-old learning-disabled male and female students (P < 0.0001 for both groups) and 12-15-year-old female students (P = 0.004), as compared with matched controls. A significantly higher number of learning-disabled students were found to have "clinical anxiety" [24.64% vs 4.35%, crude odds ratio (OR) = 7.19, 95% confidence interval (CI) 2.91-17.78, P = 0.0001], as compared with the controls regardless of gender, age group, presence of comorbid attention-deficit/hyperactivity disorder (ADHD), or associated medical conditions. A significantly higher proportion of 8-11-year-old learning-disabled students, especially males, were found to have "clinical anxiety" as compared with 12-15-year-old learning-disabled students (crude OR = 4.38, 95% CI 1.94-9.92, P = 0.0004). Gender, presence of comorbid ADHD or associated medical conditions, and type of school attended or curriculum did not impact the prevalence of "clinical anxiety" in learning-disabled students. Interpretation and Conclusions: Students with newly diagnosed SpLD have greater odds of being "clinically anxious" relative to their regular peers. We recommend screening for anxiety in children with SpLD immediately after diagnosis so that their optimum rehabilitation can be facilitated.

In May 2003, an indigenously developed liposomal amphotericin B (Fungisome) was introduced in the Indian market for the treatment of systemic fungal infections and visceral leishmaniasis. The present post marketing study assessed the safety and effectiveness of Fungisome in actual clinical practice.Retrospective post marketing surveillance from four cities of India.The present study was carried out for a period of 6 months (Jun-Nov 2004), a year after the introduction of the drug. A list of doctors who had prescribed and procured the drug was obtained from the distributor. Consent to participate and scrutinize the patients' source notes were obtained from the concerned doctors. All patients who had received Fungisome treatment were included. Data was collected from the patient's source notes on a predesigned proforma. They were then analyzed by descriptive statistics. Cost of Fungisome was calculated on the basis of dose used and number of days of treatment.Data were available for 109/144 patients from 35/40 physicians. Fungisome was administered at 1-3 mg/kg/day for 7-76 days. No serious adverse events related to the drug were observed in the study. Mild infusion-related adverse events were reported in 40 (36%), moderate in 11 (10%) of patients and severe in 2 (1.8%). None of the adverse events were certain to Fungisome exposure, 12 (11%) were probable, 28 (25 %) were possible, and 13 (11.9%) were unlikely. Of the 91 assessable patients (received at least eight doses of Fungisome) for efficacy complete response was observed in 67 (73.6%), 16 (17.5%) had partial responses, and 8 (8.7%) of patients had no response. The acquisition cost per day and per course treatment of different fungal infections ranged from (apprx) Rs 4500-8000 and 0.9-2.1 lakh respectively.This postmarketing study documents the safety, tolerability, effectiveness and cost advantage of indigenously developed liposomal amphotericin B in the treatment of systemic fungal infections and febrile neutropenia in actual clinical practice.

Background : There is need to investigate the use of liposomal amphotericin B in cryptococcal meningitis in India. Aims : To compare the efficacy, safety, duration of treatment and cost of two doses of liposomal amphotericin B (Amp B) (Fungisome TM ) in cryptococcal meningitis in HIV/AIDS patients. Settings and Design : Prospective, randomized, multicenter study in tertiary care hospitals across India. Materials and Methods : Adult patients with culture-proven cryptococcal meningitis with HIV/AIDS were randomized to receive either 1 (Group A) or 3 mg/kg/day of Fungisome (Group B). Clinical efficacy and tolerability, laboratory evaluations and mycological response were assessed daily, twice weekly and weekly respectively. The patients were assessed at four and eight-week follow-up. Statistics : We calculated average and standard deviation for the various parameters. Results : The time to show clinical response was 13.66 days (1 mg) and 9.55 days (3 mg). In Group B (n=6 complete response), 50% patients responded within one week by microbial conversion, 83% in two weeks and 100% in three weeks. Patients with 1 mg dose (n=4 complete response), none showed microbial conversion within one week, 75% responded in two weeks, whereas one patient took four weeks. The average duration of treatment was 36.5±14.4 and 26.5±5.89 (S.D.) days in 1 and 3 mg/kg/day respectively. Drug was tolerated with little renal, hepatic or hematological toxicity. The cost was found to be 3.81 lacs and 1.74 lacs with 3mg/kg/day and 1mg/kg/day respectively. Conclusion : Higher dose showed better efficacy and quicker microbial conversion of Cerebrospinal fluid (CSF) (cerebrospinal fluid) than 1 mg/kg/day. It shortened the duration of treatment in days by 27% while drug cost almost doubled (Clinical trial registration number: ISRTCN 52812742)

The Declaration of Helsinki (DoH) was adopted by the World Medical Association (WMA) in 1964, as a statement of ethical principles, to provide guidance to physicians and other participants in medical research involving human subjects. Having undergone several amendments, the most recent version was approved on 18 October 2008, by the WMA General Assembly at Seoul, South Korea, replacing all previous versions. This version highlights issues such as, participant safety, the need to include participants from otherwise underrepresented groups, clinical trial registration, post-study access, usage of data and human tissues, compensating participants with research-related injury, and usage of placebo. In this article, we discuss the major aspects of the 2008 version, including the impact of this version on all stakeholders in research, including, investigators, ethics committee members, sponsors, authors, editors, and reviewers.