Childhood Corporal Punishment and Future Perpetration of Physical Dating Violence.

OBJECTIVE: To test whether experiencing childhood corporal punishment is linked to later perpetration of dating violence. STUDY DESIGN: Young adults (n = 758; 61% female; mean age of 20 years), originally recruited for a longitudinal study as 9th- and 10th-grade Texas high school students, were asked about their childhood experiences with corporal punishment and physical abuse, as well as current experiences with dating violence. A path model was used to determine whether childhood corporal punishment was related to recent perpetration of physical dating violence, while controlling for childhood physical abuse, age, sex, ethnicity, and socioeconomic status. RESULTS: In all, 19% of participants (n = 134) reported physical dating violence perpetration and 68% reported experiencing corporal punishment as children (n = 498). Analysis showed a significant positive association between corporal punishment and physical perpetration of dating violence (OR 1.30, 95% CI 1.07-1.59). Even after controlling for sex, ethnicity, age, parental education, and child physical abuse, childhood corporal punishment was associated significantly with physical dating violence perpetration (aOR 1.29, 95% CI 1.02-1.62). CONCLUSIONS: The finding that childhood corporal punishment was associated with perpetration of young adult physical dating violence, even after controlling for several demographic variables and childhood physical abuse, adds to the growing literature demonstrating deleterious outcomes associated with corporal punishment.

A Short-Term Evaluation of a Hospital No Hit Zone Policy to Increase Bystander Intervention in Cases of Parent-to-Child Violence.

This study used a pre/post design to evaluate the implementation of a hospital-wide No Hit Zone (NHZ) bystander intervention around parent-to-child hitting. A total of 2,326 staff completed the pre-NHZ survey and received training about the NHZ policy; 623 staff completed the post-test survey 10 months later. A group of 225 parents participated in the pre-NHZ survey and a second group of 180 participated in the post-NHZ survey, also 10 months later. Compared to staff in the pre-NHZ group, staff in the post-NHZ group had more negative attitudes about spanking and more positive attitudes about intervention when parents hit children in the hospital. Few differences were found among the parent pre- and post-groups. This study demonstrated that NHZs are a feasible way to inform and train hospital staff in ways to intervene during incidents of parent-to-child hitting to promote a safe and healthy medical environment.

Role of Direct and Indirect Violence Exposure on Externalizing Behavior in Children.

The objective of this study was to examine the association between externalizing behaviors and indirect violence exposure, assessed both within the household and at the community level, as well as the interaction effect of indirect and direct violence exposure. A sample of parents of children ages 4-15 who have not been referred or enrolled in child welfare (n = 82) were recruited from the greater New Orleans community. Externalizing behavior was assessed with the Child Behavior Checklist (CBCL). The child's indirect exposure to violence included witnessing community violence, witnessing physical assault, and witnessing fighting or domestic violence at home. Direct exposure to violence included the child experiencing physical aggression from a caregiver. All assessments were based on caregiver reports. To decrease potential for confounding, children were matched for analysis based on age, Hurricane Katrina exposure, and their propensity to be exposed to high indirect violence. Cumulative indirect exposure to violence was significantly positively correlated with CBCL scores. After controlling for key covariates, CBCL externalizing T score increased significantly by approximately 1.25 points for each level increase in indirect violence exposure (ß = 1.25, SE = 0.57, p = 0.027). There also was a significant interaction between indirect and direct exposure to violence in the association with CBCL score (ß = -0.08, SE = 0.03, p = 0.002). These findings extend previous research by demonstrating that exposure to both direct and cross-contextual indirect violence influences externalizing behaviors in children. Additionally, the findings suggest that community and household social environments are both important targets for interventions designed to decrease externalizing behaviors and improve long-term outcomes for youth at risk of exposure to violence.

SNS01-T modulation of eIF5A inhibits B-cell cancer progression and synergizes with bortezomib and lenalidomide.

The high rates of recurrence and low median survival in many B-cell cancers highlight a need for new targeted therapeutic modalities. In dividing cells, eukaryotic translation initiation factor 5A (eIF5A) is hypusinated and involved in regulation of protein synthesis and proliferation, whereas the non-hypusinated form of eIF5A is a potent inducer of cell death in malignant cells. Here, we demonstrate the potential of modulating eIF5A expression as a novel approach to treating B-cell cancers. SNS01-T is a nonviral polyethylenimine-based nanoparticle, designed to induce apoptosis selectively in B-cell cancers by small interfering RNA-mediated suppression of hypusinated eIF5A and plasmid-based overexpression of a non-hypusinable eIF5A mutant. In this study, we show that SNS01-T is preferentially taken up by malignant B cells, inhibits tumor growth in multiple animal models of B-cell cancers without damaging normal tissues, and synergizes with the current therapies bortezomib and lenalidomide to inhibit tumor progression. The results collectively demonstrate the potential of SNS01-T as a novel therapeutic for treatment of a diverse range of B-cell malignancies.

A systematic review of universal campaigns targeting child physical abuse prevention.

The purpose of this review was to better understand the impact of universal campaign interventions with a media component aimed at preventing child physical abuse (CPA). The review included 17 studies featuring 15 campaigns conducted from 1989 to 2011 in five countries. Seven studies used experimental designs, but most were quasi-experimental. CPA incidence was assessed in only three studies and decreased significantly in two. Studies also found significant reductions in relevant outcomes such as dysfunctional parenting, child problem behaviors and parental anger as well as increases in parental self-efficacy and knowledge of concepts and actions relevant to preventing child abuse. The following risk factors were most frequently targeted in campaigns: lack of knowledge regarding positive parenting techniques, parental impulsivity, the stigma of asking for help, inadequate social support and inappropriate expectations for a child's developmental stage. The evidence base for universal campaigns designed to prevent CPA remains inconclusive due to the limited availability of rigorous evaluations; however, Triple-P is a notable exception. Given the potential for such interventions to shift population norms relevant to CPA and reduce rates of CPA, there is a need to further develop and rigorously evaluate such campaigns.

From neighborhood to household: connections between neighborhood vacant and abandoned property and family violence.

Rates of family violence, including intimate partner violence (IPV) and child maltreatment, remain high in the U.S. and contribute to substantial health and economic costs. How neighborhood environment may influence family violence remains poorly understood. We examine the association between neighborhood vacant and abandoned properties and family violence, and the role collective efficacy may play in that relationship. Data were used from a longitudinal cohort of 218 maternal-child dyads in a southern U.S. city known for elevated rates of violence. Women were matched on their propensity score, for living in a neighborhood with elevated vacant and cited properties. Analyses accounting for clustering in neighborhood and matched groups were conducted to examine the association between neighborhood vacant and abandoned property and family violence, and the potential mediating relationship of collective efficacy. The likelihood of experiencing child maltreatment at 12-months of age was more than twice as high for children living in neighborhoods with a high vacant and cited property rates compared to women living in neighborhoods with fewer vacant and cited properties (OR=2.11, 95% CI=1.03, 4.31). Women living in neighborhoods characterized by high levels of vacant and cited properties were also more than twice as likely to report IPV (OR=2.52, 95% CI=1.21, 5.25). Associations remained mostly stable after controlling for key covariates. Collective efficacy did not act as a mediator in the relationship between vacant and cited properties and family violence. Reducing neighborhood vacant and cited properties may be an important target for interventions focused on reducing family violence.

Role of p38 and JNK MAPK signaling pathways and tumor suppressor p53 on induction of apoptosis in response to Ad-eIF5A1 in A549 lung cancer cells.

BACKGROUND: The eukaryotic translation initiation factor 5A1 (eIF5A1) is a highly conserved protein involved in many cellular processes including cell division, translation, apoptosis, and inflammation. Induction of apoptosis is the only function of eIF5A1 that is known to be independent of post-translational hypusine modification. In the present study, we investigated the involvement of mitogen- and stress-activated protein kinases during apoptosis of A549 lung cancer cells infected with adenovirus expressing eIF5A1 or a mutant of eIF5A1 that cannot be hypusinated (eIF5A1K50A). METHODS: Using adenoviral-mediated transfection of human A549 lung cancer cells to over-express eIF5A1 and eIF5A1K50A, the mechanism by which unhypusinated eIF5A1 induces apoptosis was investigated by Western blotting, flow cytometry, and use of MAPK and p53 inhibitors. RESULTS: Phosphorylation of ERK, p38 MAPK, and JNK was observed in response to adenovirus-mediated over-expression of eIF5A1 or eIF5A1K50A, along with phosphorylation and stabilization of the p53 tumor suppressor protein. Synthetic inhibitors of p38 and JNK kinase activity, but not inhibitors of ERK1/2 or p53 activity, significantly inhibited apoptosis induced by Ad-eIF5A1. Importantly, normal lung cells were more resistant to apoptosis induced by eIF5A1 and eIF5A1K50A than A549 lung cancer cells. CONCLUSIONS: Collectively these data indicate that p38 and JNK MAP kinase signaling are important for eIF5A1-induced cell death and that induction of apoptosis was not dependent on p53 activity.

Modulation of eIF5A expression using SNS01 nanoparticles inhibits NF-κB activity and tumor growth in murine models of multiple myeloma.

Despite recent advances in the first-line treatment of multiple myeloma, almost all patients eventually experience relapse with drug-resistant disease. New therapeutic modalities are needed, and to this end, SNS01, a therapeutic nanoparticle, is being investigated for treatment of multiple myeloma. The antitumoral activity of SNS01 is based upon modulation of eukaryotic translation initiation factor 5A (eIF5A), a highly conserved protein that is involved in many cellular processes including proliferation, apoptosis, differentiation and inflammation. eIF5A is regulated by post-translational hypusine modification, and overexpression of hypusination-resistant mutants of eIF5A induces apoptosis in many types of cancer cells. SNS01 is a polyethylenimine (PEI)-based nanoparticle that contains both a B-cell-specific expression plasmid expressing a non-hypusinable mutant of eIF5A and a small interfering RNA (siRNA) which depletes endogenous hypusinated eIF5A. Reducing hypusine-modified eIF5A levels was found to inhibit phosphorylation and activity of ERK MAPK and nuclear factor-κB (NF-κB), and thus sensitize myeloma cells to apoptosis resulting from transfection of a plasmid expressing eIF5A(K50R). SNS01 exhibited significant antitumoral activity in both KAS-6/1 (95% inhibition; P < 0.05) and RPMI 8226 (59% inhibition; P < 0.05) multiple myeloma xenograft models following systemic administration. These results highlight the potential of using this approach as a new therapeutic strategy for multiple myeloma.

Parental Spanking and Subsequent Risk for Child Aggression in Father-Involved Families of Young Children.

This study examined separate and combined maternal and paternal use of spanking with children at age 3 and children's subsequent aggressive behavior at age 5. The sample was derived from a birth cohort study and included families (n = 923) in which both parents lived with the child at age 3. In this sample, 44% of 3-year-olds were spanked 2 times or more in the past month by either parent or both parents. In separate analyses, being spanked more than twice in the prior month at age 3, by either mother or father, was associated with increased child aggression at 5 years. In combined analyses, there was a dose-response association; the greatest risk for child aggression was reported when both parents spanked more than twice in the prior month (adjusted odds ratio: 2.01; [confidence interval: 1.03-3.94]). Violence prevention initiatives should target and engage mothers and fathers in anticipatory guidance efforts aimed at increasing the use of effective and non-aggressive child discipline techniques and reducing the use of spanking.

Peptide-Affinity Isolation of Extracellular Vesicles and Cell-Free DNA From Human Plasma.

Extracellular vesicles (EVs) are membrane-bound nanoparticles that carry DNA, RNA, and protein cargoes and are found in a variety of biofluids. EVs, along with cell-free DNA (cfDNA), have attracted interest as a source of biomarker material for liquid biopsy, a process in which a sample of body fluid is used for the detection or monitoring of disease. The Vn96 synthetic peptide facilitates the isolation of both EVs and cfDNA from multiple body fluids, including human plasma, placing it as a versatile tool for the capture of multiple biomarker materials for disease detection and/or treatment monitoring. In this chapter, we describe an optimized protocol for Vn96-mediated isolation of EVs and cfDNA from human plasma samples, as well as downstream methods for EV enumeration and DNA, RNA, and protein extraction from the material captured by Vn96 for use in biomarker discovery or detection.

Renal protection during 177lutetium DOTATATE molecular radiotherapy in children: a proposal for safe amino acid infusional volume during peptide receptor radionuclide therapy.

Peptide receptor radionuclide therapy (PRRT) using radiolabelled somatostatin analogues such as 177-lutetium DOTATATE is an effective treatment modality for neuroendocrine tumours, paragangliomas, and neuroblastomas. However, renal and haematopoietic toxicities are the major limitations of this therapeutic approach. The renal toxicity of PRRT is mediated by renal proximal tubular reabsorption and interstitial retention of the radiolabelled peptides resulting in excessive renal irradiation that can be dose-limiting. To protect the kidneys from PRRT-induced radiation nephropathy, basic amino acids are infused during PRRT as they competitively bind to the proximal tubular cells and prevent uptake of the radionuclide. In adults, 1 L of a basic amino acid solution consisting of arginine and lysine is infused over 4 h commencing 30 min prior to PRRT. However, this volume of amino acids infused over 4 h is excessive in small children and can result in hemodynamic overload. This is all the more relevant in paediatric oncology, as many of the children may have been heavily pretreated and so may have treatment-related renal and or cardiac impairment. We have therefore developed the following guidelines for safe paediatric dosing of renal protective amino acid infusions during PRRT. Our recommendations have been made taking into consideration the renal physiology in small children and the principles of safe fluid management in children.

Perceived social norms, expectations, and attitudes toward corporal punishment among an urban community sample of parents.

Despite the fact that corporal punishment (CP) is a significant risk factor for increased aggression in children, child physical abuse victimization, and other poor outcomes, approval of CP remains high in the United States. Having a positive attitude toward CP use is a strong and malleable predictor of CP use and, therefore, is an important potential target for reducing use of CP. The Theory of Planned Behavior suggests that parents' perceived injunctive and descriptive social norms and expectations regarding CP use might be linked with CP attitudes and behavior. A random-digit-dial telephone survey of parents from an urban community sample (n = 500) was conducted. Perceived social norms were the strongest predictors of having positive attitudes toward CP, as follows: (1) perceived approval of CP by professionals (ß = 0.30), (2) perceived descriptive norms of CP use (ß = 0.22), and (3) perceived approval of CP by family and friends (ß = 0.19); also, both positive (ß = 0.13) and negative (ß = -0.13) expected outcomes for CP use were strong predictors of these attitudes. Targeted efforts are needed to both assess and shift the attitudes and practices of professionals who influence parents regarding CP use; universal efforts, such as public education campaigns, are needed to educate parents and the general public about the high risk/benefit ratio for using CP and the effectiveness of non-physical forms of child discipline.

A retrospective study of malaria in pediatric oncology patients in Senegal.

We retrospectively studied the outcome of malaria infection in pediatric oncology patients presenting to a single institution in Senegal, West Africa over a 10-year period (2000 to 2009). We investigated whether myelosuppression (secondary to chemotherapy) was associated with increased case fatality from malaria. Anonymized clinical and laboratory data were recorded. Severe anemia was defined as hemoglobin less than 6 g/dL, leucopenia as total white blood cell count less than 4×109/L, neutropenia as less than 1×109/L, and "lymphopenia" as non-neutrophil component less than 2.5×109/L. Primary outcome was death within 1 month of malaria diagnosis, from coma or multiple organ failure, in the absence of another infectious cause. Data analysis was carried out with SPSS (v16.0) using Fisher exact test (P<0.05, significant). Fifty-five malarial cases were confirmed in 54 patients (total 400 patients; overall incidence 14%). Four cases were excluded because of lack of outcome data. Of the remaining 51 episodes, at 1 month after malaria diagnosis, 46 recovered (90.2%) and 5 died (9.8%). There was no association with severe anemia, leucopenia, neutropenia, or lymphopenia (P=1.00, P=0.28, P=0.53, and P=0.22, respectively). Despite the high incidence of myelosuppression in pediatric oncology patients, we found no evidence that this was associated with increased fatality of malaria episodes.

Educating Parents About Corporal Punishment and Effective Discipline: Pediatricians' Preparedness, Motivation, and Barriers.

OBJECTIVE: To assess US pediatricians' preparedness, motivation, and barriers related to educating parents about corporal punishment (CP) and effective child discipline. METHODS: A random sample of 1500 pediatricians was drawn from a nationwide database in the United States. A self-administered questionnaire was sent via mail in 2016. The response rate (53%; n = 787) was maximized via repeated survey mailings and use of cash incentives. RESULTS: The majority of respondents were White (69%), female (59%) and were members of the American Academy of Pediatrics (85%). Most pediatricians felt somewhat prepared to advise parents about child discipline, particularly CP, and perceived their colleagues to be slightly less prepared than themselves. Although most (72%) respondents believed it was "extremely/very" likely that parents valued their advice about child discipline, only 36% believed parents were "extremely/very" likely to follow their advice. Most respondents were highly motivated to participate in activities designed to change norms regarding CP. The most common strategy pediatricians identified for improving child behavior was being consistent with rules (71%). Perceived barriers to providing child discipline advice to parents included lack of time (90%), lack of insurance reimbursement (48%), and lack of training and educational resources (47%). CONCLUSIONS: Pediatricians are a key source of professional advice for parents about how to discipline children safely. Given this, along with strong approval and use of CP in the United States and its harm for children, the current findings suggest a strong need for pediatricians to receive additional training on how to advise parents about child discipline along with removal of barriers to providing such advice.

Effects of Sequential Prepaid Incentives on Response Rates, Data Quality, Sample Representativeness, and Costs in a Mail Survey of Physicians.

While collecting high quality data from physicians is critical, response rates for physician surveys are frequently low. A proven method for increasing response in mail surveys is to provide a small, prepaid monetary incentive in the initial mailing. More recently, researchers have begun experimenting with adding a second cash incentive in a follow-up contact in order to increase participation among more reluctant respondents. To assess the effects of sequential incentives on response rates, data quality, sample representativeness, and costs, physicians (N = 1,500) were randomly assigned to treatments that crossed the amount of a first ($5 or $10) and second ($0, $5, or $10) incentive to form the following groups: Group $5/$5; Group $5/$10; Group $10/$0; Group $10/$5; and Group $10/$10. Overall, second incentives were associated with higher response rates and lower costs per completed survey, and while they had no effect on item nonresponse, they increased sample representativeness.

A multiparametric extraction method for Vn96-isolated plasma extracellular vesicles and cell-free DNA that enables multi-omic profiling.

Extracellular vesicles (EVs) have been recognized as a rich material for the analysis of DNA, RNA, and protein biomarkers. A remaining challenge for the deployment of EV-based diagnostic and prognostic assays in liquid biopsy testing is the development of an EV isolation method that is amenable to a clinical diagnostic lab setting and is compatible with multiple types of biomarker analyses. We have previously designed a synthetic peptide, known as Vn96 (ME kit), which efficiently isolates EVs from multiple biofluids in a short timeframe without the use of specialized lab equipment. Moreover, it has recently been shown that Vn96 also facilitates the co-isolation of cell-free DNA (cfDNA) along with EVs. Herein we describe an optimized method for Vn96 affinity-based EV and cfDNA isolation from plasma samples and have developed a multiparametric extraction protocol for the sequential isolation of DNA, RNA, and protein from the same plasma EV and cfDNA sample. We are able to isolate sufficient material by the multiparametric extraction protocol for use in downstream analyses, including ddPCR (DNA) and 'omic profiling by both small RNA sequencing (RNA) and mass spectrometry (protein), from a minimum volume (4 mL) of plasma. This multiparametric extraction protocol should improve the ability to analyse multiple biomarker materials (DNA, RNA and protein) from the same limited starting material, which may improve the sensitivity and specificity of liquid biopsy tests that exploit EV-based and cfDNA biomarkers for disease detection and monitoring.

Apoptosis induction by eIF5A1 involves activation of the intrinsic mitochondrial pathway.

The regulatory role of eukaryotic translation initiation factor 5A1 (eIF5A1) in apoptosis was examined using HT-29 and HeLa S3 cells. eIF5A is the only known protein to contain the unusual amino acid, hypusine, and eIF5A1 is one of two human eIF5A family members. Two observations indicated that eIF5A1 is involved in apoptosis. First, siRNA-mediated suppression of eIF5A1 resulted in inhibition of apoptosis induced by various apoptotic stimuli, and second, adenovirus-mediated over-expression of eIF5A1 strongly induced apoptotic cell death. A mutant of eIF5A1 incapable of being hypusinated also induced apoptosis when over-expressed indicating that unhypusinated eIF5A1 is the pro-apoptotic form of the protein. Over-expression of eIF5A1 or of the mutant resulted in loss of mitochondrial transmembrane potential, translocation of Bax to the mitochondria, release of cytochrome c, caspase activation, up-regulation of p53, and up-regulation of Bim, a pro-apoptotic BH3-only Bcl-2 family protein. In addition, Bim(L) and Bim(S), the pro-apoptotic alternative spliced forms of Bim, were induced in response to over-expression of eIF5A1. Thus eIF5A1 appears to induce apoptosis by activating the mitochondrial apoptotic pathway. Proteomic analyses indicated that, of 1,899 proteins detected, 131 showed significant changes in expression (P or=1.5) within 72 h of eIF5A1 up-regulation. Among these are proteins involved in translation and protein folding, transcription factors, proteins mediating proteolysis, and a variety of proteins known to be directly involved in apoptosis. These observations collectively indicate that unhypusinated eIF5A1 plays a central role in the regulation of apoptosis.

Intimate partner violence, maternal stress, nativity, and risk for maternal maltreatment of young children.

OBJECTIVES: We examined the associations of intimate partner violence (IPV) and maternal risk factors with maternal child maltreatment risk within a diverse sample of mothers. METHODS: We derived the study sample (N=2508) from the Fragile Families and Child Well-Being Study. We conducted regression analyses to examine associations between IPV, parenting stress, major depression, key covariates, and 4 proxy variables for maternal child maltreatment. RESULTS: Mothers reported an average of 25 acts of psychological aggression and 17 acts of physical aggression against their 3-year-old children in the year before the study, 11% reported some act of neglect toward their children during the same period, and 55% had spanked their children during the previous month. About 40% of mothers had experienced IPV by their current partner. IPV and maternal parenting stress were both consistent risk factors for all 4 maltreatment proxy variables. Although foreign-born mothers reported fewer incidents of child maltreatment, the IPV relative risk for child maltreatment was greater for foreign-born than for US-born mothers. CONCLUSIONS: Further integration of IPV and child maltreatment prevention and intervention efforts is warranted; such efforts must carefully balance the needs of adult and child victims.

The association between perceived injunctive norms toward corporal punishment, parenting support, and risk for child physical abuse.

The use of corporal punishment (CP) is a strong risk factor for many poor outcomes for children including child maltreatment. The use of CP occurs within social contexts which are important to understand. Although it is known that perceived social norms regarding CP are related to its use, the specific role that a mother's primary support person plays in influencing attitudes toward and use of CP remains unknown. The current study assessed linkages between maternal perceived social support in parenting and perceived injunctive norms of CP from her primary source of support, with maternal attitudes toward and use of CP. Survey data were collected from female primary caregivers (N = 436) of children age 2 to 7 years (mean age = 3.7) enrolled in Special Supplemental Nutrition Program for Women, Infants and Children (WIC) clinics in Southeastern Louisiana. Most frequently, the biological father of the child (37.9%) and the maternal grandmother of the child (24.2%) were identified as the participant's primary source of social support in parenting. Perceived injunctive norms of this support person toward CP use were significantly and positively associated with attitudes toward, AOR = 5.97, 95% CI = [4.04, 8.82], and use of CP, AOR = 3.77, 95% CI = [2.55, 5.59]. However, perceived social support was not associated with these outcomes and also did not moderate these associations. Findings suggest that efforts to reduce maternal risk for child physical abuse and use of CP must include the mother's primary source of social support if they are to be successful.

Cumulative experiences of violence among high-risk urban youth.

This study examines type-specific and cumulative experiences of violence among a vulnerable population of youth. Sixty high-risk, shelter-dwelling, urban youth were interviewed regarding their history of childhood maltreatment, exposure to community violence (ECV), and experience with intimate partner violence (IPV). Results show a high prevalence and high degree of overlap among multiple types of violence exposure. Childhood physical, sexual (CSA), and emotional (CEA) abuse were interrelated and were associated with ECV. Cumulative experiences of childhood abuse (CCA) had a graded association with IPV victimization. In multivariate analyses, CCA and ECV were independently associated with IPV victimization. Gender moderated the effect of one association: CEA raised the risk of IPV victimization for girls but not for boys. Only CSA predicted IPV perpetration. Findings suggest that cumulative exposures to violence create cumulative risk for experiencing more violence. Shelter-dwelling, urban youth may be particularly vulnerable to this additive effect.