Impact of new diagnostic criteria for gestational diabetes.

AIM: In January 2015, the diagnostic and therapeutic criteria for gestational diabetes changed, with the goal of increasing the sensitivity of diagnosis and improving overall glycemic control, and thus reducing adverse pregnancy outcomes. Our primary aim was to evaluate the effect of the new guidelines on the incidence of diagnosis of gestational diabetes and the incidence of therapeutic interventions. Our secondary aim was to look at the incidence of adverse pregnancy outcomes. METHODS: A retrospective clinical audit was conducted at a regional hospital to compare the incidence of gestational diabetes, and the specific maternal and neonatal outcomes before and after the change in guidelines was implemented. Data were collected via chart review for a 6-month period before and after the change in guidelines in January 2015. Data collected included demographics, neonatal and maternal outcomes, and the treatment type used for patients diagnosed with gestational diabetes. RESULTS: There was a significant increase in the incidence of diagnosis of gestational diabetes (9.8-19.6%; P < 0.001), and an overall increase in the use of pharmacological treatments for gestational diabetes. There was no significant difference in the incidence of the adverse outcomes measured, including cesarean delivery and macrosomia. There was no significant change in mean fetal weight. CONCLUSION: Despite a doubling of the incidence of diagnosis of gestational diabetes, and a consequent increase in pharmacological interventions, the change in diagnostic and therapeutic criteria did not significantly reduce the neonatal or maternal adverse outcomes measured.

Discovery of Novel Oral Protein Synthesis Inhibitors of Mycobacterium tuberculosis That Target Leucyl-tRNA Synthetase.

The recent development and spread of extensively drug-resistant and totally drug-resistant resistant (TDR) strains of Mycobacterium tuberculosis highlight the need for new antitubercular drugs. Protein synthesis inhibitors have played an important role in the treatment of tuberculosis (TB) starting with the inclusion of streptomycin in the first combination therapies. Although parenteral aminoglycosides are a key component of therapy for multidrug-resistant TB, the oxazolidinone linezolid is the only orally available protein synthesis inhibitor that is effective against TB. Here, we show that small-molecule inhibitors of aminoacyl-tRNA synthetases (AARSs), which are known to be excellent antibacterial protein synthesis targets, are orally bioavailable and effective against M. tuberculosis in TB mouse infection models. We applied the oxaborole tRNA-trapping (OBORT) mechanism, which was first developed to target fungal cytoplasmic leucyl-tRNA synthetase (LeuRS), to M. tuberculosis LeuRS. X-ray crystallography was used to guide the design of LeuRS inhibitors that have good biochemical potency and excellent whole-cell activity against M. tuberculosis Importantly, their good oral bioavailability translates into in vivo efficacy in both the acute and chronic mouse models of TB with potency comparable to that of the frontline drug isoniazid.

Treatment of Skin Inflammation with Benzoxaborole Phosphodiesterase Inhibitors: Selectivity, Cellular Activity, and Effect on Cytokines Associated with Skin Inflammation and Skin Architecture Changes.

Psoriasis and atopic dermatitis are skin diseases affecting millions of patients. Here, we characterize benzoxaborole phosphodiesterase (PDE)-4 inhibitors, a new topical class that has demonstrated therapeutic benefit for psoriasis and atopic dermatitis in phase 2 or phase 3 studies. Crisaborole [AN2728, 4-((1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yl)oxy)benzonitrile], compd2 [2-ethoxy-6-((1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yl)oxy)nicotinonitrile], compd3 [6-((1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yl)oxy)-2-(2-isopropoxyethoxy)nicotinonitrile], and compd4 [5-chloro-6-((1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yl)oxy)-2-((4-oxopentyl)oxy)nicotinonitrile] are potent PDE4 inhibitors with similar affinity for PDE4 isoforms and equivalent inhibition on the catalytic domain and the full-length enzyme. These benzoxaboroles are less active on other PDE isozymes. Compd4 binds to the catalytic domain of PDE4B2 with the oxaborole group chelating the catalytic bimetal and overlapping with the phosphate in cAMP during substrate hydrolysis, and the interaction extends into the adenine pocket. In cell culture, benzoxaborole PDE4 inhibitors suppress the release of tumor necrosis factor-α, interleukin (IL)-23, IL-17, interferon-γ, IL-4, IL-5, IL-13, and IL-22, and these cytokines contribute to the pathologic changes in skin structure and barrier functions as well as immune dysregulation in atopic dermatitis and psoriasis. Treatment with compd3 or N(6),2'-O-dibutyryladenosine 3',5'-cyclic monophosphate increases cAMP response element binding protein phosphorylation in human monocytes and decreases extracellular signal-regulated kinase phosphorylation in human T cells; these changes lead to reduced cytokine production and are among the mechanisms by which compd3 blocks cytokine release. Topical compd3 penetrates the skin and suppresses phorbol myristate acetate-induced IL-13, IL-22, IL-17F, and IL-23 transcription and calcipotriol-induced thymic stromal lymphopoietin expression in mouse skin. Skin thinning is a major dose-limiting side effect of glucocorticoids. By contrast, repeated application of compd3 did not thin mouse skin. These findings show the potential benefits and safety of benzoxaborole PDE4 inhibitors for the treatment of psoriasis and atopic dermatitis.

Discovery of a novel class of boron-based antibacterials with activity against gram-negative bacteria.

Gram-negative bacteria cause approximately 70% of the infections in intensive care units. A growing number of bacterial isolates responsible for these infections are resistant to currently available antibiotics and to many in development. Most agents under development are modifications of existing drug classes, which only partially overcome existing resistance mechanisms. Therefore, new classes of Gram-negative antibacterials with truly novel modes of action are needed to circumvent these existing resistance mechanisms. We have previously identified a new a way to inhibit an aminoacyl-tRNA synthetase, leucyl-tRNA synthetase (LeuRS), in fungi via the oxaborole tRNA trapping (OBORT) mechanism. Herein, we show how we have modified the OBORT mechanism using a structure-guided approach to develop a new boron-based antibiotic class, the aminomethylbenzoxaboroles, which inhibit bacterial leucyl-tRNA synthetase and have activity against Gram-negative bacteria by largely evading the main efflux mechanisms in Escherichia coli and Pseudomonas aeruginosa. The lead analogue, AN3365, is active against Gram-negative bacteria, including Enterobacteriaceae bearing NDM-1 and KPC carbapenemases, as well as P. aeruginosa. This novel boron-based antibacterial, AN3365, has good mouse pharmacokinetics and was efficacious against E. coli and P. aeruginosa in murine thigh infection models, which suggest that this novel class of antibacterials has the potential to address this unmet medical need.

Inhibition of Toll-like receptor-mediated inflammation in vitro and in vivo by a novel benzoxaborole.

Pro-inflammatory cytokines play a critical role in the development of autoimmune and inflammatory diseases. Targeting the cytokine environment has proven efficient for averting inflammation. In this study, we reported that 6-[4-(aminomethyl)-2-chlorophenoxyl]benzo[c][1,2]oxaborol-1(3H)-ol (AN3485), a benzoxaborole analog, inhibited TLR2-, TLR3-, TLR4-, and TLR5-mediated TNF-α, IL-1ß, and IL-6 release from human PBMCs and isolated monocytes with IC(50) values ranging from 18 to 580 nM, and the inhibition was mediated at the transcriptional level. Topical administration of AN3485 significantly reduced PMA-induced contact dermatitis and oxazolone-induced delayed-type hypersensitivity in mice, indicating its capability of penetrating skin and potential topical application in skin inflammation. Oral administration of AN3485 showed dose-dependent suppression of LPS-induced TNF-α and IL-6 production in mice with an ED(90) of 30 mg/kg. Oral AN3485, 35 mg/kg, twice a day, suppressed collagen-induced arthritis in mice over a 20-day period. The potent anti-inflammatory activity in in vitro and in vivo disease models makes AN3485 an attractive therapeutic lead for a variety of cutaneous and systemic inflammatory diseases.

Deconstructing the externalizing spectrum: growth patterns of overt aggression, covert aggression, oppositional behavior, impulsivity/inattention, and emotion dysregulation between school entry and early adolescence.

The purpose of this study was to determine whether five subcomponents of children's externalizing behavior showed distinctive patterns of long-term growth and predictive correlates. We examined growth in teachers' ratings of overt aggression, covert aggression, oppositional defiance, impulsivity/inattention, and emotion dysregulation across three developmental periods spanning kindergarten through Grade 8 (ages 5-13 years). We also determined whether three salient background characteristics, family socioeconomic status, child ethnicity, and child gender, differentially predicted growth in discrete categories of child externalizing symptoms across development. Participants were 543 kindergarten-age children (52% male, 81% European American, 17% African American) whose problem behaviors were rated by teachers each successive year of development through Grade 8. Latent growth curve analyses were performed for each component scale, contrasting with overall externalizing, in a piecewise fashion encompassing three developmental periods: kindergarten-Grade 2, Grades 3-5, and Grades 6-8. We found that most subconstructs of externalizing behavior increased significantly across the early school age period relative to middle childhood and early adolescence. However, overt aggression did not show early positive growth, and emotion dysregulation significantly increased across middle childhood. Advantages of using subscales were most clear in relation to illustrating different growth functions between the discrete developmental periods. Moreover, growth in some discrete subcomponents was differentially associated with variations in family socioeconomic status and ethnicity. Our findings strongly affirmed the necessity of adopting a developmental approach to the analysis of growth in children's externalizing behavior and provided unique data concerning similarities and differences in growth between subconstructs of child and adolescent externalizing behavior.

Longitudinal links between spanking and children's externalizing behaviors in a national sample of White, Black, Hispanic, and Asian American families.

This study examined whether the longitudinal links between mothers' use of spanking and children's externalizing behaviors are moderated by family race/ethnicity, as would be predicted by cultural normativeness theory, once mean differences in frequency of use are controlled. A nationally representative sample of White, Black, Hispanic, and Asian American families (n = 11,044) was used to test a cross-lagged path model from 5 to 8 years old. While race/ethnic differences were observed in the frequency of spanking, no differences were found in the associations of spanking and externalizing over time: Early spanking predicted increases in children's externalizing while early child externalizing elicited more spanking over time across all race/ethnic groups.

The Effect of CASA on Child Welfare Permanency Outcomes.

The present study is the largest and most rigorous study to date on the effects of being appointed a Court Appointed Special Advocate (CASA) on permanency outcomes of children in foster care. The intent-to-treat study accounts for selection bias by applying inverse probability weighting to logistic and sequential logistic regressions in a large sample of children in foster care in the state of Texas (N = 31,754). Overall, children appointed a CASA have significantly lower odds than children without a CASA of achieving permanency. They have lower odds of being reunified, greater odds of being adopted (if not reunified), and lower odds of being placed in permanent kin guardianship (if not reunified or adopted) than children who are not appointed CASA. This study makes an additional contribution by looking beyond the aggregate effect of CASA on permanency by examining the effect of CASA for different age groups and different types of first placement after removal.

School readiness and later achievement.

Using 6 longitudinal data sets, the authors estimate links between three key elements of school readiness--school-entry academic, attention, and socioemotional skills--and later school reading and math achievement. In an effort to isolate the effects of these school-entry skills, the authors ensured that most of their regression models control for cognitive, attention, and socioemotional skills measured prior to school entry, as well as a host of family background measures. Across all 6 studies, the strongest predictors of later achievement are school-entry math, reading, and attention skills. A meta-analysis of the results shows that early math skills have the greatest predictive power, followed by reading and then attention skills. By contrast, measures of socioemotional behaviors, including internalizing and externalizing problems and social skills, were generally insignificant predictors of later academic performance, even among children with relatively high levels of problem behavior. Patterns of association were similar for boys and girls and for children from high and low socioeconomic backgrounds.

Changes in parents' spanking and reading as mechanisms for Head Start impacts on children.

This study examined whether Head Start, the nation's main two-generation program for low-income families, benefits children in part through positive changes in parents' use of spanking and reading to children. Data were drawn from the 3-year-old cohort of the national evaluation of the Head Start program known as the Head Start Impact Study (N = 2,063). Results indicated that Head Start had small, indirect effects on children's spelling ability at Age 4 and their aggression at Age 4 through an increase in parents' reading to their children. Taken together, the results suggest that parents play a role in sustaining positive benefits of the Head Start program for children's behavior and literacy skills, one that could be enhanced with a greater emphasis on parent involvement and education. (PsycINFO Database Record

The stability of elementary school contexts from kindergarten to third grade.

The nature and measurement of school contexts have been the foci of interest in community, developmental, and school psychology for decades. In this paper, we tested the stability of six elementary school-context factors over time, using a nationally representative and longitudinal sample of schools from the Early Childhood Longitudinal Study, Kindergarten Class of 1998-1999 (ECLS-K), and systems theories as a conceptual framework. Confirmatory factor analyses and tests of measurement equivalence revealed that six latent factors fit the data equally well across kindergarten, first grade, and third grade: school strain, school safety practices, school academic performance, school instructional resources, positive school climate, and school violence and crime. The factors were highly stable across the early elementary school years, with standardized stability coefficients ranging from .87 to .99 between kindergarten and first grade and from .71 to .98 between the first and third grades. Equivalence in the two sets of stability coefficients was also found across time. Both the magnitude and equivalence of the stability coefficients were robust to the inclusion of five key exogenous school characteristics as covariates in the model. Results suggest that elementary school contexts are remarkably stable over time and shed light on methodological considerations regarding the treatment of school-level measures in analyses that examine links between school context and children's academic and developmental trajectories.

Child effortful control as a mediator of parenting practices on externalizing behavior: evidence for a sex-differentiated pathway across the transition from preschool to school.

An explanatory model for children's development of disruptive behavior across the transition from preschool to school was tested. It was hypothesized that child effortful control would mediate the effects of parenting on children's externalizing behavior and that child sex would moderate these relations. Participants were 241 children (123 boys) and their parents and teachers. Three dimensions of parenting, warm responsiveness, induction, and corporal punishment, were assessed via maternal report when children were 3 years old. Child effortful control at age 3 was measured using laboratory tasks and a mother-report questionnaire. Mothers and teachers contributed ratings of child externalizing behavior at age 6. Results showed that the hypothesized model fit the data well and that the pattern of associations between constructs differed for boys and girls. For boys, parental warm responsiveness and corporal punishment had significant indirect effects on children's externalizing behavior three years later, mediated by child effortful control. Such relations were not observed for girls. These findings support a sex-differentiated pathway to externalizing behavior across the transition from preschool to school.

A direct LC/MS/MS method for the determination of ciclopirox penetration across human nail plate in in vitro penetration studies.

Due to severe chelating effect caused by N-hydroxylpyridone group of ciclopirox, there is no published direct HPLC or LC/MS/MS method for the determination of ciclopirox in any in vitro or in vivo matrix. Instead, the time-consuming pre-column derivatization methods have been adapted for indirect analysis of ciclopirox. After overcoming the chelating problem by using K(2)EDTA coated tubes, a direct, sensitive and high-throughput LC/MS/MS method was successfully developed and validated to determine the amount of ciclopirox that penetrated across the nail plate during in vitro nail penetration studies. The method involved adding a chemical analog, chloridazon as internal standard (IS) in K(2)EDTA coated tubes, mixing IS with ciclopirox in a 96-well plate and then proceeding to LC/MS/MS analysis. The MS/MS was selected to monitor m/z 208.0-->135.8 and 221.8-->77.0 for ciclopirox and IS, respectively, using positive electrospray ionization. The method was validated over a concentration range of 8-256 ng/mL, yielding calibration curves with correlation coefficients greater than 0.9991 with a lower limit of quantitation (LLOQ) of 8 ng/mL. The assay precision and accuracy were evaluated using quality control (QC) samples at three concentration levels. Analyzed concentrations ranged from 101% to 113% of their respective nominal concentration levels with coefficients of variation (CV) below 10.6%. The average recovery of ciclopirox from nail matrix was 101%. The validated method was successfully used to analyze the ciclopirox formulation and in vitro nail penetration samples.

The novel sensitive and high throughput determination of cefepime in mouse plasma by SCX-LC/MS/MS method following off-line microElution 96-well solid-phase extraction to support systemic antibiotic programs.

A sensitive and high throughput off-line microElution 96-well solid-phase extraction (SPE) followed by strong cation exchange (SCX) liquid chromatography with tandem mass spectrometry (LC/MS/MS) quantification for determination of cefepime has been developed and validated in mouse plasma. Using the chemical analog, ceftazidime as an internal standard (IS), the linear range of the method for the determination of cefepime in mouse plasma was 4-2048 ng/mL with the lower limit of quantitation level (LLOQ) of 4 ng/mL. The inter- and intra-assay precision and accuracy of the method were below 9.05% and ranged from 95.6 to 113%, respectively, determined by quality control (QC) samples at five concentration levels including LLOQ. After microElution SPE, 71.1% of cefepime was recovered. The application of the validated assay for the determination of cefepime in mouse pharmacokinetics (PK) samples after intravenous (IV) and subcutaneous (SC) doses was demonstrated.