The incidence of osteopenia of prematurity in preterm infants without phosphate supplementation: A prospective, observational study.

ABSTRACT: To meet their requirements for bone mineralization, it is recommended that preterm infants receive nutritional support containing calcium and phosphate. There are no clear data on the incidence of osteopenia of prematurity (OFP) in preterm infants without phosphate supplementation.This study aimed to investigate the incidence of OFP in preterm infants without phosphate supplementation and its relationship with the duration of parenteral nutrition (PN).This was a prospective and observational study.This study included 30 infants aged <32 gestational weeks and weighed <1500 g at birth. All infants received PN according to a standard protocol, beginning on day 1 with calcium, without phosphate. Starting from the first day of life, all infants received human milk without fortifiers. Oral vitamin D (400 IU/d) was administered when enteral nutrition reached 100 mL/kg/d.The diagnosis of OFP was based on radiographs that were taken of both wrists. Serum alkaline phosphatase (ALP) was measured 3 times: at the start of PN (ALP 1), at the end of PN (ALP 2), and at discharge or the expected due date (ALP 3). Radiographs were obtained on the same day as ALP 3. The duration of PN was analyzed in the presence of OFP using receiver operating characteristic curve analysis.Among the 30 infants, 13 (43%) were diagnosed with OFP. The duration of PN was significantly longer in the OFP group than in the group without OFP (16 vs 12 days; P < .05). The provision of PN for >15 days significantly increased the risk of OFP (odds ratio, 5.40; 95% confidence interval, 1.12-26.04; P = .035).We found a high incidence of OFP in preterm infants without phosphate supplementation. An association was found between the duration of PN and the incidence of OFP. Further research is needed to prevent the development of osteopenia in preterm infants.

Human milk oligosaccharides and their association with late-onset neonatal sepsis in Peruvian very-low-birth-weight infants.

BACKGROUND: Oligosaccharides are the third most abundant component in human milk. They are a potential protective agent against neonatal sepsis. OBJECTIVES: We aimed to explore the association between human milk oligosaccharides (HMOs) and late-onset sepsis in very-low-birth-weight infants, and to describe the composition and characteristics of HMOs in Peruvian mothers of these infants. METHODS: This is a secondary data analysis of a randomized clinical trial. We conducted a retrospective cohort study of mothers and their very-low-birth-weight (<1500 g) infants with ≥1 milk sample and follow-up data for >30 d. HMOs were measured by high performance liquid chromatography (HPLC). We used factor analysis and the Mantel-Cox test to explore the association between HMOs and late-onset neonatal sepsis. RESULTS: We included 153 mother-infant pairs and 208 milk samples. Overall, the frequency of the secretor phenotype was 93%. Secretors and nonsecretors were defined by the presence and near-absence of α1-2-fucosylated HMOs, respectively. The most abundant oligosaccharides were 2'-fucosyllactose, lacto-N-fucopentaose (LNFP) I, and difucosyllacto-N-tetraose in secretors and lacto-N-tetraose and LNFP II in nonsecretors. Secretors had higher amounts of total oligosaccharides than nonsecretors (11.45 g/L; IQR: 0.773 g/L compared with 8.04 g/L; IQR: 0.449 g/L). Mature milk samples were more diverse in terms of HMOs than colostrum (Simpson's Reciprocal Diversity Index). We found an association of factor 3 in colostrum with a reduced risk of late-onset sepsis (HR: 0.63; 95% CI: 0.41, 0.97). Fucosyl-disialyllacto-N-hexose (FDSLNH) was the only oligosaccharide correlated to factor 3. CONCLUSIONS: These findings suggest that concentrations of different HMOs vary from one individual to another according to their lactation period and secretor status. We also found that FDSLNH might protect infants with very low birth weight from late-onset neonatal sepsis. Confirming this association could prove 1 more mechanism by which human milk protects infants against infections and open the door to clinical applications of HMOs.This trial was registered at clinicaltrials.gov as NCT01525316.

Predicted Metabolic Pathway Distributions in Stool Bacteria in Very-Low-Birth-Weight Infants: Potential Relationships with NICU Faltered Growth.

Many very-low-birth-weight (VLBW) infants experience growth faltering in early life despite adequate nutrition. Early growth patterns can affect later neurodevelopmental and anthropometric potentials. The role of the dysbiotic gut microbiome in VLBW infant growth is unknown. Eighty-four VLBW infants were followed for six weeks after birth with weekly stool collection. DNA was extracted from samples and the V4 region of the 16S rRNA gene was sequenced with Illumina MiSeq. A similar microbiota database from full-term infants was used for comparing gut microbiome and predicted metabolic pathways. The class Gammaproteobacteria increased or remained consistent over time in VLBW infants. Out of 228 metabolic pathways that were significantly different between term and VLBW infants, 133 pathways were significantly lower in VLBW infants. Major metabolic differences in their gut microbiome included pathways involved in decreased glycan biosynthesis and metabolism, reduced biosynthetic capacity, interrupted amino acid metabolism, changes that could result in increased infection susceptibility, and many other system deficiencies. Our study reveals poor postnatal growth in a VLBW cohort who had dysbiotic gut microbiota and differences in predicted metabolic pathways compared to term infants. The gut microbiota in VLBW infants likely plays an important role in postnatal growth.

Targeted Breast Milk Fortification for Very Low Birth Weight (VLBW) Infants: Nutritional Intake, Growth Outcome and Body Composition.

Despite improvements in nutritional management, preterm infants continue to face high rates of postnatal growth restriction. Because variability in breast milk composition may result in protein and energy deficits, targeted fortification has been advocated. We conducted an interventional study to compare body composition and growth outcomes of very low birth weight infants fed targeted protein-fortified human milk (HM) with those fed standard fortified HM. If mother's own milk was not available, donor milk was used. Weekly analysis of HM with mid-infrared spectroscopy was conducted and additional protein was added to the fortified HM to ensure a protein intake of 4 g/kg/day. Weekly anthropometric measurements were done. Prior to discharge or at 37 weeks, corrected age skinfold thickness (SFT) measurements as well as body composition measurement using air displacement plethysmography were done. Among 36 preterm infants enrolled, those in the targeted group (n = 17) received more protein and had a larger flank SFT at study end than those in the standard group (n = 19). A pilot post-hoc analysis of subjects having at least 30 intervention days showed a 3% higher fat-free mass in the targeted group. Use of a targeted fortification strategy resulted in a higher protein intake and fat-free mass among those receiving longer intervention.

Genetic predisposition for vitamin D deficiency is not associated with adverse outcome of very low birth weight infants: A cohort study from the German Neonatal Network.

OBJECTIVE: Postnatal vitamin D supplementation is standard of care in neonates and preterm infants. Despite routine supplementation of vitamin D, a wide range of complications related to vitamin D deficiency has been described in the literature. Since standard vitamin D supplementation might be not sufficient in preterm infants with a genetic predisposition for vitamin D deficiency, we investigated the outcome of preterm infants with regard to their genetic estimated vitamin D levels. METHODS: Preterm infants with a birth weight below 1500 grams were included in the German Neonatal Network at the time of their birth and tested at the age of five. The vitamin D level was genetically calculated based on three single nucleotide polymorphisms (SNPs: rs12794714, rs7944926 and rs2282679) which alter vitamin D synthesis pathways. Specific alleles of these polymorphisms are validated markers for low plasma vitamin D levels. Outcome data were based on baseline data at the time of birth, typical complications of prematurity, body measurements at the age of five and occurrence of bone fractures. T-test and Fisher's exact test were used for statistical comparison. RESULTS: According to their genetic predisposition, 1,924 preterm infants were divided into groups of low (gsVitD < 20. Percentile), intermediate and high vitamin D level estimates. Low genetic vitamin D level estimates could not be shown to be associated with any adverse outcome measures examined. The analyses covered data on aforementioned determinants. CONCLUSION: Low genetic vitamin D level estimates could not be shown to be associated with previously described adverse outcome in preterm infants.

High-dose parenteral amino acid intake in very low birthweight infants: what is the current evidence?

PURPOSE OF REVIEW: There is uncertainty regarding optimal dosing for parenteral amino acids in preterm infants and wide variability exists in clinical practice. There is new data from clinical trials trying to address these concerns. We review the recent evidence on parenteral high-dose amino acid intake in very low birth weight (VLBW) neonates with a focus on relevant clinical outcomes. RECENT FINDINGS: Preterm infants often receive less protein than intended in the first week of life. Parenteral amino acid administration in doses that exceed requirements, however, leads to increased oxidation and higher blood urea concentrations. Amino acid doses greater than 3.5 g/kg/day have not shown to improve mortality, neonatal morbidities including sepsis, necrotizing enterocolitis, chronic lung disease, growth parameters or neurodevelopmental outcomes at 2 years of age. SUMMARY: Parenteral amino acid administration in VLBW infants should be initiated soon after birth at a dose of at least 1.5 g/kg/day to maintain anabolism. The maximum dose for parenteral amino acid should be between 2.5 and 3.5 g/kg/day, with adequate nonprotein calories and micronutrients to ensure efficient protein utilization and growth.

Vitamin D deficiency and respiratory morbidity among African American very low birth weight infants.

BACKGROUND: Very low birth weight infants (VLBWI) have unexplained variation in respiratory morbidity, including respiratory distress syndrome (RDS) and bronchopulmonary dysplasia (BPD). We examined a potential association to serum 25-hydroxyvitamin D (s-25OHD) on day one. STUDY DESIGN: Prospective, observational study on 89 VLBWI (≤1250 g). S-25OHD (day one and 21) and respiratory severity score (RSS) (day one) were examined. Other respiratory morbidities including BPD were compared between infants with s-25OHD ≤ 10 ng/ml (deficient) versus >10 ng/ml (adequate). RESULTS: Eighty one neonates (91%) were African Americans. The mean (SD) birthweight was 868 (229) g, gestational age 27 (2) weeks. On day one, mean (SD) s-25OHD was 15.48 (8.31) ng/ml, with 32 (37%) being vitamin D deficient. The deficiency and adequate VLBWI groups had similar birthweight; 860 (262) vs 873 (210) g, and gestational age; 27 (2) vs 27 (2) weeks. In 78 survivors, s-25OHD rose from 15.48 (8.31) ng/ml day one to 52.36 (22.49) ng/ml day 21 after supplementation, p < 0.001. On day one, increasing RSS was inversely related to s-25OHD, trend p = 0.054. Compared to the adequate group, the deficiency group had higher RSS (5.0 ±â€¯2.7 vs 3.6 ±â€¯1.9), required surfactant therapy more frequently (91% vs 72%), and needed home oxygen therapy more often (48% vs 26%), p ≤ 0.05 for all. Among infants with BPD, the severity of disease was inversely related to s-25OHD, trend p < 0.09. CONCLUSION: Lower levels of s-25OHD were associated with increased severity of RDS and BPD among a cohort of mostly African American VLBWI.

Half-life of plasma phytosterols in very low birth weight preterm infants on routine parenteral nutrition with vegetable oil-based lipid emulsions.

BACKGROUND: Phytosterols in vegetable oil (VO)-based lipid emulsions (LE) likely contribute to parenteral nutrition-associated cholestasis (PNAC) in preterm infants. No characterization of plasma phytosterol half-lives has been done in very low birth weight (VLBW) preterm infants receiving parenteral nutrition (PN) with LE. METHODS: In a prospective cohort study, 45 VLBW preterm infants who received PN underwent serial blood sample measurements of sitosterol (SITO), campesterol (CAMP), and stigmasterol (STIGM). Plasma phytosterol half-lives were calculated from the phytosterol concentrations-decay curves by using a single-compartment model. RESULTS: After the stop of the intravenous LE, study infants had significantly lower plasma total CAMP, STIGM and SITO concentrations. The decay of plasma phytosterol concentrations was monoexponential. Half-life of plasma total CAMP, STIGM and SITO was 13.5 ± 6.9, 10.3 ± 4.5 and 10.3 ± 4.0 days, respectively. Plasma phytosterol half-lives did not correlate with gestational age, birth weight, cumulative phytosterol intakes and plasma conjugated bilirubin. CONCLUSION: VLBW preterm infants on PN with LE had rather long plasma phytosterol half-lives similar to hypercholesterolemic adults and phytosterolemic homozygotes patients. We speculate that the accumulation of phytosterols could contribute to their vulnerability to PNAC. CLINICAL TRIAL REGISTRY: The Ethics Committee of Marche-Italy (DG/469); www.clinicaltrials.gov (identification number NCT02758834).

Growth and Nutritional Biomarkers of Preterm Infants Fed a New Powdered Human Milk Fortifier: A Randomized Trial.

OBJECTIVES: The aim of this study was to assess growth and nutritional biomarkers of preterm infants fed human milk (HM) supplemented with a new powdered HM fortifier (nHMF) or a control HM fortifier (cHMF). The nHMF provides similar energy content, 16% more protein (partially hydrolyzed whey), and higher micronutrient levels than the cHMF, along with medium-chain triglycerides and docosahexaenoic acid. METHODS: In this controlled, multicenter, double-blind study, a sample of preterm infants ≤32 weeks or ≤1500 g were randomized to receive nHMF (n = 77) or cHMF (n = 76) for a minimum of 21 days. Weight gain was evaluated for noninferiority (margin = -1 g/day) and superiority (margin = 0 g/day). Nutritional status and gut inflammation were assessed by blood, urine, and fecal biochemistries. Adverse events were monitored. RESULTS: Adjusted mean weight gain (analysis of covariance) was 2.3 g/day greater in nHMF versus cHMF; the lower limit of the 95% CI (0.4 g/day) exceeded both noninferiority (P < 0.001) and superiority margins (P = 0.01). Weight gain rate (unadjusted) was 18.3 (nHMF) and 16.8 g ·â€Škg ·â€Šday (cHMF) between study days 1 and 21 (D1-D21). Length and head circumference (HC) gains between D1 and D21 were not different. Adjusted weight-for-age z score at D21 and HC-for-age z score at week 40 corrected age were greater in nHMF versus cHMF (P = 0.013, P = 0.003 respectively). nHMF had higher serum blood urea nitrogen, pre-albumin, alkaline phosphatase, and calcium (all within normal ranges; all P ≤ 0.019) at D21 versus cHMF. Both HMFs were well tolerated with similar incidence of gastrointestinal adverse events. CONCLUSIONS: nHMF providing more protein and fat compared to a control fortifier is safe, well-tolerated, and improves the weight gain of preterm infants.

Transcutaneous bilirubin monitoring predicts unexplained late-onset hemolysis in a very low birthweight infant.

BACKGROUND: In term infants, transcutaneous bilirubin (TcB) monitoring can be used to predict hemolytic hyperbilirubinemia. However, it is not clear whether the technique can also be used to predict unexplained late-onset hemolysis in very low birthweight (VLBW) infants. CASE PRESENTATION: The case was an infant with a birthweight of 1154 g who developed unexplained late-onset hemolysis at 8 days of age. The hyperbilirubinemia rapidly worsened, and therefore both phototherapy and exchange transfusion were performed. TcB levels were measured using the JM-105 jaundice meter and found to have increased by >3 mg/dL since before the onset, demonstrating for the first time that the device clearly detects changes in hemolytic rate. CONCLUSIONS: Although TcB levels did not correspond directly with total serum bilirubin levels in VLBW infants, the two values exhibited parallel changes in this case. Therefore, serial TcB monitoring may be useful in the early prediction of unexplained late-onset hemolysis in VLBW infants.

LCPUFAs as conditionally essential nutrients for very low birth weight and low birth weight infants: metabolic, functional, and clinical outcomes-how much is enough?

Preterm infants are denied the rapid accumulation of docosahexaenoic acid (DHA) occurring during the third trimester in utero. The potential benefit of long-chain polyunsaturated fatty acids (LCPUFAs) has generated interest over the last 3 decades. Early intervention trials assessed the effects of supplementing infant formulas lacking DHA with concentrations equivalent to LCPUFA in milk of women from Westernized societies, leading to the inclusion of LCPUFA by the year 2000. Recently attention has been on determining the optimal dose of DHA and on whether there is in advantage in matching the higher doses of late pregnancy.

Early versus late enteral prophylactic iron supplementation in preterm very low birth weight infants: a randomised controlled trial.

OBJECTIVES: To evaluate whether preterm very low birth weight (VLBW) infants receiving early iron (EI) supplementation (2 mg/kg/day elemental iron) at 2 weeks postnatal age have improved serum ferritin levels compared with late iron (LI) supplementation at 6 weeks postnatal age. DESIGN: Single-blinded parallel-group interventional randomised controlled trial. SETTING: Tertiary care centre in southern India. INTERVENTIONS: Randomised at 2 weeks postnatal age to EI and LI groups and evaluated at 2, 6 and 12 weeks postnatal age. OUTCOME: The primary outcome was serum ferritin level at 12 weeks, and the secondary outcomes were the incidence of neonatal morbidities, haemoglobin level, anthropometric parameters and blood transfusion requirements. RESULTS: Of the 104 babies randomised, outcomes were analysed in 46 and 47 babies in EI and LI groups, respectively. Serum ferritin level was significantly higher (p<0.001) at 12 weeks (82±5 vs 63±3 ng/mL) in the EI group. Haemoglobin (10.1±0.4 vs 9.2±0.4 g/dL) and mean corpuscular haemoglobin concentration (31±0.5 vs 29.4±0.5 g/dL) were also significantly (p<0.001) higher at 12 weeks in the EI group. There was a significant decrease of ferritin in the LI group and significant increase in ferritin in the EI group at 6 weeks compared with 2 weeks. There were no significant differences in the incidences of neonatal morbidities (necrotising enterocolitis, periventricular leukomalacia, retinopathy of prematurity), anthropometric parameters and blood transfusion requirements between the two groups. CONCLUSIONS: EI supplementation in preterm VLBW infants improves serum ferritin and haemoglobin levels. TRIAL REGISTRATION: CTRI/2013/01/003277.

Safety and efficacy of early parenteral lipid and high-dose amino acid administration to very low birth weight infants.

OBJECTIVE: To assess the efficacy and safety of early parenteral lipid and high-dose amino acid (AA) administration from birth onwards in very low birth weight (VLBW, birth weight <1500 g) infants. STUDY DESIGN: VLBW infants (n = 144; birth weight 862 ± 218 g; gestational age 27.4 ± 2.2 weeks) were randomized to receive 2.4 g of AA kg(-1) · d(-1) (control group), or 2.4 g AA kg(-1) · d(-1) plus 2-3 g lipids kg(-1) · d(-1) (AA + lipid group), or 3.6 g AA kg(-1) · d(-1) plus 2-3 g lipids kg(-1) · d(-1) (high AA + lipid group) from birth onwards. The primary outcome was nitrogen balance. The secondary outcomes were biochemical variables, urea rate of appearance, growth rates, and clinical outcome. RESULTS: The nitrogen balance on day 2 was significantly greater in both intervention groups compared with the control group. Greater amounts of AA administration did not further improve nitrogen balance compared with standard AA dose plus lipids and was associated with high plasma urea concentrations and high rates of urea appearance. No differences in other biochemical variables, growth, or clinical outcomes were observed. CONCLUSIONS: In VLBW infants, the administration of parenteral AA combined with lipids from birth onwards improved conditions for anabolism and growth, as shown by improved nitrogen balance. Greater levels of AA administration did not further improve the nitrogen balance but led to increased AA oxidation. Early lipid initiation and high-dose AA were well tolerated.

Calcium absorption in very low birth weight infants with and without bronchopulmonary dysplasia.

OBJECTIVE: To evaluate the effects of early bronchopulmonary dysplasia (BPD) on calcium (Ca) metabolism and growth in very low birth weight (VLBW) infants. STUDY DESIGN: A dual-tracer, stable isotope method was used to assess Ca absorption in VLBW infants. Infants with early BPD received energy-dense feedings and mild fluid restriction. RESULTS: Sixteen of 41 preterm infants were classified as having early BPD. Fractional Ca absorption (early BPD, 58.4 ± 4.6% versus no early BPD, 50.3 ± 4.0%, P = .2), total Ca absorption (early BPD, 127 ± 14 mg/kg/d versus no early BPD, 104 ± 9 mg/kg/d, P = .9), and Ca retention (early BPD, 99.6 ± 10.0 mg/kg/d versus no early BPD, 91.0 ± 9.8 mg/kg/d, P = .2) were similar among groups. There was no significant difference in weight gain, linear growth, or head circumference growth between groups. CONCLUSIONS: The ability of VLBW infants with early BPD and fluid restriction to grow and accrete calcium is similar to those without early BPD. The use of high caloric density feedings in VLBW infants with early BPD can help achieve bone and overall growth outcomes close to those achievable in utero.

Chemical aspects on dental hard tissues in primary teeth from preterm infants.

Preterm children with very low birth weight suffer from several neonatal and postnatal complications that may affect the mineralization of teeth. Clinical and morphological studies have shown enamel aberrations in teeth from preterm children. In this study, the chemical composition in enamel and dentin was compared in primary teeth from preterm children and full-term children, and the relationship between the chemical composition and the morphological appearance was investigated. Enamel and dentin in 17 exfoliated primary teeth, from 14 children with a gestational age below 29 wk, were investigated and compared with 36 exfoliated primary teeth from full-term children, using X-ray microanalyses (XRMA). In comparison with the teeth from the controls, the teeth from preterm children had a higher relative value of carbon (C), a lower relative value of calcium (Ca), a lower ratio of calcium/phosphorus (Ca/P) and a lower ratio of Ca/C throughout the outer part of the enamel. In dentin, the relative values for P were higher, and Ca/P ratio was lower, at the dentin-pulp junction. The Ca/P ratio indicated normal hydroxyapatite in the crystals in enamel and dentin. The lower ratio of Ca/C in the bulk and outer part of the enamel indicated more porous enamel.

Nutritional support for extremely low-birth weight infants: abandoning catabolism in the neonatal intensive care unit.

PURPOSE OF REVIEW: Obviously, the ultimate goal in neonatology is to achieve a functional outcome in premature infants that is comparable to healthy term-born infants. As nutrition is one of the key factors for normal cell growth, providing the right amount and quality of nutrients could prove pivotal for normal development. However, many premature infants are catabolic during the first week of life, which has directly been linked to growth failure, disease, and suboptimal long-term outcome. This review describes the progress in research on parenteral nutrition for premature infants with a focus on amino acids and the influence of nutrition on later outcome. RECENT FINDINGS: Although randomized clinical trials on early nutrition for premature infants remain relatively sparse, evidence is accumulating on its beneficial effects both on the short-term and long-term. However, some research also warns for adverse effects. SUMMARY: Despite the fact that substantially improved nutritional therapies for preterm neonates have been implemented, still, some reluctance exists when it comes to providing high amounts of nutrition to the most immature infants. Pros and cons are outlined, as well as deficits in knowledge, when it comes to providing the optimal nutrient strategy in the first postnatal phase.

Human milk fortifiers in very low birth weight infants.

The use of HMF remains an important option and has become common practice in all neonatal intensive care units. However, optimal composition of fortifiers is still undefined and more data are needed on safety and long-term benefits. Further research should be directed toward comparisons between different proprietary preparations, evaluating both short-term and long-term outcomes and adverse effects, in search of the best method of fortification.

Can magnetic resonance spectroscopy predict neurodevelopmental outcome in very low birth weight preterm infants?

OBJECTIVE: To determine if metabolite ratios at near-term age predict outcome in very low birth weight preterm infants at 18 to 24 months adjusted age. STUDY DESIGN: Thirty-six infants (birth weight

Induction of early meconium evacuation promotes feeding tolerance in very low birth weight infants.

BACKGROUND: A delay in reaching full enteral feeding is linked to poorer outcome in preterm neonates. Meconium retention has been viewed as a cause of bowel dysfunction in very low birth weight infants (VLBWI). Thus, adequate evacuation of meconium could help to promote feeding tolerance. OBJECTIVES: Our goal was to determine the effect of the induction of early meconium evacuation on feeding tolerance in VLBWI. METHODS: An observational study involving two subsequent periods was performed in inborn infants with birth weights of <1,500 g, before (control) and after (study) the induction of early meconium evacuation by routine glycerin enema. The total duration of these periods was from January 2003 to December 2005. To evaluate feeding tolerance, we measured time to achieve full enteral feeding. Complications such as sepsis and necrotizing enterocolitis were compared. RESULTS: The study group achieved full enteral feeding significantly faster than the control group (hazard ratio (HR) = 2.9; 95% confidence interval (CI) = 1.8-4.8), and this effect was more definite in infants with a birth weight of <1,000 g (HR = 4.6; 95% CI = 1.9-11.1). The study group passed first meconium faster than the control group (median = 1.4 vs. 3.7 days; p < 0.001). Sepsis, especially as determined by positive culture in central venouscatheter, was significantly reduced in the study group (7.7 vs. 27.8%; p = 0.02). CONCLUSIONS: The induction of early meconium evacuation had a significantly positive effect on feeding tolerance and sepsis prevention in VLBWI.