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To estimate the association between timing of administration of adjunctive azithromycin for prophylaxis at unscheduled cesarean delivery and maternal infection and neonatal morbidity.We conducted a secondary analysis of a randomized trial of adjunctive azithromycin prophylaxis in patients with singleton gestations who were undergoing unscheduled cesarean delivery. The primary exposure was the timing of initiation of the study drug (after skin incision or 0-30 minutes, more than 30-60 minutes, or more than 60 minutes before skin incision). The primary outcome was a composite of endometritis, wound infection, and other maternal infections occurring up to 6 weeks after cesarean delivery. Secondary outcomes included composite neonatal morbidity, neonatal intensive care unit admission for longer than 72 hours, and neonatal sepsis. The association of azithromycin with outcomes was compared within each antibiotic timing group and presented as risk ratios (RRs) with 95% CIs. A Breslow-Day homogeneity test was applied to assess differences in association by antibiotic timing.Of 2,013 participants, antibiotics were initiated after skin incision (median 3 minutes, range 0-229 minutes) in 269 (13.4%), 0-30 minutes before skin incision in 1,378 (68.5%), more than 30-60 minutes before skin incision in 270 (13.4%), and more than 60 minutes before skin incision (median 85 minutes, range 61-218 minutes) in 96 (4.8%). The RRs (95% CIs) of the infectious composite outcome for azithromycin compared with placebo were significantly lower for groups that initiated azithromycin after skin incision or within 1 hour before skin incision (after skin incision: RR 0.31, 95% CI 0.13-0.76; 0-30 minutes before: RR 0.62, 95% CI 0.44-0.89; more than 30-60 minutes before: 0.31, 95% CI 0.13-0.66). Risks were not significantly different in patients who received azithromycin more than 60 minutes before skin incision (RR 0.59, 95% CI 0.10-3.36). Results were similar when endometritis and wound infections were analyzed separately. Neonatal outcomes were not significantly different for azithromycin compared with placebo across all timing groups.Adjunctive azithromycin administration up to 60 minutes before or at a median of 3 minutes after skin incision was associated with reduced risks of maternal composite postoperative infection in unscheduled cesarean deliveries.ClinicalTrials.gov, NCT01235546.

This article addresses community corrections (CC) training from the perspective of a former practitioner. Though CC training has received modest consideration, academies’ roles in reinforcing occupational cultures are nearly absent from the literature. This article addresses this gap with an autobiographical account of an academy experience and shows that not only did the profession appear to attract candidates with public safety orientations, but also that the academy reinforced those orientations through a disproportionate focus on use of force and officer safety. The article considers challenges policymakers and managers face when attempting to implement reform in public safety cultures.

For non-treatment-seeking women who use substances during pregnancy, immediately postpartum may be an optimum time for intervention. Our study tested a novel, brief, hospital-initiated, adaptive motivational interviewing plus acceptance and commitment therapy (MIACT) intervention to facilitate treatment initiation and reproductive planning postpartum among mothers who used substances during pregnancy.Mothers (N = 64) with an infant admitted to a neonatal intensive care unit were enrolled if they or their infant tested positive for an illicit substance at delivery or had a documented positive drug screen during pregnancy. A parallel group, randomized controlled design assigned participants to MIACT or conventional care (CC), with assessments at week 2 and 4 during treatment and follow-up at 2 and 6 months post treatment. Bayesian generalized linear modeling was used to evaluate outcomes as a function of treatment.Results indicated that during treatment the MIACT group demonstrated an 84% probability of benefit relative to CC with regard to initiating treatment (RR=1.5), however the effect was not seen at follow-up. MIACT was also associated with an increased probability of attending a postpartum obstetrics visit (RR=1.4), and receiving contraception during treatment and at both follow-ups, with posterior probabilities of 96% or higher and relative risks ranging from 1.5 to 5.1 at varying timepoints. Substance use rates for the MIACT versus CC were higher at follow-up.Brief, hospital-initiated interventions can assist postpartum mothers who use substances to enter treatment and obtain contraception in order to reduce future substance-exposed pregnancies.

This paper explored the role that social entrepreneurship may play in helping to improve euthanasia and live release rates in animal shelters. This paper used a qualitative, comparative ethnographic study that included semi-structured interviews, participant observation, and archival research. It compared two large animal shelters from the U.S. and Australia. Collectively, 21 formal interviews, more than 30 informal interviews, and participant observation were conducted over a 6-month time frame between the two countries. Findings indicate that three main factors may contribute to the transformation of non-profit animals shelters and result in improved euthanasia and live release rates, as well as animal caregiver burnout. These include: (1) professionalizing shelter management, (2) engaging with non-profit social enterprise activities, and (3) improving the efficiency of daily operations. In this paper, we argue that by embracing non-profit social enterprise activities, animal shelters may improve anthropocentric animal shelter activities to positively affect human and non-human rights, welfare, and agency. We do not contend that non-profit animal shelters should sacrifice their stated mission or ethics to include business practices. Rather, by professionalizing management and operations that include self-sustaining diverse revenue streams, it may free up time and resources to make a greater effect in positive non-human animal welfare and outcomes.

Preeclampsia (PE) is a life-threatening hypertensive renal disorder of pregnancy. Soluble fms-like tyrosine kinase 1 (sFlt-1), an anti-angiogenic factor, is elevated and contributes to PE. However, molecular basis underlying its up-regulation in PE remains unclear. Here we report that hypoxia inducible factor-1α (HIF-1α), an important transcriptional factor, and U2AF65, a key molecule involved in alternative splicing, are significantly increased in the placentasof PE patients compared to the controls. Using two animal models of PE including angiotensin receptor type 1 receptor agonistic autoantibody (AT1-AA) and LIGH (a TNF-α superfamily member)-induced PE mouse model coupled with in vivo nanoliposome-delivery system to specifically knockdown HIF-1α and U2AF65, we found that knockdown of HIF-1α or U2AF65 significantly attenuated AT1-AA-induced hypertension (HIF-1α siRNA: 137±4mmHg; U2AF65 siRNA: 140±5mmHg, vs. AT1-AA group 164±3mmHg, p

Preeclampsia (PE) is a serious pregnancy disease characterized by hypertension and proteinuria. Despite intensive research efforts, the underlying cause of PE remains a mystery. PE is, however, associated with abnormalities of the immune system. Here we report that the levels of C-reactive protein (CRP), an important acute phase reactant, were significantly elevated in the plasma of human with PE at the third trimester. Next, we found that CRP protein levels in the placentas of PE patients were also significantly increased compared to controls. In an effort to determine the exact role of elevated CRP in PE, we infused CRP into pregnant mice. We found that injection of CRP into pregnant mice induced hypertension (170 mmHg mean systolic vs. 125 mmHg mean systolic control; pin vivo evidence that inhibition of NK3R by SB222200 or knockdown of NK3R by specific siRNA in a potent nanoparticle delivery system significantly reduced CRP-induced hypertension and proteinuria in pregnant mice (170 mmHg mean systolic CRP-injected vs. 130 mmHg mean systolic siRNA NK3R; p

Preeclampsia (PE) is a serious hypertensive disease of pregnancy associated with the presence of the major angiotensin receptor AT1-agnostic autoantibodies (AT1-AAs) that cause the defining PE features when introduced into pregnant mice. To understand AT1-AA-mediated receptor activation in PE, we explored the role of tissue transglutaminases (TG2), the most ubiquitous member of a group of enzymes modifying proteins by catalyzing the formation of ε-(γ-glutamyl)-lysine isopeptide bonds. TG2, a versatile protein that can also function as a G protein, is enriched in the syncytiotrophoblasts of placenta, the key organ in PE pathogenesis. Western blot analysis and IHC-IF double staining initially revealed that TG2 and transglutaminase (TG)-mediated isopeptide modification levels are increased approximately 2X in PE vs normotensive (NT) placental tissue (n=4 or 5, p2 >0.5, pin vivo experiments in which TG inhibitor cystamine, or siRNA-mediated TG2 knockdown, significantly attenuated AT1-AA-induced PE features in pregnant mice including hypertension (PE=160±6 vs PE+cystamine=133±3mmHg, pTG2 siRNA=137±7mmHg, pTG2 siRNA=26±6ng albumin/mg creatine, p

Background: Preeclampsia (PE), a life-threatening hypertensive pregnancy disorder, has long been speculated to be associated with placental hypoxia. Adenosine (Ado) is a signaling molecule well known to be induced by hypoxia. Ado levels are increased in the fetomaternal circulation of PE patients and correlated to its severity. However, the causative factors for its induction and pathophysiologic role of elevated Ado in PE are undetermined. Methods & Results: Using RT-PCR profiling of purinergic components in the human placentas, we found that CD73, a key enzyme producing extracellular Ado, was elevated most in the placentas of PE patients. To determine the exact role of elevated CD73 in Ado production, we took advantage of a well-established PE model: pregnant mice infused with angiotensin type 1 receptor agonistic antibody (AT1-AA), an emerging pathogenic factor known to contribute to PE. Similar to human studies, we found that both CD73 expression and Ado levels were significantly increased in the placentas of AT1-AA-injected pregnant mice compared to the controls. To determine whether elevated placental Ado is dependent on increased placental CD73 and contributes to pathophysiology of PE, we took both genetic and pharmacological approaches. We found that AT1-AA-mediated placental Ado production was reduced in CD73-deficient pregnant mice. As such, AT1-AA-induced features of PE including hypertension and proteinuria also significantly reduced (BP: 166 to 144 mmHg, proteinuria: 42 to 31 mg/g creatinine). Similarly, we found polyethylene glycol-linked adenosine deaminase (PEG-ADA), a drug that has successfully treated ADA-deficient patients by lowering Ado, ameliorated PE features significantly (BP: 170 to 141 mmHg, proteinuria: 39 to 28 mg/g creatinine). Mechanistically, we further revealed that HIF-1a is a key transcription factor underlying increased CD73 expression, Ado elevation, and subsequent sFlt-1 induction and disease development. Conclusions: Our studies revealed i) a pathologic nature of chronic elevated placental Ado in PE; ii) HIF-1a-dependent CD73 upregulation in placenta underlying Ado induction, sFlt-1 elevation and PE features; and iii) novel diagnostic markers and therapeutic possibilities for the disease.

Preeclampsia (PE) is a prevalent life-threatening complication of pregnancy featuring hypertension, placental abnormality, and renal damage. The condition is associated with the presence of agonistic autoantibodies (AT1-AA) capable of activating the major angiotensin receptor, AT1R, and believed to contribute to disease pathogenesis. Tissue transglutaminase (tTG), a prominent member of a family of enzymes that crosslink proteins by catalyzing the formation of inter- or intra-molecular ε-(γ-glutamyl)- lysine isopeptide bonds, is known to interact with G protein-coupled receptors and contribute to hypertension. Thus, we hypothesize that AT1-AA may function via tTG to crosslink AT1R and contribute to pathophyhsiology of PE. To test this hypothesis, using immunoprecipation with anti-tTG antibody, we successfully pulled down more AT1R from human trophoblast (HTR) cells treated with IgG from PE women than IgG from normotensive (NT) women, thereby providing initial evidence for the promotional effect of AT1-AA on tTG and AT1R interaction. Subsequently, we measured tTG and its modification on AT1R in both NT and PE placentas. We found increased levels of tissue transglutaminase (∼2 folds), ε-(γ-glutamyl)- lysine isopeptides (∼2 folds), and AT1R with ε-(γ-glutamyl)- lysine isopeptide bonds at the microvillous membrane of PE placentas, indicating that tTG-induced AT1 receptor modification is elevated in PE placenta. Finally, in an effort to determine the role of elevated tTG in AT1-AA-induced PE in vivo, we treated PE-IgG injected pregnant mice with cystamine, a potent tTG inhibitor. Compared with PE-IgG injected mice, less AT1 receptor with ε-(γ-glutamyl)- lysine isopeptide bonds was found in the placental labyrinth zone of PE-IgG injected mice treated with cystamine. Moreover, cystamine treatment significantly attenuated key features associated with PE including hypertension (from 159.5±5.6 to 132.6±2.7 mm Hg) and proteinuria (from 106.5±37.8 to 38.5±6.9 ng albumin/mg creatine) in the PE-IgG-injected pregnant mice as well. Taken together, here we report a previously unrecognized role of tTG in the pathogenesis of PE by crosslinking AT1Rs and suggest a novel therapeutics for the disease.

We sought to evaluate whether 17 alpha-hydroxyprogesterone caproate (17-OHP) reduces preterm birth (PTB) in nulliparous women with a midtrimester cervical length (CL)30 mm.In this multicenter randomized controlled trial, nulliparous women with a singleton gestation between 16 and 22 3/7 weeks with an endovaginal CL30 mm (10th percentile in this population) were randomized to weekly intramuscular 17-OHP (250 mg) or placebo through 36 weeks. The primary outcome was PTB37 weeks.The frequency of PTB did not differ between the 17-OHP (n = 327) and placebo (n = 330) groups (25.1% vs 24.2%; relative risk, 1.03; 95% confidence interval, 0.79-1.35). There also was no difference in the composite adverse neonatal outcome (7.0% vs 9.1%; relative risk, 0.77; 95% confidence interval, 0.46-1.30).Weekly 17-OHP does not reduce the frequency of PTB in nulliparous women with a midtrimester CL30 mm.