Effect of a multicomponent intervention on achievement and improvements in quality-of-care indices among people with Type 2 diabetes in South Asia: the CARRS trial.

AIMS: To evaluate whether and what combinations of diabetes quality metrics were achieved in a multicentre trial in South Asia evaluating a multicomponent quality improvement intervention that included non-physician care coordinators to promote adherence and clinical decision-support software to enhance physician practices, in comparision with usual care. METHODS: Using data from the Centre for Cardiometabolic Risk Reduction in South Asia (CARRS) trial, we evaluated the proportions of trial participants achieving specific and combinations of five diabetes care targets (HbA1c <53 mmol/mol [7%], blood pressure <130/80 mmHg, LDL cholesterol <2.6 mmol/L, non-smoking status, and aspirin use). Additionally, we examined the proportions of participants achieving the following risk factor improvements from baseline: ≥11-mmol/mol (1%) reduction in HbA1c , ≥10-mmHg reduction in systolic blood pressure, and/or ≥0.26-mmol/l reduction in LDL cholesterol. RESULTS: Baseline characteristics were similar in the intervention and usual care arms. Overall, 12.3%, 29.4%, 36.5%, 19.5% and 2.2% of participants in the intervention group and 16.2%, 38.3%, 31.6%, 11.3% and 0.8% of participants in the usual care group achieved any one, two, three, four or five targets, respectively. We noted sizeable improvements in HbA1c , blood pressure and cholesterol, and found that participants in the intervention group were twice as likely to achieve improvements in all three indices at 12 months that were sustained over 28 months of the study [relative risk 2.1 (95% CI 1.5,2.8) and 1.8 (95% CI 1.5,2.3), respectively]. CONCLUSIONS: The intervention was associated with significantly higher achievement of and greater improvements in composite diabetes quality care goals. However, among these higher-risk participants, very small proportions achieved the complete group of targets, which suggests that achievement of multiple quality-of-care goals is challenging and that other methods may be needed in closing care gaps.

The INtegrating DEPrEssioN and Diabetes treatmENT (INDEPENDENT) study: Design and methods to address mental healthcare gaps in India.

INTRODUCTION: Depression and diabetes are highly prevalent worldwide and often co-exist, worsening outcomes for each condition. Barriers to diagnosis and treatment are exacerbated in low and middle-income countries with limited health infrastructure and access to mental health treatment. The INtegrating DEPrEssioN and Diabetes treatmENT (INDEPENDENT) study tests the sustained effectiveness and cost-effectiveness of a multi-component care model for individuals with poorly-controlled diabetes and depression in diabetes clinics in India. MATERIALS AND METHODS: Adults with diabetes, depressive symptoms (Patient Health Questionnaire-9 score≥10), and ≥1 poorly-controlled cardiometabolic indicator (either HbA1c≥8.0%, SBP≥140mmHg, and/or LDL≥130mg/dl) were enrolled and randomized to the intervention or usual care. The intervention combined collaborative care, decision-support, and population health management. The primary outcome is the between-arm difference in the proportion of participants achieving combined depression response (≥50% reduction in Symptom Checklist score from baseline) AND one or more of: ≥0.5% reduction in HbA1c, ≥5mmHg reduction in SBP, or ≥10mg/dl reduction in LDL-c at 24months (12-month intervention; 12-month observational follow-up). Other outcomes include control of individual parameters, patient-centered measures (i.e. treatment satisfaction), and cost-effectiveness. RESULTS: The study trained seven care coordinators. Participant recruitment is complete - 940 adults were screened, with 483 eligible, and 404 randomized (196 to intervention; 208 to usual care). Randomization was balanced across clinic sites. CONCLUSIONS: The INDEPENDENT model aims to increase access to mental health care and improve depression and cardiometabolic disease outcomes among complex patients with diabetes by leveraging the care provided in diabetes clinics in India (clinicaltrials.gov number: NCT02022111).

Identification of Novel PROP1 and POU1F1 Mutations in Patients with Combined Pituitary Hormone Deficiency.

Growth hormone deficiency (GHD) results from variations affecting the production and release of growth hormone (GH) and is of 2 types: isolated growth hormone deficiency (IGHD) and combined pituitary hormone deficiency (CPHD). IGHD results from mutations in GH1 and GHRHR while CPHD is associated with defects in transcription factor genes PROP1, POU1F1, and HESX1. The present study reports on screening of POU1F1, PROP1, and HESX1 in CPHD patients and the novel variations identified. Fifty-one CPHD patients from 49 unrelated families clinically diagnosed on the basis of biochemical and imaging investigations along with 100 controls were enrolled. Detailed family history was noted from all participants and 5 ml blood samples drawn were processed for DNA isolation followed by direct sequencing of POU1F1, PROP1, and HESX1genes. Of the 51 patients, 8 were females and 43 were males. Mean height standard deviation score (SDS) and weight SDS were -5.50 and -2.76, respectively. Thirty-six of the 51 patients underwent MRI of which 9 (25%) had normal pituitary structure and morphology while 27 (75%) showed abnormalities. Molecular analysis revealed 10 (20%) patients to have POU1F1 and PROP1 mutations/variations of which 5 were novel and 2 previously reported. No mutations were identified in HESX1. The novel variations identified were absent in the 100 healthy individuals screened and the control database Exome Aggregation Consortium (ExAC). Reported POU1F1 and PROP1 mutation hotspots were absent in our patients. Instead, novel POU1F1 changes were identified suggesting existence of a distinct mutation spectrum in our population.

Global Consensus Recommendations on Prevention and Management of Nutritional Rickets

"BACKGROUND: Vitamin D and calcium deficiencies are common worldwide, causing nutritional rickets and osteomalacia, which have a major impact on health, growth, and development of infants, children, and adolescents; the consequences can be lethal or can last into adulthood. The goals of this evidence-based consensus document are to provide health care professionals with guidance for prevention, diagnosis, and management of nutritional rickets and to provide policy makers with a framework to work toward its eradication. EVIDENCE: A systematic literature search examining the definition, diagnosis, treatment, and prevention of nutritional rickets in children was conducted. Evidence-based recommendations were developed using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) system that describes the strength of the recommendation and the quality of supporting evidence. PROCESS: Thirty-three nominated experts in pediatric endocrinology, pediatrics, nutrition, epidemiology, public health, and health economics evaluated the evidence on specific questions within five working groups. The consensus group, representing 11 international scientific organizations, participated in a multiday conference in May 2014 to reach a global evidence-based consensus. RESULTS: This consensus document defines nutritional rickets and its diagnostic criteria and describes the clinical management of rickets and osteomalacia. Risk factors, particularly in mothers and infants, are ranked, and specific prevention recommendations including food fortification and supplementation are offered for both the clinical and public health contexts. CONCLUSION: Rickets, osteomalacia, and vitamin D and calcium deficiencies are preventable global public health problems in infants, children, and adolescents. Implementation of international rickets prevention programs, including supplementation and food fortification, is urgently required."

Impact of vitamin D fortified milk supplementation on vitamin D status of healthy school children aged 10-14 years.

UNLABELLED: Vitamin D deficiency is a major public health problem, needing immediate attention. We studied the effect of vitamin D fortification of milk in school children. Our results show that fortification of milk is safe and effective strategy to deal with widespread vitamin D deficiency. INTRODUCTION: Vitamin D deficiency among school children and adolescents is a well-documented major public health problem, needing immediate attention. To assess the effect of vitamin D fortified milk on serum 25 hydroxy vitamin D [S.25(OH)D] levels, we carried out a prospective double-blind randomized control trial in apparently healthy school children, aged 10-14 years. METHODS: Of 776 subjects recruited out of 796 who consented, 713 (boys-300; girls-413) completed the study. Subjects were randomized into three groups. Group A (n = 237) received 200 ml of unfortified milk per day while group B (n = 243) and group C (n = 233) received 200 ml of milk fortified with 600 IU (15 µg) and 1,000 IU (25 µg) of vitamin D per day for 12 weeks. Serum calcium, phosphate, alkaline phosphatase, S.25(OH)D, and urinary calcium/creatinine ratio were estimated at baseline and after supplementation. RESULTS: Hypovitaminosis D [25(OH)D < 20 ng/ml] was observed in 92.3 % subjects with mean S.25(OH)D level of 11.69 ± 5.36 ng/ml. There was no significant difference in S.25(OH)D levels among the three groups at baseline. The mean percentage change in S.25(OH)D level in groups B (137.97 %) and C (177.29 %.) were significantly greater than group A (-5.25 %). The percentage of subjects having S.25(OH)D levels >20 ng/ml following supplementation were 5.9 % in group A, 69.95 % in group B, and 81.11 % in group C in comparison to 6.32 %, 4.9 % and 12 %, respectively, at baseline. CONCLUSION: Fortification of milk with vitamin D is an effective and safe strategy in improving S.25(OH)D levels in children aged 10-14 years.

Percentage body fat in apparently healthy school children from northern India.

CONTEXT: Increased prevalence of obesity in childhood and adolescence, defined by the use of body mass index (BMI), has drawn attention towards direct measurement of body fat. OBJECTIVE: To develop age-and sex-specific reference distribution of body fat in apparently healthy North-Indian children in the age group of 7-17 years and to assess agreement between obesity (defined by BMI) and excess body fat. DESIGN: Study subjects for this cross sectional study included 1640 apparently healthy school children (825 boys; 815 girls) aged 7-17 years. Total body fat was measured by dual energy X-rays absorptiometry (DXA). The excess body fat by DXA was defined by two methods, prevalence matching and with the use of 85th and 95th centile cutoffs. RESULTS: The mean ± SD, 3rd, 10th, 25th, 50th, 75th, 90th and 97th centile values of percentage body fat (PBF) are presented. PBF was highly correlated with BMI in both boys and girls (all boys: r=0.76, P<0.0001; all girls r=0.81, P<0.0001). There was no significant difference noted in PBF between boys and girls at the age of 7-8 years. From 9 years onwards, girls had significantly higher PBF than boys. Moderate degree of agreement was observed between BMI and PBF by DXA by both methods. CONCLUSIONS: Smoothened reference distribution of PBF for North-Indian children and adolescents in Delhi are provided. Indian children accumulate more body fat during peri-pubertal years in comparison with US children.

An unusual cause of reversible axonal neuropathy and hypertension in a 10-year-old girl.

A 10-year-old girl, who was referred with refractory epilepsy, had 1.5 years of episodic abnormal behavior. On examination, she also had hypertension and peripheral neuropathy. Hypoglycemia with correspondingly high insulin levels was documented during a confusional episode. MRI of the abdomen revealed an islet cell tumor in the body of the pancreas. One year after tumor excision, both the neuropathy and hypertension showed remarkable improvement. A final diagnosis of insulinoma with hypoglycemic axonal neuropathy and hypertension (reversed with tumor excision) was made. Insulinoma is the commonest cause of hyperinsulinemic hypoglycemia in adults, but is rare in childhood. To our knowledge, distal symmetrical motor-sensory axonal neuropathy has been described in only 40 patients, and hypertension has not been reported with insulinoma.

Plasma testosterone in adult normoglycaemic men: impact of hyperinsulinaemia.

This study analysed the relationship of plasma testosterone with ß-cell secretion, insulin sensitivity and other pituitary-target gland hormones in normoglycaemic adult men. The sample frame was the 'Offspring of individuals with diabetes study' database. A total of 358 offspring of individuals with type-2 diabetes (T2DM) and 287 individuals without known family history of T2DM were recruited for the study. Normoglycaemic men aged ≥18 years (maximum 55) were selected for this analysis. All participants underwent 75 g oral glucose tolerance test (OGTT); blood samples were collected at 0, 30, 60 and 120 min for plasma insulin and C-peptide. Total testosterone, cortisol, adrenocorticotropic hormone, thyroid stimulating hormone and thyroxine (T4) were measured in the fasting sample. A total of 164 men (age 28 ± 7.7 years) were included in analysis. Testosterone correlated negatively with BMI, waist to hip ratio (WHR), area under curve (AUC) of C-peptide and insulin (during OGTT) and was positively correlated with insulin sensitivity (r ~ 0.4). Cortisol and T4 positively correlated (weak) with testosterone (r ~ 0.2). In multivariate analysis, AUC C-peptide, BMI, WHR (negatively) and cortisol (positively) were related to testosterone. Concluding, testosterone correlated negatively with BMI and ß-cell secretion. There was a positive association of testosterone with insulin sensitivity, cortisol and T4.

The effect of growth hormone deficiency on size-corrected bone mineral measures in pre-pubertal children.

UNLABELLED: Growth hormone deficiency (GHD) in children has been frequently perceived to be a cause of low bone mass accrual. The confounding effects of poor growth limit the interpretation of prior studies of bone health in GHD. We studied size-corrected bone mineral measures in 30 pre-pubertal GHD children and 75 healthy controls. Our study shows that size-corrected whole-body bone mineral content of GHD children were comparable with controls. INTRODUCTION: The purpose of this study is to evaluate the effects of GHD on size-corrected bone measures at the lumbar spine (LS) and the whole body (WB). METHODS: LS bone area (BA), LS bone mineral content (BMC), WB BA, WB BMC, and lean body mass (LBM) were measured in 30 pre-pubertal GHD children and 75 controls by dual-energy X-ray absorptiometry. Multiple linear regressions were used to calculate size-corrected (Sc) LS BA(Sc), LS BMC(Sc), WB BA(Sc), and WB BMC(Sc) from control subjects using height and age as independent variables. Furthermore, the relationship between muscle and bone was studied by first assessing LBM for height (LBM(Ht)) and then determining WB BMC for LBM (WB BMC(LBM)). All values were converted to Z-scores and compared with the control. RESULTS: At diagnosis, WB BMC(Sc) Z-score of GHD children was not significantly different from controls. However, mean Z-scores of LS BA(Sc) (-0.89 ± 0.84, p < 0.0001), LS BMC(Sc) (-0.70 ± 1.1, p < 0.001), WB BA(Sc) (-0.65 ± 1.0, p < 0.006), and LBM(Ht) (-0.66 ± 1.7, p < 0.01) were significantly reduced, and WB BMC(Lbm) (0.78 ± 1.5, p < 0.003) was significantly higher in GHD children than controls. CONCLUSION: Size-corrected WB BMC of GHD children were comparable with controls, and bones were normally adapted for muscle mass. Determinants of bone strength which may primarily be affected by GHD are muscle mass, bone size, and geometry rather than bone mass.

Reference intervals of serum lipid profile in healthy Indian school children and adolescents.

OBJECTIVE: To develop age and sex specific reference intervals of serum lipid parameters in healthy Indian children in the age group of 6-17 years. PARTICIPANTS: Study subjects were selected from the schools of Delhi. Children with BMI either in overweight or obese category were excluded to generate reference intervals. The final analysis included 3076 children with BMI in normal range for age. RESULTS: The mean±SD, 3rd, 10th, 25th, 50th, 75th, 90th and 97th centile values of lipid parameters are presented. All these parameters were significantly higher in girls than in boys. About 89.2% subjects had total cholesterol in acceptable range while 9.1% had borderline elevated and 1.5% had elevated TC. Optimal serum triglyceride levels were seen in 45.1% subjects while optimal levels of HDL cholesterol were seen in 0.3% subjects only. CONCLUSIONS: Reference intervals of serum lipid parameters for healthy Indian children (6-17 years) are presented.

Identification of a novel mutation in an Indian patient with CAII deficiency syndrome.

Carbonic anhydrase II (CAII) deficiency syndrome characterized by osteopetrosis (OP), renal tubular acidosis (RTA), and cerebral calcifications is caused by mutations in the carbonic anhydrase 2 (CA2) gene. Severity of this disorder varies depending on the nature of the mutation and its effect on the protein. We present here, the clinical and radiographic details along with, results of mutational analysis of the CA2 gene in an individual clinically diagnosed with renal tubular acidosis, osteopetrosis and mental retardation and his family members to establish genotype-phenotype correlation. A novel homozygous deletion mutation c.251delT was seen in the patient resulting in a frameshift and a premature stop codon at amino acid position 90 generating a truncated protein leading to a complete loss of function and a consequential deficiency of the enzyme making this a pathogenic mutation. Confirmation of clinical diagnosis by molecular methods is essential as the clinical features of the CAII deficiency syndrome are similar to other forms of OP but the treatment modalities are different. Genetic confirmation of the diagnosis at an early age leads to the timely institution of therapy improving the growth potential, reduces other complications like fractures, and aids in providing prenatal testing and genetic counseling to the parents planning a pregnancy.

Reference intervals of serum calcium, ionized calcium, phosphate and alkaline phosphatase in healthy Indian school children and adolescents.

OBJECTIVE: To develop age- and sex-specific reference interval of serum total calcium, ionized calcium, inorganic phosphates and alkaline phosphatase in healthy Indian children in the age group of 6-17 years. DESIGN AND METHOD: Subjects for this study were selected from the schools of Delhi. The final analysis included 3,327 children in the age group of 6-17 years (1707 boys; 1620 girls). RESULTS: The mean, standard deviation, 5th, 25th, 50th, 75th, 90th, 95th and 97th centile values of biochemical parameters for boys and girls are presented. All these parameters were significantly higher in boys than girls except serum ionized calcium. Serum total calcium (r -0.1362, p<0.001), serum inorganic phosphate (r -0.45, p<0.001) and serum alkaline phosphatase (r -0.5587, p<0.001) have shown inverse relationship with age. CONCLUSIONS: Reference interval of selected biochemical parameters for healthy Asian-Indian children in the age group of 6-17 years is presented.

Congenital adrenal hyperplasia: Results of medical therapy on appearance of external genitalia.

OBJECTIVE: Girls with congenital adrenal hyperplasia show a variable degree of genital masculinization at birth. Antenatal dexamethazone treatment for the mother is known to reduce the severity of this condition. There are however few data on the effect of postnatal steroid therapy on the cosmetic appearance of the external genitalia. PATIENTS AND METHOD: We report the appearance of the external genitalia of three girls with classical congenital adrenal hyperplasia followed up by steroid therapy alone. RESULTS: Growth of the labia majora and a relative reduction in clitoral size improved the appearance of the external genitalia in these three girls. CONCLUSION: There seems to be improvement in the external appearance of genitalia with postnatal steroid therapy. This could allay parental concerns and help in the planning of corrective surgery peripubertally with the informed consent of the child.

Tuberculosis of the thyroid gland: magnetic resonance imaging appearances.

Tuberculosis involving the thyroid gland is a rare occurrence. We report a case of cytologically-diagnosed thyroid gland tuberculosis in a 21-year-old man who presented with thyroid swelling of short duration, and describe the magnetic resonance (MR) imaging appearances of the lesion, which to our knowledge, has not been previously described. We also report a rare complication of abscess formation in the track of the fine needle aspiration. The intermediate signal intensity of the lesions on both T1- and T2-weighted MR images may provide a clue about tuberculosis, as clinical suspicion is low due to the rarity of the disease.

PET/CT localisation of a scapular haemangiopericytoma with tumour-induced osteomalacia.

Oncogenic osteomalacia, or tumour-induced osteomalacia (TIO), is a rare paraneoplastic syndrome characterised by hypophosphataemia, phosphaturia, inappropriately low serum levels of 1,25-dihydroxyvitamin D for hypophosphataemia. TIO is caused by mesenchymal tumours that secrete phosphaturic substances, leading to increased renal wasting of phosphates. These tumours are very small in size and grow slowly. Localisation of these tumours has always been difficult with the available biochemical and imaging techniques. At times, despite all efforts, the tumour could not be localised. We report our experience with a 42-year-old woman with TIO where whole-body magnetic resonance imaging could not localise the tumour, a scapular haemangiopericytoma. PET/CT was helpful in the localisation of the tumour which, when surgically removed, resulted in the normalisation of biochemical parameters with clinical improvement.

Does Paget's disease exist in India?: A series of 21 patients.

OBJECTIVE: Paget's disease of bone has been described as a few case reports from India. The aim of the present study is to document the existence of Paget's disease (PD) in India. MATERIAL AND METHODS: We describe demography, clinical manifestations, biochemical and radiological profile and the treatment outcome of 21 patients of PD. RESULTS: Mean (+/-SD) age of these patients at presentation was 49.2 +/- 17.6 years and the male to female ratio was 2.5:1. Common clinical manifestations included backache, headache and bone pains. Others were fracture, joint pain, deafness, gait ataxia, visual impairment and difficulty in biting. Two patients presented with hydrocephalus and one had recurrent paraparesis. Fifteen (71.4%) patients had polyostotic and six (28.6%) had monoostotic Paget's disease. More commonly involved bones were skull and spine (61.9%) followed by pelvis (38.1%), femur (33.3%), tibia (9%) and ulna (9%). Mean (+/-SD) serum alkaline phosphatase at diagnosis was 1514 +/- 1168 IU/L and nine months after treatment with bisphosphonates decreased to 454 +/- 406 IU/ L(P<0.03). CONCLUSION: This illustrates that Paget's disease does exist in India and a high index of suspicion is required to clinch the diagnosis.

Correlation of cell counts and indices in testicular FNAC with histology in male infertility.

OBJECTIVE: To evaluate the value of percentage cell counts and cell indices in testicular fine needle aspiration cytology (FNAC) in male infertility and their correlation with histologic categories as seen in open testicular biopsies. STUDY DESIGN: Differential cell counts were performed, and cell indices, including spermatic index, Sertoli cell index and sperm-Sertoli cell index, were calculated in testicular fine needle aspiration (FNA) smears in 30 azoospermic males whose open testicular biopsies were classified as normal spermatogenesis in 10 cases, maturation arrest in 5, hypospermatogenesis in 6, Sertoli cell only syndrome in 5 and tubular/peritubular sclerosis in 4. RESULTS: In normal spermatogenesis, FNA smears showed up to 40% Sertoli cells, and spermatozoa were the predominant spermatogenetic cell type. There was a progressive increase in Sertoli cell percentage and Sertoli cell index and reduction in spermatozon percentage, spermatic index and sperm-Sertoli cell index with increasing severity of reduction in spermatogenesis in different histologic categories. The differences between mean counts and indices in normal spermatogenesis and other histologic categories were statistically significant (P < .01). CONCLUSION: The percent cell counts and cell indices in testicular FNAC correlate with histologic categories and are useful in evaluating male infertility.

Growth charts suitable for evaluation of Indian children.

OBJECTIVE: To assess the suitability of recently published reference anthropometric data for evaluation of the growth of children in our region. SETTING: Referral Pediatric Endocrinology Clinic in tertiary level care hospital. SUBJECTS: 280 normal school children and 155 children referred for growth retardation to the clinic in 1993 and 1994. METHODS: Heights of school children were plotted on growth charts created from recently published reference growth data of children from high socioeconomic group families. The case records of 155 children referred for growth evaluation were retrospectively analyzed for (i) etiology of short stature, (ii) height percentile based on previously used Indian Council of Medical Research (ICMR) references, and (iii) height percentile and standard deviation scores based on the new references. RESULTS: 93% of school children fell above and 7% below the 5th centile of the new height references. Of the 129 clinic children diagnosed to have growth retardation, 128 fell below the 5th centile of the new references. However, 38 of these (29.5%) fell above the 5th centile of ICMR references. These included patients with pathological causes of short stature. Twenty four of 26 children labelled as having no growth problem fell above the 5th centile of new reference data. CONCLUSIONS: The 5th height centile of new reference data from high socioeconomic group children is an appropriate cut off below which to evaluate children for short stature in our region. It will allow earlier identification and treatment than the hitherto used ICMR percentiles, and yet is not expected to result in over investigation of normal children.