Effect of Antenatal Oral Vitamin D Supplementation on Serum 25(OH)D Concentration in Exclusively Breastfed Infants at 6 Months of age - A Randomized Double-Blind Placebo-Controlled Trial.

OBJECTIVE: To compare the proportion of exclusively breastfed (EBF) infants having severe vitamin D deficiency (25(OH)D concentration <11 ng/mL) at 6 months of age when mothers were supplemented with 300,000 IU Vitamin D3 or placebo during the third trimester of pregnancy. METHODS: In this randomized double-blind placebo-controlled trial, we recruited 100 pregnant women who were willing to exclusively breastfeed their babies for 6 months at 30-32 weeks gestation and the infants born to them. Pregnant women were randomized to receive either oral vitamin D3 60,000 IU or placebo, given weekly for 5 weeks during the third trimester. Serum 25(OH)D, calcium, phosphorus and alkaline phosphatase concentration were measured in all participants at recruitment, in the cord blood at delivery, and in infants at 6 months of age. The proportion of infants developing severe vitamin D deficiency and rickets at 6 months was assessed. RESULTS: A total 72 mother-infant dyads followed till 6 months. At enrolment, the mean (SD) serum 25(OH)D concentration were comparable in mothers in the intervention and control groups (12.90 (5.84) vs 12.84 (5.88), P = 0.96). The mean (SD) 25(OH)D concentration (ng/mL) in the cord blood was significantly higher in the intervention group compared to the control group [42.14 (17.08) vs 12.74 (6.28); P = 0.002]. The mean (SD) serum 25(OH)D levels (ng/mL) in the infants at 6 months' age were higher in the intervention group compared to the control group [31.82 (10.89) vs 12.46 (5.68); P < 0.001]. No infant in the intervention group had severe vitamin D deficiency at 6 months' age compared to 54.3% infants in the control group (P < 0.001). No infant in the intervention group developed rickets. CONCLUSIONS: Oral supplementation of vitamin D3 to pregnant women in the third trimester prevents severe hypovitaminosis D in the EBF infants at 6-months of age.

Effect of Valproate Monotherapy on Thyroid Function Tests and Magnesium Levels in Children With Epilepsy.

BACKGROUND: Antiseizure drug valproate alters thyroid functions. Magnesium is implicated in the pathogenesis of epilepsy and it may affect the efficacy of valproate and thyroid functions. OBJECTIVE: To study the effect of six months of valproate monotherapy on thyroid functions and serum magnesium levels. To study the association among these levels and the effects of clinicodemographic profile. MATERIALS AND METHOD: Children aged three to 12 years presenting with newly diagnosed epilepsy were enrolled. A venous blood sample was collected for estimation of thyroid function test (TFT), magnesium, and valproate levels at onset and after six months of valproate monotherapy. Valproate levels and TFT were analyzed by chemiluminescence and magnesium by colorimetric method. RESULTS: Thyroid stimulating hormone (TSH) increased significantly from 2.14±1.64 µIU/ml at enrollment to 3.64±2.15 µIU/ml at six months (p<0.001), free thyroxine (FT4) decreased significantly (p<0.001). Serum magnesium (Mg) decreased from 2.30±0.29 mg/dl to 1.94±0.28 mg/dl (p<0.001). At six months, eight out of 45 (17.77%) participants had significantly increased mean TSH levels (p=0.008). Serum valproate levels were not associated significantly with TFT and Mg (p<0.05). There was no effect of age, sex, or repeat seizures on the measured parameters. CONCLUSION: The TFT and Mg levels are altered by six months of valproate monotherapy in children with epilepsy. Hence we suggest monitoring and supplementation if required.

Daily vs. monthly oral vitamin D3 for treatment of symptomatic vitamin D deficiency in infants: a randomized controlled trial.

OBJECTIVES: Compare the efficacy and safety of daily vs. monthly oral vitamin D3 in treating symptomatic vitamin D deficiency in infants. METHODS: 90 infants with symptomatic vitamin D deficiency were randomized into Daily (D) [46 infants] and Bolus (B) [44 infants] groups to receive oral vitamin D3, daily (2000 IU/day) and bolus (60,000 IU/month) for three months respectively. Both groups received daily oral calcium @50 mg/kg/day. Serum calcium (Ca), phosphate (P), alkaline phosphatase (ALP), 25-hydroxy cholecalciferol [25(OH)D], parathyroid hormone (PTH) levels, urine calcium: creatinine ratio and radiological score were assessed at baseline, 4 and 12 weeks. At the end of 12 weeks, 78 infants were available for evaluation of efficacy and safety of both regimens. RESULTS: Both regimens led to a statistically significant increase in Ca and P levels and fall in ALP and PTH levels from baseline to 4 and 12 weeks of therapy, with no inter-group difference. Infants in group D had statistically significant higher mean 25(OH)D levels as compared to group B at 4 weeks (group D 130.89 ± 43.43 nmol/L, group B - 108.25 ± 32.40 nmol/L; p - 0.012) and 12 weeks (group D - 193.69 ± 32.47 nmol/L, group B - 153.85 ± 33.60 nmol/L; p<0.001). Eight infants [group D - 6/41 (14.6 %); group B - 2/37 (5.4 %), p=0.268] developed mild asymptomatic hypercalcemia without hypercalciuria at 12 weeks that corrected spontaneously within a week. CONCLUSIONS: Both daily and monthly oral vitamin D3 in equivalent doses are efficacious and safe for treating symptomatic vitamin D deficiency in infants.

Sunlight Exposure vs Oral Vitamin D Supplementation for Prevention of Vitamin D Deficiency in Infancy: A Randomized Controlled Trial.

OBJECTIVE: To compare the efficacy of sunlight exposure and oral vitamin D3 supplementation to achieve vitamin D sufficiency in infants at 6 months of age. DESIGN: Open-label randomized controlled trial. SETTING: Public hospital in Northern India (28.7°N). PARTICIPANT: Breastfed infants at 6-8 weeks of age. INTERVENTION: Randomized to receive sunlight exposure (40% body surface area for a minimum of 30 minutes/week) or oral vitamin D3 supplementation (400 IU/day) till 6 months of age. OUTCOME: Primary - proportion of infants having vitamin D sufficiency (>20 ng/mL). Secondary - proportion of infants developing vitamin D deficiency (<12ng/mL) and rickets in both the groups at 6 months of age. RESULTS: Eighty (40 in each group) infants with mean (SD) age 47.8 (4.5) days were enrolled. The proportion of infants with vitamin D sufficiency increased after intervention in the vitamin D group from 10.8% to 35.1% (P=0.01) but remained the same in sunlight group (13.9%) and was significant on comparison between both groups (P=0.037). The mean (SD) compliance rate was 72.9 (3.4) % and 59.7 (23.6) % in the vitamin D and sunlight group, respectively (P=0.01). The geometric mean (95% CI) serum 25(OH) D levels in the vitamin D and sunlight group were 16.23 (13.58-19.40) and 11.89 (9.93-14.23) ng/mL, respectively; (P=0.02), after adjusting baseline serum 25(OH)D with a geometric mean ratio of 1.36 (1.06-1.76). Two infants in sunlight group developed rickets. CONCLUSION: Oral vitamin D3 supplementation is more efficacious than sunlight in achieving vitamin D sufficiency in breastfed infants during the first 6 months of life due to better compliance.

Matrix Gla Protein Levels Are Associated With Arterial Stiffness and Incident Heart Failure With Preserved Ejection Fraction.

OBJECTIVE: Arterial stiffness is a risk factor for cardiovascular disease, including heart failure with preserved ejection fraction (HFpEF). MGP (matrix Gla protein) is implicated in vascular calcification in animal models, and circulating levels of the uncarboxylated, inactive form of MGP (ucMGP) are associated with cardiovascular disease-related and all-cause mortality in human studies. However, the role of MGP in arterial stiffness is uncertain. Approach and Results: We examined the association of ucMGP levels with vascular calcification, arterial stiffness including carotid-femoral pulse wave velocity (PWV), and incident heart failure in community-dwelling adults from the Framingham Heart Study. To further investigate the link between MGP and arterial stiffness, we compared aortic PWV in age- and sex-matched young (4-month-old) and aged (10-month-old) wild-type and Mgp+/- mice. Among 7066 adults, we observed significant associations between higher levels of ucMGP and measures of arterial stiffness, including higher PWV and pulse pressure. Longitudinal analyses demonstrated an association between higher ucMGP levels and future increases in systolic blood pressure and incident HFpEF. Aortic PWV was increased in older, but not young, female Mgp+/- mice compared with wild-type mice, and this augmentation in PWV was associated with increased aortic elastin fiber fragmentation and collagen accumulation. CONCLUSIONS: This translational study demonstrates an association between ucMGP levels and arterial stiffness and future HFpEF in a large observational study, findings that are substantiated by experimental studies showing that mice with Mgp heterozygosity develop arterial stiffness. Taken together, these complementary study designs suggest a potential role of therapeutically targeting MGP in HFpEF.

Effective Dose of Prophylactic Oxytocin Infusion During Cesarean Delivery in 90% Population of Nonlaboring Patients With Preeclampsia Receiving Magnesium Sulfate Therapy and Normotensives: An Up-Down Sequential Allocation Dose-Response Study.

BACKGROUND: Oxytocin administration during cesarean delivery is the first-line therapy for the prevention of uterine atony. Patients with preeclampsia may receive magnesium sulfate, a drug with known tocolytic effects, for seizure prophylaxis. However, no study has evaluated the minimum effective dose of oxytocin during cesarean delivery in women with preeclampsia. METHODS: This study compared the effective dose in 90% population (ED90) of oxytocin infusion for achieving satisfactory uterine tone during cesarean delivery in nonlaboring patients with preeclampsia who were receiving magnesium sulfate treatment with a control group of normotensives who were not receiving magnesium sulfate. This prospective dual-arm dose-finding study was based on a 9:1 biased sequential allocation design. Oxytocin infusion was initiated at 13 IU/h, on clamping of the umbilical cord, in the first patient of each group. Uterine tone was graded as satisfactory or unsatisfactory by the obstetrician at 4 minutes after initiation of oxytocin infusion. The dose of oxytocin infusion for subsequent patients was decided according to the response exhibited by the previous patient in the group; it was increased by 2 IU/h after unsatisfactory response or decreased by 2 IU/h or maintained at the same level after satisfactory response, in a ratio of 1:9. Oxytocin-associated side effects were also evaluated. Dose-response data for the groups were evaluated using a log-logistic function and ED90 estimates were derived from fitted equations using the delta method. RESULTS: The ED90 of oxytocin was significantly greater for the preeclampsia group (n = 27) than for the normotensive group (n = 40) (24.9 IU/h [95% confidence interval {CI}, 22.4-27.5] and 13.9 IU/h [95% CI, 12.4-15.5], respectively); the difference in dose requirement was 10.9 IU/h (95% CI, 7.9-14.0; P < .001). The number of patients with oxytocin-related hypotension, defined as a decrease in systolic blood pressure >20% from baseline or to <90 mm Hg, was significantly greater in the preeclampsia group (92.6% vs 62.5%; P = .030), while other side effects such as ST-T depression, nausea/vomiting, headache, and flushing, were not significantly different. There was no significant difference in the need for additional uterotonic or uterine massage, estimated blood loss, and need for re-exploration for uncontrolled bleeding. CONCLUSIONS: Patients with preeclampsia receiving preoperative magnesium therapy need a greater intraoperative dose of oxytocin to achieve satisfactory contraction of the uterus after fetal delivery, as compared to normotensives.

Need for Palliative Care in Patient with Rheumatoid Arthritis: A Cross-sectional Observational Study.

OBJECTIVES: Rheumatoid arthritis (RA) is a chronic disorder causing inflammation in the joints and achieving remission is often the primary goal of physicians. We evaluated the suffering from RA and assessed the need for palliative care services in these patients. MATERIALS AND METHODS: This cross-sectional observational study was done in 100 adult RA cases who attended the outpatient department. The Disease Activity Score 28 (DAS28), Health Assessment Questionnaire Disability Index, depression, anxiety and stress score, Short Form 36 Health Survey and numeric rating scale were assessed. The relationship between DAS28 with the other parameters and scores was assessed using Spearman's rho correlation coefficient. RESULTS: About 90% of patients in our study were female and majority (50%) had a moderate disease activity. The DAS28 showed a positive correlation with the degree of depression (r = 0.671, P = 0.000), anxiety (r = 0.609, P = 0.000) and stress levels (r = 0.474, P = 0.000). The patients with severe disease had a poor quality of life (QoL) [physical functioning (r = -0.737, P = 0.000); role limitation (r = -0.662, P = 0.000); emotional problem (r = -0.676, P = 0.000); energy/fatigue (r = -0.638, P = 0.000); social functioning (r = -0.658, P = 0.000); emotional well-being (r = -0.605, P = 0.000); general health (r = -0.643, P = 0.000); health change (r = -0.376, P = 0.000) and numerical rating scale score for pain (r = 0.656, P = 0.000)]. CONCLUSION: RA patients with high disease activity suffer from depression, anxiety, stress and poor QoL. Palliative care physicians and rheumatologists must be vested with the power to provide comprehensive care to these patients.

Hypoxia ameliorates brain hyperoxia and NAD+ deficiency in a murine model of Leigh syndrome.

Leigh syndrome is a severe mitochondrial neurodegenerative disease with no effective treatment. In the Ndufs4-/- mouse model of Leigh syndrome, continuously breathing 11% O2 (hypoxia) prevents neurodegeneration and leads to a dramatic extension (~5-fold) in lifespan. We investigated the effect of hypoxia on the brain metabolism of Ndufs4-/- mice by studying blood gas tensions and metabolite levels in simultaneously sampled arterial and cerebral internal jugular venous (IJV) blood. Relatively healthy Ndufs4-/- and wildtype (WT) mice breathing air until postnatal age ~38 d were compared to Ndufs4-/- and WT mice breathing air until ~38 days old followed by 4-weeks of breathing 11% O2. Compared to WT control mice, Ndufs4-/- mice breathing air have reduced brain O2 consumption as evidenced by an elevated partial pressure of O2 in IJV blood (PijvO2) despite a normal PO2 in arterial blood, and higher lactate/pyruvate (L/P) ratios in IJV plasma revealed by metabolic profiling. In Ndufs4-/- mice, hypoxia treatment normalized the cerebral venous PijvO2 and L/P ratios, and decreased levels of nicotinate in IJV plasma. Brain concentrations of nicotinamide adenine dinucleotide (NAD+) were lower in Ndufs4-/- mice breathing air than in WT mice, but preserved at WT levels with hypoxia treatment. Although mild hypoxia (17% O2) has been shown to be an ineffective therapy for Ndufs4-/- mice, we find that when combined with nicotinic acid supplementation it provides a modest improvement in neurodegeneration and lifespan. Therapies targeting both brain hyperoxia and NAD+ deficiency may hold promise for treating Leigh syndrome.

Identifying responders to oral iron supplementation in heart failure with a reduced ejection fraction: a post-hoc analysis of the IRONOUT-HF trial.

BACKGROUND: The IRONOUT-HF trial previously demonstrated that oral iron supplementation minimally increased iron stores and did not improve exercise capacity in patients with heart failure with a reduced ejection fraction (HFrEF) and iron deficiency. METHODS: The IRONOUT-HF trial was a double-blind, placebo-controlled, randomized clinical trial designed to test the efficacy and safety of oral iron polysaccharide compared to matching placebo among patients with HFrEF and iron deficiency. Study participants received oral iron polysaccharide 150 mg twice daily or matching placebo for 16 weeks. Response to oral iron was defined as a ferritin level >300 ng/mL or a ferritin level 100-300 ng/mL with a transferrin saturation >20% at the end of the study. RESULTS: The final analytical cohort included 98 patients with HFrEF and iron deficiency at baseline. Study participants had a median (25, 75) age of 63 years (54 years, 71 years), included 40% women (N = 39). After 16 weeks of therapy, 24 patients (24%) responded to oral iron supplementation while 74 patients (76%) remained iron deficient despite treatment. There was no association between response to oral iron supplementation and improvement in functional status (i.e. peak VO2 or anaerobic threshold), myocardial stress (i.e. NT-proBNP levels), or HRQOL (i.e. Kansas City Cardiomyopathy Questionnaire) at week 16. CONCLUSION: This study failed to identify a subset of responders more likely to derive a clinical benefit from oral iron therapy and does not support its routine use in patients with symptomatic HFrEF and iron deficiency.

Calciphylaxis-as a drug induced adverse event.

INTRODUCTION: Calciphylaxis is a rare but devastating disease with a mortality rate up to 50% in 1 year. It is characterized by profoundly painful ischemic skin lesions and vascular calcification that affects predominantly patients with end stage renal disease. The use of certain medications is an important modifiable risk factor in calciphylaxis and discontinuation of these is a mainstay of treatment. AREAS COVERED: This review will provide an overview of calciphylaxis and will focus on how certain therapeutic agents can affect the risk of calcification and associated thrombosis, key processes involved in the development of calciphylaxis. EXPERT OPINION: Calciphylaxis treatment requires a multi-modal approach including prevention, risk factor management, wound care, reperfusion, and use of fibrinolytics and antioxidants. Patients with end stage renal disease represent the most affected population. This population often has multiple medications prescribed, some worth reconsidering before starting or continuing them. When possible, we recommend stopping all potentially contributing medications in patients with calciphylaxis, including warfarin, active vitamin D, calcium supplements, and iron.

Effect of Oral Iron Repletion on Exercise Capacity in Patients With Heart Failure With Reduced Ejection Fraction and Iron Deficiency: The IRONOUT HF Randomized Clinical Trial.

IMPORTANCE: Iron deficiency is present in approximately 50% of patients with heart failure with reduced left ventricular ejection fraction (HFrEF) and is an independent predictor of reduced functional capacity and mortality. However, the efficacy of inexpensive readily available oral iron supplementation in heart failure is unknown. OBJECTIVE: To test whether therapy with oral iron improves peak exercise capacity in patients with HFrEF and iron deficiency. DESIGN, SETTING, AND PARTICIPANTS: Phase 2, double-blind, placebo-controlled randomized clinical trial of patients with HFrEF (<40%) and iron deficiency, defined as a serum ferritin level of 15 to 100 ng/mL or a serum ferritin level of 101 to 299 ng/mL with transferrin saturation of less than 20%. Participants were enrolled between September 2014 and November 2015 at 23 US sites. INTERVENTIONS: Oral iron polysaccharide (n = 111) or placebo (n = 114), 150 mg twice daily for 16 weeks. MAIN OUTCOMES AND MEASURES: The primary end point was a change in peak oxygen uptake (V̇o2) from baseline to 16 weeks. Secondary end points were change in 6-minute walk distance, plasma N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels, and health status as assessed by Kansas City Cardiomyopathy Questionnaire (KCCQ, range 0-100, higher scores reflect better quality of life). RESULTS: Among 225 randomized participants (median age, 63 years; 36% women) 203 completed the study. The median baseline peak V̇o2 was 1196 mL/min (interquartile range [IQR], 887-1448 mL/min) in the oral iron group and 1167 mL/min (IQR, 887-1449 mL/min) in the placebo group. The primary end point, change in peak V̇o2 at 16 weeks, did not significantly differ between the oral iron and placebo groups (+23 mL/min vs -2 mL/min; difference, 21 mL/min [95% CI, -34 to +76 mL/min]; P = .46). Similarly, at 16 weeks, there were no significant differences between treatment groups in changes in 6-minute walk distance (-13 m; 95% CI, -32 to 6 m), NT-proBNP levels (159; 95% CI, -280 to 599 pg/mL), or KCCQ score (1; 95% CI, -2.4 to 4.4), all P > .05. CONCLUSIONS AND RELEVANCE: Among participants with HFrEF with iron deficiency, high-dose oral iron did not improve exercise capacity over 16 weeks. These results do not support use of oral iron supplementation in patients with HFrEF. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT02188784.

Seven versus 10 days antibiotic therapy for culture-proven neonatal sepsis: A randomised controlled trial.

AIM: Optimal duration of parenteral antibiotics for treating neonatal sepsis ranges from 7-14 days. We compared the efficacy of 7 versus 10 days duration of intravenous antibiotics for neonatal septicaemia. METHODS: We randomised blood culture-proven septic neonates (≥32 weeks and birth weight ≥1.5 kg) to receive either 7 or 10 days duration of intravenous antibiotics. We followed up neonates upto 28 days after stopping antibiotics for treatment failure defined by reappearance of clinical sepsis with a blood culture growing the same organism as cultured earlier, or in the absence of a positive culture, the presence of C-reactive protein and as adjudicated by an expert committee. RESULTS: A total of 132 neonates were randomised to receive either 7 (n = 66) or 10 (n = 66) days duration of antibiotic therapy. Out of 128 neonates (64 per group) followed up, two (one per group) were regarded as 'treatment failure', and two were labelled as fresh episodes of sepsis (both in 10-day group). The risk (95% confidence interval) for treatment failure in the 7-day group was (1.0 (0.064-15.644) was not significantly higher. Neonates in both groups had comparable need for oxygen, inotropic support and blood products, duration of oxygen therapy and time to attainment of full feeds. The duration of hospitalisation was significantly longer in the 10-day group. CONCLUSION: A 7-day course of intravenous antibiotics may be sufficient to treat neonatal sepsis with the advantage of shorter hospital stay, but a larger meta-analysis would be required to state this with a degree of certainty.

Vitamin K-Dependent Carboxylation of Matrix Gla Protein Influences the Risk of Calciphylaxis.

Matrix Gla protein (MGP) is a potent inhibitor of vascular calcification. The ability of MGP to inhibit calcification requires the activity of a vitamin K-dependent enzyme, which mediates MGP carboxylation. We investigated how MGP carboxylation influences the risk of calciphylaxis in adult patients receiving dialysis and examined the effects of vitamin K deficiency on MGP carboxylation. Our study included 20 patients receiving hemodialysis with calciphylaxis (cases) and 20 patients receiving hemodialysis without calciphylaxis (controls) matched for age, sex, race, and warfarin use. Cases had higher plasma levels of uncarboxylated MGP (ucMGP) and carboxylated MGP (cMGP) than controls. However, the fraction of total MGP that was carboxylated (relative cMGP concentration = cMGP/[cMGP + uncarboxylated MGP]) was lower in cases than in controls (0.58±0.02 versus 0.69±0.03, respectively; P=0.003). In patients not taking warfarin, cases had a similarly lower relative cMGP concentration. Each 0.1 unit reduction in relative cMGP concentration associated with a more than two-fold increase in calciphylaxis risk. Vitamin K deficiency associated with lower relative cMGP concentration in multivariable adjusted analyses (ß=-8.99; P=0.04). In conclusion, vitamin K deficiency-mediated reduction in relative cMGP concentration may have a role in the pathogenesis of calciphylaxis. Whether vitamin K supplementation can prevent and/or treat calciphylaxis requires further study.

Sunlight Exposure and Vitamin D Status in Breastfed Infants.

OBJECTIVE: To correlate the sunlight exposure in first 6 months to vitamin D status at 6 months of age in predominantly breastfed infants; and to quantify the sunlight exposure required to achieve serum 25(OH)D level >20 ng/mL, by 6 months of age. DESIGN: Design: Prospective cohort. SETTING: Tertiary-care hospital predominantly catering to urban poor population in Delhi. PARTICIPANTS: 132 healthy infants, delivered at term, and predominantly breastfed were enrolled at 6-8 weeks of age. Of these, 100 infants were available for final evaluation at 6 months of age (mean (SD) follow-up: 126 (17) days). METHODS: Baseline maternal vitamin D (serum 25(OH)D) levels were obtained at enrolment. The mothers were asked to maintain a daily record of duration of sunlight exposure, timing of exposure, and body surface area exposed, for the infant, on a pre-designed proforma, till the child was 6 months of age. Infant's serum 25(OH)D was measured at 6 months of age. MAIN OUTCOME MEASURES: Cumulative Sun Index was calculated as a composite measure of overall duration/time/body surface area exposed to sunlight; and correlated with the infant serum 25(OH)D after adjusting for baseline maternal serum 25(OH)D levels, season of exposure, and skin color of the infant. Sun index for exposure in morning (before 10 am) and afternoon (10 am-3 pm) were also correlated to vitamin D status. RESULTS: Of 100 mother-infant pairs completing the study, 90 mothers had vitamin D deficiency (serum 25(OH)D <12 ng/mL). The median duration of exposure of infants to sunlight was 17 min per week, on 6% of body surface area. Vitamin D levels of 67 (67%) infants at 6 months were less than 12 ng/mL and another 23% had insufficient levels (12-20 ng/mL). Cumulative sun index correlated positively to infant's serum 25(OH)D level at 6 months of age (r= 0.461, P<0.001). Increment in afternoon sun index by 1 unit increased the serum 25(OH)D level by 1.07 ng/mL (95% CI 0.37, 1.78; P= 0.003). A minimum 30 minute weekly afternoon sunlight exposure, between 10 am and 3 pm, over 40% body area (infant clothed in diapers, in prone position) for at least 16 weeks, was estimated requirement to achieve sufficient vitamin D levels (>20 ng/mL) by 6 months of age. CONCLUSION: There is a significant positive correlation between afternoon sunlight exposure and infant's vitamin D levels, independent of maternal vitamin D status. Randomized controlled trials are suggested to explore the effectiveness of this simple intervention to prevent or treat vitamin D deficiency in children.

Oral Iron Therapy for Heart Failure With Reduced Ejection Fraction: Design and Rationale for Oral Iron Repletion Effects on Oxygen Uptake in Heart Failure.

UNLABELLED: : Iron deficiency is present in ≈50% of patients with heart failure and is an independent predictor of mortality. Despite growing recognition of the functional and prognostic significance of iron deficiency, randomized multicenter trials exploring the use of oral iron supplementation in heart failure, a therapy that is inexpensive, readily available, and safe, have not been performed. Moreover, patient characteristics that influence responsiveness to oral iron in patients with heart failure have not been defined. Although results of intravenous iron repletion trials have been promising, regularly treating patients with intravenous iron products is both expensive and poses logistical challenges for outpatients. Herein, we describe the rationale for the Oral Iron Repletion effects on Oxygen Uptake in Heart Failure (IRONOUT HF) trial. This National Institute of Health-sponsored trial will investigate oral iron polysaccharide compared with matching placebo with the primary end point of change in exercise capacity as measured by peak oxygen consumption at baseline and at 16 weeks. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT02188784.

Repletion of Iron Stores With the Use of Oral Iron Supplementation in Patients With Systolic Heart Failure.

BACKGROUND: Iron deficiency is associated with reduced functional capacity and increased mortality in patients with heart failure with reduced ejection fraction (HFrEF). Correction of iron deficiency in HFrEF patients with the use of intravenous iron improves symptoms, quality of life, and exercise performance. Whether oral iron improves iron stores in HFrEF patients is unknown. We conducted a retrospective study to assess the efficacy of oral iron supplementation in iron-deficient HFrEF patients. METHODS AND RESULTS: Iron-deficient HFrEF patients with a record of oral iron supplementation and iron studies before and ∼180 days after supplementation were identified. Iron deficiency was defined as ferritin <100 ng/mL or as ferritin 100-300 ng/mL with transferrin saturation (Tsat) <20%. Spearman correlation was performed to assess for treatment responsiveness. In 105 patients, ferritin (from median 39 ng/mL to 75 ng/mL), Tsat (from 10% to 21%), iron (from 34 µg/dL to 69 µg/dL), and hemoglobin (from 10.4 g/dL to 11.6 g/dL) values increased (P < .0001), whereas total iron-binding capacity decreased (from 343 to 313 µg/dL; P = .0007) at 164 days after initiation of oral iron supplementation. CONCLUSIONS: In this retrospective study, oral iron supplementation improved iron stores similarly to previously reported results with the use of intravenous iron repletion in HFrEF patients, suggesting that oral iron merits prospective evaluation as an intervention strategy in HFrEF.

300,000 IU or 600,000 IU of oral vitamin D3 for treatment of nutritional rickets: a randomized controlled trial.

OBJECTIVE: To evaluate the non-inferiority of a lower therapeutic dose (300,000 IU) in comparison to standard dose (600,000) IU of Vitamin D for increasing serum 25(OH) D levels and achieving radiological recovery in nutritional rickets. DESIGN: Randomized, open-labeled, controlled trial. SETTING: Tertiary care hospital. PARTICIPANTS: 76 children (median age 12 mo) with clinical and radiologically confirmed rickets. INTERVENTION: Oral vitamin D3 as 300,000 IU (Group 1; n=38) or 600,000 IU (Group 2; n=38) in a single day. OUTCOME VARIABLES: Primary: Serum 25(OH)D, 12 weeks after administration of vitamin D3; Secondary: Radiological healing and serum parathormone at 12 weeks; and clinical and biochemical adverse effects. RESULTS: Serum 25(OH)D levels [geometric mean (95% CI)] increased significantly from baseline to 12 weeks after therapy in both the groups [Group 1: 7.58 (5.50­10.44) to 16.06 (12.71­ 20.29) ng/mL, P<0.001]; Group 2: 6.57 (4.66­9.25) to 17.60 (13.71­22.60, P<0.001]. The adjusted ratio of geometric mean serum 25(OH)D levels at 12 weeks between the groups (taking baseline value as co-variate) was 0.91 (95% CI: 0.65­1.29). Radiological healing occurred in all children by 12 weeks. Both groups demonstrated significant (P<0.05) and comparable fall in the serum parathormone and alkaline phosphatase levels at 12 weeks. Relative change [ratio of geometric mean (95% CI)] in serum PTH and alkaline phosphatase, 12 weeks after therapy, were 0.98 (0.7­1.47) and 0.92 (0.72­1.19), respectively. The serum 25(OH)D levels were deficient (<20 ng/mL) in 63% (38/60) children after 12 weeks of intervention [Group 1: 20/32 (62.5%); Group 2: 18/28 (64.3%)]. No major clinical adverse effects were noticed in any of the children. Hypercalcemia was documented in 2 children at 4 weeks (1 in each Group) and 3 children at 12 weeks (1 in Group 1 and 2 in Group 2). None of the participants had hypercalciuria or hypervitaminosis D. CONCLUSION: A dose of 300,000 IU of vitamin D3 is comparable to 600,000 IU, administered orally, over a single day, for treating rickets in under-five children although there is an unacceptably high risk of hypercalcemia in both groups. None of the regime is effective in normalization of vitamin D status in majority of patients, 3 months after administering the therapeutic dose.

Pulmonary hypertension in lambs transfused with stored blood is prevented by breathing nitric oxide.

BACKGROUND: During extended storage, erythrocytes undergo functional changes. These changes reduce the viability of erythrocytes leading to release of oxyhemoglobin, a potent scavenger of nitric oxide. We hypothesized that transfusion of ovine packed erythrocytes (PRBC) stored for prolonged periods would induce pulmonary vasoconstriction in lambs, and that reduced vascular nitric oxide concentrations would increase this vasoconstrictor effect. METHODS: We developed a model of autologous stored blood transfusion in lambs (n = 36). Leukoreduced blood was stored for either 2 days (fresh PRBC) or 40 days (stored PRBC). Fresh or stored PRBC were transfused into donors instrumented for awake hemodynamic measurements. Hemodynamic effects of PRBC transfusion were also studied after infusion of N-nitro-L-arginine methyl-ester (25 mg/kg) or during inhalation of nitric oxide (80 ppm). RESULTS: Cell-free hemoglobin levels were higher in the supernatant of stored PRBC than in supernatant of fresh PRBC (Mean ± SD, 148 ± 20 vs. 41 ± 13 mg/dl, respectively, P < 0.001). Pulmonary artery pressure during transfusion of stored PRBC transiently increased from 13 ± 1 to 18 ± 1 mmHg (P < 0.001) and was associated with increased plasma hemoglobin concentrations. N-nitro-L-arginine methyl-ester potentiated the increase in pulmonary arterial pressure induced by transfusing stored PRBC, whereas inhalation of nitric oxide prevented the vasoconstrictor response. CONCLUSIONS: Our results suggest that patients with reduced vascular nitric oxide levels because of endothelial dysfunction may be more susceptible to adverse effects of transfusing blood stored for prolonged periods. These patients might benefit from transfusion of fresh PRBC, when available, or inhaled nitric oxide supplementation to prevent the pulmonary hypertension associated with transfusion of stored PRBC.