Near-Term Fetal Hypoxia-Ischemia in Rabbits MRI Can Predict Muscle Tone Abnormalities and Deep Brain Injury

Background and Purpose-The pattern of antenatal brain injury varies with gestational age at the time of insult. Deep brain nuclei are often injured at older gestational ages. Having previously shown postnatal hypertonia after preterm fetal rabbit hypoxia-ischemia, the objective of this study was to investigate the causal relationship between the dynamic regional pattern of brain injury on MRI and the evolution of muscle tone in the near-term rabbit fetus. Methods-Serial MRI was performed on New Zealand white rabbit fetuses to determine equipotency of fetal hypoxia-ischemia during uterine ischemia comparing 29 days gestation (E29, 92% gestation) with E22 and E25. E29 postnatal kits at 4, 24, and 72 hours after hypoxia-ischemia underwent T2- and diffusion-weighted imaging. Quantitative assessments of tone were made serially using a torque apparatus in addition to clinical assessments. Results-Based on the brain apparent diffusion coefficient, 32 minutes of uterine ischemia was selected for E29 fetuses. At E30, 58% of the survivors manifested hind limb hypotonia. By E32, 71% of the hypotonic kits developed dystonic hypertonia. Marked and persistent apparent diffusion coefficient reduction in the basal ganglia, thalamus, and brain stem was predictive of these motor deficits. Conclusions-MRI observation of deep brain injury 6 to 24 hours after near-term hypoxia-ischemia predicts dystonic hypertonia postnatally. Torque-displacement measurements indicate that motor deficits in rabbits progressed from initial hypotonia to hypertonia, similar to human cerebral palsy, but in a compressed timeframe. The presence of deep brain injury and quantitative shift from hypo-to hypertonia may identify patients at risk for developing cerebral palsy. (Stroke. 2012;43:2757-2763.)

Growth standards of patients with Noonan and Noonan-like syndromes with mutations in the RAS/MAPK pathway

Noonan syndrome (NS) and Noonan-like syndromes (NLS) are autosomal dominant disorders caused by heterozygous mutations in genes of the RAS/MAPK pathway. The aim of the study was to construct specific growth charts for patients with NS and NLS. Anthropometric measurements (mean of 4.3 measurements per patient) were obtained in a mixed cross-sectional and longitudinal mode from 127 NS and 10 NLS patients with mutations identified in PTPN11 (n?=?90), SOS1 (n?=?14), RAF1 (n?=?10), KRAS (n?=?8), BRAF (n?=?11), and SHOC2 (n?=?4) genes. Height, weight, and body mass index (BMI) references were constructed using the lambda, mu, sigma (LMS) method. Patients had birth weight and length within normal ranges for gestational age although a higher preterm frequency (16%) was observed. Mean final heights were 157.4?cm [-2.4 standard deviation score (SDS)] and 148.4?cm (-2.2?SDS) for adult males and females, respectively. BMI SDS was lower when compared to Brazilian standards (BMI SDS of -0.9 and -0.5 SDS for males and females, respectively). Patients harboring mutations in RAF1 and SHOC2 gene were shorter than other genotypes, whereas patients with SOS1 and BRAF mutations had more preserved postnatal growth. In addition, patients with RAF1 and BRAF had the highest BMI whereas patients with SHOC2 and KRAS mutations had the lowest BMI. The present study established the first height, weight, and BMI reference curves for NS and NLS patients, based only on patients with a proven molecular cause. These charts can be useful for the clinical follow-up of patients with NS and NLS. (c) 2012 Wiley Periodicals, Inc.

Factors Associated with Height Catch-Up and Catch-Down Growth Among Schoolchildren

In developed countries, children with intrauterine growth restriction (IUGR) or born preterm (PT) tend to achieve catch-up growth. There is little information about height catch-up in developing countries and about height catch-down in both developed and developing countries. We studied the effect of IUGR and PT birth on height catch-up and catch-down growth of children from two cohorts of liveborn singletons. Data from 1,463 children was collected at birth and at school age in Ribeirao Preto (RP), a more developed city, and in Sao Luis (SL), a less developed city. A change in z-score between schoolchild height z-score and birth length z-score >= 0.67 was considered catch-up; a change in z-score <=-0.67 indicated catch-down growth. The explanatory variables were: appropriate weight for gestational age/PT birth in four categories: term children without IUGR (normal), IUGR only (term with IUGR), PT only ( preterm without IUGR) and preterm with IUGR; infant's sex; maternal parity, age, schooling and marital status; occupation of family head; family income and neonatal ponderal index (PI). The risk ratio for catch-up and catch-down was estimated by multinomial logistic regression for each city. In RP, preterms without IUGR (RR = 4.13) and thin children (PI<10th percentile, RR = 14.39) had a higher risk of catch-down; catch-up was higher among terms with IUGR (RR = 5.53), preterms with IUGR (RR = 5.36) and children born to primiparous mothers (RR = 1.83). In SL, catch-down was higher among preterms without IUGR (RR = 5.19), girls (RR = 1.52) and children from low-income families ( RR = 2.74); the lowest risk of catch-down (RR = 0.27) and the highest risk of catch-up (RR = 3.77) were observed among terms with IUGR. In both cities, terms with IUGR presented height catch-up growth whereas preterms with IUGR only had height catch-up growth in the more affluent setting. Preterms without IUGR presented height catch-down growth, suggesting that a better socioeconomic situation facilitates height catch-up and prevents height catch-down growth.

Whither lung EIT: Where are we, where do we want to go and what do we need to get there?

Breathing moves volumes of electrically insulating air into and out of the lungs, producing conductivity changes which can be seen by electrical impedance tomography (EIT). It has thus been apparent, since the early days of EIT research, that imaging of ventilation could become a key clinical application of EIT. In this paper, we review the current state and future prospects for lung EIT, by a synthesis of the presentations of the authors at the 'special lung sessions' of the annual biomedical EIT conferences in 2009-2011. We argue that lung EIT research has arrived at an important transition. It is now clear that valid and reproducible physiological information is available from EIT lung images. We must now ask the question: How can these data be used to help improve patient outcomes? To answer this question, we develop a classification of possible clinical scenarios in which EIT could play an important role, and we identify clinical and experimental research programmes and engineering developments required to turn EIT into a clinically useful tool for lung monitoring.

Influence of Mid-Trimester Amniotic Fluid on Endogenous and Lipopolysaccharide-Mediated Responses of Mononuclear Lymphoid Cells

Problem We evaluated the influence of amniotic fluid (AF) on immune mediator production by mononuclear leukocytes. Method of study Thirty mid-gestation AFs were incubated with peripheral blood mononuclear cells (PBMCs) in the presence or absence of lipopolysaccharide (LPS). Supernatants were tested for interleukin (IL) -6, 10, 12, 23, tumor necrosis factor-alpha (TNF-alpha) and monocyte chemotactic protein (MCP)-1. Results Endogenous mediator production was minimal or non-detectable. AF stimulated endogenous MCP-1, IL-6 and TNF-alpha release. In the presence of LPS, production of MCP-1 and IL-10 by PBMCs was enhanced eightto ninefold by AF. Release of IL-6 and IL-23 was enhanced less than twofold by the addition of AF while TNF-alpha production was unchanged. AF-stimulated mediator production was similar irrespective of pregnancy outcome. Conclusion Selective AF stimulation of LPS-mediated MCP-1 and IL-10 release may be a mechanism to promote antibody production and the influx of phagocytic cells to engulf pathogens while downregulating the production of pro-inflammatory cytokines.

Birth in Brazil: national survey into labour and birth

Background: Caesarean section rates in Brazil have been steadily increasing. In 2009, for the first time, the number of children born by this type of procedure was greater than the number of vaginal births. Caesarean section is associated with a series of adverse effects on the women and newborn, and recent evidence suggests that the increasing rates of prematurity and low birth weight in Brazil are associated to the increasing rates of Caesarean section and labour induction. Methods: Nationwide hospital-based cohort study of postnatal women and their offspring with follow-up at 45 to 60 days after birth. The sample was stratified by geographic macro-region, type of the municipality and by type of hospital governance. The number of postnatal women sampled was 23,940, distributed in 191 municipalities throughout Brazil. Two electronic questionnaires were applied to the postnatal women, one baseline face-to-face and one follow-up telephone interview. Two other questionnaires were filled with information on patients' medical records and to assess hospital facilities. The primary outcome was the percentage of Caesarean sections (total, elective and according to Robson's groups). Secondary outcomes were: post-partum pain; breastfeeding initiation; severe/near miss maternal morbidity; reasons for maternal mortality; prematurity; low birth weight; use of oxygen use after birth and mechanical ventilation; admission to neonatal ICU; stillbirths; neonatal mortality; readmission in hospital; use of surfactant; asphyxia; severe/near miss neonatal morbidity. The association between variables were investigated using bivariate, stratified and multivariate model analyses. Statistical tests were applied according to data distribution and homogeneity of variances of groups to be compared. All analyses were taken into consideration for the complex sample design. Discussion: This study, for the first time, depicts a national panorama of labour and birth outcomes in Brazil. Regardless of the socioeconomic level, demand for Caesarean section appears to be based on the belief that the quality of obstetric care is closely associated to the technology used in labour and birth. Within this context, it was justified to conduct a nationwide study to understand the reasons that lead pregnant women to submit to Caesarean sections and to verify any association between this type of birth and it's consequences on postnatal health.

Visual impairment in children with spastic cerebral palsy measured by psychophysical and electrophysiological grating acuity tests

Background: This study measured grating visual acuity in 173 children between 6-48 months of age who had different types of spastic cerebral palsy (CP). Method: Behavioural acuity was measured with the Teller Acuity Cards (TAC) using a staircase psychophysical procedure. Electrophysiological visual acuity was estimated using the sweep VEP (sVEP). Results: The percentage of children outside the superior tolerance limits was 44 of 63 (69%) and 50 of 55 (91%) of tetraplegic, 36 of 56 (64%) and 42 of 53 (79%) of diplegic, 10 of 48 (21%) and 12 of 40 (30%) of hemiplegic for sVEP and TAC, respectively. For the sVEP, the greater visual acuity deficit found in the tetraplegic group was significantly different from that of the hemiplegic group (p < 0.001). In the TAC procedure the mean visual acuity deficits of the tetraplegic and diplegic groups were significantly different from that of hemiplegic group (p < 0.001). The differences between sVEP and TAC means of visual acuity difference were statistically significant for the tetraplegic (p < 0.001), diplegic (p < 0.001), and hemiplegic group (p = 0.004). Discussion: Better visual acuities were obtained in both procedures for hemiplegic children compared to diplegic or tetraplegic. Tetraplegic and diplegic children showed greater discrepancies between the TAC and sVEP results. Inter-ocular acuity difference was more frequent in sVEP measurements. Conclusions: Electrophysiologically measured visual acuity is better than behavioural visual acuity in children with CP.

Prenatal and Neonatal Adaptations with a Focus on the Respiratory System

Contents Among the modifications that occur during the neonatal period, pulmonary development is the most critical. The neonate's lungs must be able to perform adequate gas exchange, which was previously accomplished by the placenta. Neonatal respiratory distress syndrome is defined as insufficient surfactant production or pulmonary structural immaturity and is specifically relevant to preterm newborns. Prenatal maternal betamethasone treatment of bitches at 55days of gestation leads to structural changes in the neonatal lung parenchyma and consequently an improvement in the preterm neonatal respiratory condition, but not to an increase in pulmonary surfactant production. Parturition represents an important challenge to neonatal adaptation, as the uterine and abdominal contractions during labour provoke intermittent hypoxia. Immediately after birth, puppies present venous mixed acidosis (low blood pH and high dioxide carbon saturation) and low but satisfactory Apgar scores. Thus, the combination of physiological hypoxia during birth and the initial effort of filling the pulmonary alveoli with oxygen results in anaerobiosis. As a neonatal adaptation follow-up, the Apgar analysis indicates a tachypnoea response after 1h of life, which leads to a shift in the blood acidbase status to metabolic acidosis. One hour is sufficient for canine neonates to achieve an ideal Apgar score; however, a haemogasometric imbalance persists. Dystocia promotes a long-lasting bradycardia effect, slows down Apgar score progression and aggravates metabolic acidosis and stress. The latest data reinforce the need to accurately intervene during canine parturition and offer adequate medical treatment to puppies that underwent a pathological labour.

Invasive candidiasis and oral manifestations in premature newborns

Objective: To investigate prevalence of invasive candidiasis in a Neonatal Intensive Care Unit and to evaluate oral diseases and Candida spp. colonization in low birth weight preterm newborns. Methods: A descriptive epidemiological study performed in two stages. First, prevalence of candidiasis was analyzed in a database of 295 preterm patients admitted to hospital for over 10 days and birth weight less than 2,000g. In the second stage, oral changes and Candida spp. colonization were assessed in 65 patients weighing less than 2,000g, up to 4 week-old, hospitalized for over 10 days and presenting oral abnormalities compatible with fungal lesions. Swab samples were collected in the mouth to identify fungi. Results: Prevalence of candidiasis was 5.4% in the database analyzed. It correlated with prolonged hospital length of stay (p<0.001), in average, 31 days, and 85% risk of developing infection in the first 25 days. It correlated with low birth weight (p<0.001), with mean of 1,140g. The most frequent alterations were white soft plaques, detachable, in oral mucosa and tongue. Intense oral colonization by Candida spp was observed (80%). Conclusions: The frequency of invasive candidiasis was low and correlated with low birth weight and prolonged hospital stay. The most common oral changes were white plaques compatible with pseudomembranous candidiasis and colonization by Candida spp. was above average.

Chest associated to motor physiotherapy improves cardiovascular variables in newborns with respiratory distress syndrome

Background We aimed to evaluate the effects of chest and motor physiotherapy treatment on hemodynamic variables in preterm newborns with respiratory distress syndrome. Methods We evaluated heart rate (HR), respiratory rate (RR), systolic (SAP), mean (MAP) and diastolic arterial pressure (DAP), temperature and oxygen saturation (SO2%) in 44 newborns with respiratory distress syndrome. We compared all variables between before physiotherapy treatment vs. after the last physiotherapy treatment. Newborns were treated during 11 days. Variables were measured 2 minutes before and 5 minutes after each physiotherapy treatment. We applied paired Student t test to compare variables between the two periods. Results HR (148.5 ± 8.5 bpm vs. 137.1 ± 6.8 bpm - p < 0.001), SAP (72.3 ± 11.3 mmHg vs. 63.6 ± 6.7 mmHg - p = 0.001) and MAP (57.5 ± 12 mmHg vs. 47.7 ± 5.8 mmHg - p = 0.001) were significantly reduced after 11 days of physiotherapy treatment compared to before the first session. There were no significant changes regarding RR, temperature, DAP and SO2%. Conclusions Chest and motor physiotherapy improved cardiovascular parameters in respiratory distress syndrome newborns.

Fatores associados ao nascimento pré-termo em Campina Grande, Paraíba, Brasil: um estudo caso-controle

A case-control study (2008-2009) analyzed risk factors for preterm birth in the city of Campina Grande, Paraíba State, Brazil. A total of 341 preterm births and 424 controls were included. A multiple logistic regression model was used. Risk factors for preterm birth were: previous history of preterm birth (OR = 2.32; 95%CI: 1.25-4.29), maternal age (OR = 2.00; 95%CI: 1.00-4.03), inadequate prenatal care (OR = 2.15; 95%CI: 1.40-3.27), inadequate maternal weight gain (OR = 2.33; 95%CI: 1.45-3.75), maternal physical injury (OR = 2.10; 95%CI: 1.22-3.60), hypertension with eclampsia (OR = 17.08; 95%CI: 3.67-79.43) and without eclampsia (OR = 6.42; 95%CI: 3.50-11.76), hospitalization (OR = 5.64; 95%CI: 3.47-9.15), altered amniotic fluid volume (OR = 2.28; 95%CI: 1.32-3.95), vaginal bleeding (OR = 1.54; 95%CI: 1.01-2.34), and multiple gestation (OR = 22.65; 95%CI: 6.22-82.46). High and homogeneous prevalence of poverty and low maternal schooling among both cases and controls may have contributed to the fact that socioeconomic variables did not remain significantly associated with preterm birth.

Comparison of physical properties of two exogenous surfactants: new parameter.

The pulmonary surfactant has essential physical properties for normal lung function. The most important property is the surface tension. In this work, it was evaluated the surface tension of two commercial exogenous surfactants used in surfactant replacement therapy, poractant alfa (Curosurf, Chiesi Farmaceuticals, Italy) and beractant (Survanta, Abbott Laboratories, USA) using new parameters. A Langmuir film balance (Minitrough, KSV Instruments, Finland) was used to measure surface tension of poractant alfa and beractant samples. For both samples, we prepared a solution of 1 mg/m dissolved in chloroform (100π`), which was applied over a subphase of milli-Q water (175 ml) in the chamber of the balance. The chamber has two moving barriers that can change its surface area between a maximal value of 112.5 cm 2 , and a minimal value of 22.5 cm 2, defining a balance cycle. Each surfactant had its surface tension evaluated during 20 balance cycles for three times. Four quantities were calculated from the experiment: Minimum Surface Tension (MTS), defined as the surface tension at minimal surface area during the first cycle; Mean Work Cycle (MWC), defined as the mean hysteresis area of the measured surface tension curve of the last 16 balance cycles; Critical Active Surface Area in Compression (CASAC) or in Expansion (CASAE), defined as the maximal chamber area where the surfactant is active on the surface in compression or expansion. The t-test was applied to verify for statistical significance of the results. Comproved with the MST is the same reported in literature, the differences between MWC, CASAC, and CASAE were statistically significant (p<0.001). The MWC, CASAC and CASAE were higher for poractant alfa than for beractant. A higher MWC for poractant alfa means higher elastic recoil of the lung in comparison with beractant. Using a different methodology, our results showed that poractant alfa is probably more effective in a surfactant replacement therapy than beractant due the use of poractant alfa in relation to the use of beractant in preterm infants with Respiratory Distress Syndrome (RDS).

Trasmissione post-natale del citomegalovirus attraverso il latte materno al neonato VLBW

Introduction Postnatal human cytomegalovirus (CMV) infection is usually asymptomatic in term babies, while preterm infants are more susceptible to symptomatic CMV infection. Breastfeeding plays a dominant role in the epidemiology of transmission of postnatal CMV infection, but the risk factors of symptomatic CMV infection in preterm infants are unknown. Patients and Methods Between December 2003 and August 2006, eighty Very Low Birth Weight (VLBW) preterm infants (gestational age ≤ 32 weeks and birth weight < 1500 g), admitted to the Neonatal Intensive Care Unit of St Orsola-Malpighi General Hospital, Bologna were recruited. All of them were breastfed for at least one month. During the first week of life, serological test for CMV was performed on maternal blood. Furthermore, urinary CMV culture was performed in all the infants in order to exclude a congenital CMV infection. Urine samples from each infant were collected and processed for CMV culture once a week. Once every 15 days a blood sample was taken from each infant to evaluate the complete blood count, the hepatic function and the C reactive protein. In addition, samples of fresh breast milk were processed weekly for CMV culture. A genetic analysis of virus variant was performed in the urine of the infected infants and in their mother’s milk to confirm the origin of infection. Results We evaluated 80 VLBW infants and their 68 mothers. Fifty-three mothers (78%) were positive for CMV IgG antibodies, and 15 (22%) were seronegative. In the seronegative group, CMV was never isolated in breast milk, and none of the 18 infants developed viruria; in the seropositive group, CMV was isolated in 21 out of 53 (40%) mother’s milk. CMV was detected in the urine samples of 9 out of 26 (35%) preterm infants, who were born from 21 virolactia positive mothers. Six of these infants had clinically asymptomatic CMV infection, while 3 showed a sepsis-like illness with bradycardia, tachypnea and repeated desaturations. Eight out of nine infants showed abnormal hematologic values. The detection of neutropenia was strictly related to CMV infection (8/9 infected infants vs 17/53 non infected infants, P<.005), such as the detection of an increase in conjugated bilirubin (3/9 infected infants vs 2/53 non infected infants, P<.05). The degree of neutropenia was not different between the two groups (infected/non infected). The use of hemoderivatives (plasma and/or IgM–enriched immunoglobulin) in order to treat a suspected/certain infection in newborn with GE< 28 ws was seen as protective against CMV infection (1/4 infected infants vs 18/20 non infected infants [GE<28 ws]; P<.05). Furthermore, bronchopulmonary dysplasia (defined both as oxygen-dependency at 30 days of life and 36 ws of postmenstrual age) correlated with symptomatic infection (3/3 symptomatic vs 0/6 asymptomatic: P<.05). Conclusion Our data suggest that CMV infection transmitted to preterm newborn through human milk is always asymptomatic when newborns are clinically stable. Otherwise, the infection can worsen a preexisting disease such as bronchopulmonary dysplasia. Human milk offers many nutritional and psychological advantages to preterm newborns: according to our data, there’s no reason to contraindicate it neither to pasteurize the milk of all the mothers of preterm infants who are CMV seropositive.

Apnea e reflusso gastroesofageo nel neonato pretermine

Objective: To document the existence of a relationship between apnea of prematurity (AOP) and gastroesophageal reflux (GER) in preterm infants. Setting: One Neonatal Intensive Care Unit Patients: Twenty-six preterm infants (gestational age<32 weeks) with recurrent apneas. Intervention: Simultaneous and synchronized recording of polysomnography and pH-impedance monitoring (pH-MII). Polysomnography detects and characterizes apneas, by recording of breathing movement, nasal airflow, electrocardiogram, pulse oximeter saturation. pH-MII is the state-of-theart methodology for GER detection in preterm newborns. Main outcome measures: Relationship between AOP and GER, which were considered temporally related if both started within 30 seconds of each other. Results: One-hundred-fifty-four apneas out of 1136 were temporally related to GER. The frequency of apnea during the one-minute time around the onset of GER was significantly higher than the one detected in the GER-free period (p=0.03). Furthermore, the frequency of apnea in the 30 seconds after GER (GER-triggered apneas) was greater than that detected in the 30 seconds before (p=0.01). A great inter-individual variability was documented in the proportion of GERtriggered apneas. A strong correlation between total number of apneas and the difference between apneas detected 30 seconds after and before GER was found (p=0.034). Conclusions: Our data show that a variable rate of apneas can be triggered by GER in very preterm infant. Further studies are needed to recognise clinical features which identify those patients who are more susceptible to GER-triggered apneas.

Validazione e applicazioni cliniche della metodica NIRA (Near Infrared Reflectance Analysis) per la valutazione del contenuto nutrizionale del latte materno in terapia intensiva neonatale

Phase 1: To validate Near-Infrared Reflectance Analysis (NIRA) as a fast, reliable and suitable method for routine evaluation of human milk’s nitrogen and fat content. Phase 2: To determine whether fat content, protein content and osmolality of HM before and after fortification may affect gastroesophageal reflux (GER) in symptomatic preterm infants. Patients and Methods: Phase 1: 124 samples of expressed human milk (55 from preterm mothers and 69 from term mothers) were used to validate NIRA against traditional methods (Gerber method for fat and Kjeldhal method for nitrogen). Phase 2: GER was evaluated in 17 symptomatic preterm newborns fed naïve and fortified HM by combined pH/intraluminal-impedance monitoring (pH-MII). HM fat and protein content was analysed by a Near-Infrared-Reflectance-Analysis (NIRA). HM osmolality was tested before and after fortification. GER indexes measured before and after fortification were compared, and were also related with HM fat and protein content and osmolality before and after fortification. Results: Phase 1: · A strong agreement was found between traditional methods’ and NIRA’s results (expressed as g/100 g of milk), both for fat and nitrogen content in term (mean fat content: NIRA=2.76; Gerber=2.76; mean nitrogen content: NIRA=1.88; Kjeldhal =1.92) and preterm (mean fat content: NIRA=3.56; Kjeldhal=3.52; mean nitrogen content: NIRA=1.91; Kjeldhal =1.89) mother’s milk. · Nitrogen content of the milk samples, measured by NIRA, ranged from 1.18 to 2.71 g/100 g of milk in preterm milk and from 1.48 to 2.47 in term milk; fat content ranged from 1.27 to 6.23 g/100 g of milk in preterm milk and from 1.01 to 6.01 g/100 g of milk in term milk. Phase 2: · An inverse correlation was found between naïve HM protein content and acid reflux index (RIpH: p=0.041, rho=-0.501). · After fortification, osmolality often exceeded the values recommended for infant feeds; furthermore, a statistically significant (p<.05) increase in non acid reflux indexes was observed. Conclusions: NIRA can be used as a fast, reliable and suitable tool for routine monitoring of macronutrient content of human milk. Protein content of naïve HM may influence acid GER in preterm infants. A standard fortification of HM may worsen non acid GER indexes and, due to the extreme variability in HM composition, may overcome both recommended protein intake and HM osmolality. Thus, an individualized fortification, based on the analysis of the composition of naïve HM, could optimize both nutrient intake and feeding tolerance.