Setting priorities in child health research in India for 2016-2025: a CHNRI exercise undertaken by the Indian Council for Medical Research and INCLEN Trust.

BACKGROUND: Millennium Development Goal 4 (MDGs) mobilised countries to reduce child mortality by two thirds the 1990 rate in 2015. While India did not reach MDG 4, it considerably reduced child mortality in the MDG-era. Efficient and targeted interventions and adequate monitoring are necessary to further progress in improvements to child health. Looking forward to the Sustainable Development Goal (SDG)-era, the Indian Council of Medical Research and The INCLEN Trust International conducted a national research priority setting exercise for maternal, child, newborn health, and maternal and child nutrition. Here, results are reported for child health. METHODS: The Child Health and Nutrition Research Initiative (CHNRI) method for research priority setting was employed. Research ideas were crowd-sourced from a network of child health experts from across India; these were refined and consolidated into research options (ROs) which were scored against five weighted criteria to arrive weighted Research Priority Scores (wRPS). National and regional priority lists were prepared. RESULTS: 90 experts contributed 596 ideas that were consolidated into 101 research options (ROs). These were scored by 233 experts nationwide. National wRPS for ROs ranged between 0.92 and 0.51. The majority of the top research priorities related to development of cost-effective interventions and their implementation, and impact evaluations, improving data quality; and monitoring of existing programs, or improving the management of morbidities. The research priorities varied between regions, the Economic Action Group and North-Eastern states prioritised questions relating to delivering interventions at community- or household-level, whereas the North-Eastern states and Union Territories prioritised research questions involving managing and measuring malaria, and the Southern and Western states prioritised research questions involving pharmacovigilance of vaccines, impact of newly introduced vaccines, and delivery of vaccines to hard-to-reach populations. CONCLUSIONS: Research priorities varied geographically, according the stage of development of the area and mostly pertained to implementation sciences, which was expected given diversity in epidemiological profiles. Priority setting should help guide investment decisions by national and international agencies, therefore encouraging researchers to focus on priority areas. The ICMR has launched a grants programme for implementation research on maternal and child health to pursue research priorities identified by this exercise.

Comparison of ocular pharmacokinetics of etoposide and its nanoemulsion after subtenon administration in rabbits.

Background Subtenon anticancer drugs are given as an adjunct to systemic chemotherapy for conditions like retinoblatoma. This study evaluated the ocular kinetics of nano-emulsion formulation of etoposide (NanoEt) and compared it with an equal dose of commercially available alcohol-based etoposide formulation in healthy rabbits. Methods A nanoemulsion formulation of NanoEt was developed and then evaluated for its ocular kinetics by subtenon administration in healthy rabbits. After the sterile subtenon administration of the drug, the eyes were enucleated after CO2 euthanasia at time intervals of 2 h, 6 h, 12 h, and 24 h, and ocular tissues, blood, and plasma were separated. The concentration of etoposide in the ocular tissues and blood was quantified using liquid chromatography tandem mass spectrometry (LC MS/MS). Results This study found that subtenon injection of NanoEt showed 24 times higher concentration in rabbit retina compared to an equal dose of conventional marketed formulation. Based on the ocular tissue bioavailability calculations (AUC0-24), the present study revealed that the formulation enhanced 90% ocular bioavailability of etoposide, when it was injected in the form of nano-emulsion in most of the tissues. Conclusions NanoEt has better bioavailability compared to the commercial alcohol-based formulation for subtenon injection. Low systemic exposure showed further advantage for its projected use in retinoblastoma (Rb) as an adjunct therapy. Further studies in Rb animal models are required to evaluate its safety and efficacy, for its clinical utility.

Research priorities in Maternal, Newborn, & Child Health & Nutrition for India: An Indian Council of Medical Research-INCLEN Initiative.

In India, research prioritization in Maternal, Newborn, and Child Health and Nutrition (MNCHN) themes has traditionally involved only a handful of experts mostly from major cities. The Indian Council of Medical Research (ICMR)-INCLEN collaboration undertook a nationwide exercise engaging faculty from 256 institutions to identify top research priorities in the MNCHN themes for 2016-2025. The Child Health and Nutrition Research Initiative method of priority setting was adapted. The context of the exercise was defined by a National Steering Group (NSG) and guided by four Thematic Research Subcommittees. Research ideas were pooled from 498 experts located in different parts of India, iteratively consolidated into research options, scored by 893 experts against five pre-defined criteria (answerability, relevance, equity, investment and innovation) and weighed by a larger reference group. Ranked lists of priorities were generated for each of the four themes at national and three subnational (regional) levels [Empowered Action Group & North-Eastern States, Southern and Western States, & Northern States (including West Bengal)]. Research priorities differed between regions and from overall national priorities. Delivery domain of research which included implementation research constituted about 70 per cent of the top ten research options under all four themes. The results were endorsed in the NSG meeting. There was unanimity that the research priorities should be considered by different governmental and non-governmental agencies for investment with prioritization on implementation research and issues cutting across themes.

Setting research priorities for maternal, newborn, child health and nutrition in India by engaging experts from 256 indigenous institutions contributing over 4000 research ideas: a CHNRI exercise by ICMR and INCLEN.

BACKGROUND: Health research in low- and middle- income countries (LMICs) is often driven by donor priorities rather than by the needs of the countries where the research takes place. This lack of alignment of donor's priorities with local research need may be one of the reasons why countries fail to achieve set goals for population health and nutrition. India has a high burden of morbidity and mortality in women, children and infants. In order to look forward toward the Sustainable Development Goals, the Indian Council of Medical Research (ICMR) and the INCLEN Trust International (INCLEN) employed the Child Health and Nutrition Research Initiative's (CHNRI) research priority setting method for maternal, neonatal, child health and nutrition with the timeline of 2016-2025. The exercise was the largest to-date use of the CHNRI methodology, both in terms of participants and ideas generated and also expanded on the methodology. METHODS: CHNRI is a crowdsourcing-based exercise that involves using the collective intelligence of a group of stakeholders, usually researchers, to generate and score research options against a set of criteria. This paper reports on a large umbrella CHNRI that was divided into four theme-specific CHNRIs (maternal, newborn, child health and nutrition). A National Steering Group oversaw the exercise and four theme-specific Research Sub-Committees technically supported finalizing the scoring criteria and refinement of research ideas for the respective thematic areas. The exercise engaged participants from 256 institutions across India - 4003 research ideas were generated from 498 experts which were consolidated into 373 research options (maternal health: 122; newborn health: 56; child health: 101; nutrition: 94); 893 experts scored these against five criteria (answerability, relevance, equity, innovation and out-of-box thinking, investment on research). Relative weights to the criteria were assigned by 79 members from the Larger Reference Group. Given India's diversity, priorities were identified at national and three regional levels: (i) the Empowered Action Group (EAG) and North-Eastern States; (ii) States and Union territories in Northern India (including West Bengal); and (iii) States and Union territories in Southern and Western parts of India. CONCLUSIONS: The exercise leveraged the inherent flexibility of the CHNRI method in multiple ways. It expanded on the CHNRI methodology enabling analyses for identification of research priorities at national and regional levels. However, prioritization of research options are only valuable if they are put to use, and we hope that donors will take advantage of this prioritized list of research options.

Role of organic cation transporters in the ocular disposition of its intravenously injected substrate in rabbits: implications for ocular drug therapy.

The present study was conducted to test the hypothesis; OCT may be active from blood-to-vitreous for the uptake of its substrates. Ocular uptake of Tetraethylammonium (TEA) across blood ocular barriers and the tissue distribution was evaluated in vivo in New Zealand albino rabbits after intravenous administration. Quinidine (blocker) pretreatment resulted in a significant (p < 0.05) reduction in the Area Under the Curve (AUC) of TEA in vitreous (4.2 fold) and aqueous humor (1.8 fold) as compared to the control group which supports the role of OCT in uptake transport of its substrate across Blood ocular barrier. The blockade of OCT also affected the elimination of its substrate resulting in increased plasma levels. In most of the tissues, OCT are functionally present from apical to basolateral. The gene expression studies also showed the presence of OCT1, OCTN1 and OCTN2 in various ocular tissues studied. The present findings suggest that OCT are functionally active in blood ocular barriers and involved in the transport of its substrate from blood-to-vitreous humor.

Evaluation of the functional importance of organic cation transporters on the ocular disposition of its intravitreally injected substrate in rabbits.

PURPOSE: To evaluate the functional role of organic cation transporters (OCT) and ocular tissue distribution of intravitreally injected OCT substrate tetraethylammonium (TEA) in presence of OCT blocker (quinidine). METHODS: New Zealand albino rabbits of either sex were used. Intravitreal quinidine pretreatment was made 30 min before the administration of TEA. Modulation of vitreous and ocular tissue kinetics of OCT substrate was evaluated with or without blocker pretreatment. Gamma scintigraphy was also performed to visualize the vitreous residence of (99m)Tc-labelled TEA in the presence and absence of blocker. RESULTS: Intravitreally injected quinidine did not significantly alter the ocular disposition of TEA. TEA showed less significant posterior elimination kinetics and slow anterior elimination which resulted in longer residence time of TEA in eye after intravitreal administration. CONCLUSIONS: Intravitreally injected OCT substrates may follow an anterior elimination pathway and prolonged residence time in vitreous humor. The present study shows that OCT may not be active from vitreous-to-blood route in the blood-retinal barrier.

Development and validation of a highly sensitive LC-MS/MS method for organic cation transporter (OCT) substrate tetraethylammonium (TEA) in rabbits.

Tetraethylammonium is widely used as a probe in organic cation transporters studies. A simple, highly sensitive, and specific method using direct protein precipitation was developed using Hydrophilic Interaction Liquid Chromatography coupled with positive electrospray ionization tandem mass spectrometry for the determination of tetraethylammonium (TEA) in rabbit plasma. Isocratic separation was achieved using a ZIC-HILIC column with acetonitrile and 5mM ammonium acetate in the ratio of 8:2 containing 0.1% formic acid. Acquisition was performed in multiple reaction monitoring mode with the transitions: m/z 130→100 and 130→86 for TEA and m/z 276.1→142.2 for internal standard (homatropine). This method was validated to determine selectivity, linearity, sensitivity, precision, accuracy, recovery and stability. A good linearity was found within a range of 1.53-784.6 ng/mL. The above method has been demonstrated for its capability to estimate the plasma levels of TEA after its topical instillation in rabbit eyes. This method provides an accurate, precise and sensitive tool for determining TEA levels for transporter studies.

Prophylaxis of central nervous system leukemia: a case of chronic myeloid leukemia with lymphoid blast crisis treated with imatinib mesylate.

BACKGROUND: Chronic myeloid leukemia (CML) in blast crisis has a dismal prognosis. Imatinib mesylate (IM) is a new drug which has been shown to induce complete hematological remission in 55% and complete cytogenetic response in 22% of the patients with CML in blast crisis. METHODS: A child with CML in lymphoid blast crisis was diagnosed by complete hematological and bone marrow examination. There was no central nervous system (CNS) leukemia at presentation. The child was treated with IM at a daily dose of 400 mg. RESULTS: The child showed remission after IM administration for 28 days and remained in remission till 59 days. On day 59 she experienced headache and vomiting. Results of cerebrospinal fluid taken for cytopathology showed CNS leukemia. MCP 841 protocol for ALL and weekly intrathecal triple therapy (ITT) was given. CONCLUSIONS: Along with IM treatment in patients with CML in blast crisis, weekly ITT with hydrocortisone, cytosine arabinoside and methotrexate should be recommended to prevent CNS involvement.

Hodgkin's disease in Indian children: outcome with chemotherapy alone.

BACKGROUND: To assess the efficacy of chemotherapy alone, using four cycles of COPP alternating with four cycles of ABVD in all stages of childhood Hodgkin's disease (HD). PROCEDURE: Between January 1991 and February 2001, 148 previously untreated patients were investigated, treated, and analyzed for remission and survival. RESULTS: There were 134 boys and 14 girls with a median age of 8 years, 75% were less than 10 years old. 63.5% had advanced stage disease (IIB-IV). B symptoms were present in 54.4% of cases; bulky mediastinal mass in 18 cases (12.2%); spleen and bone marrow involvement in 22 (14.9%) and four cases (2.7%), respectively. Mixed cellularity (MC) subtype was found in 86.0%. Response to treatment was evaluated in 133 patients: complete remission (CR) was achieved in 121 patients (91.0%), partial remission (PR) in seven (5.3%), progression occurred in two (1.5%), and three (2.3%) died on therapy. Four patients with mediastinal residual disease were given additional involved field radiotherapy. Out of 111 patients analyzable, five (4.5%) have relapsed 6-30 months after completing chemotherapy, and were treated with additional cycles of ABVD and low-dose involved field radiotherapy. The 5-year actuarial overall survival (OS) and event-free survival (EFS) are 91.5 and 87.9%, respectively. Advanced stage, B symptoms, anemia, spleen, and marrow involvement were adverse prognostic factors for survival. CONCLUSIONS: Chemotherapy alone with alternating COPP/ABVD, without additional radiotherapy, provides high rates of durable remission and is an effective therapy in childhood HD, even in case of large mediastinal mass and peripheral or abdominal bulky disease.

Significance of splenomegaly in childhood Hodgkin disease.

OBJECTIVES: Spleen involvement in childhood Hodgkin disease (HD) has not been described extensively. The authors' purpose was to study the clinicoradiologic features and prognostic significance of splenomegaly and that of splenic involvement in childhood HD. METHODS: One hundred forty-one children presenting with HD between January 1991 and February 2001 and treated with chemotherapy alone (4 COPP/4 ABVD) were included in the study. Radiotherapy was given in four patients with residual mediastinal disease. Patients were staged clinically and assessed for splenic deposits by computed tomography, ultrasonography, or both. RESULTS: Splenic involvement was seen in 22 children (15.6%). On univariate analysis, spleen deposits were significantly correlated with constitutional symptoms (P = 0.02), splenomegaly on physical examination (P < 0.001), involvement of three or more lymph node areas (P = 0.006), involvement of subdiaphragmatic lymph nodes (P = 0.01), mediastinal involvement (P = 0.001), and bulky disease (P = 0.005). Multivariate analysis retained enlarged spleen, involvement of three or more lymph node areas, and bulky disease as significant risk factors for spleen involvement. Relapse occurred significantly more in children with splenic involvement (P = 0.04) and in those with splenomegaly (P = 0.04). Presence of splenic deposits was an adverse prognostic factor for 5-year event-free survival (67.5% vs. 93.0%, P = 0.01). CONCLUSIONS: Enlarged spleen, involvement of three or more lymph node areas, and bulky disease are predictable risk factors for HD splenic deposits. Splenic involvement on computed tomography scan or ultrasonography is significantly associated with relapse and contributes to a poorer outcome of HD in children treated with chemotherapy alone.

Bone relapse in acute lymphoblastic leukemia.

Acute lymphoblastic leukemia (ALL) can occasionally relapse in unusual extramedullary sites like bone. Here we present a 6.5-year old boy with 'T' cell ALL who developed a swelling in left tibia which was infiltrated with lymphoblasts 7 months after completion of chemotherapy. Bone marrow and cerebrospinal fluid were negative for blasts. This is the first reported case of bone relapse in ALL from India. We discuss the previous cases of isolated bone relapse in ALL reported in English literature.

Adenoid cystic carcinoma of the lacrimal gland.

Adenoid cystic carcinoma (ACC) of the lacrimal gland is a rare tumor from the epithelial structure. It is rare in children. The authors report a case of ACC in a girl child. Extensive excision of the tumor is advised to prevent later recurrences. Local control can be better achieved by a combination of radiochemotherapy as ACC has been shown to recur event after 10 years.

Superior vena cava syndrome.

OBJECTIVE: In order to study the clinical profile of children presenting with superior vena cava syndrome (SVCS), case records of all children presenting with SVCS over a 10-year period were retrospectively analyzed. METHODS: Twenty one children (20 males and 1 female) with a median age of 10.0 years (range 5.0 to 12.0 years) were detected to have an underlying hematological malignancy. T-cell acute lymphoblastic leukemia accounted for a major share (57%) in the underlying etiology; 33% of the subjects had non-Hodgkin's lymphoma (T-cell lymphoblastic lymphoma). RESULT: No Patient required radiotherapy or urgent thoracotomy. Among survivors (n=11), who were alive and well at the time of writing this report, the median follow-up was 6.5 years, (range 0.5-9.6 years). T-cell ALL and lymphoblastic lymphoma are common underlying causes of SVCS in Indian children. CONCLUSION: The value of diagnostic interventions performed under local anaesthesia and prebiopsy corticosteroids usage was found to be reassuring since long-term survival without disease is achievable.