An Alternative Consent Process for Minimal Risk Research in the ICU.

OBJECTIVES: Seeking consent for minimal risk research in the ICU poses challenges, especially when the research is time-sensitive. Our aim was to determine the extent to which ICU patients or surrogates support a deferred consent process for a minimal risk study without the potential for direct benefit. DESIGN: Prospective cohort study. SETTING: Five ICUs within a tertiary care hospital. PATIENTS: Newly admitted ICU patients 18 years old or older. INTERVENTIONS: We administered an eight-item verbal survey to patients or surrogates approached for consent to participate in a minimal risk, ICU-based study. The parent study involved noninvasive collection of biosamples and clinical data at the time of ICU admission and again 3 days later. If patients had capacity at the time of ICU admission, or if a surrogate was readily available, consent was sought prior to initial sample collection; otherwise, a waiver of consent was granted, and deferred consent was sought 3 days later. Quantitative and qualitative data were analyzed. MEASUREMENTS AND MAIN RESULTS: One hundred fifty-seven individuals were approached for consent to participate in the parent study; none objected to the consent process. One hundred thirty-five of 157 (86%) competed the survey, including 94 who consented to the parent study and 41 who declined. Forty-four of 60 individuals (73%) approached for deferred consent responded positively to the question "Did we make the right choice in waiting until now to ask your consent?" three of 60 (5%) responded negatively, and 13 of 60 (22%) made a neutral or unrelated response. The most common reason given for endorsing the deferred consent process was the stress of the early ICU experience 25 of 44 (61%). CONCLUSIONS: Most patients and surrogates accept a deferred consent process for minimal risk research in the ICU. For appropriate ICU-based research, investigators and Institutional Review Boards should consider a deferred consent process if the subject lacks capacity and an appropriate surrogate is not readily available.

Prophylaxis for Stress Ulcers With Proton Pump Inhibitors Is Not Associated With Increased Risk of Bloodstream Infections in the Intensive Care Unit.

BACKGROUND & AIMS: Proton pump inhibitors (PPIs) have been associated with increased risk of infection, likely because of changes in intestinal epithelial permeability and the gastrointestinal microbiome. PPIs are frequently given to patients in the intensive care unit (ICU) to prevent stress ulcers. These patients are at risk for bloodstream infections (BSIs), so we investigated the relationship between PPI use and BSIs among patients in the ICU. METHODS: We performed a retrospective cohort study of adults (≥18 years) admitted to 1 of 14 ICUs within a hospital network of 3 large hospitals from 2008 through 2014. The primary exposure was PPI use for stress ulcer prophylaxis in the ICU. The primary outcome was BSI, confirmed by culture analysis, arising 48 hours or more after admission to the ICU. Subjects were followed for 30 days after ICU admission or until death, discharge, or BSI. Multivariable Cox proportional hazards modeling was used to test the association between PPIs and BSI after controlling for patient comorbidities and other clinical factors. RESULTS: We analyzed data from 24,774 patients in the ICU, including 756 patients (3.1%) who developed BSIs while in the ICU. The cumulative incidence of BSI was 3.7% in patients with PPI exposure compared with 2.2% in patients without PPI exposure (log-rank test, P < .01). After adjusting for potential confounders, PPI exposure was not associated with increased risk of BSI while in the ICU (adjusted hazard ratio, 1.08; 95% confidence interval, 0.91-1.29). Comorbidities, antibiotic use, and mechanical ventilation were all independently associated with increased risk for BSIs. CONCLUSIONS: In a retrospective study of patients in the ICU, administration of PPIs to prevent bleeding was not associated with increased risk of BSI. These findings indicate that concern for BSI should not affect decisions regarding use of PPIs in the ICU.

A Tale of Two Baby-Friendly Hospitals: Comparison of a Military and a Civilian Experience.

OBJECTIVE: To compare and contrast military hospital and civilian hospital experiences of achieving Baby-Friendly designation, and to examine administration and staff responses as well as institutional and patient postimplementation outcomes. MATERIALS AND METHODS: Staff, administration, and chairs of Baby-Friendly committees at both hospitals were interviewed. CONCLUSION: Motivating factors and perceived administrative support were similar at both institutions. Both sites saw an increase in exclusive breastfeeding rates upon discharge to a rate of 80-90%, and both noted an overall increase in delivery rates, which may also be attributed to achieving Baby-Friendly designation. Significant differences included the amount of time it took to achieve Baby-Friendly status, the number of specialties represented on the Baby-friendly committee, the percentage of employees who received training, pediatrics involvement and support, and funding sources for staff training.

Students' ratings of teacher support and academic and social-emotional well-being.

Data on students' perceptions of teacher social support, academic functioning, and social-emotional functioning were collected from a sample of 796 7th and 8th grade middle school students using the Child and Adolescent Social Support Scale (CASSS; Malecki, Demaray, & Elliott, 2000), Iowa Tests of Basic Skills (ITBS) and school records, and the Behavior Assessment Scale for Children, Second Edition, Adolescent Version, (BASC-2 SRP-A; Reynolds & Kamphaus, 2004). The purpose of the current study was to examine possible gender differences in perceptions of the frequency and importance of different types of teacher support and the related academic and social-emotional outcomes. Girls rated Emotional and Appraisal Support as more important than did boys. Teacher Emotional Support was significantly and positively related to grade point average (GPA) for boys and girls. For girls only, Emotional and Informational Support were significantly related to ITBS Reading scores, and Emotional, Informational, and Instrumental Support were significantly related to ITBS Math scores. Regarding social-emotional variables, Emotional Support was significantly and negatively related to School Problems, Internalizing Problems, Inattention/Hyperactivity, and overall Emotional Symptoms and positively related to Personal Adjustment for both boys and girls. Furthermore, Emotional Support from teachers was more strongly related to Inattention/Hyperactivity for girls than boys. These results emphasize the importance of providing teacher social support, especially emotional support, to students in early adolescence and recognizing gender differences in the function of specific types of teacher support.

Hiwi mediated tumorigenesis is associated with DNA hypermethylation.

Expression of Piwi proteins is confined to early development and stem cells during which they suppress transposon migration via DNA methylation to ensure genomic stability. Piwi's genomic protective function conflicts with reports that its human ortholog, Hiwi, is expressed in numerous cancers and prognosticates shorter survival. However, the role of Hiwi in tumorigenesis has not been examined. Here we demonstrate that (1) over-expressing Hiwi in sarcoma precursors inhibits their differentiation in vitro and generates sarcomas in vivo; (2) transgenic mice expressing Hiwi (mesodermally restricted) develop sarcomas; and (3) inducible down-regulation of Hiwi in human sarcomas inhibits growth and re-establishes differentiation. Our data indicates that Hiwi is directly tumorigenic and Hiwi-expressing cancers may be addicted to Hiwi expression. We further show that Hiwi associated DNA methylation and cyclin-dependent kinase inhibitor (CDKI) silencing is reversible along with Hiwi-induced tumorigenesis, via DNA-methyltransferase inhibitors. Our studies reveal for the first time not only a novel oncogenic role for Hiwi as a driver of tumorigenesis, but also suggest that the use of epigenetic agents may be clinically beneficial for treatment of tumors that express Hiwi. Additionally, our data showing that Hiwi-associated DNA hyper-methylation with subsequent genetic and epigenetic changes favoring a tumorigenic state reconciles the conundrum of how Hiwi may act appropriately to promote genomic integrity during early development (via transposon silencing) and inappropriately in adult tissues with subsequent tumorigenesis.

A transgenic, mesodermal specific, Dkk1 mouse model recapitulates a spectrum of human congenital limb reduction defects.

Congenital limb reduction defects occurring in isolation of other developmental abnormalities continue to be an important medical problem in which little progress has been made. Herein we generated transgenic mice expressing Dkk1 in an appendicular mesodermal pattern. Prx1-Dkk1 mice recapitulate a full spectrum of human congenital limb reduction defects, without other developmental issues, and have normal life-spans. Importantly, a close examination of the inheritance pattern suggests that there is a significant degree of incomplete penetrance as progeny of phenotypically positive or phenotypically negative, but genotypically positive Prx1-Dkk1 mice, consistently give rise to both phenotypically positive mice and phenotypically normal-appearing mice. Thus, this heterogeneous phenotype is reproducible with each generation regardless of the phenotype of the parents. We further go on to identify that mesenchymal stem cells from Prx1-Dkk1 mice have limited proliferative ability, but normal differentiation potential, which may explain the mechanism for the limb reduction defects observed. We believe Prx1-Dkk1 mice may prove useful in the future to study the mechanisms underlying the development of congenital limb reduction defects.

PPARγ agonists enhance ET-743-induced adipogenic differentiation in a transgenic mouse model of myxoid round cell liposarcoma.

Myxoid round cell liposarcoma (MRCLS) is a common liposarcoma subtype characterized by a translocation that results in the fusion protein TLS:CHOP as well as by mixed adipocytic histopathology. Both the etiology of MRCLS and the mechanism of action of TLS:CHOP remain poorly understood. It was previously shown that ET-743, an antitumor compound with an unclear mechanism of action, is highly effective in patients with MRCLS. To identify the cellular origin of MRCLS, we engineered a mouse model in which TLS:CHOP was expressed under the control of a mesodermally restricted promoter (Prx1) in a p53-depleted background. This model resembled MRCLS histologically as well as functionally in terms of its specific adipocytic differentiation-based response to ET-743. Specifically, endogenous mesenchymal stem cells (MSCs) expressing TLS:CHOP developed into MRCLS in vivo. Gene expression and microRNA analysis of these MSCs showed that they were committed to adipocytic differentiation, but unable to terminally differentiate. We also explored the method of action of ET-743. ET-743 downregulated TLS:CHOP expression, which correlated with CEBPα expression and adipocytic differentiation. Furthermore, PPARγ agonists enhanced the differentiation process initiated by ET-743. Our work highlights how clinical observations can lead to the generation of a mouse model that recapitulates human disease and may be used to develop rational treatment combinations, such as ET-743 plus PPARγ agonists, for the treatment of MRCLS.

Perinatal hospice. Comprehensive care for the family of the fetus with a lethal condition.

OBJECTIVE: To describe our experience in providing a program of structured interdisciplinary care for the families of fetuses prenatally diagnosed with a lethal congenital anomaly. STUDY DESIGN: We developed a comprehensive "perinatal hospice" program for the supportive care of families with fetuses known to have a lethal condition. Upon prenatal diagnosis of a lethal fetal condition, parents were presented with the option of elective pregnancy termination versus a multi-disciplinary program of ongoing supportive care until the time of spontaneous labor or until delivery was required for obstetric indications. We evaluated patient use of this new service and the natural history of pregnancies managed in this fashion. RESULTS: The population consisted of 33 patients carrying a fetus with a clearly delineated lethal anomaly. Twenty-eight (85%) chose to participate in the perinatal hospice program. Of these, 11/28 (39%) had an intrauterine fetal death and 17/28 (61%) delivered a live-born infant. Among the live-born infants were 12 vaginal deliveries, 4 preterm and 8 at term. Obstetric indications or maternal request resulted in cesarean delivery for 5/28 (18%), 4 preterm and 1 at term, all live born. All live-born infants died within 20 minutes to 2 months. There were no maternal complications. CONCLUSION: The availability of a structured program providing ongoing, comprehensive, multidisciplinary, supportive perinatal care offers a tangible and safe alternative to early elective pregnancy termination for patients carrying a fetus with a lethal congenital condition.