A comprehensive molecular study identified 12 complementation groups with 56 novel FANC gene variants in Indian Fanconi anemia subjects.

Fanconi anemia (FA) is a rare autosomal or X-linked genetic disorder characterized by chromosomal breakages, congenital abnormalities, bone marrow failure (BMF), and cancer. There has been a discovery of 22 FANC genes known to be involved in the FA pathway. This wide number of pathway components makes molecular diagnosis challenging for FA. We present here the most comprehensive molecular diagnosis of FA subjects from India. We observed a high frequency (4.42 ± 1.5 breaks/metaphase) of chromosomal breakages in 181 FA subjects. The major clinical abnormalities observed were skin pigmentation (70.2%), short stature (46.4%), and skeletal abnormalities (43.1%), along with a few minor clinical abnormalities. The combination of Sanger sequencing and Next Generation Sequencing could molecularly characterize 164 (90.6%) FA patients and identified 12 different complementation groups [FANCA (56.10%), FANCG (16.46%), FANCL (12.80%), FANCD2 (4.88%), FANCJ (2.44%), FANCE (1.22%), FANCF (1.22%), FANCI (1.22%), FANCN (1.22%), FANCC (1.22%), FANCD1 (0.61%) and FANCB (0.61%)]. A total of 56 novel variants were identified in our cohort, including a hotspot variant: a deletion of exon 27 in the FANCA gene and a nonsense variant at c.787 C>T in the FANCG gene. Our comprehensive molecular findings can aid in the stratification of molecular investigation in the diagnosis and management of FA patients.

Efficacy of ready-to-use therapeutic food in malnourished children with cancer: Results of a randomized, open-label phase 3 trial.

BACKGROUND: The adverse influence of undernutrition in children with cancer may be remediated by early nutritional intervention. This study assessed the efficacy of ready-to-use therapeutic food (RUTF) in improving nutritional status and reducing treatment-related toxicities (TRTs) in such children. METHODS: In a randomized controlled phase-3 open-label trial, severely and moderately undernourished children with cancer were randomized 1:1 to receive standard nutritional therapy (SNT) or SNT+RUTF for 6 weeks. The primary outcome (weight gain >10%) and secondary outcomes (improved/maintained nutritional status, improved body composition) were assessed after 6 weeks. TRTs were assessed over 6 months. RESULTS: Between July 2015 and March 2018, 260 subjects were enrolled, 126 were analyzable in both arms at 6 weeks. More children on RUTF had weight gain (98 [77.8%] vs. 81 [64.2%], p = .025) with a greater increase in fat mass as a percentage of body mass (median 2% [IQR -0.12 to 4.9] vs. 0.5% [IQR -1.45 to 2.27, p = .005]) but a greater loss of lean mass (median -1.86% [IQR -4.4 to 0.50] vs. -0.4% [IQR -2.4 to 1.4, p = .007]) compared to the SNT arm. Fewer subjects on the RUTF arm had episodes of severe infection (10.6% vs. 31%, p < .0001), treatment delays (17.7% vs. 39%, p < .0001), and severe mucositis (11% vs. 23.8%, p = .006) compared to the SNT arm. The odds of developing TRTs on the RUTF arm were lower even after adjusting for improvement in nutritional status. CONCLUSIONS: RUTF is efficacious in improving weight gain and nutritional status in undernourished children with cancer and decreases TRTs. Incorporating RUTF into a healthy, balanced diet should be considered in undernourished children with cancer.

A Randomized Trial of Factor VIII and Neutralizing Antibodies in Hemophilia A.

BACKGROUND: The development of neutralizing anti-factor VIII alloantibodies (inhibitors) in patients with severe hemophilia A may depend on the concentrate used for replacement therapy. METHODS: We conducted a randomized trial to assess the incidence of factor VIII inhibitors among patients treated with plasma-derived factor VIII containing von Willebrand factor or recombinant factor VIII. Patients who met the eligibility criteria (male sex, age <6 years, severe hemophilia A, and no previous treatment with any factor VIII concentrate or only minimal treatment with blood components) were included from 42 sites. RESULTS: Of 303 patients screened, 264 underwent randomization and 251 were analyzed. Inhibitors developed in 76 patients, 50 of whom had high-titer inhibitors (≥5 Bethesda units). Inhibitors developed in 29 of the 125 patients treated with plasma-derived factor VIII (20 patients had high-titer inhibitors) and in 47 of the 126 patients treated with recombinant factor VIII (30 patients had high-titer inhibitors). The cumulative incidence of all inhibitors was 26.8% (95% confidence interval [CI], 18.4 to 35.2) with plasma-derived factor VIII and 44.5% (95% CI, 34.7 to 54.3) with recombinant factor VIII; the cumulative incidence of high-titer inhibitors was 18.6% (95% CI, 11.2 to 26.0) and 28.4% (95% CI, 19.6 to 37.2), respectively. In Cox regression models for the primary end point of all inhibitors, recombinant factor VIII was associated with an 87% higher incidence than plasma-derived factor VIII (hazard ratio, 1.87; 95% CI, 1.17 to 2.96). This association did not change in multivariable analysis. For high-titer inhibitors, the hazard ratio was 1.69 (95% CI, 0.96 to 2.98). When the analysis was restricted to recombinant factor VIII products other than second-generation full-length recombinant factor VIII, effect estimates remained similar for all inhibitors (hazard ratio, 1.98; 95% CI, 0.99 to 3.97) and high-titer inhibitors (hazard ratio, 2.59; 95% CI, 1.11 to 6.00). CONCLUSIONS: Patients treated with plasma-derived factor VIII containing von Willebrand factor had a lower incidence of inhibitors than those treated with recombinant factor VIII. (Funded by the Angelo Bianchi Bonomi Foundation and others; ClinicalTrials.gov number, NCT01064284; EudraCT number, 2009-011186-88.).

Molecular genotyping of clinically important blood group antigens in patients with thalassaemia.

BACKGROUND & OBJECTIVES: In multitransfused thalassaemic patients, haemagglutination fails to phenotype the patient's blood group antigens due to the presence of donor-derived erythrocytes. DNA-based methods can overcome the limitations of haemagglutination and can be used to determine the correct antigen profile of these patients. This will facilitate the procurement of antigen-matched blood for transfusion to multitransfused patients. Thus, the aim of this study was to compare the serological phenotyping of common and clinically important antigens of Rh, Duffy, Kell, Kidd and MNS blood group systems with molecular genotyping amongst multitransfused thalassaemic patients. METHODS: Blood samples from 200 patients with thalassaemia and 100 'O' group regular blood donors were tested using standard serological techniques and polymerase chain reaction-based methods for common antigens/alleles (C, c, D, E, e, Fya, Fyb, Jka, Jkb, K, k, M, N, S, s). RESULTS: Genotyping and phenotyping results were discordant in 77 per cent of thalassaemic patients for five pairs of antithetical antigens of Rh, Duffy, Kell and Kidd blood group systems. In the MNS blood group system, 59.1 per cent of patients showed discrepancy. The rate of alloimmunization among thalassaemics was 7.5 per cent. INTERPRETATION & CONCLUSIONS: Molecular genotyping enabled the determination of the actual antigen profile in multitransfused thalassaemia patients. This would help reduce the problem of alloimmunization in such patients and would also aid in the better management of transfusion therapy.

Clinical, Immunological, and Molecular Findings of Patients with p47phox Defect Chronic Granulomatous Disease (CGD) in Indian Families.

Chronic granulomatous disease (CGD) is a group of inherited disorder of phagocytes, resulting from mutations in the components of the NADPH oxidase complex. Reduced or absent oxygen radical synthesis seen in these patients leads to impaired killing of intracellular bacteria and fungi. CGD clinically presents with recurrent and life-threatening infections as well as granulomatous inflammatory responses. p47phox encoded by the NCF1 gene is the most common autosomal recessive form of CGD which is often clinically milder. Here, we are presenting the data on clinical and immunological findings in 21 Indian patients with Del GT mutation in the NCF1 gene. Diagnosis of these patients was based on detailed clinical evaluation, measurement of respiratory burst activity by nitro blue tetrazolium and dihydrorhodamine-1,2,3 assay, expression of p47phox by flow cytometry, and molecular confirmation by GeneScan method. Seventeen male and four female patients with median age of onset of 1 year ranging from 1.5 months to 6 years were included in the study. Sixty-two percent (13 out of 21) of patients belonged to a consanguineous marriage with only one family having a history of a previous sibling death. Significant variability in clinical presentation was observed in spite of identical genetic defect ranging from asymptomatic to very severe presentation leading to early death or requiring transplantation. However, none of these patients showed difference in immunological parameters to account for this variability. Thus, this study highlights the phenotypic heterogeneity seen in these patients with Del GT mutation in the NCF1 gene and its implication in management of these patients.

Molecular characterization of leukocyte adhesion deficiency-I in Indian patients: identification of 9 novel mutations.

PURPOSE: Leukocyte adhesion deficiency type-I (LAD-I) is caused by mutations in the ITGB2 gene, encoding the ß2-subunit of ß2-integrin (CD18) which leads to markedly reduced expression of CD18 on leukocytes resulting into recurrent life threatening infections. Here we aim to identify the molecular defects underlying LAD-I in Indian patients and correlate with the clinical presentation. METHODS: Blood was collected from 30 patients and their parents for absolute neutrophil count, expression of CD18 and CD11 by flow cytometry and DNA extraction. PCR and DNA sequencing of the ITGB2 gene was done for mutation characterization. RESULTS: Phenotypically, 22 patients were LAD-I(0), 1 was LAD-I(-) and 7 were LAD-I(+) showing no expression and reduced expression of CD18 respectively. Nine novel mutations in 15 patients and 11 known mutations in 16 patients were detected. Prenatal diagnosis was performed for 5 families. CONCLUSION: In this study 30 patients were phenotypically and genotypically evaluated for a less known disease LAD-I. Unavailability of curative options to majority of the patients and high cost of supportive care emphasize the need to increase awareness about a suspicious case so that timely management can be given to the patient and prenatal diagnosis can be offered to their families.

Guidelines for screening, diagnosis and management of hemoglobinopathies.

The ß-thalassemias and sickle cell disorders are a major health burden in India. Diagnosis and management of these disorders both in adults and in newborns using appropriate approaches and uniform technology are important in different regions of a vast and diverse country as India. In view of a National Thalassemia Control Program to be launched soon, a need was felt for guidelines on whom to screen, cost-effective technologies that are to be used as well as for establishing prenatal diagnosis programs in regional centers. Newborn screening for sickle cell disorders is in its infancy in India and uniform approaches need to be followed. Also, included are guidelines for monitoring and managing patients who are now growing older and need comprehensive care as well as management of complications of the disease.

The Indian Academy of Pediatrics and Directorate General of Health Services, Government of India White Paper on Transition of Care for Youth with Special Health Care Needs.

Over the years, survival of children with chronic diseases has significantly improved and a large proportion of them now are entering into adulthood. Transition of Care (ToC) of such patients with having childhood onset of chronic diseases to the adult health care system is well organized in developed countries, although it is an emerging concept in India. In situations where the systems for ToC are not in place, such cases are fraught with unsatisfactory health outcomes. With proper ToC in place, these patients are likely to receive uninterrupted care by the adult care physicians and hence reach their full potential. This document highlights the need, rationale and way forward for ToC of youth with special health care needs (YSHCN) across the country. It also describes the standard operating procedures to develop the ToC at a hospital level for clinicians and administrators.

Attitudes and acceptability of children, caregivers, and healthcare providers about using telemedicine for pediatric HIV care in a resource-limited setting.

BACKGROUND: The Pediatric HIV Telemedicine Initiative is a video-linked delivery of expert services, designed to reach those previously unable to access expert HIV care. The present qualitative study was designed to understand the acceptability of telemedicine [TM] by patients, their caregivers and health care providers in the anti-retroviral therapy (ART) centers in Maharashtra. METHODS: We conducted focus group discussions with caregivers at six ART centres (three linked with TM facilities and three not linked with TM). We also conducted in-depth interviews with medical officers, counselors, and pharmacists at each centre. The data from the interviews were transcribed and translated into English for analysis. The qualitative data were analyzed using thematic framework approach. RESULTS: Children and caregivers who had participated in telemedicine consultation through video conference found the process acceptable, were comfortable communicating during these sessions, and did not have any specific problem to report. The advantages of TM were: consultation without having to travel to other cities; economic advantage; and prompt consultation. The total time spent during the process and technical difficulties during the TM sessions were some of the challenges. The medical officers had the opportunity to discuss difficult cases with the expert during the TM session. Some sessions were also considered a 'group counseling' session, wherein several children and caregivers were able to interact and learn from each other and motivate each other. The health care providers at the three centers that did not currently have TM facilities expressed a desire to have these services at their centers as well. According to them, these facilities will help them address complicated and difficult pediatric HIV cases. Currently, they send their patients to referral centers or other hospitals. Since, many of these referral hospitals are situated in bigger cities, less than 50% of patients access care at these centers This is mostly due to the time constraints and finances (travel/stay) required for accessing these centres. DISCUSSION: TM was a feasible, acceptable, and desired approach for care of children living with HIV/AIDS. It provides support to their caregivers as well as their care providers. The ART staff from the telemedicine-linked peripheral centers were supportive of the use of TM and wanted these services to be initiated in the non-linked centers.

Diagnosis, Treatment and Prevention of Nutritional Anemia in Children: Recommendations of the Joint Committee of Pediatric Hematology-Oncology Chapter and Pediatric and Adolescent Nutrition Society of the Indian Academy of Pediatrics.

JUSTIFICATION: Anemia in children is a significant public health problem in our country. Comprehensive National Nutrition Survey 2016-18 provides evidence that more than 50% of childhood anemia is due to an underlying nutritional deficiency. The National Family Health Survey-5 has reported an increase in the prevalence of anemia in the under-five age group from 59% to 67.1% over the last 5 years. Clearly, the existing public health programs to decrease the prevalence of anemia have not shown the desired results. Hence, there is a need to develop nationally acceptable guidelines for the diagnosis, treatment and prevention of nutritional anemia. OBJECTIVE: To review the available literature and collate evidence-based observations to formulate guidelines for diagnosis, treatment and prevention of nutritional anemia in children. PROCESS: These guidelines have been developed by the experts from the Pediatric Hematology-Oncology Chapter and the Pediatric and Adolescent Nutrition (PAN) Society of the Indian Academy of Pediatrics (IAP). Key areas were identified as: epidemiology, nomenclature and definitions, etiology and diagnosis of iron deficiency anemia (IDA), treatment of IDA, etiology and diagnosis of vitamin B12 and/or folic acid deficiency, treatment of vitamin B12 and/or folic acid deficiency anemia and prevention of nutritional anemia. Each of these key areas were reviewed by at least 2 to 3 experts. Four virtual meetings were held in November, 2021 and all the key issues were deliberated upon. Based on review and inputs received during meetings, draft recommendations were prepared. After this, a writing group was constituted which prepared the draft guidelines. The draft was circulated and approved by all the expert group members. RECOMMENDATIONS: We recommend use of World Health Organization (WHO) cut-off hemoglobin levels to define anemia in children and adolescents. Most cases suspected to have IDA can be started on treatment based on a compatible history, physical examination and hemogram report. Serum ferritin assay is recommended for the confirmation of the diagnosis of IDA. Most cases of IDA can be managed with oral iron therapy using 2-3 mg/kg elemental iron daily. The presence of macro-ovalocytes and hypersegmented neutrophils, along with an elevated mean corpuscular volume (MCV), should raise the suspicion of underlying vitamin B12 (cobalamin) or folic acid deficiency. Estimation of serum vitamin B12 and folate level are advisable in children with macrocytic anemia prior to starting treatment. When serum vitamin B12 and folate levels are unavailable, patients should be treated using both drugs. Vitamin B12 should preferably be started 10-14 days ahead of oral folic acid to avoid precipitating neurological symptoms. Children with macrocytic anemia in whom a quick response to treatment is required, such as those with pancytopenia, severe anemia, developmental delay and infantile tremor syndrome, should be managed using parenteral vitamin B12. Children with vitamin B12 deficiency having mild or moderate anemia may be managed using oral vitamin B12 preparations. After completing therapy for nutritional anemia, all infants and children should be advised to continue prophylactic iron-folic acid (IFA) supplementation as prescribed under Anemia Mukt Bharat guidelines. For prevention of anemia, in addition to age-appropriate IFA prophylaxis, routine screening of infants for anemia at 9 months during immunization visit is recommended.

Vitamin C Deficiency and Oxidant Levels in Children With Transfusion-Dependent b-Thalassemia.

OBJECTIVES: To study vitamin C levels in children with transfusion-dependent b-thalassemia and correlate with age, transfusions received and iron overload; and to study the effect of administering vitamin C on its levels and Malondialdehyde (MDA) in deficient patients. METHODS: This case-control study enrolled 100 children with transfusion-dependent b-thalassemia and 30 healthy controls. MDA levels before and after administration of vitamin C were performed randomly in 36 children with low vitamin C levels. RESULTS: 81/95 (85.3%) study subjects vs none in control group, had low plasma vitamin C levels (P<0.001). Vitamin C levels were low in 64 of 71 (74.7%) subjects with dietary deficiency, while none of the 19 (63.3%) controls with dietary deficiency had low levels (P=0.04). Increasing serum ferritin values correlated with vitamin C deficiency (P=0.02). The mean level of MDA reduced (P<0.001) with vitamin C supplementation. CONCLUSIONS: Low levels of vitamin C are common in children with thalassemia. Dietary counseling along with supplementation with vitamin C, in those with low levels may prevent oxidative stress.

Assessing the Effectiveness of a Telemedicine Initiative in Clinical Management of Children Living with HIV/AIDS in Maharashtra, India.

AIMS: To evaluate the effectiveness of telemedicine in the clinical management of children living with HIV/AIDS in resource-limited settings ; Background: Telemedicine is an important mechanism for service delivery in health care settings, both in resource-rich and resource-poor settings. Such service delivery mechanisms have shown to be associated with virologic suppression and higher CD4 counts. These services are also associated with improved access, shorter visiting times, and higher patient satisfaction. ; Objective: We designed the present two-group comparison study to compare the clinical evaluation and management of children in the anti-retroviral therapy (ART) centres linked to telemedicine facility with those who are not linked to this facility in Maharashtra, India. ; Methods: We analysed clinical records from six ART centres in Maharashtra; of these, 250 children were in the linked ART centres and 301 were in the non-linked ART centres. The outcomes were classified according to investigations, management, and monitoring. For management, we evaluated: 1) Initiation of cotrimoxazole prophylaxis; 2) Children not initiated on ART when required; 3) ART regime after appropriate investigations; and 4) Change of regime (if immunologically indicated). For monitoring, we assessed the haematological monitoring of children on ART. ; Results: The mean (SD) ages of children in linked and non-linked ART centres were 10.8 (4.6) and 10.9 (4.6) years, respectively (p=0.80). After adjusting for individual and structural level variables, physical examination (OR: 2.0, 95% CI; 1.2, 3.2), screening for tuberculosis (OR: 12.9, 95% CI: 2.0, 82.9) and cotrimoxazole prophylaxis were significantly more likely in the linked centres compared with non-linked centres (OR: 1.8, 95% CI: 1.4, 2.2). A higher proportion of children eligible for ART were not initiated on treatment in the non-linked centres compared with linked centres (26% vs. 8%, p=0.06). Children were less likely to be initiated on zidovudine-based regimens without baseline haemoglobin or with baseline haemoglobin of less than 9 gm% in linked centres (OR: 0.7, 95% CI: 0.6, 0.8). Similarly, children in the linked centres were less likely to have been started on nevirapine-based regimens without baseline liver enzymes (OR: 0.8, 95% CI: 0.7, 0.9). ; Conclusion: Thus, the overall clinical management of Children Living with HIV/ AIDS (CLHA) was better in ART centres linked with the telemedicine initiative compared with those who were not linked. Children in the linked ART centres were more likely to have a complete baseline assessment (physical, hematological, radiological, and screening for TB); the presence of a pediatrician in the centres was helpful.

Reaching the Unreached: Providing Quality Care to HIV-Infected Children through Telemedicine-An Innovative Pilot Initiative from Maharashtra, India.

BACKGROUND: The National AIDS Control Organization (NACO) of India created the Regional Pediatric Antiretroviral Therapy (ART) Center; this was subsequently upgraded to seven Pediatric Centers of Excellence (PCoEs) to strengthen the quality of treatment and care of children living with HIV/AIDS (CLHAs). In October 2013, the pediatric HIV telemedicine initiative, an e-decentralized (care provided by local healthcare providers and support provided by a central agency through telemedicine facilities) model of expert pediatric HIV care and referral services, was established as a pilot project at the Pediatric Center of Excellence for HIV Care in Maharashtra. We designed the present study to compare management, compliance to ART, and mortality in children in the ART centers linked to the PCoE through telemedicine versus those that are not linked to the PCoE. METHODS: It was a retrospective cross-sectional study of secondary data from CLHAs from October 2013 through August 2015 in the ART centers to document the intermediate outcomes and to determine if the initiative has improved the quality of care for the CLHAs enrolled in the linked ART centers with nonlinked ART centers. The centers in which the telemedicine sessions were conducted regularly were called linked-regular centers and in whom it was conducted irregularly (less than the median of 12 videoconference cases), it was called a linked-irregular center. Data from 2803 children in 31 linked (1365 in irregular and 1438 in regular centers) and 2608 children in 28 nonlinked centers were analyzed. The outcomes in children in the pre-ART group (ART naïve) were (1) alive on pre-ART, (2) lost to follow-up on pre-ART, (3) death during the pre-ART period, (4) eligible but not initiated on ART, and (5) missing baseline and latest CD4 counts. The outcomes of children on ART were (1) alive on ART, (2) lost to follow-up on ART, (3) death on ART, and (4) missing baseline and latest CD4 counts. RESULTS: We found that a higher proportion of children in the linked-regular centers (79% vs. 70%, p < 0.001) and linked-irregular centers (76% vs. 70%, p = 0.04) was alive compared with that in the nonlinked centers in the pre-ART group. In this group, the proportion of children with missing baseline CD4 counts and latest CD4 counts was significantly low in linked (regular centers) centers. In the ART group, we found that a higher proportion of children in the linked-regular centers was alive compared with that in the linked-irregular centers (77% vs. 69%, p < 0.001); the proportion was not significantly different in nonlinked centers (77% vs. 78%, p = 0.56). In this group, the proportion of missing baseline CD4 counts was significantly lower in the linked-regular centers (3% vs 13%, p<0.001) and linked-irregular centers (1% vs. 13%, p < 0.001) compared with that in the nonlinked centers. Furthermore, the latest CD4 counts were missing in a significantly lower proportion of children in the linked-regular centers compared with those in the linked-irregular centers (6% vs. 18%, p < 0.001) and nonlinked centers (6% vs. 18%, p < 0.001). CONCLUSION: Our study shows that the centers linked through telemedicine performed better in terms of patient care and treatment, with a lesser loss to follow-up and lesser deaths in CLHA. Overall, this pilot project of telemedicine for pediatric HIV has been proven to be acceptable, feasible, and effective in improving the quality of care for children living with HIV across the state of Maharashtra.

Clinical and Genetic Spectrum of a Large Cohort of Patients With Leukocyte Adhesion Deficiency Type 1 and 3: A Multicentric Study From India.

Leukocyte adhesion deficiency (LAD) syndrome is a group of inborn errors of immunity characterized by a defect in the cascade of the activation and adhesion leading to the failure of leukocyte to migrate to the site of tissue injury. Three different types of LAD have been described. The most common subtype is LAD type 1 (LAD1) caused due to defects in the ITGß2 gene. LAD type 2 (LAD2) is caused by mutations in the SLC35C1 gene leading to a generalized loss of expression of fucosylated glycans on the cell surface and LAD type 3 (LAD3) is caused by mutations in the FERMT3 gene resulting in platelet function defects along with immunodeficiency. There is a paucity of data available from India on LAD syndromes. The present study is a retrospective analysis of patients with LAD collated from 28 different centers across India. For LAD1, the diagnosis was based on clinical features and flow cytometric expression of CD18 on peripheral blood leukocytes and molecular confirmation by Sanger sequencing. For patients with LAD3 diagnosis was largely based on clinical manifestations and identification of the pathogenic mutation in the FERMT3 gene by next-generation Sequencing. Of the total 132 cases diagnosed with LAD, 127 were LAD1 and 5 were LAD3. The majority of our patients (83%) had CD18 expression less than 2% on neutrophils (LAD1°) and presented within the first three months of life with omphalitis, skin and soft tissue infections, delayed umbilical cord detachment, otitis media, and sepsis. The patients with CD18 expression of more than 30% (LAD1+) presented later in life with skin ulcers being the commonest manifestation. Bleeding manifestations were common in patients with LAD3. Persistent neutrophilic leukocytosis was the characteristic finding in all patients. 35 novel mutations were detected in the ITGß2 gene, and 4 novel mutations were detected in the FERMT3 gene. The study thus presents one of the largest cohorts of patients from India with LAD, focusing on clinical features, immunological characteristics, and molecular spectrum.

Indigenously Prepared Ready-to-use Therapeutic Food (RUTF) in Children with Severe Acute Malnutrition.

OBJECTIVE: To compare efficacy of indigenous Ready-to-use Therapeutic Food (Medical Nutrition Therapy) with Standard Nutrition Therapy in children with Severe acute malnutrition. DESIGN: Two facility-based and two community-based models: (i) Open prospective randomized controlled trial comparing Indigenous Ready-to-use Therapeutic Food (Medical Nutrition Therapy) with Standard Nutrition Therapy; (ii) Only Indigenous Ready-to-use Therapeutic Food (Medical Nutrition Therapy); (iii) Doorstep Child Care Centre; and (iv) Community-based Management of Acute Malnutrition. SETTING: (i) Urban Health Center, Dharavi, Mumbai; (ii) Two day care centers of Non-governmental Organization SNEHA - Mumbai; (iii) Urban slums, M East and L Ward, Mumbai. PARTICIPANTS: 1105 children aged 6-60 months in community or hospital inpatient/ outpatient department diagnosed as Severe Acute Malnutrition by WHO definition. INTERVENTION: All subjects received either Indigenous Ready-to-use Therapeutic Food (Medical Nutrition Therapy) or Standard Nutrition Therapy (protein calorie rich diet) for eight weeks and followed up for next four months. MAIN OUTCOME MEASURES: Mean rate of weight gain (g/kg/day), target weight, change in nutritional status. RESULTS: Rate of weight gain was higher (P<0.05) at 2 weeks on indigenous Ready-to-use Therapeutic Food (Medical Nutrition Therapy) (5.63 g/kg/day) as compared to Standard Nutrition Therapy (3.43 g/kg/day). 61.2% subjects achieved target weight compared to 47.7% controls. At 8 weeks, 82.8% subjects recovered from Severe Acute Malnutrition compared to 19.3% controls (P<0.005). The results obtained in community were comparable to facility-based indigenous Ready-to-use Therapeutic Food (Medical Nutrition Therapy). The morbidity was less in study group at follow-up. CONCLUSIONS: Indigenous Ready-to-use Therapeutic Food (Medical Nutrition Therapy) appeared to be superior to Standard Nutrition Therapy in promoting weight gain in children with Severe Acute Malnutrition.

Impact of Anemia on Outcome of HIV-Infected Pediatric Patients: A Prospective Observational Study.

INTRODUCTION: Anemia has been widely reported to predict a poorer prognosis for HIV-infected patients, both in terms of progression to AIDS and in survival. This study aimed to determine the etiology of anemia and its immunological correlation in HIV-infected children. MATERIALS AND METHODS: Four hundred and eighty-nine HIV-infected children were screened, of which 86 HIV-infected children with anemia were enrolled. Standard WHO definitions were used for anemia, HIV staging, and growth parameters. Chi-square test, t-tests, and univariate and multivariate logistic regression analyses were used to analyze the data. RESULTS: Anemia was present in 17.58% (86/489) of HIV-infected children, including 84.6% with moderate anemia, 11.5% with severe anemia, and 2.32% with mild anemia. The mean hemoglobin (Hb) among patients with CD4 count <350 cell/mm3 was lower (7.90 g%) (standard deviation 1.48) compared to those having CD4 >350 cell/mm3 (P = 0.02). Children with severe immunological stage had a significantly lower mean Hb (adjusted estimate: -1.61, 95% confidence interval: -2.65, -0.56) compared to those who had normal immune status. No statistically significant differences in mean Hb at baseline when compared to various demographic and clinical characteristics were observed in unadjusted and adjusted regression models. CONCLUSION: Hb is an easy and inexpensive tool to measure and can be used for monitoring disease progression in a resource-limited setting.

Red cell adenylate kinase deficiency in India: identification of two novel missense mutations (c.71A>G and c.413G>A).

Adenylate kinase (AK) deficiency is a rare erythroenzymopathy associated with hereditary nonspherocytic haemolytic anaemia along with mental/psychomotor retardation in few cases. Diagnosis of AK deficiency depends on the decreased level of enzyme activity in red cell and identification of a mutation in the AK1 gene. Until, only eight mutations causing AK deficiency have been reported in the literature. We are reporting two novel missense mutation (c.71A > G and c.413G > A) detected in the AK1 gene by next-generation sequencing (NGS) in a 6-year-old male child from India. Red cell AK enzyme activity was found to be 30% normal. We have screened a total of 32 family members of the patient and showed reduced red cell enzyme activity and confirm mutations by Sanger's sequencing. On the basis of Sanger sequencing, we suggest that the proband has inherited a mutation in AK1 gene exon 4 c.71A > G (p.Gln24Arg) from paternal family and exon 6 c.413G > A (p.Arg138His) from maternal family. Bioinformatics tools, such as SIFT, Polymorphism Phenotyping v.2, Mutation Taster, MutPred, also confirmed the deleterious effect of both the mutations. Molecular modelling suggests that the structural changes induced by p.Gln24Arg and p.Arg138His are pathogenic variants having a direct impact on the structural arrangement of the region close to the active site of the enzyme. In conclusion, NGS will be the best solution for diagnosis of very rare disorders leading to better management of the disease. This is the first report of the red cell AK deficiency from the Indian population.

Can telemedicine initiative be an effective intervention strategy for improving treatment compliance for pediatric HIV patients: Evidences on costs and improvement in treatment compliance from Maharashtra, India.

BACKGROUND: India has recently introduced telemedicine initiatives to enhance access to specialized care at a low cost for the pediatric HIV patients, who face multiple challenges due to growing disease burden and limited preparedness of the health system to address it. There are limited evidences on the cost-effectiveness of these interventions. This study was undertaken in Maharashtra, a province, located in the western region of the country, to inform policy regarding the effectiveness of this programme. The objective was to estimate the unit cost of ART services for pediatric HIV patients and examine the efficiency in the use of resource and treatment compliance resulting from telemedicine initiatives in pediatric HIV compared to usual ART services. METHODS: We selected 6 ART centers (3 from linked centers linked to Pediatric HIV Centre of Excellence (PCoE) and 3 from non-linked centers) randomly from three high, middle and low ART centers, categorized on the basis of case load in each arm. A bottom up costing methodology was adopted to understand the unit cost of services. Loss to follow up and timeliness of the visits were compared between the two arms and were linked to the cost. RESULTS: The average cost per-visit was INR 1803 in the linked centers and that for the non-linked centers was INR 3412. There has been 5 percentage point improvement in lost to follow-up in the linked centers compared to non-linked centers against a back-drop of a reduction in per-pediatric patient cost of INR 557. The linkage has resulted in increase in timeliness of the visits in linked centers compared to non-linked centers. DISCUSSION AND CONCLUSION: The telemedicine linkage led to an increase in the case load leading to a decrease in cost. The evidence on efficiency in the use of resource and improvement in treatment compliance as suggested by this study could be used to scale up this initiative.

HLA- B*5701 Allele in HIV-infected Indian Children and its Association with Abacavir Hypersensitivity.

OBJECTIVE: To determine the prevalence of HLA-B*5701 allele in HIV-infected children, and to find its association with Abacavir hypersensitivity. METHODS: Children (2 to 18 y) already on, or to be initiated on Abacavir were included for PCR sequencing to detect HLA-B*5701. OUTCOME MEASURES WERE: proportion with HLA B*5701 allele and hypersensitivity with Abacavir. Abacavir was stopped if patient tested positive for HLA-B*5701 allele. RESULTS: 100 children (median age 11 y) were enrolled; 10 were already on Abacavir. HLA-B*5701 positivity was observed in 11 (11%) children. Two of these 11 children developed hypersensitivity after initiation of Abacavir. Abacavir was thereafter stopped in all who tested HLA-B*5701 positive, irrespective of the development of hypersensitivity reaction. CONCLUSION: HLA-B*5701 allele was present in 11 (11%) of HIV-infected children, of which two developed Abacavir hypersensitivity. None of the patients without the allele developed hypersensitivity.