Search

Abstract Background The location specific motor pattern generation properties of the spinal cord along its rostro-caudal axis have been demonstrated. However, it is still unclear that these differences are due to the different spinal interneuronal networks underlying locomotions or there are also segmental differences in motoneurons innervating different limbs. Frogs use their fore- and hindlimbs differently during jumping and swimming. Therefore we hypothesized that limb innervating motoneurons, located in the cervical and lumbar spinal cord, are different in their morphology and dendritic signal transfer properties. The test of this hypothesis what we report here. Results Discriminant analysis classified segmental origin of the intracellularly labeled and three-dimensionally reconstructed motoneurons 100% correctly based on twelve morphological variables. Somata of lumbar motoneurons were rounder; the dendrites had bigger total length, more branches with higher branching orders and different spatial distributions of branch points. The ventro-medial extent of cervical dendrites was bigger than in lumbar motoneurons. Computational models of the motoneurons showed that dendritic signal transfer properties were also different in the two groups of motoneurons. Whether log attenuations were higher or lower in cervical than in lumbar motoneurons depended on the proximity of dendritic input to the soma. To investigate dendritic voltage and current transfer properties imposed by dendritic architecture rather than by neuronal size we used standardized distributions of transfer variables. We introduced a novel combination of cluster analysis and homogeneity indexes to quantify segmental segregation tendencies of motoneurons based on their dendritic transfer properties. A segregation tendency of cervical and lumbar motoneurons was detected by the rates of steady-state and transient voltage-amplitude transfers from dendrites to soma at all levels of synaptic background activities, modeled by varying the specific dendritic membrane resistance. On the other hand no segregation was observed by the steady-state current transfer except under high background activity. Conclusions We found size-dependent and size-independent differences in morphology and electrical structure of the limb moving motoneurons based on their spinal segmental location in frogs. Location specificity of locomotor networks is therefore partly due to segmental differences in motoneurons driving fore-, and hindlimbs.

It is not known how school closure affected child maltreatment. We conducted a retrospective cohort, linear mixed-models study of 133 counties (comprising 8,582,479 children) in Virginia between 2018 and 2021. Exposure was the opening of schools at least 2 days a week. Outcomes were referrals and incidence of child maltreatment reported to the Department of Social Services. In 2020-2021, there were descriptively more referrals (in-person: 50.9 per 10,000 [95% CI: 47.9, 54.0]; virtual: 45.8 per 10,000 [95% CI: 40.7, 50.9]) and incidence (in-person: 3.7 per 10,000 [95% CI: 3.3, 4.2]; virtual: 2.9 per 10,000 [95% CI: 2.3, 3.5]) of child maltreatment in counties with in-person schooling, though these differences did not reach statistical significance. The referral rate variations (between pandemic and pre-pandemic eras) of counties with in-person schooling was significantly greater than rate changes in counties with virtual schooling during the summer period. There were no differences in incidence in any quarter. Higher poverty within a county was associated with both higher referrals and incidence. Our findings suggest that child maltreatment is driven primarily by underlying differences in counties (namely, poverty) rather than the type of schooling children receive., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

The tumor suppressor von Hippel-Lindau, pVHL, is a multifaceted protein. One function is to dock to the hypoxia-inducible transcription factor (HIF) and recruit a larger protein complex that destabilizes HIF via ubiquitination, preventing angiogenesis and tumor development. pVHL also binds to the tumor suppressor p53 to activate specific p53 target genes. The oncogene Mdm2 impairs the formation of the p53-pVHL complex and activation of downstream genes by conjugating nedd8 to pVHL. While Mdm2 can impact p53 and pVHL, how pVHL may impact Mdm2 is unclear. Like p53 somatic mutations, point mutations are evident in pVHL that are common in renal clear cell carcinomas (RCC). In patients with RCC, Mdm2 levels are elevated, and we examined whether there was a relationship between Mdm2 and pVHL. TCGA and DepMap analysis revealed that mdm2 gene expression was elevated in RCC with vhl point mutations or copy number loss. In pVHL reconstituted or deleted isogenetically match RCC or MEF cell lines, Mdm2 was decreased in the presence of pVHL. Furthermore, through analysis using genetic and pharmacological approaches, we show that pVHL represses Mdm2 gene expression by blocking the MAPK-Ets signaling pathway and blocks Akt-mediated phosphorylation and stabilization of Mdm2. Mdm2 inhibition results in an increase in the p53-p21 pathway to impede cell growth. This finding shows how pVHL can indirectly impact the function of Mdm2 by regulating signaling pathways to restrict cell growth., Competing Interests: Competing interests statement:The authors declare no competing interest.

Importance: Mortality rates in US youth have increased in recent years. An understanding of the role of racial and ethnic disparities in these increases is lacking., Objective: To compare all-cause and cause-specific mortality trends and rates among youth with Hispanic ethnicity and non-Hispanic American Indian or Alaska Native, Asian or Pacific Islander, Black, and White race., Design, Setting, and Participants: This cross-sectional study conducted temporal analysis (1999-2020) and comparison of aggregate mortality rates (2016-2020) for youth aged 1 to 19 years using US Centers for Disease Control and Prevention Wide-Ranging Online Data for Epidemiologic Research database. Data were analyzed from June 30, 2023, to January 17, 2024., Main Outcomes and Measures: Pooled, all-cause, and cause-specific mortality rates per 100 000 youth (hereinafter, per 100 000) for leading underlying causes of death were compared. Injuries were classified by mechanism and intent., Results: Between 1999 and 2020, there were 491 680 deaths among US youth, including 8894 (1.8%) American Indian or Alaska Native, 14 507 (3.0%) Asian or Pacific Islander, 110 154 (22.4%) Black, 89 251 (18.2%) Hispanic, and 267 452 (54.4%) White youth. Between 2016 and 2020, pooled all-cause mortality rates were 48.79 per 100 000 (95% CI, 46.58-51.00) in American Indian or Alaska Native youth, 15.25 per 100 000 (95% CI, 14.75-15.76) in Asian or Pacific Islander youth, 42.33 per 100 000 (95% CI, 41.81-42.86) in Black youth, 21.48 per 100 000 (95% CI, 21.19-21.77) in Hispanic youth, and 24.07 per 100 000 (95% CI, 23.86-24.28) in White youth. All-cause mortality ratios compared with White youth were 2.03 (95% CI, 1.93-2.12) among American Indian or Alaska Native youth, 0.63 (95% CI, 0.61-0.66) among Asian or Pacific Islander youth, 1.76 (95% CI, 1.73-1.79) among Black youth, and 0.89 (95% CI, 0.88-0.91) among Hispanic youth. From 2016 to 2020, the homicide rate in Black youth was 12.81 (95% CI, 12.52-13.10) per 100 000, which was 10.20 (95% CI, 9.75-10.66) times that of White youth. The suicide rate for American Indian or Alaska Native youth was 11.37 (95% CI, 10.30-12.43) per 100 000, which was 2.60 (95% CI, 2.35-2.86) times that of White youth. The firearm mortality rate for Black youth was 12.88 (95% CI, 12.59-13.17) per 100 000, which was 4.14 (95% CI, 4.00-4.28) times that of White youth. American Indian or Alaska Native youth had a firearm mortality rate of 6.67 (95% CI, 5.85-7.49) per 100 000, which was 2.14 (95% CI, 1.88- 2.43) times that of White youth. Black youth had an asthma mortality rate of 1.10 (95% CI, 1.01-1.18) per 100 000, which was 7.80 (95% CI, 6.78-8.99) times that of White youth., Conclusions and Relevance: In this study, racial and ethnic disparities were observed for almost all leading causes of injury and disease that were associated with recent increases in youth mortality rates. Addressing the increasing disparities affecting American Indian or Alaska Native and Black youth will require efforts to prevent homicide and suicide, especially those events involving firearms.

Purpose: Women and children continue to miss preventive visits. Which neighborhood factors predict inadequate prenatal care (PNC) and well-child visit (WCV) attendance remain unclear., Description: In a retrospective case-control study at Virginia Commonwealth University Health System, mothers with less than 50% adherence or initiation after 5 months gestation were eligible as cases and those with ≥ 80% adherence and initiation before 5 months were eligible as controls. Children in the lowest quintile of adherence were eligible as cases and those with ≥ 80% of adherence were eligible as controls. Cases and controls were randomly selected at a 1:2 ratio and matched on birth month. Covariates were derived from the 2018 American Community Survey. A hotspot was defined as a zip code tabulation area (ZCTA) with a proportion of controls less than 0.66. ZCTAs with fewer than 5 individuals were excluded. Weighted quantile regression was used to determine which covariates were most associated with inadequate attendance., Assessment: We identified 38 and 35 ZCTAs for the PNC and WCV analyses, respectively. Five of 11 hotspots for WCV were also hotspots for PNC. Education and income predicted 51% and 34% of the variation in missed PNCs, respectively; language, education and transportation difficulties explained 33%, 29%, and 17% of the variation in missed WCVs, respectively. Higher proportions of Black residents lived in hotspots of inadequate PCV and WCV attendance., Conclusion: Neighborhood-level factors performed well in predicting inadequate PCV and WCV attendance. The disproportionate impact impact of inadequate PCV and WCV in neighborhoods where higher proportions of Black people lived highlights the potential influence of systemic racism and segregation on healthcare utilization., (© 2023. The Author(s).)

In lung, thromboxane A2 (TXA2) activates the TP receptor to induce proinflammatory and bronchoconstrictor effects. Thus, TP receptor antagonists and TXA2 synthase inhibitors have been tested as potential asthma therapeutics in humans. Th9 cells play key roles in asthma and regulate the lung immune response to allergens. Herein, we found that TXA2 reduces Th9 cell differentiation during allergic lung inflammation. Th9 cells were decreased approximately 2-fold and airway hyperresponsiveness was attenuated in lungs of allergic mice treated with TXA2. Naive CD4+ T cell differentiation to Th9 cells and IL-9 production were inhibited dose-dependently by TXA2 in vitro. TP receptor-deficient mice had an approximately 2-fold increase in numbers of Th9 cells in lungs in vivo after OVA exposure compared with wild-type mice. Naive CD4+ T cells from TP-deficient mice exhibited increased Th9 cell differentiation and IL-9 production in vitro compared with CD4+ T cells from wild-type mice. TXA2 also suppressed Th2 and enhanced Treg differentiation both in vitro and in vivo. Thus, in contrast to its acute, proinflammatory effects, TXA2 also has longer-lasting immunosuppressive effects that attenuate the Th9 differentiation that drives asthma progression. These findings may explain the paradoxical failure of anti-thromboxane therapies in the treatment of asthma.

Cohen syndrome is an autosomal recessive disorder caused by VPS13B ( COH1 ) gene mutations. This syndrome is significantly underdiagnosed and is characterized by intellectual disability, microcephaly, autistic symptoms, hypotension, myopia, retinal dystrophy, neutropenia, and obesity. VPS13B regulates intracellular membrane transport and supports the Golgi apparatus structure, which is critical for neuron formation. We generated induced pluripotent stem cells from two patients with pronounced manifestations of Cohen syndrome and differentiated them into neural stem cells and neurons. Using transmission electron microscopy, we documented multiple new ultrastructural changes associated with Cohen syndrome in the neuronal cells. We discovered considerable disturbances in the structure of some organelles: Golgi apparatus fragmentation and swelling, endoplasmic reticulum structural reorganization, mitochondrial defects, and the accumulation of large autophagosomes with undigested contents. These abnormalities underline the ultrastructural similarity of Cohen syndrome to many neurodegenerative diseases. The cell models that we developed based on patient-specific induced pluripotent stem cells can serve to uncover not only neurodegenerative processes, but the causes of intellectual disability in general.

Background: Developmental disabilities (DD) affect over 10% of children 0 to 5 years of age, and early interventions are known to improve outcomes, yet barriers remain in connecting children to these services., Objective: To identify gaps in services for young children with DD and established risk conditions in Virginia., Methods: Data from the 2018 Virginia All Payers Claim Database and the American Community Survey were used to estimate the proportion of children with DD, and among those children, the proportion that received at least one intervention service. Logistic and binomial regression models were used to examine the socio-demographic associations with having developmental needs met, at the individual and zip code tabulation (ZCTA) level., Results: Approximately 12% of children 0 to 5 years were found to have DD or established risk condition diagnosis, and only 54% of these received intervention services during that year. Individual-level analyses suggest that odds of having developmental needs met are higher among older children, boys, and children with public insurance. ZCTA-level analyses suggested higher odds of developmental needs being met in areas with higher levels of unemployment, while areas with high proportions of people with limited English proficiency and a high school education or less had lower odds of having needs met., Conclusions: Receiving early childhood developmental services in Virginia is associated with having public insurance and living in an area with higher levels of unemployment, higher education, and English-proficiency. Efforts are needed to improve delivery of services overall, specifically targeted to those areas with high levels of unmet need., (Copyright © 2022 Academic Pediatric Association. Published by Elsevier Inc. All rights reserved.)

Purpose: Primary care is the foundation of the health care workforce and the only part that extends life and improves health equity. Previous research on the geographic and specialty distribution of physicians has relied on the American Medical Association's Masterfile, but these data have limitations that overestimate the workforce., Methods: We present a pragmatic, systematic, and more accurate method for identifying primary care physicians using the National Plan and Provider Enumeration System (NPPES) and the Virginia All-Payer Claims Database (VA-APCD). Between 2015 and 2019, we identified all Virginia physicians and their specialty through the NPPES. Active physicians were defined by at least 1 claim in the VA-APCD. Specialty was determined hierarchically by the NPPES. Wellness visits were used to identify non-family medicine physicians who were providing primary care., Results: In 2019, there were 20,976 active physicians in Virginia, of whom 5,899 (28.1%) were classified as providing primary care. Of this primary care physician workforce, 52.4% were family medicine physicians; the remaining were internal medicine physicians (18.5%), pediatricians (16.8%), obstetricians and gynecologists (11.8%), and other specialists (0.5%). Over 5 years, the counts and relative percentages of the workforce made up by primary care physicians remained relatively stable., Conclusions: Our novel method of identifying active physicians with a primary care scope provides a realistic size of the primary care workforce in Virginia, smaller than some previous estimates. Although the method should be expanded to include advanced practice clinicians and to further delineate the scope of practice, this simple approach can be used by policy makers, payers, and planners to ensure adequate primary care capacity., (© 2022 Annals of Family Medicine, Inc.)

Carbapenem-resistant Acinetobacter baumannii (CRAB) can cause serious infections that are associated with high mortality rates. During the course of an infection, many CRAB isolates are able to form biofilms, which are recalcitrant to several antibiotics and can be difficult to treat. Polymyxin-based regimens are a first-line treatment option for CRAB infections, but they have not been optimized against both planktonic and biofilm phases of growth. The objective of this study was to identify polymyxin-based combinations that are active against planktonic and biofilm populations of CRAB. Four CRAB isolates (meropenem MICs: 8-256 mg/L) capable of forming biofilms were used in each experiment. The activities of polymyxin B alone and in combination with ampicillin/sulbactam, meropenem, minocycline, and rifampin were assessed using time-kill assays, with the CRAB isolates grown in planktonic and biofilm phases. Viable colony counts were used to detect the bactericidal activity and synergy of the antibiotic combinations. Against the planktonic populations, polymyxin B combined with meropenem, minocycline, ampicillin/sulbactam, and rifampin caused 3.78, -0.15, 4.38, and 3.23 mean log 10 CFU/mL reductions against all isolates at 24 h, respectively. Polymyxin B combined with meropenem, ampicillin/sulbactam, or rifampin was synergistic against 75-100% (3/4 or 4/4) of CRAB isolates. Against biofilms, polymyxin B combined with meropenem, minocycline, ampicillin/sulbactam, and rifampin caused 1.86, 1.01, 0.66, and 3.55 mean log 10 CFU/mL reductions against all isolates at 24 h, respectively. Only the combination of polymyxin B and rifampin retained bactericidal activity or synergy against any of the isolates when grown as biofilms (50% of isolates). The combination of polymyxin B and rifampin may be promising for CRAB infections that have planktonic and biofilm populations present.

This update on pediatric medical overuse identifies and provides concise summaries of 10 impactful articles related to pediatric medical overuse from the years 2019 to 2020., Competing Interests: CONFLICT OF INTEREST DISCLOSURES: The authors have indicated they have no conflicts of interest relevant to this article to disclose., (Copyright © 2022 by the American Academy of Pediatrics.)

Background and Objectives: The American Academy of Pediatrics recommends against the routine use of β-agonists, corticosteroids, antibiotics, chest radiographs, and viral testing in bronchiolitis, but use of these modalities continues. Our objective for this study was to determine the patient, provider, and health care system characteristics that are associated with receipt of low-value services., Methods: Using the Virginia All-Payers Claims Database, we conducted a retrospective cross-sectional study of children aged 0 to 23 months with bronchiolitis (code J21, International Classification of Diseases, 10th Revision ) in 2018. We recorded medications within 3 days and chest radiography or viral testing within 1 day of diagnosis. Using Poisson regression, we identified characteristics associated with each type of overuse., Results: Fifty-six percent of children with bronchiolitis received ≥1 form of overuse, including 9% corticosteroids, 17% antibiotics, 20% β-agonists, 26% respiratory syncytial virus testing, and 18% chest radiographs. Commercially insured children were more likely than publicly insured children to receive a low-value service (adjusted prevalence ratio [aPR] 1.21; 95% confidence interval [CI]: 1.15-1.30; P < .0001). Children in emergency settings were more likely to receive a low-value service (aPR 1.24; 95% CI: 1.15-1.33; P < .0001) compared with children in inpatient settings. Children seen in rural locations were more likely than children seen in cities to receive a low-value service (aPR 1.19; 95% CI: 1.11-1.29; P < .0001)., Conclusions: Overuse in bronchiolitis remains common and occurs frequently in emergency and outpatient settings and rural locations. Quality improvement initiatives aimed at reducing overuse should include these clinical environments., Competing Interests: POTENTIAL CONFLICT OF INTEREST: Dr Krist is a member of the US Preventive Services Task Force. This article does not necessarily represent the views and policies of the US Preventive Services Task Force., (Copyright © 2021 by the American Academy of Pediatrics.)

Objective: Prenatal care (PNC) and well child visit (WCV) attendance are associated with improved health outcomes. We aimed to determine if the factors affecting maternal and child attendance are similar or different., Methods: We conducted a retrospective case control study at Virginia Commonwealth University Health System. We used the Adequacy of Prenatal Care Utilization Index and the American Academy of Pediatrics recommendations to assess the adequacy of PNC and WCV attendance, respectively. Mothers with less than 50% visit adherence or initiation after 5 months gestation were eligible as cases and those with 80% or more adherence and initiation before 5 months were eligible as controls. Children in the lowest quintile of adherence were eligible as cases and those with 80% or more adherence were eligible as controls. Cases and controls were randomly selected at a 1:2 ratio from the eligible subjects and frequency matched on birth month., Results: In adjusted analyses, mothers and children who were publicly insured or who were uninsured had higher odds of poor preventive visit attendance. Mothers who experienced intimate partner violence and had more living children were more likely to have poor attendance. Children whose mothers had younger age, greater number of pregnancies and transportation difficulties had poorer attendance., Conclusions: While lack of insurance and public insurance remained significantly associated with both poor PNC and WCV attendance, other factors varied between groups. Expanding eligibility requirements and streamlining enrollment and renewal processes may improve two generations of preventive visit attendance., (Copyright © 2020 Academic Pediatric Association. Published by Elsevier Inc. All rights reserved.)

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Mutations in the tumor suppressor TP53 are rare in renal cell carcinomas. p53 is a key factor for inducing antiangiogenic genes and RCC are highly vascularized, which suggests that p53 is inactive in these tumors. One regulator of p53 is the Mdm2 oncogene, which is correlated with high-grade, metastatic tumors. However, the sole activity of Mdm2 is not just to regulate p53, but it can also function independent of p53 to regulate the early stages of metastasis. Here, we report that the oncoprotein Mdm2 can bind directly to the tumor suppressor VHL, and conjugate nedd8 to VHL within a region that is important for the p53-VHL interaction. Nedd8 conjugated VHL is unable to bind to p53 thereby preventing the induction of antiangiogenic factors. These results highlight a previously unknown oncogenic function of Mdm2 during the progression of cancer to promote angiogenesis through the regulation of VHL. Thus, the Mdm2-VHL interaction represents a pathway that impacts tumor angiogenesis.

Purpose: Despite the benefits of well-child care visits, up to one-half of these visits are missed. Little is known about why children miss them, so we undertook a qualitative study to elucidate these factors., Methods: We interviewed 17 caregivers whose children had missed well-child visits and 6 clinicians, focusing on 3 areas: the value of well-child visits, barriers to attendance, and facilitators of attendance. Transcripts were analyzed with a grounded theory approach and thematic analysis., Results: Caregivers and clinicians identified similar important aspects of well-child visits: immunizations, detection of disease, and monitoring of growth and development. Both groups identified similar barriers to attendance: transportation, difficulty taking time off from work, child care, and other social stressors., Conclusions: Further work to explore how addressing social determinants of health might improve attendance of well-child visits is needed., (© 2020 Annals of Family Medicine, Inc.)

Clonal hematopoiesis of indeterminate potential (CHIP) increases with age and is associated with increased risks of hematological malignancies. While TP53 mutations have been identified in CHIP, the molecular mechanisms by which mutant p53 promotes hematopoietic stem and progenitor cell (HSPC) expansion are largely unknown. Here we discover that mutant p53 confers a competitive advantage to HSPCs following transplantation and promotes HSPC expansion after radiation-induced stress. Mechanistically, mutant p53 interacts with EZH2 and enhances its association with the chromatin, thereby increasing the levels of H3K27me3 in genes regulating HSPC self-renewal and differentiation. Furthermore, genetic and pharmacological inhibition of EZH2 decreases the repopulating potential of p53 mutant HSPCs. Thus, we uncover an epigenetic mechanism by which mutant p53 drives clonal hematopoiesis. Our work will likely establish epigenetic regulator EZH2 as a novel therapeutic target for preventing CHIP progression and treating hematological malignancies with TP53 mutations.

Background: Adult opioid use and neonatal abstinence syndrome (NAS) are growing public health problems in the United States (U.S.). Our objective was to determine how opioid use disorder treatment access impacts the relationship between adult opioid use and NAS., Methods: We conducted a cross-sectional state-level ecologic study using 36 states with available Healthcare Cost and Utilization Project State Inpatient Databases in 2014. Opioid use disorder treatment access was determined by the: 1) proportion of people needing but not receiving substance use treatment, 2) density of buprenorphine-waivered physicians, and 3) proportion of individuals in outpatient treatment programs (OTPs). The incidence of NAS was defined as ICD-9 code 779.5 (drug withdrawal syndrome in newborn) from any discharge diagnosis field per 1000 live births in that state., Results: Unmet need for substance use disorder treatment correlated with NAS (r = 0.54, 95% CI: 0.26-0.73). The correlation between adult illicit drug use/dependence and NAS was higher in states with a lower density of buprenorphine-waivered physicians and individuals in OTPs., Conclusions: Measures of opioid use disorder treatment access dampened the correlation between illicit drug use/dependence and NAS. Future studies using community- or individual-level data may be better poised to answer the question of whether or not opioid use disorder treatment access improves NAS relative to adult opioid use.

Background and Objectives: It is unclear which specific well-child visits (WCVs) are most frequently missed and whether age-specific patterns of attendance differ by race or insurance type., Methods: We conducted a retrospective cohort study of children 0 to 6 years old between 2011 and 2016 within 2 health networks spanning 20 states. WCVs were identified by using International Classification of Diseases, Ninth and 10th Revisions and Current Procedural Terminology codes. We calculated adherence to the 13 American Academy of Pediatrics-recommended WCVs from birth to age 6 years. To address data completeness, we made 2 adherence calculations after a child's last recorded WCV: 1 in which we assumed all subsequent WCVs were attended outside the network and 1 in which we assumed none were., Results: We included 152 418 children in our analysis. Most children were either publicly insured (77%) or uninsured (14%). The 2-, 4-, and 6-month visits were the most frequently attended (63% [assuming no outside care after the last recorded WCV] to 90% [assuming outside care]), whereas the 15- and 18-months visits (41%-75%) and 4-year visit (19%-49%) were the least frequently attended. Patients who were publicly insured and uninsured (versus privately insured) had higher odds of missing WCVs. Hispanic and Asian American (versus non-Hispanic white) patients had higher odds of attending WCVs., Discussion: The 15- and 18-month WCVs as well as the 4-year WCV are the least frequently attended WCVs. The former represent opportunities to identify developmental delays, and the latter represents an opportunity to assess school readiness., Competing Interests: POTENTIAL CONFLICT OF INTEREST: Dr Krist is a member of the US Preventive Services Task Force, but this article does not necessarily represent the views and policies of the US Preventive Services Task Force; the other authors have indicated they have no potential conflicts of interest to disclose., (Copyright © 2018 by the American Academy of Pediatrics.)

The transcription factors p53 and p73 are critical to the induction of apoptotic cell death, particularly in response to cell stress that activates c-Jun N-terminal kinase (JNK). Mutations in the DNA-binding domain of p53, which are commonly seen in cancers, result in conformational changes that enable p53 to interact with and inhibit p73, thereby suppressing apoptosis. In contrast, wild-type p53 reportedly does not interact with p73. We found that JNK-mediated phosphorylation of Thr 81 in the proline-rich domain (PRD) of p53 enabled wild-type p53, as well as mutant p53, to form a complex with p73. Structural algorithms predicted that phosphorylation of Thr 81 exposes the DNA-binding domain in p53 to enable its binding to p73. The dimerization of wild-type p53 with p73 facilitated the expression of apoptotic target genes [such as those encoding p53-up-regulated modulator of apoptosis (PUMA) and Bcl-2-associated X protein (BAX)] and, subsequently, the induction of apoptosis in response to JNK activation by cell stress in various cells. Thus, JNK phosphorylation of mutant and wild-type p53 promotes the formation of a p53/p73 complex that determines cell fate: apoptosis in the context of wild-type p53 or cell survival in the context of the mutant. These findings refine our current understanding of both the mechanistic links between p53 and p73 and the functional role for Thr 81 phosphorylation., (Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Mouse double minute 2 (Mdm2) and MdmX dimerize in response to low levels of genotoxic stress to function in a ubiquitinating complex, which signals for destabilization of p53. Under growth conditions, Mdm2 functions as a neddylating ligase, but the importance and extent of MdmX involvement in this process are largely unknown. Here we show that when Mdm2 functions as a neddylating enzyme, MdmX is stabilized. Furthermore, we demonstrate that under growth conditions, MdmX enhances the neddylation activity of Mdm2 on p53 and is a substrate for neddylation itself. Importantly, MdmX knockdown in MCF-7 breast cancer cells resulted in diminished neddylated p53, suggesting that MdmX is important for Mdm2-mediated neddylation. Supporting this finding, the lack of MdmX in transient assays or in p53/MdmX-/- MEFs results in decreased or altered neddylation of p53 respectively; therefore, MdmX is a critical component of the Mdm2-mediated neddylating complex. c-Src is the upstream activator of this Mdm2-MdmX neddylating pathway and loss of Src signaling leads to the destabilization of MdmX that is dependent on the RING (Really Interesting New Gene) domain of MdmX. Treatment with a small molecule inhibitor of neddylation, MLN4924, results in the activation of Ataxia Telangiectasia Mutated (ATM). ATM phosphorylates Mdm2, converting Mdm2 to a ubiquitinating enzyme which leads to the destabilization of MdmX. These data show how distinct signaling pathways engage neddylating or ubiquitinating activities and impact the Mdm2-MdmX axis., Competing Interests: CONFLICTS OF INTEREST The authors declare that they have no conflicts of interest.

Metastasis of cancer cells to distant organ systems is a complex process that is initiated with the programming of cells in the primary tumor. The formation of distant metastatic foci is correlated with poor prognosis and limited effective treatment options. We and others have correlated Mouse double minute 2 (Mdm2) with metastasis; however, the mechanisms involved have not been elucidated. Here, it is reported that shRNA-mediated silencing of Mdm2 inhibits epithelial-mesenchymal transition (EMT) and cell migration. In vivo analysis demonstrates that silencing Mdm2 in both post-EMT and basal/triple-negative breast cancers resulted in decreased primary tumor vasculature, circulating tumor cells, and metastatic lung foci. Combined, these results demonstrate the importance of Mdm2 in orchestrating the initial stages of migration and metastasis. Implication: Mdm2 is the major factor in the initiation of metastasis. Mol Cancer Res; 15(11); 1598-607. ©2017 AACR ., (©2017 American Association for Cancer Research.)

Background: International adoption of HIV-infected children is becoming increasingly common. Their health has not yet been described., Methods: HIV-infected international adoptees or refugees in foster care aged 0-20 years followed at Seattle Children's Hospital or Children's Hospital Colorado between January 1, 2004 and May 31, 2013 were included. Parameters were collected through retrospective chart review of baseline (first 6 months at study site) and annual follow-up visits., Results: Africa (90%) was the primary region of origin for the 79 children who met inclusion criteria. Median follow-up was 3 years (range: 0-7). At baseline, acute malnutrition was uncommon (8%); however, stunting occurred in 32%. Most stunting resolved during the study period. The most common medical issues at baseline were dermatologic (Tinea and Molluscum contagiosum) and gastrointestinal (parasites and diarrhea). Almost half (48%) had either mental health issues or behavioral problems. Educational delays (50%) were also common. Upon adoption, only 1% was severely (CD4% < 15%) immunosuppressed. Fifty-nine (75%) were on antiretroviral therapy (ART); 45 of these (76%) had suppressed viral load (VL). Of 14 children on ART with detectable VL, 11 (79%) demonstrated non-nucleoside reverse transcriptase inhibitor resistance and 1 (7%) protease inhibitor resistance., Conclusions: In this cohort of HIV-infected international adoptees, severe immunosuppression was uncommon. Most medical issues were mild. Stunting was common at baseline but largely resolved. Mental health issues, behavioral problems, and educational delays were common. Most children were on ART at adoption and most of these showed suppressed VL. Non-nucleoside reverse transcriptase inhibitor mutations were present in most viremic children.

Objective: Cardiac dysfunction may contribute to high mortality in severely malnourished children. Our objective was to assess the effect of malnutrition on cardiac function in hospitalised African children., Design: Prospective cross-sectional study., Setting: Public referral hospital in Blantyre, Malawi., Patients: We enrolled 272 stable, hospitalised children ages 6-59 months, with and without WHO-defined severe acute malnutrition., Main Outcome Measures: Cardiac index, heart rate, mean arterial pressure, stroke volume index and systemic vascular resistance index were measured by the ultrasound cardiac output monitor (USCOM, New South Wales, Australia). We used linear regression with generalised estimating equations controlling for age, sex and anaemia., Results: Our primary outcome, cardiac index, was similar between those with and without severe malnutrition: difference=0.22 L/min/m(2) (95% CI -0.08 to 0.51). No difference was found in heart rate or stroke volume index. However, mean arterial pressure and systemic vascular resistance index were lower in children with severe malnutrition: difference=-8.6 mm Hg (95% CI -12.7 to -4.6) and difference=-200 dyne s/cm(5)/m(2) (95% CI -320 to -80), respectively., Conclusions: In this largest study to date, we found no significant difference in cardiac function between hospitalised children with and without severe acute malnutrition. Further study is needed to determine if cardiac function is diminished in unstable malnourished children., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)

We conducted a matched case-control study of 566 HIV-infected children in Botswana during a 2009-2010 measles outbreak to identify the risk factors for measles. Children in the oldest age quartile (≥13.1 years) were 4-fold more likely to acquire measles than those in the youngest quartile (<7.1 years). HIV-infected older children and adolescents may benefit from additional measles vaccination.

Conventional wisdom suggests that if there is a vaccine that is effective in preventing a disease, vaccine uptake will increase when the disease risk is high. Recent evidence, however, suggests that this may not always be the case. In a study we conducted in Washington State, we found no population-level increase in pertussis vaccination of infants during a pertussis epidemic. In this paper, we aim to review what is known about the history of vaccine uptake during epidemics of vaccine-preventable disease, the challenges facing public health campaigns responding to these epidemics, and how the effect of a vaccine-preventable disease epidemic on vaccine uptake can be studied.

Background and Objectives: Washington State experienced a pertussis epidemic from October 2011 to December 2012. There was wide variation in incidence by county. The objectives of this study were to determine how the pertussis epidemic affected infant vaccination in Washington State and whether the incidence in counties modified this effect., Methods: We conducted an ecologic before-after study to compare the proportion of infants up to date (UTD) with a pertussis-containing vaccine at time points before (September 30, 2011), during (September 30, 2012), and after (September 30, 2013) the epidemic. Children aged 3 to 8 months enrolled in the Washington State Immunization Information System with documented county of residence were included. UTD status was determined as ≥ 1, ≥ 2, or ≥ 3 doses of a pertussis-containing vaccine at ages 3, 5, and 7 months, respectively. Generalized linear models with extension to the binomial family and clustered robust standard errors were used to examine differences in the proportion of UTD infants between preepidemic and either epidemic or postepidemic points. The potential modifying effect of pertussis incidence by county was examined., Results: We found no significant difference in statewide UTD status with a pertussis-containing vaccine between preepidemic and either epidemic (absolute difference 2.1%; 95% confidence interval, -1.6 to 5.9) or postepidemic (absolute difference 0.2%; 95% confidence interval, -4.0 to 4.5) time points. There was no significant modification by county pertussis incidence. There was wide variation in the absolute difference in UTD status across counties., Conclusions: A statewide pertussis epidemic does not appear to have significantly changed the proportion of infants who were UTD with a pertussis-containing vaccine., (Copyright © 2014 by the American Academy of Pediatrics.)

The European discovery and settlement of the Americas revealed unforeseen dimensions and gave rise to unpremeditated ways of coping with the resulting problems. This paper traces out the enduring social and cultural implications of this foundational encounter.