To bite the hand that feeds you: A case of thrombotic microangiopathy due to Tiger snake bite.

This report details the case of a 51-year-old man with a Tiger snake bite who developed systemic envenomation, coagulopathy and thrombotic microangiopathy (TMA) requiring renal replacement therapy. He received plasma exchange as additional therapy while awaiting confirmation of the cause of the TMA. We discuss clinical decision making in detection of systemic envenomation and management of the rare complication of TMA, as well as current Australian guidelines around antivenom administration. This is the fourth known documented case of TMA from a Tiger snake bite in Australia.

Retrospective Use of Patients' Characteristics to Assess Variation in Prenatal Care Utilization.

OBJECTIVE: We used patients' medical and psychosocial risk factors to explore prenatal care utilization and health outcomes to inform prenatal care tailoring. STUDY DESIGN: This retrospective cohort study assessed patients who gave birth at an academic institution from January 1 to December 31, 2018, using electronic health record (EHR) data. Patients were categorized into four phenotypes based on medical/psychosocial risk factors available in the EHR: Completely low risk; High psychosocial risk only; High medical risk only; and Completely high risk. We examined patient characteristics, visit utilization, nonvisit utilization (e.g., phone calls), and outcomes (e.g., preterm birth, preeclampsia) across groups. RESULTS: Of 4,681 patients, the majority were age 18 to 35 (3,697, 79.0%), White (3,326, 70.9%), multiparous (3,263, 69.7%), and Completely high risk (2,752, 58.8%). More Black and Hispanic patients had psychosocial risk factors than White patients. Patients with psychosocial risk factors had fewer prenatal visits (10, interquartile range [IQR]: 8-12) than those without (11, IQR: 9-12). Patients with psychosocial risk factors experienced less time in prenatal care, more phone calls, and fewer EHR messages across the same medical risk group. Rates of preterm birth and gestational hypertension were incrementally higher with additional medical/psychosocial risk factors. CONCLUSION: Data readily available in the EHR can assess the compounding influence of medical/psychosocial risk factor on patients' care utilization and outcomes. KEY POINTS: · Medical and psychosocial needs in pregnancy can inform patient phenotypes and are associated with prenatal care use and outcomes.. · Patient phenotypes are associated with prenatal care use and outcomes.. · Patients with high psychosocial risk spent less time in prenatal care and had more phone calls in pregnancy.. · Tailored prenatal care models may proactively address differences in patient's needs..

Case report of a pan-cytokeratin negative NUT midline carcinoma of pulmonary origin, a BRD3-NUT variant: Challenges in cytomorphologic presentation.

NUT carcinoma is an aggressive malignancy defined genetically by a balanced translocation of the NUT gene on chromosome 15q14, most commonly associated with the bromodomain-containing protein 4 (BRD4) gene on 19p13.1 but less frequently with variant genes, including BRD3 and NSD-3. We present a case report of a metastatic pulmonary NUT carcinoma found to have a BRD3-NUT fusion and to have only focal pan-cytokeratin staining. Biopsy of the pulmonary mass revealed dyscohesive cells with enlarged nuclei, prominent nucleoli and high nuclear to cytoplasmic ratio without areas of squamous differentiation. Initial immunohistochemical stains were positive for NUT, p63 and retained SMARCA4, while negative for Lu-5 (pan-cytokeratin), TTF-1, p40, S100 protein, OCT-4, HMB-45, SMA, and PAX-8. Tempus ×T assay revealed a BRD3-NUTM1 fusion gene. Post-mortem analysis revealed an ill-defined mass abutting the trachea and superior vena cava, as well as a perirenal mass.

Diffuse large B-cell lymphoma: a consensus practice statement from the Australasian Lymphoma Alliance.

Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoma subtype, accounting for 30-40% of lymphoma diagnoses. Although aggressive, cure is achievable in approximately 60% of cases with primary chemoimmunotherapy, and in a further substantial minority by salvage therapy and autologous stem cell transplantation. Despite promising activity in early phase clinical trials, no intensified or novel treatment regimen has improved outcomes over R-CHOP21 in randomised studies. However, there remain several areas of controversy including the most appropriate prognostic markers, central nervous system prophylaxis and the optimal treatment for patients with high-risk disease. This position statement presents an evidence-based synthesis of the literature for application in Australasian practice.

Developing and implementing core competencies in children's environmental health for students, trainees and healthcare providers: a narrative review.

Knowledge of the health impacts of environmental exposures (such as pollution disasters, poor air quality, water contamination, climate change) on children's health has dramatically increased in the past 40 years. The World Health Organization (WHO) estimated that 23% of all deaths worldwide were attributable to the environment, and 26% of deaths in children less than 5 years old could be prevented with removal of environmental risks factors. Yet, little has permeated medical education, leaving pediatric providers ill equipped to address these issues. To address this gap, members from the Pediatric Environmental Health Specialty Units, a United States nationwide network of academically affiliated experts who have created numerous environmental health educational materials and programs, have identified fifteen core environmental health (EH) competencies needed by health care providers to enable them to effectively address environmental health concerns. These competencies can serve as the foundation for the development and implementation of relevant educational programs. The core EH competencies are based upon these foundational elements: 1) Definition of "children's environmental health" that describes how environmental exposures (positive and negative) in early life influence the health and development in childhood and across the entire human life span 2) Children are not "little adults" and so have unique vulnerabilities to environmental hazards; 3) Environmental health inequities exist, causing some children to have a disproportionate amount of unhealthy exposures and consequently a greater risk of adverse effects; 4) Climate change will translate to numerous adverse health effects that will particularly affect children worldwide. In this article, the authors describe the core environmental health competencies and provide resources, online tools, strategies, and examples targeted to all levels of training and practice to better enable leaders and educators to bring this important content to the forefront.

Zanubrutinib (BGB-3111) plus obinutuzumab in patients with chronic lymphocytic leukemia and follicular lymphoma.

Zanubrutinib (BGB-3111) is a next-generation Bruton tyrosine kinase inhibitor designed to be more selective with fewer off-target effects. We conducted a phase 1 study to assess the safety of its combination with obinutuzumab and evaluate early efficacy in 81 patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) or relapsed/refractory (R/R) follicular lymphoma (FL). In this phase 1b study, zanubrutinib was tolerable at 160 mg twice daily or 320 mg once daily combined with IV obinutuzumab in patients with CLL/SLL (n = 45) and FL (n = 36). Common adverse events (AEs) included upper respiratory tract infection (51%; n = 23), neutropenia (44%; n = 20), contusion (33%; n = 15), cough, diarrhea, or fatigue (27%; n = 12 each), and pyrexia (22%; n = 10) in CLL/SLL patients and upper respiratory tract infection (39%; n = 14), contusion (28%; n = 10), fatigue (25%; n = 9), and cough (22%; n = 8) in FL patients. Neutropenia was the most common grade 3/4 AE (CLL/SLL, 31% [n = 14]; FL, 14% [n = 5]). Five patients required temporary dose reductions, and 5 discontinued the study drug because of AEs. Overall response rate (ORR) was 100% (n = 20) in treatment-naïve CLL patients and 92% (n = 23) in R/R CLL patients. ORR in 36 R/R FL patients was 72% (n = 26), with 14 complete and 12 partial responses. Median follow-up was 29 months (range, 8-37) for CLL patients and 20 months (range, 2-37) for FL patients. Zanubrutinib and obinutuzumab combination therapy was generally well tolerated. This trial was registered at www.clinicaltrials.gov as #NCT02569476.

Biochemical and Structural Characterization of XoxG and XoxJ and Their Roles in Lanthanide-Dependent Methanol Dehydrogenase Activity.

Lanthanide (Ln)-dependent methanol dehydrogenases (MDHs) have recently been shown to be widespread in methylotrophic bacteria. Along with the core MDH protein, XoxF, these systems contain two other proteins, XoxG (a c-type cytochrome) and XoxJ (a periplasmic binding protein of unknown function), about which little is known. In this work, we have biochemically and structurally characterized these proteins from the methyltroph Methylobacterium extorquens AM1. In contrast to results obtained in an artificial assay system, assays of XoxFs metallated with LaIII , CeIII , and NdIII using their physiological electron acceptor, XoxG, display Ln-independent activities, but the Km for XoxG markedly increases from La to Nd. This result suggests that XoxG's redox properties are tuned specifically for lighter Lns in XoxF, an interpretation supported by the unusually low reduction potential of XoxG (+172 mV). The X-ray crystal structure of XoxG provides a structural basis for this reduction potential and insight into the XoxG-XoxF interaction. Finally, the X-ray crystal structure of XoxJ reveals a large hydrophobic cleft and suggests a role in the activation of XoxF. These studies enrich our understanding of the underlying chemical principles that enable the activity of XoxF with multiple lanthanides in vitro and in vivo.

Structures of Class Id Ribonucleotide Reductase Catalytic Subunits Reveal a Minimal Architecture for Deoxynucleotide Biosynthesis.

Class I ribonucleotide reductases (RNRs) share a common mechanism of nucleotide reduction in a catalytic α subunit. All RNRs initiate catalysis with a thiyl radical, generated in class I enzymes by a metallocofactor in a separate ß subunit. Class Id RNRs use a simple mechanism of cofactor activation involving oxidation of a MnII2 cluster by free superoxide to yield a metal-based MnIIIMnIV oxidant. This simple cofactor assembly pathway suggests that class Id RNRs may be representative of the evolutionary precursors to more complex class Ia-c enzymes. X-ray crystal structures of two class Id α proteins from Flavobacterium johnsoniae ( Fj) and Actinobacillus ureae ( Au) reveal that this subunit is distinctly small. The enzyme completely lacks common N-terminal ATP-cone allosteric motifs that regulate overall activity, a process that normally occurs by dATP-induced formation of inhibitory quaternary structures to prevent productive ß subunit association. Class Id RNR activity is insensitive to dATP in the Fj and Au enzymes evaluated here, as expected. However, the class Id α protein from Fj adopts higher-order structures, detected crystallographically and in solution. The Au enzyme does not exhibit these quaternary forms. Our study reveals structural similarity between bacterial class Id and eukaryotic class Ia α subunits in conservation of an internal auxiliary domain. Our findings with the Fj enzyme illustrate that nucleotide-independent higher-order quaternary structures can form in simple RNRs with truncated or missing allosteric motifs.

Brain-wide cellular resolution imaging of Cre transgenic zebrafish lines for functional circuit-mapping.

Decoding the functional connectivity of the nervous system is facilitated by transgenic methods that express a genetically encoded reporter or effector in specific neurons; however, most transgenic lines show broad spatiotemporal and cell-type expression. Increased specificity can be achieved using intersectional genetic methods which restrict reporter expression to cells that co-express multiple drivers, such as Gal4 and Cre. To facilitate intersectional targeting in zebrafish, we have generated more than 50 new Cre lines, and co-registered brain expression images with the Zebrafish Brain Browser, a cellular resolution atlas of 264 transgenic lines. Lines labeling neurons of interest can be identified using a web-browser to perform a 3D spatial search (zbbrowser.com). This resource facilitates the design of intersectional genetic experiments and will advance a wide range of precision circuit-mapping studies.

Opportunistic screening for alcohol use problems in adolescents attending emergency departments: an evaluation of screening tools.

OBJECTIVE: To estimate and compare the optimal cut-off score of Alcohol Use Disorders Identification Test (AUDIT) and AUDIT-C in identifying at-risk alcohol consumption, heavy episodic alcohol use, ICD-10 alcohol abuse and alcohol dependence in adolescents attending ED in England. DESIGN: Opportunistic cross-sectional survey. SETTING: 10 emergency departments across England. PARTICIPANTS: Adolescents (n = 5377) aged between their 10th and 18th birthday who attended emergency departments between December 2012 and May 2013. MEASURES: Scores on the AUDIT and AUDIT-C. At-risk alcohol consumption and monthly episodic alcohol consumption in the past 3 months were derived using the time-line follow back method. Alcohol abuse and alcohol dependence was assessed in accordance with ICD-10 criteria using the MINI-KID. FINDINGS: AUDIT-C with a score of 3 was more effective for at-risk alcohol use (AUC 0.81; sensitivity 87%, specificity 97%), heavy episodic use (0.84; 76%, 98%) and alcohol abuse (0.98; 91%, 90%). AUDIT with a score of 7 was more effective in identifying alcohol dependence (0.92; 96%, 94%). CONCLUSIONS: The 3-item AUDIT-C is more effective than AUDIT in screening adolescents for at-risk alcohol use, heavy episodic alcohol use and alcohol abuse. AUDIT is more effective than AUDIT-C for the identification of alcohol dependence.

Metal-free class Ie ribonucleotide reductase from pathogens initiates catalysis with a tyrosine-derived dihydroxyphenylalanine radical.

All cells obtain 2'-deoxyribonucleotides for DNA synthesis through the activity of a ribonucleotide reductase (RNR). The class I RNRs found in humans and pathogenic bacteria differ in (i) use of Fe(II), Mn(II), or both for activation of the dinuclear-metallocofactor subunit, ß; (ii) reaction of the reduced dimetal center with dioxygen or superoxide for this activation; (iii) requirement (or lack thereof) for a flavoprotein activase, NrdI, to provide the superoxide from O2; and (iv) use of either a stable tyrosyl radical or a high-valent dimetal cluster to initiate each turnover by oxidizing a cysteine residue in the α subunit to a radical (Cys•). The use of manganese by bacterial class I, subclass b-d RNRs, which contrasts with the exclusive use of iron by the eukaryotic Ia enzymes, appears to be a countermeasure of certain pathogens against iron deprivation imposed by their hosts. Here, we report a metal-free type of class I RNR (subclass e) from two human pathogens. The Cys• in its α subunit is generated by a stable, tyrosine-derived dihydroxyphenylalanine radical (DOPA•) in ß. The three-electron oxidation producing DOPA• occurs in Escherichia coli only if the ß is coexpressed with the NrdI activase encoded adjacently in the pathogen genome. The independence of this new RNR from transition metals, or the requirement for a single metal ion only transiently for activation, may afford the pathogens an even more potent countermeasure against transition metal-directed innate immunity.

Genome Plasticity of agr-Defective Staphylococcus aureus during Clinical Infection.

Therapy for bacteremia caused by Staphylococcus aureus is often ineffective, even when treatment conditions are optimal according to experimental protocols. Adapted subclones, such as those bearing mutations that attenuate agr-mediated virulence activation, are associated with persistent infection and patient mortality. To identify additional alterations in agr-defective mutants, we sequenced and assembled the complete genomes of clone pairs from colonizing and infected sites of several patients in whom S. aureus demonstrated a within-host loss of agr function. We report that events associated with agr inactivation result in agr-defective blood and nares strain pairs that are enriched in mutations compared to pairs from wild-type controls. The random distribution of mutations between colonizing and infecting strains from the same patient, and between strains from different patients, suggests that much of the genetic complexity of agr-defective strains results from prolonged infection or therapy-induced stress. However, in one of the agr-defective infecting strains, multiple genetic changes resulted in increased virulence in a murine model of bloodstream infection, bypassing the mutation of agr and raising the possibility that some changes were selected. Expression profiling correlated the elevated virulence of this agr-defective mutant to restored expression of the agr-regulated ESAT6-like type VII secretion system, a known virulence factor. Thus, additional mutations outside the agr locus can contribute to diversification and adaptation during infection by S. aureus agr mutants associated with poor patient outcomes.

Structural Basis for Superoxide Activation of Flavobacterium johnsoniae Class I Ribonucleotide Reductase and for Radical Initiation by Its Dimanganese Cofactor.

A ribonucleotide reductase (RNR) from Flavobacterium johnsoniae ( Fj) differs fundamentally from known (subclass a-c) class I RNRs, warranting its assignment to a new subclass, Id. Its ß subunit shares with Ib counterparts the requirements for manganese(II) and superoxide (O2-) for activation, but it does not require the O2--supplying flavoprotein (NrdI) needed in Ib systems, instead scavenging the oxidant from solution. Although Fj ß has tyrosine at the appropriate sequence position (Tyr 104), this residue is not oxidized to a radical upon activation, as occurs in the Ia/b proteins. Rather, Fj ß directly deploys an oxidized dimanganese cofactor for radical initiation. In treatment with one-electron reductants, the cofactor can undergo cooperative three-electron reduction to the II/II state, in contrast to the quantitative univalent reduction to inactive "met" (III/III) forms seen with I(a-c) ßs. This tendency makes Fj ß unusually robust, as the II/II form can readily be reactivated. The structure of the protein rationalizes its distinctive traits. A distortion in a core helix of the ferritin-like architecture renders the active site unusually open, introduces a cavity near the cofactor, and positions a subclass-d-specific Lys residue to shepherd O2- to the Mn2II/II cluster. Relative to the positions of the radical tyrosines in the Ia/b proteins, the unreactive Tyr 104 of Fj ß is held away from the cofactor by a hydrogen bond with a subclass-d-specific Thr residue. Structural comparisons, considered with its uniquely simple mode of activation, suggest that the Id protein might most closely resemble the primordial RNR-ß.

Alcohol Consumption, Early-Onset Drinking, and Health-Related Consequences in Adolescents Presenting at Emergency Departments in England.

PURPOSE: Globally, alcohol use is the leading cause of ill health and life years lost in adolescents, although its clinical impact is often overlooked, particularly in England where most research is based in schools. This study aims to examine the prevalence of alcohol consumption and the association between alcohol consumption and age of onset with health and social consequences among adolescents presenting to emergency departments (EDs). METHODS: Consecutive attenders (n = 5,576) aged 10-17 years at 10 EDs were included. Information was collected on general health and functioning, quality of life, alcohol use, and alcohol-related health and social consequences. RESULTS: Nearly 40% of adolescents reported the consumption of alcohol that was more than a sip in their lifetime. Age of the first alcohol consumption before the age of 15 years was associated with tobacco use (p < .001), lower quality of life (p = .003), and evidence of an alcohol use disorder (p = .002). It was also associated with general social functioning (problems with conduct p = .001 and hyperactivity p = .001) and alcohol-related health and social consequences (accident p = .046, problems with a parent p = .017, school p = .0117, or police p = .012). CONCLUSIONS: Rates of alcohol consumption in adolescents presenting to the ED were similar to those reported in schools in England and globally. Associations of alcohol consumption and earlier onset of drinking with poorer health and social functioning were observed. The ED can offer an opportunity for the identification of hazardous alcohol use in adolescents.

A Validated Open-Source Multisolver Fourth-Generation Composite Femur Model.

Synthetic biomechanical test specimens are frequently used for preclinical evaluation of implant performance, often in combination with numerical modeling, such as finite-element (FE) analysis. Commercial and freely available FE packages are widely used with three FE packages in particular gaining popularity: abaqus (Dassault Systèmes, Johnston, RI), ansys (ANSYS, Inc., Canonsburg, PA), and febio (University of Utah, Salt Lake City, UT). To the best of our knowledge, no study has yet made a comparison of these three commonly used solvers. Additionally, despite the femur being the most extensively studied bone in the body, no freely available validated model exists. The primary aim of the study was primarily to conduct a comparison of mesh convergence and strain prediction between the three solvers (abaqus, ansys, and febio) and to provide validated open-source models of a fourth-generation composite femur for use with all the three FE packages. Second, we evaluated the geometric variability around the femoral neck region of the composite femurs. Experimental testing was conducted using fourth-generation Sawbones® composite femurs instrumented with strain gauges at four locations. A generic FE model and four specimen-specific FE models were created from CT scans. The study found that the three solvers produced excellent agreement, with strain predictions being within an average of 3.0% for all the solvers (r2 > 0.99) and 1.4% for the two commercial codes. The average of the root mean squared error against the experimental results was 134.5% (r2 = 0.29) for the generic model and 13.8% (r2 = 0.96) for the specimen-specific models. It was found that composite femurs had variations in cortical thickness around the neck of the femur of up to 48.4%. For the first time, an experimentally validated, finite-element model of the femur is presented for use in three solvers. This model is freely available online along with all the supporting validation data.

Cattle and Nematodes Under Global Change: Transmission Models as an Ally.

Nematode infections are an important economic constraint to cattle farming. Future risk levels and transmission dynamics will be affected by changes in climate and farm management. The prospect of altered parasite epidemiology in combination with anthelmintic resistance requires the adaptation of current control approaches. Mathematical models that simulate disease dynamics under changing climate and farm management can help to guide the optimization of helminth control strategies. Recent efforts have increasingly employed such models to assess the impact of predicted climate scenarios on future infection pressure for gastrointestinal nematodes (GINs) in cattle, and to evaluate possible adaptive control measures. This review aims to consolidate progress in this field to facilitate further modeling and application.