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BACKGROUND: Empiric administration of ampicillin and gentamicin is recommended for newborns at risk of early-onset sepsis (EOS). There are limited data on antimicrobial susceptibility of all EOS pathogens. METHODS: Retrospective review of antimicrobial susceptibility data from a prospective EOS surveillance study of infants born ≥22 weeks’ gestation and cared for in Neonatal Research Network centers 4/2015–3/2017. Non-susceptible was defined as intermediate or resistant on final result. RESULTS: We identified 239 pathogens (235 bacteria, 4 fungi) in 235 EOS cases among 217,480 live-born infants. Antimicrobial susceptibility data were available for 189/239 (79.1%) isolates. Among 81 gram-positive isolates with ampicillin and/or gentamicin susceptibility data, all were susceptible in vitro to either ampicillin or gentamicin. Among gram-negative isolates with ampicillin and/or gentamicin susceptibility data, 72/94 (76.6%) isolates were non-susceptible to ampicillin, 8/94 (8.5%) were non-susceptible to gentamicin, and 7/96 (7.3%) isolates were non-susceptible to both. Five percent or less of tested gram-negative isolates were non-susceptible to each of 3(rd) or 4(th) generation cephalosporins, piperacillin-tazobactam and carbapenems. Overall, we estimated that 8% of EOS cases were caused by isolates non-susceptible to both ampicillin and gentamicin; these were most likely to occur among preterm, very-low birth weight infants. CONCLUSIONS: The vast majority of contemporary EOS pathogens are susceptible to the combination of ampicillin and gentamicin. Clinicians may consider the addition of broader-spectrum therapy among newborns at highest risk of EOS, but we caution that neither the substitution nor the addition of one single antimicrobial agent is likely to provide adequate empiric therapy in all cases.

ObjectiveDetermine risk of death or neurodevelopmental impairment (NDI) in infants with late-onset sepsis (LOS) versus late-onset, antibiotic-treated, blood culture-negative conditions (LOCNC).DesignRetrospective cohort study.Setting24 neonatal centres.PatientsInfants born 1/1/2006–31/12/2014, at 22–26 weeks gestation, with birth weight 401–1000 g and surviving >7 days were included. Infants with early-onset sepsis, necrotising enterocolitis, intestinal perforation or both LOS and LOCNC were excluded.ExposuresLOS and LOCNC were defined as antibiotic administration for ≥5 days with and without a positive blood/cerebrospinal fluid culture, respectively. Infants with these diagnoses were also compared with infants with neither condition.OutcomesDeath or NDI was assessed at 18–26 months corrected age follow-up. Modified Poisson regression models were used to estimate relative risks adjusting for covariates occurring ≤7 days of age.ResultsOf 7354 eligible infants, 3940 met inclusion criteria: 786 (20%) with LOS, 1601 (41%) with LOCNC and 1553 (39%) with neither. Infants with LOS had higher adjusted relative risk (95% CI) for death/NDI (1.14 (1.05 to 1.25)) and death before follow-up (1.71 (1.44 to 2.03)) than those with LOCNC. Among survivors, risk for NDI did not differ between the two groups (0.99 (0.86 to 1.13)) but was higher for LOCNC infants (1.17 (1.04 to 1.31)) compared with unaffected infants.ConclusionsInfants with LOS had higher risk of death, but not NDI, compared with infants with LOCNC. Surviving infants with LOCNC had higher risk of NDI compared with unaffected infants. Improving outcomes for infants with LOCNC requires study of the underlying conditions and the potential impact of antibiotic exposure.

Background: Aerobic exercise is proposed to attenuate cognitive decline in aging. We investigated the effect of different aerobic exercise interventions and cardiorespiratory fitness (CRF) upon cognition throughout a 5-year exercise intervention in older adults.Methods: 106 older adults (52 women, age 70-77 years) were randomized into high-intensity interval training (HIIT; ∼90% peak heart rate), moderate-intensity continuous training (MICT; ∼70% peak heart rate), or control for 5 years. The HIIT and MICT groups performed supervised training twice weekly, while the control group was asked to follow the national physical activity guidelines (30 min of physical activity/day). At baseline, 1-, 3-, and 5-year follow-up, participants partook in cognitive testing (spatial memory, verbal memory, pattern separation, processing speed, working memory, and planning ability), underwent clinical testing, and filled out health-related questionnaires. Linear mixed models were used to assess the effects of the exercise group and CRF (measured as peak and max oxygen uptake) on each cognitive test. The effects of changes in CRF on changes in each cognitive test score throughout the intervention were also assessed. The associations between baseline CRF and cognitive abilities at the follow-ups were investigated using linear regressions.Results: There was no group-by-time interaction on the cognitive measures, and neither HIIT nor MICT participation was associated with better cognitive performance than control at any time point during the 5-year intervention. All groups increased their CRF similarly during the 1st year and subsequently declined back to baseline levels after 5 years. A higher CRF was associated with higher processing speed throughout the intervention while increasing CRF during the intervention was associated with better working memory and worse pattern separation. Higher CRF at baseline predicted consistently better processing speed and verbal memory performance.Conclusion: In this first 5-year randomized controlled trial investigating the effects of HIIT, MICT, and physical activity according to national guidelines on cognition, we observed no effect of exercise intervention group on cognition when compared to following the national physical activity guidelines. Still, the results showed that higher CRF and increasing CRF benefited multiple, but not all, cognitive abilities in older adults.Clinical Trial Registration:www.ClinicalTrials.gov, identifier [NCT01666340].

Author(s): Greenberg, Rachel G; Chowdhury, Dhuly; Hansen, Nellie I; Smith, P Brian; Stoll, Barbara J; Sanchez, Pablo J; Das, Abhik; Puopolo, Karen M; Mukhopadhyay, Sagori; Higgins, Rosemary D; Cotten, C Michael; Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network | Abstract: BackgroundProlonged early antibiotics in extremely premature infants may have negative effects. We aimed to assess prevalence and outcomes of provision of prolonged early antibiotics to extremely premature infants in the absence of culture-confirmed infection or NEC.MethodsCohort study of infants from 13 centers born without a major birth defect from 2008-2014 who were 401-1000 grams birth weight, 22-28 weeks gestation, and survived ≥5 days without culture-confirmed infection, NEC, or spontaneous intestinal perforation. We determined the proportion of infants who received prolonged early antibiotics, defined as ≥5 days of antibiotic therapy started at ≤72 h of age, by center and over time. Associations between prolonged early antibiotics and adverse outcomes were assessed using multivariable logistic regression.ResultsA total of 5730 infants were included. The proportion of infants receiving prolonged early antibiotics varied from 30-69% among centers and declined from 49% in 2008 to 35% in 2014. Prolonged early antibiotics was not significantly associated with death (adjusted odds ratio 1.17 [95% CI: 0.99-1.40], p = 0.07) and was not associated with NEC.ConclusionsThe proportion of extremely premature infants receiving prolonged early antibiotics decreased, but significant center variation persists. Prolonged early antibiotics were not significantly associated with increased odds of death or NEC.

Objective To assess the burden of invasive infection following surgery (surgery-associated infections [SAI]) among infants born extremely premature. Study design This was an observational, prospective study of infants born at gestational age 22-28 weeks hospitalized for >3 days, between April 1, 2011, to March 31, 2015, in academic centers of the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. SAI was defined by culture-confirmed bacteremia, fungemia, or meningitis ≤14 days following a surgical procedure. Results Of 6573 infants, 1154 (18%) who underwent surgery were of lower gestational age (mean [SD]: 25.5 [1.6] vs 26.2 [1.6], P Conclusions Surgical procedures were associated with bacteremia, fungemia, or meningitis in 7% of infants. The epidemiology of invasive postoperative infections as described in this report may inform the selection of empiric antimicrobial therapy and postoperative preventive care.

Objective To examine the timing and microbiology of neonatal sepsis in a population-based surveillance in the Indian community setting. Study Design All live born infants in 223 villages of Odisha state were followed at home for 60 days. Suspect sepsis cases were referred to study hospitals for further evaluation including blood culture. Results Of 12,622 births, 842 were admitted with suspected sepsis of whom 95% were 4–60 days old. Culture confirmed incidence of sepsis was 6.7/1000 births with 51% Gram negatives (Klebsiella predominating) and 26% Gram positives (mostly Staphylococcus aureus). A very high level of resistance to penicillin and ampicillin, moderate resistance to cephalosporins, and extremely low resistance to Gentamicin and Amikacin was observed. Conclusion The bacterial burden of sepsis in the Indian community is not high. Judicious choice of empiric antibiotics, antibiotic stewardship, and alternate modalities should be considered for the management or prevention of neonatal sepsis in India.

Early symptoms of autism spectrum disorder (ASD) develop through the second year of life, making a stable ASD diagnosis possible around 24 months of age. However, in general, children with ASD are diagnosed later. In this study we explored the use of a short observation list to detect symptoms associated with ASD in children 12–24 months of age attending typical day-care centers. The results indicate that a short observation list used by day-care teachers does not reveal sufficient properties to be independently used in young children in day-care centers. Further studies should explore multiple and repeated measures for early detection of symptoms associated with ASD in typical day-care centers.

Objective To evaluate the hypothesis that early-onset sepsis increases risk of death or neurodevelopmental impairment (NDI) among preterm infants; and that among infants without early-onset sepsis, prolonged early antibiotics alters risk of death/NDI. Study design Retrospective cohort study of infants born at the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network centers (2006-2014) at 22-26 weeks of gestation and birth weight 401-1000 g. Early-onset sepsis defined as growth of a pathogen from blood or cerebrospinal fluid culture ≤72 hours after birth. Prolonged early antibiotics was defined as antibiotics initiated ≤72 hours and continued ≥5 days without culture-confirmed infection, necrotizing enterocolitis, or spontaneous perforation. Primary outcome was death before follow-up or NDI assessed at 18-26 months corrected age. Poisson regression was used to estimate adjusted relative risk (aRR) and CI for early-onset sepsis outcomes. A propensity score for receiving prolonged antibiotics was derived from early clinical factors and used to match infants (1:1) with and without prolonged antibiotic exposure. Log binomial models were used to estimate aRR for outcomes in matched infants. Results Among 6565 infants, those with early-onset sepsis had higher aRR (95% CI) for death/NDI compared with infants managed with prolonged antibiotics (1.18 [1.06-1.32]) and to infants without prolonged antibiotics (1.23 [1.10-1.37]). Propensity score matching was achieved for 4362 infants. No significant difference in death/NDI (1.04 [0.98-1.11]) was observed with or without prolonged antibiotics among the matched cohort. Conclusions Early-onset sepsis was associated with increased risk of death/NDI among extremely preterm infants. Among matched infants without culture-confirmed infection, prolonged early antibiotic administration was not associated with death/NDI.

To determine if preterm infants with surgical necrotizing enterocolitis (sNEC) or spontaneous intestinal perforation (SIP) with short bowel syndrome (SBS) have worse neurodevelopmental and growth outcomes than those with sNEC/SIP without SBS, and those with no necrotizing enterocolitis, SIP, or SBS.We undertook a retrospective analysis of prospectively collected data from infants born between 22 and 26 weeks of gestation in the National Institute of Child Health and Human Development Neonatal Research Network centers from January 1, 2008, to December 31, 2016. Survivors were assessed at 18-26 months corrected age by standardized neurologic examination and Bayley Scales of Infant and Toddler Development, Third Edition. The primary outcome was moderate-severe neurodevelopmental impairment. Growth was assessed using World Health Organization z-score standards. Adjusted relative risks were estimated using modified Poisson regression models.Mortality was 32%, 45%, and 21% in the 3 groups, respectively. Eighty-nine percent of survivors were seen at 18-26 months corrected age. Moderate-severe neurodevelopmental impairment was present in 77% of children with SBS compared with 62% with sNEC/SIP without SBS (adjusted relative risk, 1.22; 95% CI, 1.02-1.45; P = .03) and 44% with no necrotizing enterocolitis, SIP, or SBS (adjusted relative risk, 1.60; 95% CI, 1.37-1.88; P .001). Children with SBS had lowcognitive, language, and motor scores than children with sNEC/SIP without SBS. At follow-up, length and head circumference z-scores remained more than 1 SD below the mean for children with SBS.Preterm infants with sNEC/SIP and SBS had increased risk of adverse neurodevelopmental outcomes at 18-26 months corrected age and impaired growth compared with peers with sNEC/SIP without SBS or without any of these conditions.

Importance Early-onset sepsis (EOS) remains a potentially fatal newborn condition. Ongoing surveillance is critical to optimize prevention and treatment strategies. Objective To describe the current incidence, microbiology, morbidity, and mortality of EOS among a cohort of term and preterm infants. Design, setting, and participants This prospective surveillance study included a cohort of infants born at a gestational age (GA) of at least 22 weeks and birth weight of greater than 400 g from 18 centers of the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network from April 1, 2015, to March 31, 2017. Data were analyzed from June 14, 2019, to January 28, 2020. Main outcomes and measures Early-onset sepsis defined by isolation of pathogenic species from blood or cerebrospinal fluid culture within 72 hours of birth and antibiotic treatment for at least 5 days or until death. Results A total of 235 EOS cases (127 male [54.0%]) were identified among 217 480 newborns (1.08 [95% CI, 0.95-1.23] cases per 1000 live births). Incidence varied significantly by GA and was highest among infants with a GA of 22 to 28 weeks (18.47 [95% CI, 14.57-23.38] cases per 1000). No significant differences in EOS incidence were observed by sex, race, or ethnicity. The most frequent pathogens were Escherichia coli (86 [36.6%]) and group B streptococcus (GBS; 71 [30.2%]). E coli disease primarily occurred among preterm infants (68 of 131 [51.9%]); GBS disease primarily occurred among term infants (54 of 104 [51.9%]), with 24 of 45 GBS cases (53.3%) seen in infants born to mothers with negative GBS screening test results. Intrapartum antibiotics were administered to 162 mothers (68.9%; 110 of 131 [84.0%] preterm and 52 of 104 [50.0%] term), most commonly for suspected chorioamnionitis. Neonatal empirical antibiotic treatment most frequently included ampicillin and gentamicin. All GBS isolates were tested, but only 18 of 81 (22.2%) E coli isolates tested were susceptible to ampicillin; 6 of 77 E coli isolates (7.8%) were resistant to both ampicillin and gentamicin. Nearly all newborns with EOS (220 of 235 [93.6%]) displayed signs of illness within 72 hours of birth. Death occurred in 38 of 131 infected infants with GA of less than 37 weeks (29.0%); no term infants died. Compared with earlier surveillance (2006-2009), the rate of E coli infection increased among very low-birth-weight (401-1500 g) infants (8.68 [95% CI, 6.50-11.60] vs 5.07 [95% CI, 3.93-6.53] per 1000 live births; P = .008). Conclusions and relevance In this study, EOS incidence and associated mortality disproportionately occurred in preterm infants. Contemporary cases have demonstrated the limitations of current GBS prevention strategies. The increase in E coli infections among very low-birth-weight infants warrants continued study. Ampicillin and gentamicin remained effective antibiotics in most cases, but ongoing surveillance should monitor antibiotic susceptibilities of EOS pathogens.

Background Feeding practices over the first several years of a child’s life can critically influence development. The purpose of this study was to examine associations between feeding practices and growth and neurodevelopmental outcomes at 36 months of age among children from low- and low-middle-income countries (LMIC). Methods We conducted a secondary analysis using data collected from children in India, Pakistan, and Zambia who were enrolled in a randomized controlled trial of a home-based early development intervention program called Brain Research to Ameliorate Impaired Neurodevelopment Home-based Intervention Trial. Qualitative dietary data collected at 36 months was used to assess the modified Minimum Acceptable Diet (mMAD), a measure based on a core indicator developed by the World Health Organization to measure whether young children receive the minimum number of meals recommended and adequate diversity of major food groups in their diet. Regression models were used to assess cross-sectional associations between diet and growth indices, including Z-scores for height-for-age (HAZ), weight-for-age (WAZ), weight-for-height (WHZ), head circumference (HCZ), and Bayley Scales of Infant Development II mental and psychomotor developmental measures at 36 months of age. Results Of 371 children, 174 (47%) consumed the mMAD, with significantly higher mean adjusted WHZ than those who did not meet mMAD (0.20 vs − 0.08, p = 0.05). Egg consumption was found to be significantly associated with a decreased risk of wasting [adjusted RR (95% CI): 0.37 (0.15, 0.89), p = 0.03]. HCZ at 36 months did not differ significantly for children who did and did not receive the mMAD. Conclusion Meeting the mMAD was associated with better weight-for-height outcomes at 36 months in children in these three LMIC, highlighting the importance of adequate food quantity and quality. Trial registration NCT00639184 registered on March 20, 2008.

Nearly 60% of U.S. children live in counties with particulate matter less than or equal to 2.5 μm in aerodynamic diameter (PMTo evaluate the association between ambient PMUsing an observational case-crossover design, subjects (n = 146,397) were studied if they had an ALRI diagnosis and resided on Utah's Wasatch Front. PMApproximately 77% (n = 112,467) of subjects were 0-2 years of age. The odds of ALRI encounter for these young children increased within 1 week of elevated PMIn this large sample of urban/suburban patients, short-term exposure to elevated PM

BACKGROUND: Premature infants are at high risk of early-onset sepsis (EOS) relative to term infants, and most are administered empirical antibiotics after birth. We aimed to determine if factors evident at birth could be used to identify premature infants at lower risk of EOS. METHODS: Study infants were born at 22 to 28 weeks’ gestation in Neonatal Research Network centers from 2006 to 2014. EOS was defined by isolation of pathogenic species from blood or cerebrospinal fluid culture at ≤72 hours age. Infants were hypothesized as “low risk” for EOS when delivered via cesarean delivery, with membrane rupture at delivery, and absence of clinical chorioamnionitis. Frequency of prolonged antibiotics (≥5 days) was compared between low-risk infants and all others. Risks of mortality, EOS, and other morbidities were assessed by using regression models adjusted for center, race, antenatal steroid use, multiple birth, sex, gestation, and birth weight. RESULTS: Of 15 433 infants, 5759 (37%) met low-risk criteria. EOS incidence among infants surviving >12 hours was 29 out of 5640 (0.5%) in the low-risk group versus 209 out of 8422 (2.5%) in the comparison group (adjusted relative risk = 0.24 [95% confidence interval, 0.16–0.36]). Low-risk infants also had significantly lower combined risk of EOS or death ≤12 hours. Prolonged antibiotics were administered to 34% of low-risk infants versus 47% of comparison infants without EOS. CONCLUSIONS: Delivery characteristics of extremely preterm infants can be used to identify those with significantly lower incidence of EOS. Recognition of differential risk may help guide decisions to limit early antibiotic use among approximately one-third of these infants.

This study aims to investigate 1-year hand bone loss (HBL 1-year) in early rheumatoid arthritis (RA) patients treated with a methotrexate (MTX) and intra-articular triamcinolone treat-to-target strategy +/− adalimumab and to determine if HBL 6months is associated with radiographic progression after 2 years. In a clinical trial (OPERA) of 180 treatment-naive early RA patients, bone mineral density (BMD) was estimated from hand radiographs with digital X-ray radiogrammetry (DXR) at baseline, after 6 (n = 90) and 12 months (n = 70) of follow-up. Baseline and 2-year radiographs were scored according to the Sharp/van der Heijde method. Baseline characteristics and HBL 6months (0–6 months changes in DXR-BMD) were investigated as predictors of structural damage by univariate linear (∆ total Sharp/van der Heijde score (TSS) as dependent variable) and logistic (+/−radiographic progression (∆TSS >0) as dependent variable) regression analyses. Variables with p 1-year data, HBL 1-year was median (interquartile range (IQR)) −1.9 (−3.3; −0.26 mg/cm 2) in the MTX + placebo group and −1.8 (−3.6; 0.06) mg/cm 2 in the MTX + adalimumab group, p = 0.98, Wilcoxon signed-rank. Increased HBL (compared to general population reference values) was found in 26/37 and 23/33 patients in the MTX + placebo and MTX + adalimumab groups, chi-squared = 0.99. In 90 patients with HBL 6months data and 2-year radiographic data, HBL 6months was independently associated with ∆TSS after 2 years (β = −0.086 (95% confidence interval = −0.15; −0.025) TSS unit/mg/cm 2 increase, p = 0.006) but not with presence of radiographic progression (∆TSS >0) (OR 0.96 (0.92–1.0), p = 0.10). In early RA patients treated with a methotrexate-based treat-to-target strategy, the majority of patients had increased HBL 1-year, irrespective of adalimumab; HBL 6months was independently associated with ∆TSS after 2 years.

Background Worldwide, stillbirth is one of the leading causes of death. Altered fetal growth and placental abnormalities are the strongest and most prevalent known risk factors for stillbirth. The aim of this study was to identify patterns of association between placental abnormalities, fetal growth, and stillbirth. Methods and findings Population-based case-control study of all stillbirths and a representative sample of live births in 59 hospitals in 5 geographic areas in the U.S. Fetal growth abnormalities were categorized as small (90th percentile) for gestational age at death (stillbirth) or delivery (live birth) using a published algorithm. Placental examination by perinatal pathologists was performed using a standardized protocol. Data were weighted to account for the sampling design. Among 319 singleton stillbirths and 1119 singleton live births at ≥24 weeks at death or delivery respectively, 25 placental findings were investigated. Fifteen findings were significantly associated with stillbirth. Ten of the 15 were also associated with fetal growth abnormalities (single umbilical artery; velamentous insertion; terminal villous immaturity; retroplacental hematoma; parenchymal infarction; intraparenchymal thrombus; avascular villi; placental edema; placental weight; ratio birth weight/placental weight) while 5 of the 15 associated with stillbirth were not associated with fetal growth abnormalities (acute chorioamnionitis of placental membranes; acute chorioamionitis of chorionic plate; chorionic plate vascular degenerative changes; perivillous, intervillous fibrin, fibrinoid deposition; fetal vascular thrombi in the chorionic plate). Five patterns were observed: placental findings associated with (1) stillbirth but not fetal growth abnormalities; (2) fetal growth abnormalities in stillbirths only; (3) fetal growth abnormalities in live births only; (4) fetal growth abnormalities in stillbirths and live births in a similar manner; (5) a different pattern of fetal growth abnormalities in stillbirths and live births. Conclusions The patterns of association between placental abnormalities, fetal growth, and stillbirth provide insights into the mechanism of impaired placental function and stillbirth. They also suggest implications for clinical care, especially for placental findings amenable to prenatal diagnosis using ultrasound that may be associated with term stillbirths.

Aims To examine the association between diabetes duration and hypoglycaemia symptom profiles and the presence of impaired awareness of hypoglycaemia. Methods A cross-sectional study was performed, using validated methods for recording hypoglycaemia symptoms and assessing hypoglycaemia awareness. The associations between symptom intensity, hypoglycaemia awareness and diabetes duration were examined, and the prevalence of impaired awareness was ascertained for Type 1 diabetes of differing durations. Results Questionnaires were mailed to 636 adults with Type 1 diabetes, of whom 445 (70%) returned them. A total of 440 completed questionnaires were suitable for analysis. Longer diabetes duration was associated with lower intensity of autonomic symptoms (P for trend

OBJECTIVE: Little is known about how very low birth weight (VLBW) affects survival and morbidities among infants with trisomy 13 (T13) or trisomy 18 (T18). We examined the care plans for VLBW infants with T13 or T18 and compared their risks of mortality and neonatal morbidities with VLBW infants with trisomy 21 and VLBW infants without birth defects. METHODS: Infants with birth weight 401 to 1500 g born or cared for at a participating center of the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network during the period 1994–2009 were studied. Poisson regression models were used to examine risk of death and neonatal morbidities among infants with T13 or T18. RESULTS: Of 52 262 VLBW infants, 38 (0.07%) had T13 and 128 (0.24%) had T18. Intensity of care in the delivery room varied depending on whether the trisomy was diagnosed before or after birth. The plan for subsequent care for the majority of the infants was to withdraw care or to provide comfort care. Eleven percent of infants with T13 and 9% of infants with T18 survived to hospital discharge. Survivors with T13 or T18 had significantly increased risk of patent ductus arteriosus and respiratory distress syndrome compared with infants without birth defects. No infant with T13 or T18 developed necrotizing enterocolitis. CONCLUSIONS: In this cohort of liveborn VLBW infants with T13 or T18, the timing of trisomy diagnosis affected the plan for care, survival was poor, and death usually occurred early.

Importance Birth weight (BW) is an important predictor of mortality and morbidity. At extremely early gestational ages (GAs), BW may influence decisions regarding initiation of resuscitation. Objective To characterize outcomes of liveborn infants with a BW less than 400 g. Design, Setting, and Participants This retrospective multicenter cohort study analyzed extremely preterm infants born between January 2008 and December 2016 within the National Institute of Child Health and Human Development Neonatal Research Network. Infants with a BW less than 400 g and a GA of 22 to 26 weeks were included. Active treatment was defined as the provision of any potentially lifesaving intervention after birth. Survival was analyzed for the entire cohort; neurodevelopmental impairment (NDI) was examined for those born between January 2008 and December 2015 (birth years with outcomes available for analysis). Neurodevelopmental impairment at 18 to 26 months’ corrected age (CA) was defined as a Bayley Scales of Infant and Toddler Development, Third Edition, cognitive composite score less than 85, a motor composite score less than 85, moderate or severe cerebral palsy, gross motor function classification system score of 2 or greater, bilateral blindness, and/or hearing impairment. Data were analyzed from September 2017 to October 2018. Exposures Birth weight less than 400 g. Main Outcomes and Measures The primary outcome was survival to discharge among infants who received active treatment. Analysis of follow-up data was limited to infants born from 2008 to 2015 to ensure children had reached assessment age. Within this cohort, neurodevelopmental outcomes were assessed for infants who survived to 18 to 26 months’ CA and returned for a comprehensive visit. Results Of the 205 included infants, 121 (59.0%) were female, 133 (64.9%) were singletons, and 178 (86.8%) were small for gestational age. Almost half (101 of 205 [49.3%]) received active treatment at birth. A total of 26 of 205 infants (12.7%; 95% CI, 8.5-18.9) overall survived to discharge, and 26 of 101 actively treated infants (25.7%; 95% CI, 17.6-35.4) survived to discharge. Within the subset of infants with a BW less than 400 g and a GA of 22 to 23 weeks, 6 of 36 actively treated infants (17%; 95% CI, 6-33) survived to discharge. Among infants born between 2008 and 2015, 23 of 90 actively treated infants (26%; 95% CI, 17-36) survived to discharge. Two infants died after discharge, and 2 were lost to follow-up. Thus, 19 of 90 actively treated infants (21%; 95% CI, 13-31) were evaluated at 18 to 26 months’ CA. Moderate or severe NDI occurred in 14 of 19 infants (74%). Conclusions and Relevance Infants born with a BW less than 400 g are at high risk of mortality and significant morbidity. Although 21% of infants survived to 18 to 26 months’ CA with active treatment, NDI was common among survivors.

OBJECTIVE:Our aim was to examine the impact of a single enteral dose of vitamin E on serum tocopherol levels. The study was undertaken to see whether a single dose of vitamin E soon after birth can rapidly increase the low α-tocopherol levels seen in very preterm infants. If so, this intervention could be tested as a means of reducing the risk of intracranial hemorrhage.METHODS:Ninety-three infants RESULTS:Eighty-eight infants received the study drug and were included in the analyses. The α-tocopherol levels were similar between the groups at baseline but higher in the vitamin E group at 24 hours (median 0.63 mg/dL vs 0.42 mg/dL, P = .003) and 7 days (2.21 mg/dL vs 1.86 mg/dL, P = .04). There were no differences between groups in γ-tocopherol levels. At 24 hours, 30% of vitamin E infants and 62% of placebo infants had α-tocopherol levels CONCLUSIONS:A 50-IU/kg dose of vitamin E raised serum α-tocopherol levels, but to consistently achieve α-tocopherol levels >0.5 mg/dL, a higher dose or several doses of vitamin E may be needed.

Investigation of the factors leading to stillbirth, defined as fetal death ≥ 20 weeks of gestation, should employ the best possible assessment of gestational age (GA) at the time of fetal death. Precise estimation of GA at fetal death requires accuracy of two key pieces of information: the timing of fetal death and the estimated due date (EDD). Unfortunately, precise data are often lacking, particularly regarding timing of fetal death. Some investigators have equated timing of fetal death with the time of delivery1 or have estimated timing of death from pathologic findings in the fetus or placenta2–4. Because there may be a prolonged period between fetal death and delivery, the estimated GA at time of fetal death may be overestimated, particularly when the date of delivery is used as the basis to determine the date of death. The accuracy of vital statistics data and clinicopathologic correlations are impacted when gestational age information is unreliable5,6. We describe a set of rules (the “algorithm”) developed by the Stillbirth Collaborative Research Network (SCRN) to estimate gestational age at fetal death in cases of singleton stillbirth, incorporating clinical and pathologic data. We report the results obtained by applying the algorithm and evaluate the performance of a key component using a well-dated subset of cases in which both estimated due date and timing of death were known with precision.

BACKGROUND: Possible severe bacterial infections (pSBI) continue to be a leading cause of global neonatal mortality annually. With the recent publications of simplified antibiotic regimens for treatment of pSBI where referral is not possible, it is important to know how and where to target these regimens, but data on the incidence and outcomes of pSBI are limited. METHODS: We used data prospectively collected at 7 rural community-based sites in 6 low and middle income countries participating in the NICHD Global Network's Maternal and Newborn Health Registry, between January 1, 2010 and December 31, 2013. Participants included pregnant women and their live born neonates followed for 6 weeks after delivery and assessed for maternal and infant outcomes. RESULTS: In a cohort of 248,539 infants born alive between 2010 and 2013, 32,088 (13 %) neonates met symptomatic criteria for pSBI. The incidence of pSBI during the first 6 weeks of life varied 10 fold from 3 % (Zambia) to 36 % (Pakistan), and overall case fatality rates varied 8 fold from 5 % (Kenya) to 42 % (Zambia). Significant variations in incidence of pSBI during the study period, with proportions decreasing in 3 sites (Argentina, Kenya and Nagpur, India), remaining stable in 3 sites (Zambia, Guatemala, Belgaum, India) and increasing in 1 site (Pakistan), cannot be explained solely by changing rates of facility deliveries. Case fatality rates did not vary over time. CONCLUSIONS: In a prospective population based registry with trained data collectors, there were wide variations in the incidence and case fatality of pSBI in rural communities and in trends over time. Regardless of these variations, the burden of pSBI is still high and strategies to implement timely diagnosis and treatment are still urgently needed to reduce neonatal mortality. Fil: Hibberd, Patricia L.. Massachusetts General Hospital for Children; Estados Unidos Fil: Hansen, Nellie I.. Research Triangle Park. RTI International; Estados Unidos Fil: Wang, Marie E.. Massachusetts General Hospital for Children; Estados Unidos Fil: Goudar, Shivaprasad S.. Jawaharlal Nehru Medical College; India Fil: Pasha, Omrana. Aga Khan University; Pakistán Fil: Esamai, Fabian. Moi University; Kenia Fil: Chomba, Elwyn. University of Zambia; Zambia Fil: Garces, Ana. Instituto de Nutrición de Centro América y Panamá; Guatemala Fil: Althabe, Fernando. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Instituto de Efectividad Clínica y Sanitaria; Argentina Fil: Derman, Richard J.. Christiana Health Care; Estados Unidos Fil: Goldenberg, Robert L.. Columbia University; Estados Unidos Fil: Liechty, Edward A.. Indiana University; Estados Unidos Fil: Carlo, Waldemar A.. University of Alabama at Birmingahm; Estados Unidos Fil: Hambidge, K. Michael. University of Colorado. Health Sciences Center; Argentina Fil: Krebs, Nancy F.. University of Colorado. Health Sciences Center; Argentina Fil: Buekens, Pierre. University of Tulane; Estados Unidos Fil: McClure, Elizabeth M.. Research Triangle Park. RTI International; Estados Unidos Fil: Koso Thomas, Marion. Eunice Kennedy Shriver National Institute of Child Health and Human Development; Estados Unidos Fil: Patel, Archana B.. Lata Medical Research Foundation; India

BACKGROUND AND OBJECTIVE: Little is known about in-hospital morbidities and neurodevelopmental outcomes among extremely preterm infants born to women with insulin-dependent diabetes mellitus (IDDM). We examined risks of mortality, in-hospital morbidities, and neurodevelopmental outcomes at 18 to 22 months’ corrected age between extremely preterm infants of women with insulin use before pregnancy (IBP), with insulin use started during pregnancy (IDP), and without IDDM. METHODS: Infants 22 to 28 weeks’ gestation born or cared for at a Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network center (2006–2011) were studied. Regression models compared the association between maternal IDDM and timing of insulin use and the outcomes of the 3 groups. RESULTS: Of 10 781 infants, 536 (5%) were born to women with IDDM; 58% had IBP, and 36% had IDP. Infants of mothers with IBP had higher risks of necrotizing enterocolitis (adjusted relative risk [RR] = 1.55 [95% confidence interval (CI) 1.17–2.05]) and late-onset sepsis (adjusted RR = 1.26 [95% CI 1.07–1.48]) than infants of mothers without IDDM. There was some indication of higher in-hospital mortality risk among infants of mothers with IBP compared with those with IDP (adjusted RR = 1.33 [95% CI 1.00–1.79]). Among survivors evaluated at 18 to 22 months’ corrected age, average head circumference z score was lower for infants of mothers with IBP compared with those without IDDM, but there were no differences in risk of neurodevelopmental impairment. CONCLUSIONS: In this cohort of extremely preterm infants, infants of mothers with IBP had higher risks of necrotizing enterocolitis, sepsis, and small head circumference.

BACKGROUND: Current guidelines for prevention of neonatal group B streptococcal disease recommend diagnostic evaluations and empirical antibiotic therapy for well-appearing, chorioamnionitis-exposed newborns. Some clinicians question these recommendations, citing the decline in early-onset group B streptococcal disease rates since widespread intrapartum antibiotic prophylaxis implementation and potential antibiotic risks. We aimed to determine whether chorioamnionitis-exposed newborns with culture-confirmed, early-onset infections can be asymptomatic at birth. METHODS: Multicenter, prospective surveillance for early-onset neonatal infections was conducted during 2006–2009. Early-onset infection was defined as isolation of a pathogen from blood or cerebrospinal fluid collected ≤72 hours after birth. Maternal chorioamnionitis was defined by clinical diagnosis in the medical record or by histologic diagnosis by placental pathology. Hospital records of newborns with early-onset infections born to mothers with chorioamnionitis were reviewed retrospectively to determine symptom onset. RESULTS: Early-onset infections were diagnosed in 389 of 396 586 live births, including 232 (60%) chorioamnionitis-exposed newborns. Records for 229 were reviewed; 29 (13%) had no documented symptoms within 6 hours of birth, including 21 (9%) who remained asymptomatic at 72 hours. Intrapartum antibiotic prophylaxis exposure did not differ significantly between asymptomatic and symptomatic infants (76% vs 69%; P = .52). Assuming complete guideline implementation, we estimated that 60 to 1400 newborns would receive diagnostic evaluations and antibiotics for each infected asymptomatic newborn, depending on chorioamnionitis prevalence. CONCLUSIONS: Some infants born to mothers with chorioamnionitis may have no signs of sepsis at birth despite having culture-confirmed infections. Implementation of current clinical guidelines may result in early diagnosis, but large numbers of uninfected asymptomatic infants would be treated.

BACKGROUND: Data are limited on the impact of methicillin-resistant Staphylococcus aureus (MRSA) on morbidity and mortality among very low birth weight (VLBW) infants with S aureus (SA) bacteremia and/or meningitis (B/M). METHODS: Neonatal data for VLBW infants (birth weight 401–1500 g) born January 1, 2006, to December 31, 2008, who received care at centers of the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network were collected prospectively. Early-onset (≤72 hours after birth) and late-onset (>72 hours) infections were defined by blood or cerebrospinal fluid cultures and antibiotic treatment of ≥5 days (or death 3 days, 316 (3.7%) had SA B/M. Eighty-eight had MRSA (1% of all infants, 28% of infants with SA); 228 had MSSA (2.7% of all infants, 72% of infants with SA). No infant had both MRSA and MSSA B/M. Ninety-nine percent of MRSA infections were late-onset. The percent of infants with MRSA varied by center ( P < .001) with 9 of 20 centers reporting no cases. Need for mechanical ventilation, diagnosis of respiratory distress syndrome, necrotizing enterocolitis, and other morbidities did not differ between infants with MRSA and MSSA. Mortality was high with both MRSA (23 of 88, 26%) and MSSA (55 of 228, 24%). CONCLUSIONS: Few VLBW infants had SA B/M. The 1% with MRSA had morbidity and mortality rates similar to infants with MSSA. Practices should provide equal focus on prevention and management of both MRSA and MSSA infections among VLBW infants. * Abbreviations: B/M — : bacteremia and/or meningitis BPD — : bronchopulmonary dysplasia BW — : birth weight CI — : confidence interval CSF — : cerebrospinal fluid GA — : gestational age IVH — : intraventricular hemorrhage MRSA — : methicillin-resistant Staphylococcus aureus MSSA — : methicillin-susceptible Staphylococcus aureus NEC — : necrotizing enterocolitis NICHD — : Eunice Kennedy Shriver National Institute of Child Health and Human Development NRN — : Neonatal Research Network PMA — : postmenstrual age PVL — : periventricular leukomalacia RDS — : respiratory distress syndrome ROP — : retinopathy of prematurity RR — : relative risk SA — : Staphylococcus aureus SGA — : small for gestational age VLBW — : very low birth weight

BACKGROUND: Guidelines for prevention of group B streptococcal (GBS) infection have successfully reduced early onset (EO) GBS disease. Study results suggest that Escherichia coli is an important EO pathogen. OBJECTIVE: To determine EO infection rates, pathogens, morbidity, and mortality in a national network of neonatal centers. METHODS: Infants with EO infection were identified by prospective surveillance at Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Network centers. Infection was defined by positive culture results for blood and cerebrospinal fluid obtained from infants aged ≤72 hours plus treatment with antibiotic therapy for ≥5 days. Mother and infant characteristics, treatments, and outcomes were studied. Numbers of cases and total live births (LBs) were used to calculate incidence. RESULTS: Among 396 586 LBs (2006–2009), 389 infants developed EO infection (0.98 cases per 1000 LBs). Infection rates increased with decreasing birth weight. GBS (43%, 0.41 per 1000 LBs) and E coli (29%, 0.28 per 1000 LBs) were most frequently isolated. Most infants with GBS were term (73%); 81% with E coli were preterm. Mothers of 67% of infected term and 58% of infected preterm infants were screened for GBS, and results were positive for 25% of those mothers. Only 76% of mothers with GBS colonization received intrapartum chemoprophylaxis. Although 77% of infected infants required intensive care, 20% of term infants were treated in the normal newborn nursery. Sixteen percent of infected infants died, most commonly with E coli infection (33%). CONCLUSION: In the era of intrapartum chemoprophylaxis to reduce GBS, rates of EO infection have declined but reflect a continued burden of disease. GBS remains the most frequent pathogen in term infants, and E coli the most significant pathogen in preterm infants. Missed opportunities for GBS prevention continue. Prevention of E coli sepsis, especially among preterm infants, remains a challenge.

Cytokines mediate the host immune response to infectious micro-organisms. The objective of this study was to determine whether immune regulatory interleukins (IL-4, IL-5, IL-6, and IL-10) and inflammatory cytokines (Interferon-γ [INF-γ], tumor necrosis factor-β [TNF-β], IL-2, and IL-17) are associated with an increased risk of developing blood stream bacterial/fungal infection (BSI) in extremely low birth weight (ELBW) infants. ELBW infants from 17 NICHD Neonatal Research Network centers without early onset sepsis were studied. Cytokines were measured from blood on days 1, 3, 7, 14, and 21 after birth. 996 ELBW infants contributed a minimum of 4080 unique measurements for each cytokine during the five sampling periods. Infants with BSI had lower levels of the inflammatory cytokines IL-17 (p=0.01), and higher levels of the regulatory cytokines, IL-6 (p=0.01) and IL-10 (p0.001). Higher levels of regulatory cytokines relative to pro-inflammatory cytokines were associated with increased risk of BSI even after adjusting for confounding variables. In ELBW infants, the ratio of immune regulatory cytokines to inflammatory cytokines was associated with development of BSI. Altered maturation of regulatory and inflammatory cytokines may increase the risk of serious infection in this population.

Aim: To evaluate the efficacy of various echocardiographic markers in predicting a patent ductus arteriosus (PDA) in need of treatment. Methods: Forty-five preterm infants with a mean (SD) gestational age of 27.7 (1.9) weeks underwent echocardiography at a postnatal age of 24 +/- 6 and 72 +/- 6 h. Four echocardiographic markers were studied: ductus diameter, ductal flow Doppler curves, the left atrial to aortic root (LA/Ao) ratio and Doppler pixels representing ductal shunting. Results: Twenty-eight infants had a PDA with a detectable left-to-right shunt. Of these, 12 (43%) were treated for a shunt through the PDA. Ductal diameter was the most accurate echocardiographic marker when it came to predicting a significant shunt, with a sensitivity of 89%, a specificity of 70%, a positive likelihood ratio of 2.97 and a negative likelihood ratio of 0.16 at the age of 72 h. The efficacy of the method at 72 h of age was 84%. The corresponding efficacy of the pulsatile Doppler curve was 72%, percentage of green colour pixels 63% and the LA/Ao ratio 53%. Conclusion: Ductus diameter appears to be the most important variable in determining the need for therapeutic intervention for PDA in preterm infants. (Less)

Decreases in perinatal and infant mortality1 reflect the success of sustaining the lives of infants born increasingly more preterm. However, the increased survival of infants with extremely low birthweight (ELBW; 401–1000g) may be associated with more functional disabilities.2–4 Overt neurodevelopmental impairments have been identified in up to 50% of surviving ELBW infants,2,5 and subtle deficits have been noted even more frequently.6–8 ELBW infants need ongoing developmental assessment well past infancy to identify disabilities, yet formalized testing is both time-consuming and costly, and, therefore, is often available only to the smallest or sickest newborn infants. ELBW survivors with a disability may receive major health interventions to improve their quality of life and facilitate caregiving. Many of these interventions are resource-intensive and expensive, and are performed only when the child meets certain predefined criteria, criteria which may be less relevant to the child or the caregiver. It is, therefore, necessary to measure such interventions and outcomes from the family’s perspective to assess their effectiveness. In this regard, a functional status measure would be useful both as a screening tool and as a measure of intervention outcome. Many health-related quality-of-life questionnaires have been used in adults. However, as Hack9 points out, adaptation of quality-of-life instruments for children is hampered by the necessary requirement of adding a proxy respondent. Despite this concern, several investigators have used quality-of-life measures to assess outcomes of even those born extremely preterm.10–12 Recognizing the difficulties associated with follow-up of infants born at ELBW, participants at a workshop sponsored by the National Institute of Child Health and Human Development (NICHD) developed consensus statements addressing criteria for follow-up and appropriate assessment methods and ages for evaluation. The consensus authors concluded that alternative, less costly methods and approaches should be developed to supplement current standardized testing.13 Specifically needed were assessments that are easy to administer, that provide useful information to developmental specialists, parents, and teachers, and that can be incorporated into the routine of both healthcare and educational professionals. Using the criteria from that workshop, the investigators of the NICHD Neonatal Research Network (NRN) evaluated available pediatric screening measures and chose to assess ELBW infants with the revised version of the Functional Status questionnaire (FS-II) developed by Stein and Jessop.14 The FS-II, designed for children with chronic diseases, assesses parents’ perceptions of their child in four domains: physical, psychological, cognitive, and social functioning. It can be administered by a trained layperson in less than 30 minutes, and has been used with a young sample. All of these attributes are appropriate for screening ELBW infants to assess the need for a more formal evaluation or early intervention. However, the FS-II had not been validated in a population of ELBW infants. The analyses by Stein and Jessop used data from 732 children aged 2 weeks to 16 years who were either chronically ill or well. Principal-component analysis determined the factor structure associated with the questionnaire items for four age groups (

OBJECTIVES. Our objectives were to identify factors associated with the duration of the first antibiotic course initiated in the first 3 postnatal days and to assess associations between the duration of the initial antibiotic course and subsequent necrotizing enterocolitis or death in extremely low birth weight infants with sterile initial postnatal culture results. METHODS. We conducted a retrospective cohort analysis of extremely low birth weight infants admitted to tertiary centers in 1998–2001. We defined initial empirical antibiotic treatment duration as continuous days of antibiotic therapy started in the first 3 postnatal days with sterile culture results. We used descriptive statistics to characterize center practice, bivariate analyses to identify factors associated with prolonged empirical antibiotic therapy (≥5 days), and multivariate analyses to evaluate associations between therapy duration, prolonged empirical therapy, and subsequent necrotizing enterocolitis or death. RESULTS. Of 5693 extremely low birth weight infants admitted to 19 centers, 4039 (71%) survived >5 days, received initial empirical antibiotic treatment, and had sterile initial culture results through the first 3 postnatal days. The median therapy duration was 5 days (range: 1–36 days); 2147 infants (53%) received prolonged empirical therapy (center range: 27%–85%). Infants who received prolonged therapy were less mature, had lower Apgar scores, and were more likely to be black. In multivariate analyses adjusted for these factors and center, prolonged therapy was associated with increased odds of necrotizing enterocolitis or death and of death. Each empirical treatment day was associated with increased odds of death, necrotizing enterocolitis, and the composite measure of necrotizing enterocolitis or death. CONCLUSION. Prolonged initial empirical antibiotic therapy may be associated with increased risk of necrotizing enterocolitis or death and should be used with caution.

SHORT BOWEL SYNDROME (SBS) is a devastating clinical problem that affects an estimated 20 000 Americans (children and adults). Although not consistently fatal, complications that are associated with this disorder include dehydration, malnutrition, sepsis, poor growth, and impaired neurodevelopment.1-5 SBS is defined as insufficient bowel length to digest and absorb adequately nutrients that are needed to promote appropriate growth of the infant. SBS is often the result of massive small intestinal resection in infants as a result of necrotizing enterocolitis (NEC).6,7 Overall, the number of children with this disorder seems to be increasing, likely as a result of reductions in neonatal mortality in both term and preterm neonates, putting more infants at risk for developing diseases that predispose to SBS.8,9 The related health care costs that result from treating patients with SBS and its complications are very high. The quality-of-life burden on these children and their families is also very high.1,3 The most common cause of SBS in infants is NEC.10 The incidence of NEC in extremely low birth weight (ELBW) infants is ~10%, and the associated mortality is 30%.11,12 Infants who have NEC and are surgically treated have hospital lengths of stay that exceed those of gestational age (GA)-matched infants by 60 days. On the basis of this length of stay in 1 US hospital, the estimated hospital charges for infants with NEC exceeded those of matched control subjects by more than $186 000, and the yearly additional charges related to NEC were $6.5 million.13 Multiple factors have been identified as predictors of morbidity and mortality in patients with SBS14-16; however, SBS continues to constitute a major clinical challenge for neonatologists, gastroenterologists, and nutritionists, who often collectively treat these patients. It is associated with high morbidity and mortality because of chronic malabsorption that results from reduced bowel absorptive surface area and diminished mucosal function, including gut barrier dysfunction, frequent infections, and complications that are associated with specialized parenteral and enteral feeding.2,17 In children, SBS may lead to poor growth, nutritional deficiencies, delayed neurodevelopment, and ultimately death.18-20 Data illustrating the effect of SBS on subsequent growth and neurologic development in preterm infants are sparse.20-22 We determined the incidence of surgical SBS and examined morbidity, mortality, and growth outcomes of children with and without surgical SBS in a large cohort of very low birth weight (VLBW) infants who were born between 2002 and 2005.

Probiotic, prebiotic, and synbiotic (a combination of pro- and prebiotic) supplements increasingly are being used to prevent and treat a variety of health conditions. Although colonization is considered a key element in the success of such treatments, few clinical studies have addressed colonizing ability. Studies are even more limited in neonates and infants, who may benefit most from such treatment. The present study was conducted to determine the colonizing ability, tolerance, and impact on the stool flora of 7 days of administration of a synbiotic supplement to a neonatal cohort, in preparation for a larger hospital-based trial.In this randomized, double-masked, controlled trial, healthy inborn newborns35 weeks of gestational age and1800 g birth weight were randomized between 1 and 3 days after birth to receive an oral synbiotic preparation (Lactobacillus plantarum and fructooligosaccharides) or a dextrose saline placebo. Two babies were treated with the synbiotic preparation for every 1 baby treated with the placebo. Duration of therapy was 7 days. Comprehensive stool cultures were done at baseline and on days 3, 7, 14, 21, and 28.Nineteen infants received the active study supplement and 12 infants received the placebo for 7 days. L plantarum was cultured from the stools of 84% of the treated infants after 3 days of treatment, and from 95% of infants on day 28 after birth. Of the infants, 100%, 94%, 88%, 56%, and 32% remained colonized at months 2, 3, 4, 5, and 6, respectively. In both groups, the total mean number of species and the mean log colony counts increased over time. The number of bacterial species was significantly higher on days 21 and 28 in the synbiotic preparation group compared with placebo (P = 0.002 and 0.03, respectively). There was a linear increase in the mean log gram-negative colony counts in the placebo group during the 4-week period that was significantly higher than that in the Lactobacillus group on days 14, 21, and 28 (P0.001 for each). In contrast, the supplement group had significantly higher gram-positive colony counts on days 14 (P = 0.002) and 28 (P = 0.04). Only 1 infant in the placebo group was colonized with L fermentum during the first 28 days of life. No difference was found in the percent increase in weight between baseline and day 7, but on day 28 and months 2, 3, and 6, the percent increase from baseline was higher in the probiotic-treated group (P/= 0.05). The supplement was tolerated well.The synbiotic preparation colonized quickly after 3 days of administration and the infants stayed colonized for several months after therapy was stopped. There was an increase in bacterial diversity and gram-positive organisms and a reduction of gram-negative bacterial load in the treatment group. Because a combination preparation was used, it is difficult to specifically attribute the colonization to either the probiotic or prebiotic component in this study. Larger efficacy trials are warranted to examine the mechanism of action and precise effects of these supplements.

The dietary habits and metabolic status of 14 selected ambulant type-1 diabetics, who were previously treated with conventional insulin therapy, were investigated over a period of 2 years under intensified insulin injection therapy. In this, multiple doses of regular insulin in combination with intermediate-acting insulin were injected daily and the regular metabolic controls as well as adjustment of the insulin dosage were undertaken by the patients themselves. Whereas conventional insulin therapy made exclusive use of intermediate-acting insulin, 41% of the daily dose in the intensified insulin injection therapy was regular insulin. The total daily insulin dose of 51 +/- 12 U/d was therefore not significantly different from that in the conventional insulin therapy (49 +/- 10 U/d). During the intensified insulin injection therapy the usual diabetic diet was relaxed in several aspects: neither the daily intake of fat, protein and calories, nor substitution in the diet using exchange lists was specified. Despite this liberalization HbA1c values decreased significantly from 9.3 +/- 1.2% to 7.8 +/- 0.7% (P less than 0.05) and blood lipids remained in the normal range. The results of this retrospective investigation lead to the conclusion that despite some measure of diet liberalization, selected, trained, type-1 diabetics of normal body weight and without primary dyslipoproteinaemia can attain good metabolic control under intensified insulin injection therapy.

In a prospective practice survey, the courses of treatment of 1.243 patients with allergic diseases treated with oral antihistamines were documented by allergologists. The aim of the study was to evaluate the efficacy and tolerability of third generation antihistamines following a treatment with OTC antihistamine generics. The mean age of patients was 38.4 years, the proportion of women was 56%. A total of 30% of patients were diagnosed with intermittent and 57% with persistent allergic rhinoconjunctivitis. Other allergic diseases of the airways (possibly in addition) were seen in 15%, and chronic urticaria in 16% of patients. The switch to a 3rd generation antihistamine provided benefits especially for patients with strong to severe nasal obstruction in 64% of patients with intermittent and 53% of patients with persistent rhinoconjunctivitis. Furthermore, 61% of patients with chronic urticaria suffering from strong to severe pruritus achieved an improvement of symptoms when switched to a modem antihistamine. The tolerability of the antihistamine was rated as good or very good by 84% of generic drug users and by 96% of patients receiving a 3rd generation drug. The prevalence of adverse events was 5.4% under generic drugs and 1.7% under 3rd generation antihistamines. This practice survey documented a benefit for patients with allergic diseases switched from a generic to a 3rd generation antihistamine, both for symptom improvement and better tolerability as well as for improved patient information.

To investigate whether clinical and radiographic disease control can be achieved and maintained in patients with early, active rheumatoid arthritis (RA) during the second year of aggressive treatment with conventional disease-modifying antirheumatic drugs (DMARDs) and intra-articular corticosteroid. This paper presents the results of the second year of the randomised, controlled double-blind CIMESTRA (Ciclosporine, Methotrexate, Steroid in RA) study.160 patients with early RA (duration6 months) were randomised to receive intra-articular betamethasone in any swollen joint in combination with step-up treatment with either methotrexate and placebo-ciclosporine (monotherapy) or methotrexate plus ciclosporine (combination therapy) during the first 76 weeks. At week 68 hydroxychlorochine 200 mg daily was added. From week 76-104 ciclosporine/placebo-ciclosporine was tapered to zero.American College of Rheumatology 20% improvement (ACR20), ACR50 and ACR70 levels were achieved in 88%, 79% and 59% of patients in the combination vs 72%, 62% and 54% in the monotherapy group (p = 0.03, 0.02 and 0.6 between groups). The patients globally declined from 50 to 12 vs 52 to 9, with 51% and 50% in Disease Activity Score (DAS) remission, respectively. Mean (SD) progressions in total Sharp-van der Heijde scores were 1.42 (3.52) and 2.03 (5.86) in combination and monotherapy groups, respectively (not significant). Serum creatinine levels increased by 7% in the combination group (4% in monotherapy), but hypertension was not more prevalent.Continuous methotrexate and intra-articular corticosteroid treatment resulted in excellent clinical response and disease control at 2 years, and the radiographic erosive progression was minimal. Addition of ciclosporine during the first 76 weeks resulted in significantly better ACR20 and ACR50 responses, but did not have any additional effect on remission rate and radiographic outcome.

BACKGROUND. Studies of growth and neurodevelopmental impairment in extremely low birth weight infants often exclude infants with major congenital anomalies; thus, there are few outcome data available on these infants.OBJECTIVES. The purpose of this work was to compare growth and neurodevelopmental outcomes of extremely low birth weight infants with major anomalies to extremely low birth weight infants without these findings. It was hypothesized that infants with severe anomalies would have worse growth, neurodevelopmental, and survival outcomes.METHODS. A retrospective cohort analysis was performed on 5920 extremely low birth weight infants surviving beyond 12 hours of life at 19 neonatal network centers between 1998 and 2001. Infants with significant anomalies were more likely to die before 18 to 22 months' corrected age. A total of 3705 children underwent neurodevelopmental and anthropometric evaluation at 18 to 22 months' corrected age. Statistical significance for unadjusted comparisons was determined by Wilcoxon tests for continuous variables and χ2 or Fisher's exact tests for categorical variables. Regression models were used to compare the outcomes after adjusting for potential confounders.RESULTS. Children with major congenital anomalies were more likely to have Bayley Mental Development Index scores of ≤70, Psychomotor Development Index scores of ≤70, neurodevelopmental impairment, moderate-to-severe cerebral palsy, length in the ≤10th percentile, head circumference in the ≤10th percentile, more rehospitalizations, and higher rates of early intervention use at 18 to 22 months' corrected age.CONCLUSIONS. At 18 to 22 months' corrected age, extremely low birth weight infants born with major anomalies have nearly twice the risk for neurodevelopmental impairment, increased risk of poor growth, and >3 times greater risk of rehospitalization when compared with extremely low birth weight infants without major anomalies. This information may be valuable for counseling parents regarding the outcomes of these infants and for the facilitation of appropriate support and intervention services.

Extremely preterm infants contribute disproportionately to neonatal morbidity and mortality.To review 20-year trends in maternal/neonatal care, complications, and mortality among extremely preterm infants born at Neonatal Research Network centers.Prospective registry of 34,636 infants, 22 to 28 weeks' gestation, birth weight of 401 to 1500 g, and born at 26 network centers between 1993 and 2012.Extremely preterm birth.Maternal/neonatal care, morbidities, and survival. Major morbidities, reported for infants who survived more than 12 hours, were severe necrotizing enterocolitis, infection, bronchopulmonary dysplasia, severe intracranial hemorrhage, cystic periventricular leukomalacia, and/or severe retinopathy of prematurity. Regression models assessed yearly changes and were adjusted for study center, race/ethnicity, gestational age, birth weight for gestational age, and sex.Use of antenatal corticosteroids increased from 1993 to 2012 (24% [348 of 1431 infants]) to 87% (1674 of 1919 infants]; P .001), as did cesarean delivery (44% [625 of 1431 births] to 64% [1227 of 1921]; P .001). Delivery room intubation decreased from 80% (1144 of 1433 infants) in 1993 to 65% (1253 of 1922) in 2012 (P .001). After increasing in the 1990s, postnatal steroid use declined to 8% (141 of 1757 infants) in 2004 (P .001), with no significant change thereafter. Although most infants were ventilated, continuous positive airway pressure without ventilation increased from 7% (120 of 1666 infants) in 2002 to 11% (190 of 1756 infants) in 2012 (P .001). Despite no improvement from 1993 to 2004, rates of late-onset sepsis declined between 2005 and 2012 for infants of each gestational age (median, 26 weeks [37% {109 of 296} to 27% {85 of 320}]; adjusted relative risk [RR], 0.93 [95% CI, 0.92-0.94]). Rates of other morbidities declined, but bronchopulmonary dysplasia increased between 2009 and 2012 for infants at 26 to 27 weeks' gestation (26 weeks, 50% [130 of 258] to 55% [164 of 297]; P .001). Survival increased between 2009 and 2012 for infants at 23 weeks' gestation (27% [41 of 152] to 33% [50 of 150]; adjusted RR, 1.09 [95% CI, 1.05-1.14]) and 24 weeks (63% [156 of 248] to 65% [174 of 269]; adjusted RR, 1.05 [95% CI, 1.03-1.07]), with smaller relative increases for infants at 25 and 27 weeks' gestation, and no change for infants at 22, 26, and 28 weeks' gestation. Survival without major morbidity increased approximately 2% per year for infants at 25 to 28 weeks' gestation, with no change for infants at 22 to 24 weeks' gestation.Among extremely preterm infants born at US academic centers over the last 20 years, changes in maternal and infant care practices and modest reductions in several morbidities were observed, although bronchopulmonary dysplasia increased. Survival increased most markedly for infants born at 23 and 24 weeks' gestation and survival without major morbidity increased for infants aged 25 to 28 weeks. These findings may be valuable in counseling families and developing novel interventions.clinicaltrials.gov Identifier: NCT00063063.

OBJECTIVES: To determine to what extent shared epitopes, smoking, and anti-cyclic citrullinated peptide (anti-CCP) antibodies are associated with disease activity and erosive disease in patients with rheumatoid arthritis (RA) at disease onset.METHOD: RA patients not previously treated with disease-modifying anti-rheumatic drugs (DMARDs) and with a disease duration of < 6 months (CIMESTRA study) were examined for shared epitopes, anti-CCP antibodies, immunoglobulin M rheumatoid factor (IgM-RF) and IgA-RF, radiographic erosive changes in hands and feet, and clinical disease activity.RESULTS: The study comprised 153 patients, of whom 104 (68%) were ever-smokers. The prevalence of patients with 0, 1, or 2 shared epitopes was 40 (48%), 71 (49%), and 33 (23%), respectively. Anti-CCP antibodies, IgM-RF, and IgA-RF were present in 89 (58%), 99 (65%), and 82 (54%) patients, respectively. Among smokers, erosive disease was associated with anti-CCP antibodies [odds ratio (OR) 3.9, 95% confidence interval (CI) 1.6-9.3], IgM-RF (OR 4.9, 95% CI 1.9-12), and IgA-RF (OR 2.8, 95% CI 1.2-6.4) but absent with regard to shared epitopes. Among never-smokers, erosive disease was not associated with either shared epitopes or antibodies. All antibody levels measured were associated with smoking and shared epitopes.CONCLUSIONS: Shared epitopes and smoking were associated with the production of anti-CCP antibodies and rheumatoid factors of IgM and IgA isotypes, which again were associated with erosive disease at presentation only in smokers. As shared epitopes and smoking were not directly associated with erosive disease, smoking may enhance the development of erosive disease in RA at different levels or through separate pathways.

We looked at whether flower visitation rates, pollen limitation on seed production, and phenotypic selection on flower size through female function varied across a sharp gradient in light intensity (open meadow vs. forest) within a population of the perennial plant Campanula persicifolia L. (Campanulaceae). Flower visitation rates of putative pollinators were similar in both habitats. Seed number per fruit was strongly pollen limited, with no difference in the magnitude of pollen limitation between the two habitats. This strong pollen limitation set the basis for significant phenotypic selection, through female function, on a trait that probably is important for pollinator attraction: flower size. This was revealed by path analysis and structural equation modelling. The lack of difference in pollen limitation on seed production in the two habitats may be explained by the similarity in flower visitation rates in the two habitats. Moreover, the similarity in pollen limitation in the two habitats probably resulted in a similar magnitude and direction of selection on flower size through female function. Our results suggest that pollen limitation and selection through female function may vary little across space within a popualtion despite large variation in the environmental conditions experienced by plants.

Aufgrund der zunehmenden Haufigkeit von Bienen- und Wespengiftallergien (Hymenopterengiftallergien) und der potenziell lebensbedrohenden Reaktionen ist es auch fur den allergologisch tatigen HNO-Arzt von groser Bedeutung, sich mit modernen Standards in Diagnostik und Therapie dieser allergischen Erkrankung auseinander zu setzen. In der Diagnostik sind Hauttests wie der Titrations-Prick-Test und die Bestimmung der spezifischen IgE-Antikorper im Serum von Bedeutung. Bei einer entsprechenden Anamnese sowie Testbefunden wird der Patient zunachst mit einem „Notfall-Set“ ausgestattet. Ferner ist die Indikation zur spezifischen Hyposensibilisierung (SIT) gegeben. Grundsatzlich lassen sich fur die Steigerungsphase die Schnellhyposensibilisierung und die konventionelle Hyposensibilisierung unterscheiden, wobei als Initialtherapie die in der Klinik durchgefuhrte Schnellhyposensibilisierung (Rush-SIT) besonders geeignet scheint. Bei der richtig durchgefuhrten SIT finden sich nur selten systemische anaphylaktische Nebenwirkungen. Durch eine 3–5 Jahre lang durchgefuhrte SIT kann bei 90 bis nahezu 100% der Patienten ein vollstandiger Schutz erreicht werden.

Early onset neonatal sepsis (EOS, occurring in the first 72 hours of life) remains an important cause of illness and death among very low birth weight (VLBW) preterm infants. We previously reported a change in the distribution of pathogens associated with EOS from predominantly gram-positive to primarily gram-negative organisms.To compare rates of EOS and pathogens associated with infection among VLBW infants born at centers of the National Institute of Child Health and Human Development (NICHD) Neonatal Research Network during 3 time periods: 1991-1993; 1998-2000; and 2002-2003.Prospectively collected data from the NICHD Neonatal Research Network VLBW registry were retrospectively reviewed. Rates of blood culture confirmed EOS, selected maternal and infant variables and pathogens associated with infection were compared between 2002-2003 and 2 previously published cohorts.During the past 13 years, overall rates of EOS have remained stable (15-19 per 1000 live births of infants 401-1500 g). More than one-half of early infections in the 2002-2003 cohort were caused by gram-negative organisms (53%), with Escherichia coli the most common organism (41%). Rates of group B streptococcal infections remain low (1.8 per 1000 live births). Between 1991-1993 and 1998-2000, there was a significant increase in rates of E. coli infections; but in 2002-2003, there was no significant change (7.0 per 1000 live births). Infants with EOS continue to be at significantly increased risk for death compared with uninfected infants.EOS remains an uncommon but important cause of morbidity and mortality among VLBW infants. Gram-negative organisms continue to be the predominant pathogens associated with EOS.

Background. A National Institute of Child Health and Human Development Neonatal Re- search Network randomized trial showed that vitamin A supplementation reduced bronchopulmonary dysplasia (O2 at 36 weeks' postmenstrual age) or death in extremely low birth weight (ELBW) neonates (relative risk (RR): 0.89). As with postnatal steroids or other interventions, it is important to ensure that there are no longer-term ad- verse effects that outweigh neonatal benefits. Primary Objective. To determine if vitamin A sup- plementation in ELBW infants during the first month after birth affects survival without neurodevelopmental impairment at a corrected age of 18 to 22 months. Design/Methods. Infants enrolled in the National In- stitute of Child Health and Human Development vita- min A trial were evaluated at 18 to 22 months by carefully standardized assessments: Bayley Mental Index (MDI) and Psychomotor Index (PDI), visual and hearing screens, and physical examination for cerebral palsy (CP). The medical history was also obtained. Neurode- velopmental impairment (NDI) was predefined as > 1o f MDI

Background: Specific immunotherapy (SIT) represents the only causal treatment that can be offered to allergic patients apart from allergen avoidance. In classic SIT, gradually increasing dosages of the allergen extract are injected subcutaneously. Several dosage schedules for subcutaneous SIT can be applied. The classic approach involves single injections at each therapy visit. In Cluster-SIT, two to three injections per day of treatment are given once a week during initial treatment. Patients: In this trial, we investigated 46 patients (17 female, 29 male) from 11 - 71 years (40.7 ′ 13 years) with regard to side effects of a Cluster regime during induction treatment with Novo-Helisen Depot. Four patients were treated with two different extracts, so that a total of 50 initial therapies were observed; 19 patients (41%) suffered from bronchial asthma. Results: We performed 34 treatments with mite extracts, eight treatments with grass pollen extracts and eight treatments with tree pollen extracts with 744 injections in total. The total number of enlarged local reactions (≥ grade 1) was 23, or 3.1% of all injections. Of these, 22 (3.0%) were classified as immediate reactions and one (0.1%) was a late-phase reaction. Of all enlarged local reactions, 22 (3.0%) were grade 1 reactions (5 - 8 cm) and one (0.1%) was a grade 2 reaction (8 - 12 cm). Grades 3 and 4 reactions were not observed. Only one systemic reaction was observed (0.1% of all injections). This reaction was a delayed phase reaction grade 1 (urticaria). Grades 2, 3, or 4 reactions did not occur. There were no differences in gender or age regarding the occurence of side effects (all p > 0.05). Conclusions: Frequency and severity of adverse side effects in Cluster-SIT with Novo-Helisen Depot show an excellent tolerability corresponding to the occurrence of side-effects with other dosage schedules.

Although highly active antiretroviral therapy has been shown to lower plasma HIV-1 RNA in HIV infection, many patients do not reach the target goal of undetectable viremia. We evaluated whether risk of clinical progression varies by level of viral suppression achieved.Patients in the Collaborations in HIV Outcomes Research/United States cohort who maintained stable HIV-1 RNA levels of either400, 400 to 20,000, or20,000 copies/mL during a run-in period of at least 6 months were studied. Baseline was the first day after this period.Proportional hazards models were used to quantify the relation between baseline HIV-1 RNA levels and risk of a new AIDS-defining diagnosis or death after adjusting for CD4 count, age, gender, ethnicity, study site, prior AIDS-defining diagnosis, and antiretroviral therapy history.Patients (N = 3010) were followed for up to 4.3 years after the 6-month run-in period, with 343 deaths or AIDS-defining diagnoses reported. The risk of a new AIDS-defining diagnosis or death was not significantly different in the 400 to 20,000- and400-copies/mL groups (6% vs. 7%, hazard ratio [HR] = 1.0, 95% confidence interval [CI]: 0.7-1.4; P = 0.9) but was significantly higher in the20,000-copies/mL group (26%, HR = 3.3, 95% CI: 2.5-4.4; P0.001 vs. the400-copies/mL group). Median CD4 count changes during the first year of follow-up showed increases of 75 and 13 cells/mm for the400- and 400 to 20,000-copies/mL groups, respectively, whereas the20,000-copies/mL group had a decrease of 23 cells/mm.Patients who maintained baseline HIV-1 RNA levels of 400 to 20,000 copies/mL for at least 6 months preserved immunologic status and were no more likely to die or develop a new AIDS-defining diagnosis in the time frame studied than those with baseline levels400 copies/mL. Patients with HIV-1 RNA levels20,000 copies/mL at baseline had greater clinical and immunologic deterioration. These data suggest that maintenance of moderate viremia may confer clinical benefit not seen when viremia exceeds 20,000 copies/mL, and this should be taken into account when considering the risks and benefits of continuing failing therapy.

Background The only causal treatment that can be offered to allergic patients apart from allergen avoidance is specific immunotherapy. Its efficacy depends on the specific allergen the patient is allergic to, the quality of the extract, the total amount of allergen administered to the patient and the administration schedule. Methods and patient Our patient suffered from inhalative allergy to rat epithelium with severe rhinoconjunctivitis and bronchial asthma. She regularly worked with laboratory rats as a biologist. A job-shift was impossible for the patient, and so was allergen avoidance. We therefore decided to treat the patient with specific immunotherapy. Treatment was performed as in-patient procedure with Rush-Immunotherapy in dosage increase phase. Maintenance injections were administered as out-patient. Results As early as some months after induction of the therapy, the patient felt subjective symptom relief, blood samples taken revealed decrease of total IgE and specific IgE towards rat epithelium. Therapy was continued for 18 months, specific IgE against rat epithelium could not be detected any more. The patient does not claim any allergy symptoms when working in the rat laboratory any more. Conclusions Even in unusual allergies, specific immunotherapy can be indicated. In our patient, specific immunotherapy to rat epithelium lead to complete symptom relief and enabled the patient to practise her profession without restraints.

Background and Objectives This prospective, observational study compared disease progression and death in HIV-1 patients treated with stavudine vs. zidovudine in the Collaborations in HIV Outcomes Research/U.S. (CHORUS) cohort. Methods Patients with a first occurrence of CD4 count n =3301) were grouped as: no nucleoside reverse transcriptase inhibitor (NRTI) use; other NRTI without stavudine or zidovudine; stavudine with no zidovudine, with or without other NRTIs; and zidovudine with no stavudine, with or without other NRTIs. The risk for death or disease progression was evaluated in unadjusted analyses and using a Cox proportional hazards model, adjusting for: study site, age, gender, race, route of HIV infection, previous AIDS-defining conditions, number of previous antiretroviral regiments, CD4 count, HIV-1 RNA, and treatment variables. Sensitivity analyses were conducted to determine the sensitivity of the results to major modeling assumptions. A landmark analysis was conducted to determine the absolute difference in time to event. Results During a median follow-up of 2.4 years, there were 57 deaths and 348 AIDS-defining conditions in 405 patients. Stavudine treatment compared with zidovudine resulted in a greater percentage of patients with AIDS-defining events (14.5 vs. 10.9%; P =.013), and an increased risk of disease progression (HR=1.30; 95% CI: 1.01,1.7; P =.04). This result was not sensitive to modeling assumptions. Landmark analysis demonstrated an absolute difference in time to 95% event-free survival of 2.7 months for those with a CD4⩽200 cells/μL and 11 months for those 6 months after model entry. Conclusions In unadjusted and adjusted analyses of 3301 HIV-1 infected patients, stavudine containing combination therapy was associated with an increased risk of disease progression or death compared to therapy containing zidovudine. Most of the difference was attributable to new cases of wasting.

BACKGROUND Specific immunotherapy (SIT) represents the only specific treatment that can be offered to allergic patients apart from allergen avoidance. SIT has been widely used in pollen allergic rhinitis. Clinical efficacy has been demonstrated in several controlled clinical trials and depends on the specific allergen the individual patient is sensitive to, the quality and total amount of allergen applied, and the SIT schedule. In classic SIT, gradually increasing dosages of the allergen extract are injected subcutaneously. Several dosage schedules for subcutaneous SIT can be applied. In Cluster-SIT, 2 - 3 injections per day of treatment are given once a week during induction treatment. PATIENTS In this study, we investigated 64 patients (33 female, 31 male) from 18 to 54 years (26.9 +/- 5.1 years) in terms of side-effects of Cluster-SIT during induction treatment. RESULTS The total amount of enlarged local reactions (> grade 1) was n = 77 or 15.2 % of all injections. Of these, 68 (88 %) were classified as immediate reactions, 8 (11 %) were late phase reactions and 1 (1 %) was immediate as well as late phase reaction. Of all enlarged local reactions, 48 (62 %) were grade 1 reactions, 13 (17 %) were grade 2 reactions, 13 (17 %) were grade 3 reactions and 1 (1 %) was a grade 4 reaction. The total amount of systemic reactions was n = 22 or 4.3 % of all injections. Of these, 19 (86 %) were classified as immediate reactions, 3 (14 %) were delayed reactions. Of all systemic reactions, 18 (82 %) were grade 1 reactions and 4 (18 %) grade 2 reactions. Grade 3 or grade 4 reactions did not occur. There were no differences in gender or age regarding the occurrence of side effects (all p > 0.05). CONCLUSIONS Frequency and severity of adverse side effects in Cluster-SIT correspond to those in other dosage schedules. On behalf of security aspects, Cluster-SIT could become an interesting alternative dosage schedule for dose increase during SIT. Furthermore, in Cluster-SIT with allergoids, induction treatment can be carried out in two treatment days of approximately 2.5 hours each.

Infection is a serious complication among very low birth weight (VLBW) preterm infants hospitalized in neonatal intensive care units. This article reviews studies from the National Institute of Child Health and Human Development (NICHD) Neonatal Research Network including infection data from observational studies and randomized controlled trials. Blood culture-proven early-onset sepsis (or = 72 hours) was found in less than 2% of VLBW infants, but was associated with substantial morbidity and mortality. A change in pathogens causing early-onset sepsis among Network patients has been observed over the past decade, with a significant reduction in early-onset group B streptococcal infections, but also a significant increase in early-onset Escherichia coli infections. This change is particularly worrisome, because of the high death rate associated with gram-negative infections, including E coli. Late-onset (72 hours) sepsis developed in almost a quarter of infants. The vast majority of infections were caused by gram-positive agents, especially coagulase-negative staphylococci. The risk of late-onset sepsis was inversely related to birth weight and gestational age. Infants with late-onset sepsis were at increased risk for a number of neonatal morbidities, for prolonged hospitalization, and for death. The percentage of deaths attributed to infection increased with increasing postnatal age. The increasing survival of extremely immature infants has resulted in a cohort of infants at prolonged risk for acquired infection. Successful strategies to reduce infections among VLBW infants would improve survival, reduce neonatal morbidity, and reduce the high medical and social costs of VLBW infant care.