Hydroxyurea Decouples Persistent F-Cell Elevation and Induction of γ-Globin.

Mechanisms that control the fetal-to-adult hemoglobin switch are attractive therapeutic targets in sickle cell disease. In this study, we investigated developmental γ-globin silencing in the Townes humanized knock-in mouse model, which harbors a construct containing the human γ-, ßA-, and ßS-globin genes, and examined the utility of this model in evaluation of pharmacologic induction of fetal hemoglobin (HbF). We studied mouse pups on the day of delivery (P0) to 28 days after birth (P28). Regardless of the hemoglobin genotype (SS, AS, or AA), the proportion of F cells in peripheral blood was 100% at P0, declined sharply to 20% at P2, and was virtually undetectable at P14. Developmental γ-globin silencing in Townes mice was complete at P4 in association with significantly increased BCL11A expression in the primary erythropoietic organs of the mouse. Hydroxyurea given at P2 significantly sustained elevated percentages of F cells in mice at P14. However, the percentage of F cells declined at P14 for treatment begun at P4. A lack of augmentation of γ-globin mRNA in erythroid tissues suggests that the apparent increase in HbF in red cells caused by hydroxyurea was not due to sustained or re-activation of γ-globin transcription, but was instead a function of erythropoiesis suppression. Thus, we provide new details of the hemoglobin switch in the Townes murine model that recapitulates postnatal γ- to ß-globin switch in humans and identify the myelosuppressive toxicity of hydroxyurea as a superseding factor in interpreting pharmacologic induction of HbF.

Interobserver and intraobserver reliability for 2 grading systems for gastric ulcer syndrome in horses.

BACKGROUND: Grading of equine gastric ulcer syndrome (EGUS) is undertaken in clinical and research settings, but the reliability of EGUS grading systems is poorly understood. HYPOTHESIS/OBJECTIVES: Investigate interobserver and intraobserver reliability of an established ordinal grading system and a novel visual analog scale (VAS), and assess the influence of observer experience. ANIMALS: Sixty deidentified gastroscopy videos. METHODS: Six observers (3 specialists and 3 residents) graded videos using the EGUS Council (EGUC) system and VAS. Observers graded the videos three 3 for each system, using a cross-over design with at least 1 week between each phase. The order of videos was randomized for each phase. METHODS: Interobserver and intraobserver reliability were estimated using Gwet's agreement coefficient with ordinal weights applied (AC2) for the EGUC system and the intraclass correlation coefficient (ICC) for the VAS. RESULTS: Using the EGUC system, interobserver reliability was substantial for squamous (AC2 = 0.69; 95% confidence interval [CI], 0.57-0.80) and glandular mucosa (AC2 = 0.72; 95% CI, 0.70-0.75), and intraobserver reliability was substantial for squamous (AC2 = 0.80; 95% CI, 0.71-0.90) and glandular mucosa (AC2 = 0.80; 95% CI, 0.74-0.86). Interobserver reliability using the VAS was moderate for squamous (ICC = 0.64; 95% CI, 0.31-0.96) and poor for glandular mucosa (ICC = 0.35; 95% CI, 0.06-0.64), and intraobserver reliability was moderate for squamous (ICC = 0.74; 95% CI, 0.62-0.86) and glandular mucosa (ICC = 0.56; 95% CI, 0.39-0.72). CONCLUSIONS AND CLINICAL IMPORTANCE: The EGUC system had acceptable intraobserver and interobserver reliability and performed well regardless of observer experience. Familiarity and observer experience improved reliability of the VAS.

Hemopexin deficiency promotes acute kidney injury in sickle cell disease.

Acute kidney injury (AKI) is a major clinical concern in sickle cell disease (SCD). Clinical evidence suggests that red cell alarmins may cause AKI in SCD, however, the sterile inflammatory process involved has hitherto not been defined. We discovered that hemopexin deficiency in SCD is associated with a compensatory increase in α-1-microglobulin (A1M), resulting in an up to 10-fold higher A1M-to-hemopexin ratio in SCD compared with healthy controls. The A1M-to-hemopexin ratio is associated with markers of hemolysis and AKI in both humans and mice with SCD. Studies in mice showed that excess heme is directed to the kidneys in SCD in a process involving A1M causing AKI, whereas excess heme in controls is transported to the liver as expected. Using genetic and bone marrow chimeric tools, we confirmed that hemopexin deficiency promotes AKI in sickle mice under hemolytic stress. However, AKI was blocked when hemopexin deficiency in sickle mice was corrected with infusions of purified hemopexin prior to the induction of hemolytic stress. This study identifies acquired hemopexin deficiency as a risk factor of AKI in SCD and hemopexin replacement as a potential therapy.

Factors Associated With Survival and Return to Function Following Synovial Infections in Horses.

Synovial infections (SI) are common in horses of all ages and can be associated with high rates of morbidity and mortality. Identifying factors influencing survival and return to function may be useful for management of affected individuals and determination of prognosis. The objectives of this study were to identify factors associated with survival and return to function of horses and foals with SI presented to an equine hospital. This study is a retrospective case series. Data were collected from medical records of all horses with SI that were presented to a single equine hospital between April 1st, 2008 and May 1st, 2017. Long-term follow up was obtained by a semi-structured telephone questionnaire of clinical outcomes and analysis of online race records. Univariate models were created using generalized linear and linear mixed models to assess factors associated with outcomes. Multivariable models were created using generalized linear and linear mixed models to determine factors significantly associated with outcomes. Of 186 horses presented with SI, 161/186 (86.6%) were treated and 145/161 (90.1%) survived to discharge. The majority of joints were treated with synovial lavage (93.8%). One hundred and twenty horses were included in the return to function analysis and 79 (65%) returned to function. Increasing number of days of treatment with systemic antimicrobials was associated with increased likelihood of survival for each horse (OR 1.15, 95% CI 1.04-1.27, P = 0.025) and when considering each individual synovial structure (OR 1.11, 95% CI 1.04-1.17, P = 0.004). Horses treated with doxycycline were less likely to return to function (OR 0.39, 95% CI 0.19-0.8, P = 0.031). The overall rate of survival of horses treated with SI is good. The likelihood of return to function is lower than for survival. The findings of this study, combined with relevant antimicrobial stewardship practices, can be used as a part of evidence-based decision-making when veterinarians are treating horses with SI.

Magnesium supplementation in pregnancy.

BACKGROUND: Magnesium is an essential mineral required for regulation of body temperature, nucleic acid and protein synthesis and in maintaining nerve and muscle cell electrical potentials. Many women, especially those from disadvantaged backgrounds, have low intakes of magnesium. Magnesium supplementation during pregnancy may be able to reduce fetal growth restriction and pre-eclampsia, and increase birthweight. OBJECTIVES: To assess the effects of magnesium supplementation during pregnancy on maternal, neonatal/infant and paediatric outcomes. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (31 March 2013). SELECTION CRITERIA: Randomised and quasi-randomised trials assessing the effects of dietary magnesium supplementation during pregnancy were included. The primary outcomes were perinatal mortality (including stillbirth and neonatal death prior to hospital discharge), small-for-gestational age, maternal mortality and pre-eclampsia. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed study eligibility, extracted data and assessed the risk of bias of included studies. MAIN RESULTS: Ten trials involving 9090 women and their babies were included; one trial had a cluster design (with randomisation by study centre). All 10 trials randomly allocated women to either an oral magnesium supplement or a control group; in eight trials a placebo was used, and in two trials no treatment was given to the control group. In the 10 included trials, the compositions of the magnesium supplements, gestational ages at commencement, and doses administered varied, including: magnesium oxide, 1000 mg daily from ≤ four months post-conception (one trial); magnesium citrate, 365 mg daily from ≤ 18 weeks until hospitalisation after 38 weeks (one trial), and 340 mg daily from nine to 27 weeks' gestation (one trial); magnesium gluconate, 2 to 3 g from 28 weeks' gestation until birth (one trial), and 4 g daily from 23 weeks' gestation (one trial); magnesium aspartate, 15 mmol daily (three trials, commencing from either six to 21 weeks' gestation until birth, ≤ 16 weeks' gestation until birth, or < 12 weeks until birth), or 365 mg daily from 13 to 24 weeks until birth (one trial); and magnesium stearate, 128 mg elemental magnesium from 10 to 35 weeks until birth (one trial).In the analysis of all trials, oral magnesium supplementation compared to no magnesium was associated with no significant difference in perinatal mortality (stillbirth and neonatal death prior to discharge) (risk ratio (RR) 1.10; 95% confidence interval (CI) 0.72 to 1.67; five trials, 5903 infants), small-for-gestational age (RR 0.76; 95% CI 0.54 to 1.07; three trials, 1291 infants), or pre-eclampsia (RR 0.87; 95% CI 0.58 to 1.32; three trials, 1042 women). None of the included trials reported on maternal mortality.Considering secondary outcomes, while no increased risk of stillbirth was observed, a possible increased risk of neonatal death prior to hospital discharge was shown for infants born to mothers who had received magnesium (RR 2.21; 95% CI 1.02 to 4.75; four trials, 5373 infants). One trial contributed over 70% of the participants to the analysis for this outcome; the trial authors suggested that the large number of severe congenital anomalies in the supplemented group (unlikely attributable to magnesium) and the deaths of two sets of twins (with birthweights < 750 g) in the supplemented group likely accounted for the increased risk of death observed, and thus this result should be interpreted with caution. Furthermore, when the deaths due to severe congenital abnormalities in this trial were excluded from the meta-analysis, no increased risk of neonatal death was seen for the magnesium supplemented group. Magnesium supplementation was associated with significantly fewer babies with an Apgar score less than seven at five minutes (RR 0.34; 95% CI 0.15 to 0.80; four trials, 1083 infants), with meconium-stained liquor (RR 0.79; 95% CI 0.63 to 0.99; one trial, 4082 infants), late fetal heart decelerations (RR 0.68; 95% CI 0.53 to 0.88; one trial, 4082 infants), and mild hypoxic-ischaemic encephalopathy (RR 0.38; 95% CI 0.15 to 0.98; one trial, 4082 infants). Women receiving magnesium were significantly less likely to require hospitalisation during pregnancy (RR 0.65, 95% CI 0.48 to 0.86; three trials, 1158 women).Of the 10 trials included in the review, only two were judged to be of high quality overall. When an analysis was restricted to these two trials none of the review's primary outcomes (perinatal mortality, small-for-gestational age, pre-eclampsia) were significantly different between the magnesium supplemented and control groups. AUTHORS' CONCLUSIONS: There is not enough high-quality evidence to show that dietary magnesium supplementation during pregnancy is beneficial.

Work Hours, Schedules, and Insufficient Sleep Among Mothers and Their Young Children.

Studies have linked parents' employment, work hours, and work schedules to their own sleep quality and quantity, but it is unclear whether these associations extend to children. The authors used data from the 5-year in-home survey of the Fragile Families and Child Wellbeing Study (N = 1,818) to examine the associations between maternal work hours and schedule and insufficient sleep among disadvantaged mothers and their young children. They found that mothers who worked more than 35 hours per week were more likely to experience insufficient sleep compared to mothers who worked fewer hours, whereas children were more likely to experience insufficient sleep when their mothers worked between 20 and 40 hours. Nonstandard work schedules were associated with an increased likelihood of insufficient sleep for mothers but not their children. The results highlight a potentially difficult balance between work and family for many disadvantaged working mothers in the United States.

Measuring Maternal Nonstandard Work in Survey Data.

Surveys differ in the measurement of nonstandard work, such that some surveys require respondents to indicate whether they work either a standard or a nonstandard schedule, whereas others allow respondents to indicate that they work both types of schedules. We test whether these measurement decisions influence the estimated prevalence of maternal nonstandard work, using data from two sources: the Current Population Survey (N = 1,430) and the Fragile Families and Child Wellbeing Study (N = 2,524). Using propensity score techniques, we find that giving respondents the option of reporting work at more than one type of schedule doubles the prevalence of nonstandard work, compared to allowing respondents to indicate only one type of schedule. Our results suggest that many mothers of young children regularly work at both standard and nonstandard times and that mutually exclusive conceptualizations of standard and nonstandard work schedules do not fully capture their experiences.

Mothers' night work and children's behavior problems.

Many mothers work in jobs with nonstandard schedules (i.e., schedules that involve work outside of the traditional 9-5, Monday through Friday schedule); this is particularly true for economically disadvantaged mothers. In the present article, we used longitudinal data from the Fragile Families and Child Wellbeing Survey (n = 2,367 mothers of children ages 3-5 years) to examine the associations between maternal nonstandard work and children's behavior problems, with a particular focus on mothers' night shift work. We employed 3 analytic strategies with various approaches to adjusting for observed and unobserved selection factors; these approaches provided an upper and lower bound on the true relationship between night shift work and children's behavior. Taken together, the results provide suggestive evidence for modest associations between exposure to maternal night shift work and higher levels of aggressive and anxious or depressed behavior in children compared with children whose mothers who are not working, those whose mothers work other types of nonstandard shifts, and, for aggressive behavior, those whose mothers work standard shifts.

A tale of two methods: comparing regression and instrumental variables estimates of the effects of preschool child care type on the subsequent externalizing behavior of children in low-income families.

We apply instrumental variables (IV) techniques to a pooled data set of employment-focused experiments to examine the relation between type of preschool childcare and subsequent externalizing problem behavior for a large sample of low-income children. To assess the potential usefulness of this approach for addressing biases that can confound causal inferences in child care research, we compare instrumental variables results with those obtained using ordinary least squares (OLS) regression. We find that our OLS estimates concur with prior studies showing small positive associations between center-based care and later externalizing behavior. By contrast, our IV estimates indicate that preschool-aged children with center care experience are rated by mothers and teachers as having fewer externalizing problems on entering elementary school than their peers who were not in child care as preschoolers. Findings are discussed in relation to the literature on associations between different types of community-based child care and children's social behavior, particularly within low-income populations. Moreover, we use this study to highlight the relative strengths and weaknesses of each analytic method for addressing causal questions in developmental research.

Phenobarbital prior to preterm birth for preventing neonatal periventricular haemorrhage.

BACKGROUND: Preterm infants are at risk of periventricular haemorrhage. Phenobarbital might prevent ischaemic injury or reduce fluctuations in blood pressure and blood flow in the brain. OBJECTIVES: To assess the benefits and harms of giving phenobarbital to women at risk of imminent very preterm birth with the primary aim of preventing periventricular haemorrhage in the infant. SEARCH STRATEGY: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (31 March 2008). SELECTION CRITERIA: Randomised trials with reported data that compared neonatal and maternal outcomes following prenatal exposure to phenobarbital, with outcomes in controls with or without placebo. DATA COLLECTION AND ANALYSIS: We independently assessed trial eligibility and quality and extracted data. We included eligible trials in the initial analysis and prespecified sensitivity analyses to evaluate the effect of trial quality. MAIN RESULTS: Nine trials (1752 women) were included. Analyses of all included trials showed a significant reduction in the rates of all grades of periventricular haemorrhage (PVH) (risk ratio (RR) 0.65, 95% confidence interval (CI) 0.50 to 0.83; nine trials; 1591 women) and severe grades PVH (3 and 4) (RR 0.41, 95% CI 0.20 to 0.85; eight trials; 1527 women) in infants whose mothers had been given prenatal phenobarbital. These results were influenced by trials of poor quality which contributed excessive weight in the analysis due to their higher rates of severe PVH. When only the two higher quality trials were included, these beneficial effects disappeared for all grades of PVH (RR 0.90, 95% CI 0.75 to 1.08; two trials; 945 women), and severe grades of PVH (RR 1.05, 95% CI 0.60 to 1.83; two trials; 945 women).No difference was found in the incidence of neurodevelopmental abnormalities at paediatric follow up at 18 to 24 months or seven years of age between children born to mothers given prenatal phenobarbital and children not so exposed. Maternal sedation was more likely in women receiving phenobarbital (RR 2.06, 95% CI 1.79 to 2.37; one trial; 576 women). AUTHORS' CONCLUSIONS: The evidence in this review does not support the use of prophylactic maternal phenobarbital administration to prevent periventricular haemorrhage in preterm infants or to protect them from neurological disability in childhood. Phenobarbital administration may lead to maternal sedation. If any future trials are carried out, they should measure neurodevelopmental status at follow up.

Vitamin K prior to preterm birth for preventing neonatal periventricular haemorrhage.

BACKGROUND: Preterm infants are at risk of periventricular haemorrhage. This can be a sign of brain damage that might lead to neurodevelopmental abnormalities, including cerebral palsy. It has been suggested that vitamin K might improve coagulation in preterm infants and thereby decrease the risk of periventricular haemorrhage. OBJECTIVES: The objective of this review was to assess the effects of vitamin K administered to women at risk of imminent very preterm birth to prevent periventricular haemorrhage and associated neurological injury in the infant. SEARCH STRATEGY: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (31 March 2008). SELECTION CRITERIA: Randomised or quasi-randomised trials of vitamin K administered parenterally or orally to women at risk of imminent preterm birth. The primary outcomes were neonatal mortality, neonatal neurological morbidity, as measured by the presence of periventricular haemorrhage (PVH) on ultrasound during the first week of life, and long-term neurodevelopment. Secondary outcomes included other neonatal morbidity and any maternal side effects. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed eligibility, trial quality and extracted data. MAIN RESULTS: Seven trials were included, involving 607 women. The trials were of variable quality. Antenatal vitamin K was associated with a non-significant reduction in all grades of periventricular haemorrhage (risk ratio (RR) 0.76; 95% confidence interval (CI) 0.54 to 1.06) and a significant reduction in severe PVH (grades 3 and 4) (RR 0.58; 95% CI 0.37 to 0.91) for babies receiving prenatal vitamin K compared with control babies. When the two quasi-randomised trials were excluded, antenatal vitamin K was associated with a non-significant reduction in all grades of PVH (RR 0.87; 95% CI 0.60 to 1.26) and a non-significant reduction in severe PVH (RR 0.82; 95% CI 0.49 to 1.36).There was an unfavourable effect of vitamin K on development as measured by the Bayley Mental Development Index at two years of age, however these results are derived from one trial with many participants lost to follow up. No difference was found in the incidence of other neurodevelopmental abnormalities at paediatric follow up at 18 to 24 months or seven years of age between children born to mothers given vitamin K and children not so exposed. AUTHORS' CONCLUSIONS: Vitamin K administered to women prior to very preterm birth has not been shown to significantly prevent periventricular haemorrhages in preterm infants or improve neurodevelopmental outcomes in childhood.

Impacts on children of a policy to promote employment and reduce poverty for low-income parents: new hope after 5 years.

The impacts of New Hope, a program to increase parent employment and reduce poverty, were measured 5 years after parents were randomly assigned to program or control groups. New Hope had positive effects on children's school achievement, motivation, and social behavior, primarily for boys, across the age range 6-16. In comparison to impacts measured 2 years after program onset, effects on achievement were robust, but effects on social behavior were reduced. The program produced improvements in family income and use of organized child care and activity settings, suggesting possible pathways by which the New Hope package of policies influenced children's behavior.