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To examine whether women whose partners are involved in their pregnancy are more likely to receive early prenatal care and reduce cigarette consumption over the course of the pregnancy. This study also examines sociodemographic predictors of father involvement during pregnancy. Data on 5,404 women and their partners from the first wave of the Early Childhood Longitudinal Study-Birth Cohort (ECLS-B) were used to examine the association between father involvement during pregnancy and maternal behaviors during pregnancy. Multivariate linear and logistic regression analyses were used and data were weighted to account for the complex survey design of the ECLS-B. Women whose partners were involved in their pregnancy were 1.5 times more likely to receive prenatal care in the first trimester and, among those who smoked at conception, to reduce their cigarette consumption 36% more than women whose partners were not involved in the pregnancy (p = .09). Fathers with less than a high school education were significantly less likely to be involved in their partner's pregnancy, while first-time fathers and fathers who reported wanting the pregnancy were significantly more likely to be involved. The positive benefits of father involvement often reported in the literature on child health and development can be extended into the prenatal period. Father involvement is an important, but understudied, predictor of maternal behaviors during the prenatal period, and improving father involvement may have important consequences for the health of his partner, her pregnancy, and their child.

Unbiased phenotypic screens enable identification of small molecules that inhibit pathogen growth by unanticipated mechanisms. These small molecules can be used as starting points for drug discovery programs that target such mechanisms. A major challenge of the approach is the identification of the cellular targets. Here we report GNF7686, a small molecule inhibitor of Trypanosoma cruzi, the causative agent of Chagas disease, and identification of cytochrome b as its target. Following discovery of GNF7686 in a parasite growth inhibition high throughput screen, we were able to evolve a GNF7686-resistant culture of T. cruzi epimastigotes. Clones from this culture bore a mutation coding for a substitution of leucine by phenylalanine at amino acid position 197 in cytochrome b. Cytochrome b is a component of complex III (cytochrome bc1) in the mitochondrial electron transport chain and catalyzes the transfer of electrons from ubiquinol to cytochrome c by a mechanism that utilizes two distinct catalytic sites, QN and QP. The L197F mutation is located in the QN site and confers resistance to GNF7686 in both parasite cell growth and biochemical cytochrome b assays. Additionally, the mutant cytochrome b confers resistance to antimycin A, another QN site inhibitor, but not to strobilurin or myxothiazol, which target the QP site. GNF7686 represents a promising starting point for Chagas disease drug discovery as it potently inhibits growth of intracellular T. cruzi amastigotes with a half maximal effective concentration (EC50) of 0.15 µM, and is highly specific for T. cruzi cytochrome b. No effect on the mammalian respiratory chain or mammalian cell proliferation was observed with up to 25 µM of GNF7686. Our approach, which combines T. cruzi chemical genetics with biochemical target validation, can be broadly applied to the discovery of additional novel drug targets and drug leads for Chagas disease.

ObjectiveUsing targeted neonatal echocardiography (TNE) to examine cardiopulmonary physiological impact of diuretics in preterm infants with chronic pulmonary hypertension (cPH).Study designRetrospective study comparing TNE indices pre- and ≤2 weeks (post) of initiating diuretic therapy in infants born <32 weeks gestational age with cPH.ResultsTwenty-seven neonates with mean gestational age, birthweight and interval between pre-post diuretic TNE of 27.0 ± 2.8 weeks, 859 ± 294 grams, and 7.8 ± 3.0 days respectively were studied. Diuretics was associated with improvement in pulmonary vascular resistance [pulmonary artery acceleration time (PAAT); 34.27(9.76) vs. 40.24(11.10)ms, p = 0.01), right ventricular (RV) ejection time:PAAT ratio [5.92(1.66) vs. 4.83(1.14), p < 0.01)], RV fractional area change [41.6(9.8) vs. 46.4(6.5%), p = 0.03)] and left ventricular myocardial performance index [0.55(0.09) vs. 0.41(0.23), p < 0.01)]. Post-treatment, frequency of bidirectional/right-to-left inter-atrial shunts decreased significantly (24% vs. 4%, p = 0.05).ConclusionPrimary diuretic treatment in neonates with cPH may result in improvement in PVR, RV and LV function and compliance.

ObjectiveTo describe short-term and long-term outcomes of preterm neonates with severe acute pulmonary hypertension (aPHT) in relation to response to rescue inhaled nitric oxide (iNO) therapy.DesignRetrospective cohort studyover a 6 year period.SettingTertiary neonatal intensive care unit.Patients89 neonates <35 weeks gestational age (GA) who received rescue iNO for aPHT, including 62 treated at ≤3 days of age (early aPHT).InterventionsiNO ≥ 1 hour.Main outcome measuresPositive responders (reduction in fraction of inspired oxygen (FiO2) ≥0.20 within 1 hour of iNO) were compared with non-responders. Primary outcome was survival without moderate-to-severe disability at 18 months of age.ResultsMean (SD) GA and birth weight was 27.7 (3.0) weeks and 1077 (473) gm, respectively. Median (IQR) pre-iNO FiO2 was 1.0 (1.0, 1.0). Positive response rate to iNO was 46%. Responders showed improved survival without disability (51% vs 15%; p<0.01), lower mortality (34% vs 71%; p<0.01) and disability among survivors (17% vs 50%; p=0.06). Higher GA (adjusted OR: 1.44 (95% CI 1.10 to 1.89)), aPHT in context of preterm prolonged rupture of membranes (6.26 (95% CI 1.44 to 27.20)) and positive response to rescue iNO (5.81 (95% CI 1.29 to, 26.18)) were independently associated with the primary outcome. Compared with late cases (>3 days of age), early aPHT had a higher response rate to iNO (61% vs 11%; p<0.01) and lower mortality (43% vs 78%; p<0.01).ConclusionA positive response to rescue iNO in preterm infants with aPHT is associated with survival benefit, which is not offset by long-term disability.

RationalePreterm neonates needing rescue treatments with inotropes and/or inhaled nitric oxide (iNO) (acute critical illnesses, ACIs) in neonatal intensive care units (NICUs) are at high risk of mortality. While targeted neonatal echocardiography consultations (TNE) are increasingly used to guide management, its clinical impact need evaluation.ObjectivesTo investigate clinical outcomes in relation to TNE utilisation during episodes of ACIs among preterm neonates.MethodsThis retrospective cohort study, conducted at two tertiary NICUs over 10 years, included neonates<37 weeks gestational age (GA) who developed ACIs. Patients receiving TNE-guided care (TNE within 24 hours of treatment initiation) were compared with non-TNE management. Outcomes included predischarge mortality, episode-related mortality (<7 days) and a new diagnosis of intraventricular haemorrhage≥grade 3 (IVH-3). Inverse probability of treatment weighting (IPTW) using propensity score was used to account for confounders, including site, birth years and baseline illness severity.Measurements and main resultsOf 622 included patients, 297 (48%) had TNE; median (IQR) GA at ACI was 26.4 (25.0–28.4) weeks. TNE group demonstrated higher baseline mean airway pressure, oxygen requirement and heart rate and frequently received both inotrope and iNO during ACI. IPTW analysis revealed TNE was associated with lower mortality (adjusted OR (95% CI) 0.75 (0.59 to 0.95)), episode-related mortality (0.54 (0.40 to 0.72)) and death or IVH-3 (0.78 (0.62 to 0.99)). TNE group received more varied inotropic agents, demonstrated earlier improvements in blood pressures, without increasing overall inotrpoic burden.ConclusionsAmong preterm neonates requiring rescue treatments with inotropes/iNO, TNE utilisation to guide clinical management may be associated with improved survival.

The daily injection burden of recombinant human growth hormone (r-hGH) replacement therapy to treat growth hormone deficiency (GHD) may reduce compliance and limit treatment benefit. Research is needed to evaluate patient preferences for GHD injection regimen and device features. Quantitatively evaluate factors driving preferences for r-hGH injection regimen and device features among pediatric (3-17 years, and caregivers) and adult (≥25 years) patients with GHD using a discrete choice experiment (DCE) approach. The DCE was part of a broader, cross-sectional observational field study to develop clinical outcome assessments (COAs) that assess the experience of patients taking r-hGH injections. Following ethics approval, discrete choice data were collected through an online questionnaire from consented participants recruited from eight sites in the United States. Participants were presented with 20 choice tasks, each comprising different combinations of two profiles. Participants were then shown the same set of three hypothetical device and injection profiles (ie, storage, preparation, injection type device, maintenance, dose setting, injection schedule) and asked whether they would choose each profile over their current device and schedule. Choice-based conjoint analyses were used to estimate the marginal utilities and values for treatment attributes. Subject preferences were estimated at individual and aggregate levels. Two hundred and twenty-four participants completed the DCE (n=75 adults, n=79 adolescent/caregiver dyads, n=70 child/caregiver dyads). Injection schedule was the strongest predictor of choice for the total sample and each patient group. Less frequent injection schedules were more likely to be chosen by participants. A \"ready to use\" injection was preferred, with no preference for auto-injector versus needle-free device. Most participants would choose the hypothetical injection devices and less frequent dosing over their current daily administered device schedule. Patients prefer a less frequent injection regimen for treating GHD. Addressing patient preferences may improve compliance, adherence, and ultimately, clinical outcomes.

The addition of HER2-targeted agents to neoadjuvant chemotherapy has dramatically improved pathological complete response (pCR) rates in early-stage, HER2-positive breast cancer. Nonetheless, up to 50% of patients have residual disease after treatment, while others are likely overtreated. Here, we performed multiplex spatial proteomic characterization of 122 samples from 57 HER2-positive breast tumors from the neoadjuvant TRIO-US B07 clinical trial sampled pre-treatment, after 14-21 d of HER2-targeted therapy and at surgery. We demonstrated that proteomic changes after a single cycle of HER2-targeted therapy aids the identification of tumors that ultimately undergo pCR, outperforming pre-treatment measures or transcriptomic changes. We further developed and validated a classifier that robustly predicted pCR using a single marker, CD45, measured on treatment, and showed that CD45-positive cell counts measured via conventional immunohistochemistry perform comparably. These results demonstrate robust biomarkers that can be used to enable the stratification of sensitive tumors early during neoadjuvant HER2-targeted therapy, with implications for tailoring subsequent therapy.

We previously identified association between the ID3 SNP rs11574 and carotid intima-media thickness in the Diabetes Heart Study, a predominantly White diabetic population. The nonsynonymous SNP rs11574 results in an amino acid substitution in the C-terminal region of ID3, attenuating the dominant negative function of ID3 as an inhibitor of basic HLH factor E12-mediated transcription. In the current investigation, we characterize the association between the functionally significant polymorphism in ID3, rs11574, with human coronary pathology. The Multi-Ethnic Study of Atherosclerosis (MESA) is a longitudinal study of subclinical cardiovascular disease, including non-Hispanic White (n = 2,588), African American (n = 2,560) and Hispanic (n = 2,130) participants with data on coronary artery calcium (CAC). The Coronary Assessment in Virginia cohort (CAVA) included 71 patients aged 30-80 years, undergoing a medically necessary cardiac catheterization and intravascular ultrasound (IVUS) at the University of Virginia. ID3 SNP rs11574 risk allele was associated with the presence of CAC in MESA Whites (P = 0.017). In addition, the risk allele was associated with greater atheroma burden and stenosis in the CAVA cohort (P = 0.003, P = 0.04 respectively). The risk allele remained predictive of atheroma burden in multivariate analysis (Model 1: covariates age, gender, and LDL, regression coefficient = 9.578, SE = 3.657, p = 0.0110; Model 2: covariates Model 1, presence of hypertension, presence of diabetes, regression coefficient = 8.389, SE = 4.788, p = 0.0163). We present additional cohorts that demonstrate association of ID3 SNP rs11574 directly with human coronary artery pathology as measured by CAC and IVUS: one a multiethnic, relatively healthy population with low levels of diabetes and the second a predominantly White population with a higher incidence of T2DM referred for cardiac catheterization.

Bleomycin-induced lung injury is characterized in the neonatal rat by inflammation dominated by neutrophils and macrophages, inhibited distal airway and vascular development, and pulmonary hypertension, similar to human infants with severe bronchopulmonary dysplasia. Rho-kinase (ROCK) is known to mediate lung injury in adult animals via stimulatory effects on inflammation. We therefore hypothesized that inhibition of ROCK may ameliorate bleomycin-induced lung injury in the neonatal rat. Pups received daily intraperitoneal bleomycin or saline from Postnatal Days 1 through 14 with or without Y-27632, a ROCK inhibitor. Treatment with Y-27632 prevented bleomycin-induced pulmonary hypertension, as evidenced by normalized pulmonary vascular resistance, decreased right-ventricular hypertrophy, and attenuated remodeling of pulmonary resistance arteries. Bleomycin-induced changes in distal lung architecture, including septal thinning, inhibited alveolarization, and decreased numbers of peripheral arteries and capillaries, were partially or completely normalized by Y-27632. Treatment with Y-27632 or a CXCR2 antagonist, SB265610, also abrogated tissue neutrophil influx, while having no effect on macrophages. However, treatment with SB265610 did not prevent bleomycin-induced lung injury. Lung content of angiostatic thrombospondin-1 (TSP1) was increased significantly in the lungs of bleomycin-exposed animals, and was completely attenuated by treatment with Y-27632. Thrombin-stimulated TSP1 production by primary cultured rat pulmonary artery endothelial cells was also attenuated by Y-27632. Taken together, our findings suggest a preventive effect of Y-27632 on bleomycin-mediated injury by a mechanism unrelated to inflammatory cells. Our data suggest that improvements in lung morphology may have been related to indirect stimulatory effects on angiogenesis via down-regulation of TSP1.

Current knowledge gaps pertaining to diagnosis and management of neonatal chronic pulmonary hypertension (cPH) may result in significant variability in clinical practice. The objective of the study is to understand cPH management practices in neonatal intensive care units affiliated with the Canadian Neonatal Network (CNN) and National Institute of Child Health and Human Development Neonatal Research Network (NRN). A 32-question survey seeking practice details for cPH evaluation, diagnostic criteria, conservative measures, pharmacotherapeutics, and follow-up was e-mailed to a designated physician at each center. Responses were described as frequency (percentage) and compared between CNN and NRN, where appropriate. Overall response rate was 67% (CNN 20/28 (71%), NRN 9/15 (60%)). While 8 (28%) centers had standardized management protocols, 17 (59%) routinely evaluate high-risk patients; moderate-severe chronic lung disease being the commonest indication. While interventricular septal flattening on echocardiography was the commonest listed diagnostic criterion, several adjunctive indices were also identified. Asymptomatic neonates with cPH were managed expectantly (routine care) in 50% of sites, and using various conservative measures in others. Pulmonary vasodilators were prescribed for symptomatic cases, with 60% of sites using them early (86% reporting any use). Seventy-five percent of sites use inhaled nitric oxide and sildenafil citrate as first- and second-line agents, respectively. Use of standard protocols, cardiac catheterization, and conservative measures for asymptomatic cases was more common in NRN units (p < 0.05). While there is relative homogeneity in patient identification and diagnostic criteria used for neonatal cPH, significant interunit inconsistencies still exists in routine evaluation, use of additional investigations, management of asymptomatic cases, frequency and type of conservative measures, and choice of pulmonary vasodilators.