Search

The authors comment on the findings of Krishnan et al (page 2378) that obese dialysis patients with a high BMI who undergo kidney transplantation achieve several-fold improvement in survival, and they argue that BMI restrictions for kidney transplantation should be reconsidered.

This paper reports on the current negotiations on the draft Declaration on the Rights of Indigenous Peoples, taking place under the auspices of the UN Commission on Human Rights. The draft Declaration's provision for an indigenous people's right of self-determination provides an opportunity for the world community to articulate more clearly what is meant by the right to self-determination outside traditional contexts. Part 2 of the paper describes the international legal context in which representatives of indigenous peoples make claims to self-determination, focusing on indications that a requirement of self-determination is representative government. Part 3 of the paper develops the view that self-determination should accordingly be considered as a conceptual composite incorporating provision for political participation, autonomy, choice of community, and negotiated self-determination. From this model of self-determination will flow political structures and measures which specifically take into account the particular identity and situations of indigenous peoples. Should negotiations progress, and the United Nations General Assembly eventually adopt a Declaration on the Rights of Indigenous People, the author considers that it would be likely to include a provision on self-determination in such terms. In this way, a provision on indigenous people's self-determination could make a valuable contribution to international law. [ABSTRACT FROM AUTHOR]

Objectives: Contextual factors that contribute to firearm injuries among children aged 0 to 10 are not well understood., Methods: A retrospective review of the National Fatality Review-Case Reporting System was conducted for firearm deaths of children aged 0 to 10 from 2004 to 2020. Descriptive analyses characterized child and parent demographics, incident details, firearm characteristics, and firearm use. Cluster analysis identified key clustering of contextual variables to inform prevention efforts., Results: Within the study timeframe, 1167 child firearm deaths were reported (Mage = 4.9; 63.2% male; 39.4% urban). At the time of the incident, 52.4% of firearms were reported unlocked and 38.5% loaded. Firearm deaths occurred primarily at the child's home (69.0%) or a friend or relative's home (15.9%), with most involving a handgun (80.6%). Children were supervised in 74.6% of incidents, and 38.4% of child supervisors were impaired during the incident. Cluster analysis identified incident contextual factors clustering in distinct groups, including unsupervised firearm play, long gun discharge while cleaning, hunting, or target shooting, supervised discharge within the child's home, murder-suicide events, deaths occurring in the context of intimate partner violence, and community violence firearm deaths., Conclusions: Data highlight the importance of primary prevention through secure firearm storage to prevent child firearm deaths. Efforts focused on identifying and reducing intimate partner violence, addressing community violence (eg, community greening), and implementing policy that limit firearm access (eg, domestic violence restraining orders, background checks), may reduce child firearm deaths., Competing Interests: CONFLICT OF INTEREST DISCLOSURES: The authors have indicated they have no conflicts of interest relevant to this article to disclose., (Copyright © 2024 by the American Academy of Pediatrics.)

Competing Interests: CONFLICT OF INTEREST DISCLOSURES: The authors have indicated they have no conflicts of interest relevant to this article to disclose.

Firearms are the leading cause of death for youth in the US. Safe firearm storage is an evidence-based risk reduction technique, yet many families with children maintain unsecured firearms. In rural areas where gun ownership is common and rates of firearm-related suicides are increasing, developing culturally acceptable and feasible safe storage prevention strategies may have promise for reducing morbidity and mortality. This pilot study used a community-based participatory approach to develop a culturally tailored multi-component online safe storage preventive intervention called Store Safely . Participants were 45 rural firearm owning parents representing 45 unique families (35% male, 65% female, M age = 37.88, SD = 6.14) who had at least one child living at home. Acceptability, feasibility, and preliminary impact on firearm storage behaviors were measured via pre-test and post-test self-report surveys. Of the 43 parents (43 families) retained at follow-up, 97.7% completed the intervention and 86% utilized a home safety checklist. 40% of participants reported improving their storage, offering examples such as purchasing gun locks, safes, or lockboxes; separating ammunition from weapons; reviewing or discussing the safety of current storage; and relocating firearms to reduce child access. 84% found the website culturally sensitive and would recommend the materials to other parents. This firearm safe storage preventive intervention, developed in partnership with a rural community and tailored to reflect community norms and values, was associated with high levels of parental acceptability, engagement, and behaviors in support of safe firearm storage, suggesting its promise as a firearm injury prevention strategy.

Background: Sclerotinia spp. are generalist fungal pathogens, infecting over 700 plant hosts worldwide, including major crops. While host resistance is the most sustainable and cost-effective method for disease management, complete resistance to Sclerotinia diseases is rare. We recently identified soft basal stem as a potential susceptibility factor to Sclerotinia minor infection in lettuce (Lactuca sativa) under greenhouse conditions., Results: Analysis of stem and root cell wall composition in five L. sativa and one L. serriola accessions with varying growth habits and S. minor resistance levels revealed strong association between hemicellulose constituents, lignin polymers, disease phenotypes, and basal stem mechanical strength. Accessions resistant to basal stem degradation consistently exhibited higher levels of syringyl, guaiacyl, and xylose, but lower levels of fucose in stems. These findings suggest that stem cell wall polymers recalcitrant to breakdown by lignocellulolytic enzymes may contribute to stem strength-mediated resistance against S. minor., Conclusions: The lignin content, particularly guaiacyl and syringyl, along with xylose could potentially serve as biomarkers for identifying more resistant lettuce accessions and breeding lines. Basal stem degradation by S. minor was influenced by localized microenvironment conditions around the stem base of the plants., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

We aimed to describe the frequency of treatment failure and associated risk factors for treatment failure amongst neonates with skin and soft tissue infections (SSTIs). We conducted a retrospective cohort study of neonates 0 to 28 days old with uncomplicated SSTIs presenting to the emergency department of a quaternary care children's hospital from 2009 to 2017. Data were collected via chart review. Skin and soft tissue infections included the following: cellulitis, abscess, mastitis, perirectal SSTI, carbuncle, and furuncle. Of the 202 neonates in the study, most were term, afebrile with mastitis, or perirectal SSTI. Treatment failure occurred in 8% (17/202) of neonates receiving oral antibiotics; 10 of these neonates had perirectal SSTIs and 2 had clindamycin and methicillin-resistant Staphylococcus aureus . Neonates with treatment failure had increased odds of having perirectal SSTIs (odds ratio [OR] = 4.08, 95% confidence interval [CI] = 1.46-11.31). Further studies are needed to identify strategies to prevent treatment failure in neonates with perirectal SSTIs., 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.

Levofloxacin prophylaxis reduces bloodstream infections in neutropenic patients with acute myeloid leukemia or relapsed acute lymphoblastic leukemia. A retrospective, longitudinal cohort study compares incidence of bacteremia, multidrug-resistant organisms (MDRO), and Clostridioides difficile (CDI) between time periods of levofloxacin prophylaxis implementation. Benefits were sustained without increasing MDRO or CDI., Competing Interests: All authors report no competing interests relevant to this article., (© The Author(s) 2024.)

Introduction: Family, friends, and romantic partners (i.e., supporters) play a key role in the implementation of safety and support measures for loved ones with elevated risk for suicide; yet despite the link between interpersonal factors and suicide risk, few supporter-focused interventions exist., Method: This qualitative study to inform intervention development was conducted from September 2021 to March 2022 and explored (a) the feasibility and acceptability of a single-session phone call to a support person ( n = 30, 67% female, 88% White non-Hispanic, M age = 40.3 [ SD = 17.1]) nominated during an emergency department (ED) visit for suicide risk and (b) the needs of supporters during and after a loved one's suicide crisis., Results: Of the 30 supporters nominated, 27 were eligible to participate and were contacted. Eighteen completed an interview (66%). Seven core themes with 26 subthemes were identified characterizing the supporter's experience prior to, during, and following their loved one's suicide crisis. We found moderate acceptability and feasibility of a single-session supportive phone call to a support person following an ED visit for suicide risk., Discussion: Supporters reported a period of stress prior to and during the ED visit as well as adaptive coping with continued barriers and challenges. Brief interventions aimed at improving communication between the supporter, patient, and their care team; defining roles; and enhancing practical and emotional support are likely to be acceptable and feasible. Further study is needed to determine whether brief interventions to improve supporter self-efficacy can benefit both supporter and patient. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Oncogene-induced replication stress generates endogenous DNA damage that activates cGAS-STING-mediated signalling and tumour suppression 1-3 . However, the precise mechanism of cGAS activation by endogenous DNA damage remains enigmatic, particularly given that high-affinity histone acidic patch (AP) binding constitutively inhibits cGAS by sterically hindering its activation by double-stranded DNA (dsDNA) 4-10 . Here we report that the DNA double-strand break sensor MRE11 suppresses mammary tumorigenesis through a pivotal role in regulating cGAS activation. We demonstrate that binding of the MRE11-RAD50-NBN complex to nucleosome fragments is necessary to displace cGAS from acidic-patch-mediated sequestration, which enables its mobilization and activation by dsDNA. MRE11 is therefore essential for cGAS activation in response to oncogenic stress, cytosolic dsDNA and ionizing radiation. Furthermore, MRE11-dependent cGAS activation promotes ZBP1-RIPK3-MLKL-mediated necroptosis, which is essential to suppress oncogenic proliferation and breast tumorigenesis. Notably, downregulation of ZBP1 in human triple-negative breast cancer is associated with increased genome instability, immune suppression and poor patient prognosis. These findings establish MRE11 as a crucial mediator that links DNA damage and cGAS activation, resulting in tumour suppression through ZBP1-dependent necroptosis., (© 2024. The Author(s).)

Non-suicidal self-injury (NSSI) is an alarming public health concern that is particularly widespread among adolescents. The current study examined affective responses during mother-daughter interactions in adolescent girls with and without a history of NSSI. Participants were 60 girls aged 13-17 with (n = 27) and without (n = 33) a history of NSSI and their mothers. Adolescents and their mothers completed two interaction tasks: one positive and one negative. During these interactions, facial affect was assessed via electromyography (EMG). Results of Actor-Partner Interdependence Modeling (APIM) revealed several intra- and interpersonal disruptions in affect during both tasks among dyads in which the adolescent had an NSSI history. Findings suggest deficits in both self- and co-regulation of facial affect during mother-daughter interactions involving dyads in which the adolescents reports NSSI. Ultimately, if replicated and extended in longitudinal research, these disruptions may prove to be promising targets of intervention to reduce risk for future NSSI in adolescent girls., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Weight-bearing exercise (WBE) has been identified as an appropriate approach for increasing peak bone mass, however, there is a lack of specific physical activity recommendations in this area. Thus, the aim of this systematic review is to determine the optimal mode of WBE, specifically identifying the intensity, duration, frequency, and load, to elicit the optimal effect on bone mass in young females, aged 5-18. A literature search was conducted from the 28 th of June to the 20 th of July 2021 using PubMed/Medline, Web of Science and SPORTDiscus. The search produced 1405 results, of which 15 were deemed appropriate for inclusion. The majority of studies (n=12) found a significant positive effect for at least one bone measure through their respective WBE exposure (p<0.05). Bone mass accrual was found to be site-specific depending on WBE exposure type, load, and maturity status. Also, longitudinal effects on bone mass accrual were found exclusively in gymnastics participants, even if participation level decreased (i.e., retirement). The results of this study support the use of WBE to improve parameters of bone health. However, further research is needed as the optimal mode of WBE to elicit the optimal effect on bone mass is still unclear., (Copyright: © 2022 Hylonome Publications.)

Competing Interests: The authors have no conflicts of interest to disclose.

Phenotypic evolution is usually attributed to changes in protein function or gene transcription. In principle, mutations that affect protein abundance through enhancing or attenuating protein translation also could be an important source for phenotypic evolution. However, these types of mutations remain largely unexplored in the studies of phenotypic variation in nature. Through fine-scale genetic mapping and functional interrogation, we identify a single nucleotide substitution in an anthocyanin-activating R2R3-MYB gene causing flower color variation between a pair of closely related monkeyflower ( Mimulus ) species, the hummingbird-pollinated Mimulus cardinalis , and self-pollinated Mimulus parishii . This causal mutation is located in the 5' untranslated region and generates an upstream ATG start codon, leading to attenuated protein translation and reduced flower coloration in the self-pollinated species. Together, our results provide empirical support for the role of mutations affecting protein translation, as opposed to protein function or transcript level, in natural phenotypic variation.

Background: Bloodstream infections (BSIs) cause morbidity and mortality in pediatric patients with leukemia. Antibiotic prophylaxis during periods of chemotherapy-induced neutropenia may reduce the incidence of BSIs., Procedure: A levofloxacin prophylaxis guideline was implemented for pediatric patients with acute myeloid leukemia and relapsed acute lymphoblastic leukemia. We conducted a retrospective cohort study over 4 years (2 years pre and 2 years post implementation) of the practice guideline to assess the impact on central line-associated bloodstream infections (CLABSI) and BSI events. Secondary outcomes included incidence of Clostridioides difficile-associated diarrhea, bacteremia due to multidrug-resistant organisms (MDRO), and bacteremia due to levofloxacin nonsusceptible organisms. STATA was used for data analysis., Results: Sixty-three and 72 patients met inclusion criteria for the pre- and postimplementation cohorts, respectively. Demographics were similar between the groups. We observed 60 BSI events in the pre-group versus 49 events in the post-group (p = .1). Bacteremia due to Gram-negative rods (risk ratio [RR] 0.37 [0.21, 0.66], p < .001) and National Healthcare Safety Network (NHSN) CLABSIs (RR 0.62 [0.44, 0.89], p = .01) were significantly reduced in the postimplementation group. The incidences of C. difficile-associated diarrhea and MDRO bacteremia were similar between groups. However, we observed an increase in the incidence of BSI due to Gram-negative rods that were nonsusceptible to levofloxacin (RR 3.38 [0.72, 6.65], p < .001)., Conclusion: Following implementation of a levofloxacin prophylaxis guideline, we observed a significant decrease in BSIs due to Gram-negative rods and NHSN CLABSIs. Vigilant monitoring of outcomes post guideline implementation is critical to track emergence of resistant organisms., (© 2022 The Authors. Pediatric Blood & Cancer published by Wiley Periodicals LLC.)

Parental criticism is linked to a number of detrimental child outcomes. One mechanism by which parental criticism may increase risk for negative outcomes in children is through children's neural responses to valenced information in the environment. The goal of the current study, therefore, was to examine the relation between maternal criticism and children's neural responses to monetary gains and losses. To represent daily environmental experiences of reward and punishment, we focused on reactivity to monetary gains versus losses in a guessing task. Participants were 202 children and their mothers recruited from the community. The average age of the children was 9.71 years (SD = 1.38, range = 7-11), with 52.0% of them male and 72.8% Caucasian. Mothers completed the Five Minute Speech Sample to assess expressed emotion-criticism, and of these dyads 51 mothers were rated as highly critical. In addition, children completed a simple guessing game during which electroencephalography was recorded. Children of critical mothers displayed less neural reactivity to both monetary gain and loss than children without critical mothers. Our results were at least partially independent of children's and mothers' current levels of internalizing psychopathology. These findings suggest that children exposed to maternal criticism may exhibit disruptions in adaptive responses to environmental experiences regardless of valence. Targeted interventions aimed at reducing expressed emotion-criticism may lead to changes in a child's reward responsiveness and risk for psychopathology., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Biomass pretreatment methods are commonly used to isolate carbohydrates from biomass, but they often lead to modification, degradation, and/or low yields of lignin. Catalytic fractionation approaches provide a possible solution to these challenges by separating the polymeric sugar and lignin fractions in the presence of a catalyst that promotes cleavage of the lignin into aromatic monomers. Here, we demonstrate an oxidative fractionation method conducted in the presence of a heterogeneous non-precious-metal Co-N-C catalyst and O 2 in acetone as the solvent. The process affords a 15 wt% yield of phenolic products bearing aldehydes (vanillin, syringaldehyde) and carboxylic acids ( p -hydroxybenzoic acid, vanillic acid, syringic acid), complementing the alkylated phenols obtained from existing reductive catalytic fractionation methods. The oxygenated aromatics derived from this process have appealing features for use in polymer synthesis and/or biological funneling to value-added products, and the non-alkaline conditions associated with this process support preservation of the cellulose, which remains insoluble at reaction conditions and is recovered as a solid.

We present the case of an 18-year-old female with a 1-month history of fever, headache, and double vision, whose examination revealed papilledema and cranial nerve VI palsy. Blood cultures grew Brucella abortus cattle vaccine strain RB51, which is inherently resistant to rifampin. We discuss the management of the first known case of neurobrucellosis by this strain., Competing Interests: The authors have no funding or conflicts of interest to disclose., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

We report 2 infants hospitalized with Cronobacter sakazakii meningitis. Each infant had exposure to powdered infant formula at home. Both infants survived, but 1 infant had a subdural empyema drained and developed left sensorineural hearing loss. Early advanced brain imaging is recommended in infants with C. sakazakii meningitis. Reporting to state and federal public health officials may help identify outbreaks., Competing Interests: M.S.E. is the recipient of a personal services agreement from Texas State University. The other authors have no conflicts of interest to disclose., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Cutaneous mucormycosis in children is an opportunistic fungal infection associated with significant morbidity and mortality. We describe characteristics of 12 patients with healthcare-associated cutaneous mucormycosis at Texas Children's Hospital and results of an outbreak investigation. A definitive source was not identified. Skin lesions near medical device securement sites should raise concern for mucormycosis in patients with underlying medical conditions., Competing Interests: The authors have no funding or conflicts of interest to disclose., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: An understanding of the clinical characteristics of children with coronavirus disease 2019 in diverse communities is needed to optimize the response of healthcare providers during this pandemic., Methods: We performed a retrospective review of all children presenting to the Texas Children's Hospital system with testing for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) from March 10, 2020, through June 28, 2020. Demographics were recorded for all patients undergoing testing and clinical characteristics and outcomes were recorded for children with positive tests., Results: Of 16 554 unique patients ≤ 21 years of age who were tested for SARS-CoV-2, 1215 (7.3%) patients tested positive. Infants under 1 year of age and patients aged 18-21 years had the highest percent of positive tests at 9.9% (230/2329) and 10.7% (79/739), respectively. Hispanic children accounted for 66% (802/1215) of positive tests, though they only represented 42.1% (6972/16 554) of all children tested for SARS-CoV-2. Of the 1215 children with a positive test, 55.7% had fever, 40.9% had cough, 39.8% had congestion or rhinorrhea, 21.9% had gastrointestinal complaints, and 15.9% were asymptomatic. Only 97 (8%) patients were hospitalized (of which 68% were Hispanic). Most of the hospitalized patients had underlying medical conditions (62/97, 63.9%), including obesity. Thirty-one hospitalized patients (31/97, 32%) required respiratory support and 9 patients (9/97, 9.3%) received SARS-CoV-2 antiviral therapy. Two patients died., Conclusions: A relatively high percentage of Hispanic children tested positive for SARS-CoV-2 and were hospitalized. Most of the children with detection of SARS-CoV-2 had uncomplicated illness courses; some children were critically ill; and 2 patients died., (© The Author(s) 2020. Published by Oxford University Press on behalf of The Journal of the Pediatric Infectious Diseases Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Major depressive disorder (MDD) is a highly prevalent psychiatric disorder, and recurrent depression is associated with severe and chronic impairment. Identifying markers of risk is imperative to improve our ability to predict which individuals are likely to experience a recurrence. According to cognitive theories, biases in attention for affectively-salient information may serve as one mechanism of risk. Existing research has combined participants with a single episode (sMDD) and those with recurrent MDD (rMDD); therefore, little is known about whether these biases track the severity of disease course. The current study examined attentional biases to facial displays of emotion among 115 women with a history of rMDD, sMDD, or no history of psychopathology using a passive viewing eye-tracking task. Women with rMDD exhibited significantly lower sustained attention to happy faces compared to both healthy controls and sMDD women. These results extend previous research on the presence of attentional avoidance of positive stimuli in individuals with a history of MDD and provide preliminary evidence that this bias is strongest among individuals with a history of rMDD.

Background: Suicidal thoughts and behavior can begin early in childhood and are a leading cause of death in youth. Although specific mechanisms of risk remain largely unknown, theorists and researchers highlight the importance of the parent-child relationship. The current study focused on one aspect of this relationship: the dynamic exchange of facial affect during interactions. Specifically, we examined the relation between children's history of suicidal ideation (SI) and synchrony of facial expressions during positive and negative mother-child interactions., Methods: Participants were 353 mother-child dyads. Of these, 44 dyads included a child with an SI history. Dyads engaged in positive and negative discussions during which their facial electromyography was recorded from mothers and children to index second-to-second changes in positive (zygomaticus) and negative (corrugator) facial affect., Results: Child SI dyads were characterized specifically by reduced synchrony of positive facial affect during the positive discussion compared to dyads without child SI., Conclusions: These findings suggest child SI dyads exhibit reduced synchrony of normative positive expressions during mother-child interactions. If replicated and extended in longitudinal research, these results may help to explain one mechanism of risk among children with SI., (© 2020 Association for Child and Adolescent Mental Health.)

Biased attention to sad faces is associated with depression in adults and is hypothesized to increase depression risk specifically in the presence, but not absence, of stress by modulating stress reactivity. However, few studies have tested this hypothesis, and no studies have examined the relation between attentional biases and stress reactivity during adolescence, despite evidence that this developmental window is marked by changes in depression risk, stress, and the function of attention. Seeking to address these limitations, the current study examined the impact of adolescents' sustained attention to facial displays of emotion on individual differences in both mood reactivity to real-world stress and physiological (i.e., respiratory sinus arrhythmia [RSA]) reactivity to a laboratory-based stressor. Consistent with vulnerability-stress models of attention, greater sustained attention to sad faces was associated with greater depressive reactions to real-world stress. In addition, there was preliminary evidence from exploratory analyses that the impact of sustained attention on mood and/or physiological reactivity may be moderated by adolescents' age and sex such that relations are stronger for older adolescents and girls. The results of this study contribute to the current body of research on the role of attention in stress reactivity and depression risk and highlight the importance of considering age differences when examining these relations.

We describe the clinical course of 57 children with coronavirus disease 2019 (COVID-19) cared for through a single hospital system. Most children were mildly symptomatic, and only a few patients with underlying medical conditions required hospitalization. Systemwide patient evaluation processes allowed for prompt identification and management of patients with COVID-19., (© The Author(s) 2020. Published by Oxford University Press on behalf of The Journal of the Pediatric Infectious Diseases Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Microbial surface component recognizing adhesive matrix molecules (MSCRAMMs) facilitate Staphylococcus aureus adherence to host tissue. We hypothesized that S. aureus isolates from implant-associated infections (IAIs) would differ in MSCRAMM profile and biofilm formation in vitro compared to skin and soft tissue infection (SSTI) isolates., Methods: Pediatric patients and their isolates were identified retrospectively. IAI and SSTI isolates were matched (1:4). Pulsed field gel electrophoresis was performed to group isolates as USA300 vs. non-USA300. Whole genome sequencing was performed and raw sequence data were interrogated for presence of MSCRAMMs (clfA, clfB, cna, ebh, efb, fnbpA, fnbpB, isdA, isdB, sdrC, sdrD, sdrE), biofilm-associated (icaA,D,B,C), and Panton-Valentine leukocidin (lukSF-PV) genes, accessory gene regulator group, and multilocus sequence types. In vitro biofilm formation was assessed for 47 IAI and 47 SSTI isolates using a microtiter plate assay. Conditional logistic regression was performed for analysis of matched data (STATA11, College Station, TX)., Results: Forty-seven IAI and 188 SSTI isolates were studied. IAI isolates were more often methicillin susceptible S. aureus and non-USA300 vs. SSTI isolates [34 (72%) vs. 79 (42%), p = 0.001 and 38 (81%) vs. 57 (30%) p <0.001, respectively]. Greater than 98% of isolates carried clfA, clfB, efb, isdA, isdB, and icaA,D,B,C while cna was more frequently found among IAI vs. SSTI isolates (p = 0.003). Most isolates were strong biofilm producers., Conclusions: S. aureus IAI isolates were significantly more likely to be MSSA and non-USA300 than SSTI isolates. Carriage of MSCRAMMs and biofilm formation did not differ significantly between isolates. Evaluation of genetic polymorphisms and gene expression profiles are needed to further delineate the role of adhesins in the pathogenesis of IAIs., Competing Interests: I have read the journal's policy and the authors of this manuscript have the following competing interests: SLK has a grant from Pfizer for a pneumococcal surveillance study. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Plant biologists are seeking new approaches for modifying lignin to improve the digestion and utilization of structural polysaccharides in crop cultivars for the production of biofuels, biochemicals, and livestock. To identify promising targets for lignin bioengineering, we artificially lignified maize (Zea mays L.) cell walls with normal monolignols plus 21 structurally diverse alternative monomers to assess their suitability for lignification and for improving fiber digestibility. Lignin formation and structure were assessed by mass balance, Klason lignin, acetyl bromide lignin, gel-state 2D-NMR and thioacidolysis procedures, and digestibility was evaluated with rumen microflora and from glucose production by fungal enzymes following mild acid or base pretreatments. Highly acidic or hydrophilic monomers proved unsuitable for lignin modification because they severely depressed cell wall lignification. By contrast, monomers designed to moderately alter hydrophobicity or introduce cleavable acetal, amide, or ester functionalities into the polymer often readily formed lignin, but most failed to improve digestibility, even after chemical pretreatment. Fortunately, several types of phenylpropanoid derivatives containing multiple ester-linked catechol or pyrogallol units were identified as desirable genetic engineering targets because they readily formed wall-bound polymers and improved digestibility, presumably by blocking cross-linking of lignin to structural polysaccharides and promoting lignin fragmentation during mild acidic and especially alkaline pretreatment., (Published by Elsevier B.V.)

Background: In this work, three pretreatments under investigation at the DOE Bioenergy Research Centers (BRCs) were subjected to a side-by-side comparison to assess their performance on model bioenergy hardwoods (a eucalyptus and a hybrid poplar). These include co-solvent-enhanced lignocellulosic fractionation (CELF), pretreatment with an ionic liquid using potentially biomass-derived components (cholinium lysinate or [Ch][Lys]), and two-stage Cu-catalyzed alkaline hydrogen peroxide pretreatment (Cu-AHP). For each of the feedstocks, the pretreatments were assessed for their impact on lignin and xylan solubilization and enzymatic hydrolysis yields as a function of enzyme loading. Lignins recovered from the pretreatments were characterized for polysaccharide content, molar mass distributions, β-aryl ether content, and response to depolymerization by thioacidolysis., Results: All three pretreatments resulted in significant solubilization of lignin and xylan, with the CELF pretreatment solubilizing the majority of both biopolymer categories. Enzymatic hydrolysis yields were shown to exhibit a strong, positive correlation with the lignin solubilized for the low enzyme loadings. The pretreatment-derived solubles in the [Ch][Lys]-pretreated biomass were presumed to contribute to inhibition of enzymatic hydrolysis in the eucalyptus as a substantial fraction of the pretreatment liquor was carried forward into hydrolysis for this pretreatment. The pretreatment-solubilized lignins exhibited significant differences in polysaccharide content, molar mass distributions, aromatic monomer yield by thioacidolysis, and β-aryl ether content. Key trends include a substantially higher polysaccharide content in the lignins recovered from the [Ch][Lys] pretreatment and high β-aryl ether contents and aromatic monomer yields from the Cu-AHP pretreatment. For all lignins, the 13 C NMR-determined β-aryl ether content was shown to be correlated with the monomer yield with a second-order functionality., Conclusions: Overall, it was demonstrated that the three pretreatments highlighted in this study demonstrated uniquely different functionalities in reducing biomass recalcitrance and achieving higher enzymatic hydrolysis yields for the hybrid poplar while yielding a lignin-rich stream that may be suitable for valorization. Furthermore, modification of lignin during pretreatment, particularly cleavage of β-aryl ether bonds, is shown to be detrimental to subsequent depolymerization., Competing Interests: Competing interestsThe authors declare the following competing financial interests: DBH, ELH, AB, NB (Methods of Using Multi-Ligand Metal Complexes and to Perform Oxidative Catalytic Pretreatment of Lignocellulosic Biomass—2019/0091674 A1). As a holder of this patent, we may benefit financially from advances in the technology discussed in this manuscript.

Seasonal influenza infection is associated with secondary bacterial complications involving the upper and lower respiratory tract. However, the association of influenza infection with secondary severe or complicated head and neck infections is not appreciated. We report 6 cases of head and neck infections following influenza infection in pediatric patients.

Background: Staphylococcus aureus is a significant cause of implant-associated infections (IAIs). Data detailing the optimal treatment of IAIs are lacking in children. We describe the clinical features and outcomes of pediatric patients with S. aureus IAIs seen at Texas Children's Hospital., Methods: Patients and their isolates were identified from a S. aureus surveillance database from 2008 to 2016 in Houston, TX. Demographic and clinical data were collected retrospectively. Fisher's exact was used for statistical analysis., Results: Forty-five patients with 47 IAIs were identified. Most patients had an infected orthopedic implant: 22 (47%) spinal rods and 19 (40%) with other orthopedic hardware. Thirty (64%) IAIs developed within 90 days of implant placement. Six patients had polymicrobial infections and 3 patients were bacteremic. Of the 47 IAI isolates, 34 (72%) were methicillin-susceptible S. aureus (MSSA) and 13 (28%) were methicillin-resistant S. aureus. All children underwent surgical irrigation, debridement and antibiotic therapy. Of the 47 IAI episodes, 22 of the implants were removed at time of initial presentation, 7 implants had delayed removal, and 18 implants remained in place. Successful treatment was achieved in all patients with immediate implant removal (22/22) and in 83% of patients with implant retention (15/18), including 10 patients with early postoperative infections (<3 months) and 5 patients with late postoperative infections (>3 months). Four patients had recurrence of infection., Conclusions: The majority of S. aureus IAIs were methicillin-susceptible S. aureus. All children with immediate implant removal and most children with retained implants were treated successfully with surgery and antibiotic therapy.

The current study aimed to establish whether anxiety predicts subsequent anorexia nervosa onset and maintenance. A systematic review of longitudinal studies assessing the association between stable anxiety exposures (e.g. trait anxiety/anxiety disorder pathology) and anorexia nervosa development or maintenance was undertaken. Eight studies met inclusion criteria. Seven probed the association between anxiety and anorexia nervosa onset, and one assessed the association between anxiety and anorexia nervosa maintenance. Individuals with anorexia nervosa were more likely to report childhood anxiety compared to healthy individuals, but whether childhood anxiety explains unique variance in anorexia nervosa development is unclear. Current evidence does not support longitudinal associations between specific anxiety disorders (independently of other anxiety disorders) and subsequent anorexia nervosa onset, however anxiety disorder diagnosis in general may predict increased anorexia nervosa risk. The single study probing the association between anxiety and anorexia nervosa maintenance did not find evidence supporting a relationship. The quality of individual studies was fair to high, however the body of evidence was of low quality. Further research that minimises bias, allowing for strong conclusions concerning longitudinal associations between anxiety and subsequent anorexia nervosa outcomes, is required to inform anorexia nervosa aetiology. This in turn may promote improved prevention and treatment., (Copyright © 2019. Published by Elsevier B.V.)

Maternal history of Major Depressive Disorder (MDD) dramatically increases children's risk for developing depression, highlighting the critical need for further research on the specific processes involved in the intergenerational transmission of depression. Although previous research suggests that maternal depression may adversely affect the quality of mother-child interactions, less is known about the role of maternal MDD in the moment-to-moment changes in affect that occur during these interactions. The goal of this project, therefore, was to examine synchrony of facial displays of affect during a positive (Vacation Planning) and a negative (Issues Discussion) mother-child interaction, and how this synchrony may be impacted by maternal history of MDD. In doing so, we examined both concurrent and lagged synchrony of facial affect. We recruited 341 mother-child dyads (child average age = 9.30 years; 50.1% girls; 71.6% Caucasian) with and without a maternal history of MDD. Facial electromyography (EMG), continuously recorded during those tasks, was used to index mother and child facial affect. We found that a maternal history of MDD was associated with reduced concurrent synchrony and lagged synchrony (mother facial affect predicting changes in child facial affect) of positive affect during Vacation Planning. Reduced concurrent mother-child synchrony of positive affect during the discussion was also associated with an increase in child self-reported sad affect from before to after the discussion. These findings provide promising initial evidence for how the dynamic exchange of positive affect during mother-child interactions may be disrupted in families with maternal MDD history. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Importance: The prevalence of suicide among adolescents is rising, yet little is known about effective interventions. To date, no intervention for suicidal adolescents has been shown to reduce mortality., Objective: To determine whether the Youth-Nominated Support Team Intervention for Suicidal Adolescents-Version II (YST) is associated with reduced mortality 11 to 14 years after psychiatric hospitalization for suicide risk., Design, Setting, and Participants: This post hoc secondary analysis of a randomized clinical trial used National Death Index (NDI) data from adolescent psychiatric inpatients from 2 US psychiatric hospitals enrolled in the clinical trial from November 10, 2002, to October 26, 2005. Eligible participants were aged 13 to 17 years and presented with suicidal ideation (frequent or with suicidal plan), a suicide attempt, or both within the past 4 weeks. Participants were randomized to receive treatment as usual (TAU) or YST plus TAU (YST). Evaluators and staff who matched identifying data to NDI records were masked to group. The length of NDI follow-up ranged from 11.2 to 14.1 years. Analyses were conducted between February 12, 2018, and September 18, 2018., Interventions: The YST is a psychoeducational, social support intervention. Adolescents nominated "caring adults" (mean, 3.4 per adolescent from family, school, and community) to serve as support persons for them after hospitalization. These adults attended a psychoeducational session to learn about the youth's problem list and treatment plan, suicide warning signs, communicating with adolescents, and how to be helpful in supporting treatment adherence and positive behavioral choices. The adults received weekly supportive telephone calls from YST staff for 3 months., Main Outcomes and Measures: Survival 11 to 14 years after index hospitalization, measured by NDI data for deaths (suicide, drug overdose, and other causes of premature death), from January 1, 2002, through December 31, 2016., Results: National Death Index records were reviewed for all 448 YST study participants (319 [71.2%] identified as female; mean [SD] age, 15.6 [1.3] years; 375 [83.7%] of white race/ethnicity). There were 13 deaths in the TAU group and 2 deaths in the YST group (hazard ratio, 6.62; 95% CI, 1.49-29.35; P < .01). No patients were withdrawn from YST owing to adverse effects., Conclusions and Relevance: The findings suggest that the YST intervention for suicidal adolescents is associated with reduced mortality. Because this was a secondary analysis, results warrant replication with examination of mechanisms., Trial Registration: ClinicalTrials.gov identifier: NCT00071617.

Syringyl (S) lignin content and the syringyl-to-guaiacyl (S/G) lignin ratio are important characteristics of wood and lignocellulosic biomass. Although numerous methods are available for estimating S lignin units and the S/G ratio, in this work, a new method based on Raman spectroscopy that uses the 370 cm -1 Raman band-area intensity (370-area) was developed. The reliability of the Raman approach for determining S content was first tested by the quantitative analysis of three syringyl lignin models by sampling them, separately, in dioxane and in Avicel. Good linear correlations between the 370 cm -1 intensity and model concentrations were obtained. Next, the percent syringyl (%S) lignin units in various woods were measured by correlating the 370 cm -1 Raman intensity data with values of S units in lignin determined by three regularly used methods, namely, thioacidolysis, DFRC, and 2D-HSQC NMR. The former two methods take into account only the monomers cleaved from β-O-4-linked lignin units, whereas the NMR method reports S content on the whole cell wall lignin. When the 370-area intensities and %S values from the regularly used methods were correlated, good linear correlations were obtained ( R 2 = 0.767, 0.731, and 0.804, respectively, for the three methods). The correlation with the highest R 2 , i.e., with the 2D NMR method, is proposed for estimating S units in wood lignins by Raman spectroscopy as, in principle, both represent the whole cell wall lignin and not just the portion of lignin that gets cleaved to release monomers. The Raman analysis method is quick, uses minimal harmful chemicals, is carried out nondestructively, and is insensitive to the wet or dry state of the sample. The only limitations are that the sample of wood contains at least 30% S and not be significantly fluorescent, although the latter can be mitigated in some cases.

The way individuals process socio-affective information is thought to impact their responses to social interactions, but research testing the relation between these processes is scarce, particularly among children. This study examined if children's attention to socio-affective stimuli was associated with their autonomic nervous system (ANS) reactivity during parent-child interactions. Children's sustained attention to facial expressions of emotion (afraid, happy, sad) was indexed using the late positive potential (LPP) event-related potential (ERP) component during a computer-based task. To measure ANS reactivity, children's respiratory sinus arrhythmia (RSA) was assessed at baseline and during positive and negative parent-child discussions. Enhanced LPP amplitudes in response to all emotional facial expressions, reflecting greater sustained attention to socio-affective stimuli, were associated with increased RSA reactivity during parent-child discussions. These results show correspondence between two psychophysiological substrates of emotion processing in healthy children and highlight how these systems may be synergistic forces contributing to emotion reactivity., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Public health physical activity (PA) guidelines are failing to increase levels of population PA, requiring a new approach. A national integrated marketing campaign was developed based on published literature and ethnographic research to get inactive lower socioeconomic 40-60 year olds to walk briskly for bouts of 10 or more minutes per day and move towards recommended levels of PA. National and local communications campaigns and partnerships promoted key messages and directed people to a free mobile phone app that provided the user with time, intensity and periodicity of walking, and included goal setting and encouragement to support behaviour change. Campaigns in the summers of 2017 and 2018 achieved around 500,000 downloads of the mobile phone app, with evaluation suggesting increases in brand and app awareness, and those taking action. Active 10 is a promising example of a physical activity promotion campaign based on evidence-based messages tailored for a target audience to change social norms rather than guidelines, an approach recognised as an effective population intervention for increasing walking., (Crown Copyright © 2019. Published by Elsevier Inc. All rights reserved.)

Introduction: Resident physicians may have difficulty with identifying and managing pediatric septic shock due to limited patient encounters. Simulation-based interventions can enhance competency. We developed a low-fidelity tabletop simulation game to teach pediatric septic shock and compared residents' knowledge of and comfort with recognition and management of septic shock., Methods: Pediatric and emergency medicine residents participated in an education session involving a low-fidelity, tabletop simulation in which they managed two simulated pediatric patients with septic shock. The two patients were a 12-year-old healthy male with cold shock due to a urinary tract infection and a 5-year-old female with a history of leukemia who developed warm shock due to pneumonia. Because this session was presented as a board game rather than high-fidelity simulation, learners focused on decision making rather than the mechanics of procedures. Residents completed a survey and a knowledge-based test before and after this session., Results: Twenty-three pediatric and nine emergency medicine residents participated. Correct responses for the preintervention test were 71%, compared with 83% postintervention. The difference in rates was 12% (95% confidence interval, -0.17 to -0.07; p < .0001). Residents rated this modality as being more useful than lectures or reading and as equivalent to bedside teaching and high-fidelity simulation., Discussion: Our pilot low-fidelity simulation improved resident knowledge and comfort with pediatric septic shock care. Further studies are needed to address the impact of low-fidelity simulations on patient outcomes., Competing Interests: None to report.

Brodie abscess is a subacute hematogenous osteomyelitis characterized by intraosseous abscess formation. Treatment recommendations and clinical outcomes for this unusual infection are not well established. We report 15 cases of Brodie abscess in a 10-year retrospective review of pediatric patients at Texas Children's Hospital and describe their clinical presentation and outcomes.

Plant organ development to a specific size and shape is controlled by cell proliferation and cell expansion. Here, we identify a novel Myb-like Arabidopsis gene, Development Related Myb-like1 (DRMY1), which controls cell expansion in both vegetative and reproductive organs. DRMY1 is strongly expressed in developing organs and its expression is reduced by ethylene while it is induced by ABA. DRMY1 has a Myb-like DNA-binding domain, which is predominantly localized in the nucleus and does not exhibit transcriptional activation activity. The loss-of-function T-DNA insertion mutant drmy1 shows reduced organ growth and cell expansion, which is associated with changes in the cell wall matrix polysaccharides. Interestingly, overexpression of DRMY1 in Arabidopsis does not lead to enhanced organ growth. Expression of genes involved in cell wall biosynthesis/remodeling, ribosome biogenesis and in ethylene and ABA signaling pathways is changed with the deficiency of DRMY1. Our results suggest that DRMY1 plays an essential role in organ development by regulating cell expansion either directly by affecting cell wall architecture and/or cytoplasmic growth or indirectly through the ethylene and/or ABA signaling pathways., (� The Author(s) 2018. Published by Oxford University Press on behalf of Japanese Society of Plant Physiologists. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

This study examined the effectiveness of LET's CONNECT (LC), a community mentorship program for youths who report peer social problems, which is based on a positive youth development framework. Participants were 218 youths (66.5% girls), aged 12 to 15 years, who were recruited from an urban medical emergency department and screened positive for bullying victimization, bullying perpetration, and/or low social connectedness. Youths were randomized to LC (n = 106) or the control condition (n = 112). Six-month outcomes were assessed with self-report measures of youth social connectedness, community connectedness, thwarted belongingness, depression, self-esteem, and suicidal ideation. LC was associated with a significant increase in only one of these outcomes, social connectedness (effect size = 0.4). It was associated consistently with trend-level positive changes for thwarted belongingness (decreased), depression (decreased), community connectedness, and self-esteem (effect sizes = 0.2). There was no effect on suicidal ideation (effect size = 0.0), and although not a primary outcome, eight youths in the LC condition and seven youths in the control condition engaged in suicidal behavior between baseline and follow-up. Although LC effect sizes are consistent with those from previous studies of community mentorship, there were multiple challenges to LC implementation that affected dosage and intervention fidelity, and that may account for the lack of stronger positive effects., (© 2018 Wiley Periodicals, Inc.)

Background: Trichosporonosis is an emerging and often fatal opportunistic fungal infection in immunocompromised patients, particularly those with hematologic malignancy, but data in children are lacking., Methods: We report here 3 cases of invasive infection caused by Trichosporon asahii in pediatric patients with acute lymphoblastic leukemia at Texas Children's Hospital in Houston, Texas. We also conducted a literature review and identified 16 additional reports of pediatric patients with invasive T asahii infection and an underlying malignant or nonmalignant hematologic disorder., Results: Of the 19 cases of invasive T asahii infection, the most commonly reported underlying hematologic disorder was acute lymphoblastic leukenia (47%), followed by acute myelogenous leukemia (21%). Most of the patients (94%) had neutropenia, defined as an absolute neutrophil count of <500 cells/mm3. Antifungal prophylaxis information was available in 6 of the 19 cases, and micafungin use was reported in 5 cases. Treatment regimens frequently included voriconazole monotherapy (47%) or the combination of an azole antifungal with amphotericin B (35%). The mortality rate was 58%., Conclusions: Recognizing that echinocandins, which are increasingly used for prophylaxis in patients with a hematologic malignancy, are not active against Trichosporon species is of critical importance. The recommended first-line therapy for trichosporonosis is voriconazole, but successful outcome depends largely on the underlying immune status of the host.

Background: Periorbital and orbital cellulitis cause significant pediatric morbidity. Here, we define the clinical features of and characterize isolates from children with periorbital or orbital cellulitis caused by Staphylococcus aureus at Texas Children's Hospital in Houston., Methods: Patients were identified from a prospective S aureus study database from January 2002 to July 2015. Demographic and clinical data were collected retrospectively. Isolates were genotyped by pulsed-field gel electrophoresis, and Panton-Valentine leukocidin (lukSF-PV [pvl]) genes were detected by quantitative polymerase chain reaction. Data were analyzed with the Fisher exact or Wilcoxon rank-sum test., Results: Eighty-five patients with periorbital (n = 58) or orbital (n = 27) cellulitis were identified. We found 57 (67%) methicillin-resistant S aureus (MRSA) isolates, 72 (85%) pvl-positive (pvl+) isolates, and 66 (78%) USA300 isolates. No differences in clinical characteristics were found when we compared MRSA to methicillin-susceptible (MSSA) infections or USA300 to non-USA300 infections. Patients with orbital cellulitis were hospitalized a median of 12 days (range, 2-28 days) and received antibiotics for 21 days (range, 10-32 days). Twelve (44%) patients with orbital cellulitis received steroids. Steroid treatment did not affect the length of hospitalization or duration of antibiotic treatment. Six (7%) patients with orbital cellulitis were bacteremic. Patients with periorbital cellulitis were hospitalized for a median of 3 days (range, 0-17 days) and received antibiotics for 11 days (range, 7-32 days). According to computed tomography (CT), 19 (70%) patients with orbital cellulitis and 11 (41%) with periorbital cellulitis had sinusitis., Conclusions: The majority of periorbital and orbital S aureus infections at Texas Children's Hospital were caused by MRSA, and no change was observed over time. Empirical antibiotic treatment should include coverage for MRSA. PVL might be an important virulence factor in these presentations. S aureus is associated with sinusitis and its complications.

Objective: The Peer-to-Peer Depression Awareness Program (P2P) is a school-based program that aims to decrease mental illness and promote well-being among students by empowering high school students as both learners and educators. Specific goals include improving the school climate around mental health, directing students to resources, and encouraging help-seeking behavior., Methods: In the 2015-2016 academic year, 121 students across 10 high schools organized into teams and were trained to develop and implement peer-to-peer depression awareness campaigns. Outcomes were assessed via pre- and posttest questionnaires., Results: A total of 878 students completed questionnaires. Outcomes demonstrated improved knowledge and attitudes toward depression, increased confidence in identifying and referring peers with depression, improved help-seeking intentions, and reduced stigma., Conclusions: The P2P program increased depression literacy through the use of youth-designed and youth-implemented depression awareness and outreach activities, which may ultimately result in earlier detection of depression and in fewer depression sequelae.

Youth who feel connected to people and institutions in their communities may be buffered from other risk factors in their lives. As a result, increasing connectedness has been recommended as a prevention strategy. In this study, we examined connectedness among 224 youth (ages 12-15), recruited from an urban medical emergency department, who were at elevated risk due to bullying perpetration or victimization, or low social connectedness. Regression analyses examined multiple domains of connectedness (family, school, peer, community) in relation to adjustment. Youth who felt more connected to parents reported lower levels of depressive symptoms, suicidal ideation, non-suicidal self-injury, and conduct problems, higher self-esteem and more adaptive use of free time. Youth who felt more connected to their school reported lower levels of depressive symptoms, suicidal ideation, social anxiety, and sexual activity, as well as higher levels of self-esteem and more adaptive use of free time. Community connectedness was associated with less social anxiety but more sexual activity, and peer connectedness was not related to youth adjustment in this unique sample. Findings suggest that family and school connectedness may buffer youth on a trajectory of risk, and may therefore be important potential targets for early intervention services.

Prostatic abscesses are infrequently encountered in adults and are exceedingly rare in the pediatric population. We present the case of an 11-year-old boy with a methicillin-susceptible Staphylococcus aureus prostatic abscess and bacteremia.

There are limited data regarding outcomes of patients underwent kidney autotransplantation. This study aims to investigate outcomes of such patients. The nationwide inpatient sample database was used to identify patients underwent kidney autotransplantation during 2002 to 2012. Multivariate analyses using logistic regression were performed to investigate morbidity predictors. A total of 817 patients underwent kidney autotransplantation from 2002 to 2012. The most common indication of surgery was renal artery pathology (22.7%) followed by ureter pathology (17%). Overall, 97.7 per cent of operations were performed in urban teaching hospitals. The number of procedures from 2008 to 2012 were significantly higher compared with the number of them from 2002 to 2007 (473 vs 345, P < 0.01). The overall mortality and morbidity of patients were 1.3 and 46.2 per cent, respectively. The most common postoperative complications were transplanted kidney failure (10.7%) followed by hemorrhagic complications (9.7%). Obesity [adjusted odds ratio (AOR): 9.62, P < 0.01], fluid and electrolyte disorders (AOR: 3.67, P < 0.01), and preoperative chronic kidney disease (AOR: 1.80, P = 0.03) were predictors of morbidity in patients. In conclusion, Kidney autotransplantation is associated with low mortality but a high morbidity rate. The most common indications of kidney autotransplantation are renal artery and ureter pathologies, respectively. A kidney transplant failure rate of 10.7 per cent was observed in patients with kidney autotransplantation. The most common postoperative complication was hemorrhagic in nature.