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Background: Coronavirus disease-2019 (COVID-19) causes severe illness and multi-organ dysfunction. An abnormal electrocardiogram is associated with poor outcome, and QT prolongation during the illness has been linked to pharmacological effects. This study sought to investigate the effects of the COVID-19 illness on the corrected QT interval (QTc)., Method: For 293 consecutive patients admitted to our hospital via the emergency department for COVID-19 between 01/03/20 -18/05/20, demographic data, laboratory findings, admission electrocardiograph and clinical observations were compared in those who survived and those who died within 6 weeks. Hospital records were reviewed for prior electrocardiograms for comparison with those recorded on presentation with COVID-19., Results: Patients who died were older than survivors (82 vs 69.8 years, p < 0.001), more likely to have cancer (22.3% vs 13.1%, p = 0.034), dementia (25.6% vs 10.7%, p = 0.034) and ischemic heart disease (27.8% vs 10.7%, p < 0.001). Deceased patients exhibited higher levels of C-reactive protein (244.6 mg/L vs 146.5 mg/L, p < 0.01), troponin (1982.4 ng/L vs 413.4 ng/L, p = 0.017), with a significantly longer QTc interval (461.1 ms vs 449.3 ms, p = 0.007). Pre-COVID electrocardiograms were located for 172 patients; the QTc recorded on presentation with COVID-19 was longer than the prior measurement in both groups, but was more prolonged in the deceased group (448.4 ms vs 472.9 ms, pre-COVID vs COVID, p < 0.01). Multivariate Cox-regression analysis revealed age, C-reactive protein and prolonged QTc of >455 ms (males) and >465 ms (females) (p = 0.028, HR 1.49 [1.04-2.13]), as predictors of mortality. QTc prolongation beyond these dichotomy limits was associated with increased mortality risk (p = 0.0027, HR 1.78 [1.2-2.6])., Conclusion: QTc prolongation occurs in COVID-19 illness and is associated with poor outcome., (© 2021 Wiley Periodicals LLC.)

Background: The objective of the study was to explore the disease pathways activated in the inflammatory foci of skin lesions in cutaneous lupus erythematosus (CLE) and dermatomyositis (DM)., Methods: Skin biopsies acquired from active CLE and DM lesions, patient (PC), and also healthy controls (HC) were investigated. Biopsy sections were examined by a pathologist, inflammatory foci were laser micro-dissected and captured, and proteins within captured tissue were detected in an unbiased manner by mass spectrometry. Protein pathway analysis was performed by the string-db.org platform. Findings of interest were confirmed by immunohistochemistry (IHC)., Results: Proteome investigation identified abundant expression of interferon-regulated proteins (IRP) as a common feature of CLE and DM. Interleukin (IL)-16 was the only abundant cytokine differentially expressed in CLE compared to DM. Caspase-3, an enzyme that cleaves IL-16 into its active form, was detected in low levels. Significantly higher proportion of IL-16- and caspase-3-positive cells was identified in CLE lesions in comparison with DM, PC, and HC. Proteomic results indicate more abundant complement deposition in CLE skin lesions., Conclusions: Using unbiased mass spectrometry investigation of CLE and DM inflammatory infiltrates, we confirmed that high IRP expression is a common feature of both CLE and DM, while IL-16 is the only differentially expressed cytokine in CLE. IHC confirmed high expression of IL-16 and caspase-3 in CLE. Our novel molecular findings indicate that IL-16 detection could be useful in differential diagnostics between the two conditions that can display similar histopathological appearance. IL-16 could be of interest as a future therapeutic target for CLE.

This commentary follows up on Maduakolam et al. (2020) "Beyond Diversity: Envisioning Inclusion in Medical Education Research and Practice," which introduced Culturally Responsive Universal Design for Learning (CRUDL) as an approach to accounting for learner diversity in educational theory development and curriculum design. We flesh out the principles of CRUDL, using publications in this issue of Teaching and Learning in Medicine as case examples for how the principles work in action. With this scholarly thought exercise, we seek to demonstrate the feasibility and promise of curriculum that is accountable to diverse learners and the impact of historical trauma. We also explore how research inclusive of diverse social identities could inform curriculum design by identifying how social identity, learning environment, educational activities, and learner engagement interact to produce diverse learning experiences and performance. Scholarly thought exercises such as this one may help bridge the gap between professed ideals and action with respect to inclusive medical education; CRUDL principles provide a helpful framework for planning and evaluating accountable curriculum design.

Background: During the coronavirus pandemic, our intensive care units were faced with large numbers of patients with an unfamiliar disease. To support our colleagues and to assist with diagnosis and treatment, we developed a specialist team., Methods: The acute respiratory disease support team reviewed 44 consecutive patients referred from the intensive care and coordinated therapies for pulmonary hypertension, pulmonary thrombosis, evolving lung fibrosis and large airway intervention., Results: The mortality for this group was significantly lower (34%) than the total group admitted to critical care as a whole (51%) and for those not reviewed by the team (55%; p=0.012). Pulmonary hypertension was present in 84% of the patients and pulmonary thrombosis in 52%. Thirty-two patients received sildenafil therapy and this was associated with improvement in right heart function in survivors. Ten patients with evolving fibrosis and no evidence of sepsis received high-dose steroid therapy with excellent effect. Five patients developed airway complications requiring intervention. Short time on mechanical ventilation was associated with a poorer outcome (p<0.001)., Interpretation: A specialised cardiorespiratory team approach contributes significantly to successful management of severely unwell patients with COVID-19 and offers an important platform for continuity of patient care, education and staff well-being., (© Royal College of Physicians 2021. All rights reserved.)

Patients who are abusive or aggressive in ED raise special clinical and legal challenges. These include what steps clinicians should take to exclude serious illness/injury as the cause of the behaviour and when investigations or treatments can be imposed on these patients without their consent. Using a case illustration, this paper discusses legal issues which arise in this context, including how the standard of care owed by clinicians is determined and what may constitute a breach of duty; such patients' right to consent to (or decline) tests and treatment; and when clinicians may lawfully act without consent and/or control the patient's behaviour., (© 2020 Australasian College for Emergency Medicine.)

Membranous nephropathy results from subepithelial antigen-antibody complex deposition along the glomerular basement membrane. Although PLA2R, THSD7A, and NELL-1 account for a majority (about 80%) of the target antigens, the target antigen in the remaining cases is not known. Using laser microdissection of PLA2R-negative glomeruli of patients with membranous nephropathy followed by mass spectrometry we identified a unique protein, Semaphorin 3B, in three cases. Mass spectrometry failed to detect Semaphorin-3B in 23 PLA2R-associated cases of membranous nephropathy and 88 controls. Semaphorin 3B in all three cases was localized to granular deposits along the glomerular basement membrane by immunohistochemistry. Next, an additional eight cases of Semaphorin 3B-associated membranous nephropathy were identified in three validation cohorts by immunofluorescence microscopy. In four of 11 cases, kidney biopsy also showed tubular basement membrane deposits of IgG on frozen sections. Confocal microscopy showed that both IgG and Semaphorin 3B co-localized to the glomerular basement membrane. Western blot analysis of five available sera showed reactivity to reduced Semaphorin 3B in four of four patients with active disease and no reactivity in one patient in clinical remission; there was also no reactivity in control sera. Eight of the 11 cases of Semaphorin 3B-associated membranous nephropathy were pediatric cases. Furthermore, in five cases, the disease started at or below the age of two. Thus, Semaphorin 3B-associated membranous nephropathy appears to be a distinct type of disease; more likely to be present in pediatric patients., (Copyright © 2020 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

This commentary examines the publications in Teaching and Learning in Medicine's Issue 32(5) from the perspectives of Black, female medical trainees. Its purpose is to demonstrate how including diverse perspectives in general medical education scholarship could prompt reconsideration of basic concepts and the development of richer, more nuanced, and practicable understanding of who medical learners are. An inclusive concept of medical education is a first step toward "culturally responsive universal design for learning," an approach to educational design that views barriers to learning as a systems problem, recognizes racism as a learning barrier, and offers learners multiple means to achieve academic success. Augmenting studies that explicitly target the experiences of trainees and faculty from marginalized racial groups, this commentary aims to establish a vision for what to do educationally with the knowledge that people bring diverse backgrounds and perspectives to their learning.

ADAM10 and ADAM17 expression and soluble PD-L1 (sPD-L1) predict poor prognosis in many malignancies, including in patients treated with PD-(L)1 inhibitors. The mechanism of soluble PD-L1 production and its effects are unknown. Here we uncover a novel mechanism of ADAM10- and ADAM17-mediated resistance to PD-(L)1 inhibitors. ADAM10 and ADAM17 cleave PD-L1 from the surface of malignant cells and extracellular vesicles. This cleavage produces an active sPD-L1 fragment that induces apoptosis in CD8 + T cells and compromises the killing of tumor cells by CD8 + T cells. Reduced tumor site PD-L1 protein-to-mRNA ratios predict poor outcomes and are correlated with elevated ADAM10 and ADAM17 expression in multiple cancers. These results may explain the discordance between PD-L1 immunohistochemistry and PD-(L)1 inhibitor response. Thus, including ADAM10 and ADAM17 tissue staining may improve therapy selection. Furthermore, treatment with an ADAM10/ADAM17 inhibitor may abrogate PD-(L)1 inhibitor resistance and improve clinical responses to PD-(L)1 immunotherapy., (© 2020 The Author(s). Published with license by Taylor & Francis Group, LLC.)

Media reports suggest that between 2005 and 2014 an estimated 8,500 patients were injured (including 170 deaths) in Australia by defective medical devices. An Australian representative action against two manufacturers and a supplier of certain medical devices used for the treatment of stress urinary incontinence and pelvic organ prolapse by three women representing over 700 registered class members alleging serious complications of vaginal mesh repair gave rise to a judgment in favour of the plaintiffs in late 2019. The judgment suggests that replacing a set of suspensory components of the levator ani muscle with a rigid matrix of mesh which provided strong support at the expense of flexibility may have been a misguided choice., Competing Interests: None.

Objective: To develop, test, and validate the performance of ICD-10-CM claims-based case definitions for identifying children with sickle cell anemia (SCA)., Data Sources: Medicaid administrative claims (2016) for children <18 years with potential SCA (any D57x diagnosis code) and newborn screening records from Michigan and New York State., Study Design: This study is a secondary data analysis., Data Collection/extraction Methods: Using specific SCA-related (D5700, D5701, and D5702) and nonspecific (D571) diagnosis codes, 23 SCA case definitions were applied to Michigan Medicaid claims (2016) to identify children with SCA. Measures of performance (sensitivity, specificity, area under the ROC curve) were calculated using newborn screening results as the gold standard. A parallel analysis was conducted using New York State Medicaid claims and newborn screening data., Principal Findings: In Michigan Medicaid, 1597 children had ≥1 D57x claim; 280 (18 percent) were diagnosed with SCA. Measures of performance varied, with sensitivities from 0.02 to 0.97 and specificities from 0.88 to 1.0. The case definition of ≥1 outpatient visit with a SCA-related or D571 code had the highest area under the ROC curve, with a sensitivity of 95 percent and specificity of 92 percent. The same definition also had the highest performance in New York Medicaid (n = 2454), with a sensitivity of 94 percent and specificity of 86 percent., Conclusions: Children with SCA can be accurately identified in administrative claims using this straightforward case definition. This methodology can be used to monitor trends and use of health services after transition to ICD-10-CM., (© Health Research and Educational Trust.)

Introduction: Membranous nephropathy (MN) is the most common cause of nephrotic syndrome in Caucasian adults. Phospholipase A2 receptor (PLA2R)- and exostosin 1 (EXT1)/exostosin 2 (EXT2)-associated MN represent the most common primary and secondary forms of MN. The complement profile using a proteomics approach has not been studied in these 2 common forms of MN., Methods: We used laser microdissection and mass spectrometry (MS/MS) to dissect glomeruli and identify glomerular complement proteins in PLA2R-associated ( n  = 7), EXT1/EXT2-associated MN ( n  = 21), and 11 control cases (time 0 transplant biopsies)., Results: MS/MS identified high total spectral counts for PLA2R and EXT1/EXT2 in corresponding cases of PLA2R- and EXT1/EXT2-positive MN. Both PLA2R- and EXT1/EXT2-associated MN had high spectral counts of complement proteins C3, C4, C5, C6, C7, C8, and C9. Complement protein C1 was present in low spectral counts in EXT1/EXT2-associated MN. Regulators of complement activation that were detected in MN included higher spectral counts of FH, FHR-1, FHR-5, clusterin, vitronectin and lower spectral counts of FHR-3, FHR-4, and CD59. Low spectral counts of FB and properdin, key components of the alternative pathway, also were detected. IgG4 and IgG1 were the most abundant IgG subclasses in PLA2R- and EXT1/EXT2-associated MN. Lower spectral counts for C3, C4, and C5 were detected in control cases when compared with MN., Conclusion: Significant complement activation is present in MN as evidenced by large spectral counts of complement proteins from C3- and C4-based pathways, including regulatory proteins of complement pathways. These data suggest that anticomplement drugs may be effective in treatment for MN., (© 2020 International Society of Nephrology. Published by Elsevier Inc.)

Membranous nephropathy is characterized by deposition of immune complexes along the glomerular basement membrane. PLA2R and THSD7A are target antigens in 70% and 1-5% of primary membranous nephropathy cases, respectively. In the remaining cases, the target antigen is unknown. Here, laser microdissection of glomeruli followed by mass spectrometry was used to identify novel antigen(s) in PLA2R-negative membranous nephropathy. An initial pilot mass spectrometry study in 35 cases of PLA2R-negative membranous nephropathy showed high spectral counts for neural tissue encoding protein with EGF-like repeats, NELL-1, in six cases. Mass spectrometry failed to detect NELL-1 in 23 PLA2R-associated membranous nephropathy and 88 controls. NELL-1 was localized by immunohistochemistry, which showed bright granular glomerular basement membrane staining for NELL-1 in all six cases. Next, an additional 23 NELL-1 positive cases of membranous nephropathy were identified by immunohistochemistry in a discovery cohort of 91 PLA2R-negative membranous nephropathy cases, 14 were confirmed by mass spectrometry. Thus, 29 of 126 PLA2R-negative cases were positive for NELL-1. PLA2R-associated membranous nephropathy and controls stained negative for NELL-1. We then identified five NELL-1 positive cases of membranous nephropathy out of 84 PLA2R and THSD7A-negative cases in two validation cohorts from France and Belgium. By confocal microscopy, both IgG and NELL-1 co-localized to the glomerular basement membrane. Western blot analysis showed reactivity to NELL-1 in five available sera, but no reactivity in control sera. Clinical and biopsy findings of NELL-1 positive membranous nephropathy showed features of primary membranous nephropathy. Thus, a subset of membranous nephropathy is associated with accumulation and co-localization of NELL-1 and IgG along the glomerular basement membrane, and with anti-NELL-1 antibodies in the serum. Hence, NELL-1 defines a distinct type of primary membranous nephropathy., (Copyright © 2019 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Background & Aims: Hepatic recruitment of monocyte-derived macrophages (MoMFs) contributes to the inflammatory response in non-alcoholic steatohepatitis (NASH). However, how hepatocyte lipotoxicity promotes MoMF inflammation is unclear. Here we demonstrate that lipotoxic hepatocyte-derived extracellular vesicles (LPC-EVs) are enriched with active integrin β 1 (ITGβ 1 ), which promotes monocyte adhesion and liver inflammation in murine NASH., Methods: Hepatocytes were treated with either vehicle or the toxic lipid mediator lysophosphatidylcholine (LPC); EVs were isolated from the conditioned media and subjected to proteomic analysis. C57BL/6J mice were fed a diet rich in fat, fructose, and cholesterol (FFC) to induce NASH. Mice were treated with anti-ITGβ 1 neutralizing antibody (ITGβ 1 Ab) or control IgG isotype., Results: Ingenuity® Pathway Analysis of the LPC-EV proteome indicated that ITG signaling is an overrepresented canonical pathway. Immunogold electron microscopy and nanoscale flow cytometry confirmed that LPC-EVs were enriched with activated ITGβ 1 . Furthermore, we showed that LPC treatment in hepatocytes activates ITGβ 1 and mediates its endocytic trafficking and sorting into EVs. LPC-EVs enhanced monocyte adhesion to liver sinusoidal cells, as observed by shear stress adhesion assay. This adhesion was attenuated in the presence of ITGβ 1 Ab. FFC-fed, ITGβ 1 Ab-treated mice displayed reduced inflammation, defined by decreased hepatic infiltration and activation of proinflammatory MoMFs, as assessed by immunohistochemistry, mRNA expression, and flow cytometry. Likewise, mass cytometry by time-of-flight on intrahepatic leukocytes showed that ITGβ 1 Ab reduced levels of infiltrating proinflammatory monocytes. Furthermore, ITGβ 1 Ab treatment significantly ameliorated liver injury and fibrosis., Conclusions: Lipotoxic EVs mediate monocyte adhesion to LSECs mainly through an ITGβ 1 -dependent mechanism. ITGβ 1 Ab ameliorates diet-induced NASH in mice by reducing MoMF-driven inflammation, suggesting that blocking ITGβ 1 is a potential anti-inflammatory therapeutic strategy in human NASH., Lay Summary: Herein, we report that a cell adhesion molecule termed integrin β 1 (ITGβ 1 ) plays a key role in the progression of non-alcoholic steatohepatitis (NASH). ITGβ 1 is released from hepatocytes under lipotoxic stress as a cargo of extracellular vesicles, and mediates monocyte adhesion to liver sinusoidal endothelial cells, which is an essential step in hepatic inflammation. In a mouse model of NASH, blocking ITGβ 1 reduces liver inflammation, injury and fibrosis. Hence, ITGβ 1 inhibition may serve as a new therapeutic strategy for NASH., (Copyright © 2019 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

The Family Court of Australia has stepped back from a previously perceived need for involvement in the approval of stage 1 and stage 2 treatments, for children requiring gender transformation. At present those children and their families who are in agreement need not seek authorisation of the Family Court to undertake either Stage 1 (pubarche blockade with gonadotrophin-releasing hormone agonists) or Stage 2 treatment (cross-hormone therapy such as oestrogen for transgender males). Stage 1 treatment to suppress pubarche would nowadays be commenced at Tanner stage 2 which commences as early as 9.96 years in girls and 10.14 years in boys. Suppression of puberty continues until the age of 16 years when cross hormonal treatment commences. This article questions the assertion that suppression of puberty by GnRH analogues either in cases of precocious puberty or gender dysphoria is "safe and reversible" and argues that it warrants ongoing caution, despite the Family Court having broadly accepted that assertion., Competing Interests: None.

Introduction: Terminal bleeding, a distressing symptom experience for patients, caregivers, and health professionals, occurs in a subset of patients in the palliative care setting. Terminal bleeding is often thought of as a large-volume catastrophically fatal event, but it can also occur for a longer period of time and still be the precipitating event for a patient's death. Case Report: We present the case of terminal bleeding in an 87-year-old patient with angiosarcoma, a rare aggressive vascular neoplasm that can occur anywhere in the body but tend to occur more frequently in the head and neck. Discussion: The patient's advanced age and aggressive disease presented challenges in managing the symptoms and precluded many of the conventional recommended interventions to manage bleeding. Conclusion: This case report speaks to the need for multidisciplinary planning that takes prognosis, performance status, previous therapies, and patient preferences into account when caring for patients with advanced cancer.

The delivery of water services to the poor is lagging, yet local causes and manifestations of this are not well understood. Better data is needed to identify inequalities where they occur, explore underlying reasons, and develop strategies to achieve more equitable access. A focus on the local scale is important because this is where water services are delivered, and inequalities in access can be best observed. This paper presents a mixed-methods study of poor households' access to piped water in rural Viet Nam, providing insight into local dynamics of the water/poverty nexus. Findings pointed to lower rates of piped water access for poor households across areas served by government, private and community service providers. Connection fees were found to be the primary barrier to poor households accessing available piped services. The study also found that where financial support is provided, poor households can achieve comparable or even higher rates of access. Key implications of the study are the demonstrated value of, and yet challenges associated with, rigorous local-level monitoring to ensure equitable, quality service delivery., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Introduction: Workplace stress and burnout may influence nurses' physical and emotional well-being, which can impact the quality of care patients receive and their overall satisfaction with their hospitalization., Objectives: The objectives of the study were to evaluate whether there are significant statistical relationships between nurses' perceived stress, frequency of stressors, mindfulness, emotional self-regulation, self-care habits, and patient satisfaction scores., Methods: The study took place over the course of 4 weeks. In this study, 340 nurse participants were surveyed using cross-sectional voluntary sampling design. The survey included previously developed and validated instruments. SAS v. 9.4 was used for statistical analysis., Results: Significant differences were noted in average patient satisfaction scores by perceived stress; major nursing units in the Death and Dying, Conflict with Physicians, Lack of Support, and Work Load subscales of the Nursing Stress Scale; and major nursing units and dispositional mindfulness., Conclusions: Hospital administrators can use this information in their organizations and set priorities and tailor mindfulness-based stress-reduction interventions for nursing professionals., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2019.)

The management and remediation of contaminated environments increasingly involves engagement with affected local residents. Of late, risk communication tools and guidelines have drawn attention to the stress and concern of residents as a result of heightened awareness of localised contamination and the need to address these less visible impacts of contamination when engaging with affected communities. Despite this emerging focus, there is an absence of research exploring the factors that predict resident worry about neighbourhood contamination. This paper aims to address this shortcoming by drawing on data from a cross-sectional survey of 2009 adult residents in neighbourhoods near 13 contaminated sites across Australia. Analyses used ordered logistic regression to determine the sociodemographic, environmental, and knowledge-based factors that influence residents' degree of worry. The findings suggest age, gender and income significantly affect residents' degree of worry. Being knowledgeable about the contaminant was associated with lower degrees of worry. Conversely, having a stronger sense of place within a neighbourhood predicted higher degrees of worry. Type of contaminant also impacted resident worry, with residents being less likely to worry about hydrocarbon, asbestos and waste than other types of contaminants. Our analyses suggest resident worry can be reduced through improving access to accurate information and the development of specific risk reduction strategies tailored to each neighbourhood and aimed at the heterogeneous distribution of worry amongst residential populations., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: The association between preoperative tibial subchondral bone marrow lesion (BML) patterns and outcomes after isolated meniscus allograft transplantation (MAT) are unknown., Purpose: To determine (1) if a superior classification means exists (ie, high interrater reliability [IRR]) for grading tibial subchondral BML before isolated MAT and (2) whether quality and/or severity of preoperative tibial subchondral BML patterns was associated with clinical outcomes and/or failure rates after isolated MAT., Study Design: Cohort study; Level of evidence, 3., Methods: All patients who underwent isolated MAT with a single surgeon between October 2006 and February 2017 were identified. Three means were evaluated to quantify the degree of subchondral BML in the affected tibial-sided compartment: Welsch et al, based on maximum diameter of the lesion; Costa-Paz et al, based on appearance and location of the lesion; and Filardo et al, based on severity of findings. IRR was generated and compared among the 3 classifications. The preoperative magnetic resonance imaging (MRI) subchondral BML grading scheme with the highest IRR was then used to assess for associations with postoperative outcomes for those patients with >2-year follow-up, per a Spearman correlation matrix with each reviewer's grades., Results: In total, 60 MRI scans were available for subchondral BML grading. Grader 1 identified the presence of subchondral BML in the tibia of the affected compartment in 40 (66.7%) of the available MRI scans, as compared with 38 (63.3%) for grader 2. The calculated IRRs with the Welsch et al and Costa-Paz et al classifications were rated "strong/almost perfect" agreement. A significant correlation was demonstrated between grader 1 with the Welsch et al grading scheme and outcome measures of KOOS pain (Knee injury and Osteoarthritis Outcome Score; negative correlation, P = .05), WOMAC pain (Western Ontario and McMaster Universities Osteoarthritis Index; positive correlation, P = .026), and Marx Activity Rating Scale (negative correlation, P = .019). A significant correlation was demonstrated between grader 2 with the Costa-Paz et al grading scheme and postoperative satisfaction (positive correlation, P = .018). There were no significant differences in survivorship based on gradings., Conclusion: Nearly two-thirds of patients who undergo isolated MAT have subchondral BML on preoperative MRI. Our findings suggest that increasing BML size (Welsch et al) is correlated with worse postoperative pain measures (KOOS pain, WOMAC pain) and worse activity ratings (Marx Activity Rating Scale). Additionally, increasing disruption or depression of the normal contour of the cortical surface, with or without lesion contiguity with the subjacent articular surface (Costa-Paz et al), is correlated with greater postoperative satisfaction.

Background: Children with sickle cell anemia (SCA) are at increased risk for invasive pneumococcal disease; antibiotic prophylaxis significantly reduces this risk. We calculated the proportion of children with SCA who received ≥300 days of antibiotic prophylaxis and identified predictors of such receipt., Methods: Children aged 3 months to 5 years with SCA were identified by the presence of 3 or more Medicaid claims with a diagnosis of SCA within a calendar year (2005-2012) in Florida, Illinois, Louisiana, Michigan, South Carolina, and Texas. Receipt of antibiotics was identified through claims for filled prescriptions. The outcome, receipt of ≥300 days of antibiotics, was assessed annually by using varying classifications of antibiotics. By using logistic regression with generalized estimating equations, we estimated the odds of receiving ≥300 days of antibiotics, with potential predictors of age, sex, year, state, and health services use., Results: A total of 2821 children contributed 5014 person-years. Overall, only 18% of children received ≥300 days of antibiotics. Each additional sickle cell disease-related outpatient visit (odds ratio = 1.01, 95% confidence interval: 1.01-1.02) and well-child visit (odds ratio = 1.08, 95% confidence interval: 1.02-1.13) was associated with incrementally increased odds of receiving ≥300 days of antibiotics., Conclusions: Despite national recommendations and proven lifesaving benefit, antibiotic prophylaxis rates are low among children with SCA. Numerous health care encounters may offer an opportunity for intervention; in addition, such interventions likely need to include social factors that may affect the ability for a child to receive and adhere to antibiotic prophylaxis., Competing Interests: POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose., (Copyright © 2018 by the American Academy of Pediatrics.)

Background and Objectives: Sepsis syndrome, comprising sepsis, severe sepsis, and septic shock, is a leading cause of child mortality and morbidity, for which the delivery of time-sensitive care leads to improved survival. We aimed to describe the development and testing of quality measures for in-hospital care of pediatric sepsis syndrome., Methods: Seven measures of quality of care for children hospitalized with sepsis syndrome were developed by using an iterative process including literature review, development of concepts and candidate measures, and selection of measures for feasibility and importance by 2 panels of experts. The measures were tested for reliability and validity among children 0 to 18 years of age hospitalized with sepsis syndrome from January 1, 2012, to June 30, 2013., Results: Of 27 hospitals, 59% had no protocol for the identification and treatment of pediatric sepsis syndrome. Blood culture was performed in only 70% of patients with pediatric sepsis syndrome. Antibiotics were administered within 1 hour of diagnosis in 70% of patients with pediatric severe sepsis or septic shock, and timely fluid resuscitation was performed in 50% of patients with severe sepsis or septic shock. Documentation of heart rate during fluid resuscitation of children with severe sepsis or septic shock was observed in 18% of cases. Two measures could not be rigorously tested for validity and reliability given the rarity of septic shock and were deemed infeasible., Conclusions: This multisite study to develop and validate measures of the quality of hospital care of children with sepsis syndrome highlights the existence of important gaps in delivery of care., Competing Interests: POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose., (Copyright © 2017 by the American Academy of Pediatrics.)

Expert witnesses act as “injury brokers” in contributing to the analysis of what qualifies as legally recognised and compensable injury in medical negligence litigation. The orthodox approach in Australia is that expert witnesses, like advocates, are immune from suit in negligence. In Attwells v Jackson Lalic Lawyers Pty Ltd (2016) 90 ALJR 572; [2016] HCA 16, the High Court of Australia upheld, but narrowed, advocates’ immunity. This article outlines the decision in the Atwells case and after reviewing Australian authority on expert witness immunity argues that, given the recent narrowing of the scope of advocates’ immunity, similar limitations are likely to be placed on the scope of expert witness immunity with two effects – it will be less commonly available and less predictably available.

Importance: With transcranial Doppler (TCD) screening, we can identify children and adolescents with sickle cell anemia who are at the highest risk of stroke. An accurate claims-based method for identifying children and adolescents with sickle cell anemia was recently developed and validated that establishes the necessary groundwork to enable large population-based assessments of health services utilization among children and adolescents with sickle cell anemia using administrative claims data., Objective: To assess the feasibility of using administrative claims data to identify and describe the receipt of TCD screening among children and adolescents with sickle cell anemia and to characterize opportunities for intervention., Design, Setting, and Participants: Retrospective cross-sectional study using Medicaid claims data from 2005 to 2010. Medicaid claims data were obtained from the following states: Florida, Illinois, Louisiana, Michigan, South Carolina, and Texas. Children and adolescents 2 to 16 years of age with sickle cell anemia were identified by the presence of 3 or more Medicaid claims with a diagnosis of sickle cell anemia within a calendar year (2005-2010). A total of 4775 children and adolescents contributed 10 787 person-years throughout the study period. Data were analyzed in 2015. A subset of children and adolescents enrolled for 2 or more consecutive years was identified to examine potential predictors of TCD screening, which included age, sex, previous receipt of TCD screening, state of residence, and health services utilization (well-child visits, outpatient visits, emergency department visits, and inpatient visits)., Main Outcomes and Measures: Receipt of TCD screening was assessed by year and state. Using logistic regression with generalized estimating equations, we included associated predictors in a multivariable model to estimate odds of TCD screening., Results: For a total of 4775 children and adolescents 2 to 16 years of age, TCD screening rates increased over the 6-year study period from 22% to 44% (P < .001); rates varied substantially across states. A subset of 2388 children and adolescents with sickle cell anemia (50%) was enrolled for 2 or more consecutive years. Each year of increasing age was associated with 3% lower odds of TCD screening (odds ratio, 0.97 [95% CI, 0.95-0.98]; P = .002). Previous receipt of TCD screening (odds ratio, 2.44 [95% CI, 2.11-2.81]; P < .001) and well-child visits (odds ratio, 1.10 [95% CI, 1.03-1.18]; P = .007) were associated with higher odds of receiving a TCD screening., Conclusions and Relevance: Despite national recommendations, TCD screening rates remain low. Successful strategies to improve TCD screening rates may capitalize on the numerous health care interactions among children and adolescents with sickle cell anemia.

Many Australian courts now prefer pre-hearing meetings of experts (conclaves) being convened to prepare joint reports to identify areas of agreement and disagreement, followed by concurrent expert evidence at trial. This contrasts to the traditional approach where experts did not meet before trial and did not give evidence together. Most judges, lawyers and expert witnesses favour this as a positive development in Australian legal practice, at least for civil disputes. This new approach affects medical practitioners who are called on to give expert evidence, or who are parties to disputes before the courts. Arguably, it is too soon to tell whether the relative lack of transparency at the conclave stage will give rise to difficulties in the coronial, disciplinary and criminal arenas.

Background: Diabetic Ketoacidosis (DKA) is a potentially life-threatening emergency that requires prompt diagnosis and treatment. In paediatric populations an end tidal capnography value greater than 36 mmHg was found to be 100 % sensitive in ruling out DKA., Methods: A cross sectional observational study of adults ≥ 17 years of age presenting to the emergency department between January 2014 and May 2014 with glucose > 550 mg/dL. In all patients, nasal capnography and venous blood gas analysis were performed prior to any insulin or intravenous fluid administration. The diagnosis of DKA was based on the presence of anion gap metabolic acidosis, hyperglycaemia and ketonemia. The overall diagnostic performance (area under the curve [AUC]), sensitivity, specificity and likelihood ratios at different end tidal CO2 (ETCO2) cut-offs were determined., Results: 71 patients were enrolled in the study of which 21 (30 %) met the diagnosis of DKA. The area under the curve for ETCO2 was 0.95 with a 95 % CI of 0.91 to 0.99. Test sensitivity for DKA at ETCO2 level ≥35 mmHg was 100 % (95 % CI, 83.9-100). An ETCO2 level ≤ 21 mmHg was 100 % specific (95 % CI, 92.9-100.0) for DKA., Conclusion: Nasal capnography exhibits favourable diagnostic performance in detecting patients with or without DKA among those who present to the emergency department with a glucometer reading > 550 mg/dL.

Background: Seat belt use has been associated with decreased life-threatening thoracic injuries. However, there has been an increase in soft-tissue injuries such as breast trauma., Case Report: We describe a case of a young healthy female who presented to a community hospital Emergency department without any trauma designation following a motor vehicle accident. The patient was found to have hemorrhagic shock from an intramammary hemorrhage and was treated with blood products and a temporizing external abdominal binder in preparation for a transfer to a level 1 center where she was successfully treated with angiographic embolization., Objectives: The objective of this study is to report on a case hemorrhagic shock from a breast hematoma as well as a review of the literature on previous seat belt associated breast trauma and its management in the emergency department., Conclusion: Seat belt associated breast trauma is uncommon in the emergency medicine literature. However, it can be associated with life threatening intramammary bleeding. Emergency physicians should be aware of these injuries and their proper management.

Aim: The prediction of return of spontaneous circulation (ROSC) during resuscitation of patients suffering of cardiac arrest (CA) is particularly challenging. Regional cerebral oxygen saturation (rSO2) monitoring through near-infrared spectrometry is feasible during CA and could provide guidance during resuscitation., Methods: We conducted a systematic review and meta-analysis on the value of rSO2 in predicting ROSC both after in-hospital (IH) or out-of-hospital (OH) CA. Our search included MEDLINE (PubMed) and EMBASE, from inception until April 4th, 2015. We included studies reporting values of rSO2 at the beginning of and/or during resuscitation, according to the achievement of ROSC., Results: A total of nine studies with 315 patients (119 achieving ROSC, 37.7%) were included in the meta-analysis. The majority of those patients had an OHCA (n=225, 71.5%; IHCA: n=90, 28.5%). There was a significant association between higher values of rSO2 and ROSC, both in the overall calculation (standardized mean difference, SMD -1.03; 95%CI -1.39,-0.67; p<0.001), and in the subgroups analyses (rSO2 at the beginning of resuscitation: SMD -0.79; 95%CI -1.29,-0.30; p=0.002; averaged rSO2 value during resuscitation: SMD -1.28; 95%CI -1.74,-0.83; p<0.001)., Conclusions: Higher initial and average regional cerebral oxygen saturation values are both associated with greater chances of achieving ROSC in patients suffering of CA. A note of caution should be made in interpreting these results due to the small number of patients and the heterogeneity in study design: larger studies are needed to clinically validate cut-offs for guiding cardiopulmonary resuscitation., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

There is emerging evidence, although at early stages, of various detrimental health effects after smoking shisha. With regard to the cardiovascular system, there is a significant acute rise in cardiovascular markers, such as heart rate and blood pressure. The long-term effects on the cardiovascular system are yet to be established. Shisha smoking has also been significantly associated with lung cancer. Various other forms of cancer have also been documented, but have not reached statistical significance and require further research. Finally, shisha smoking increases the risk of infection and has been associated with outbreaks in the Middle East. Therefore, with the increasing consumption of shisha in Europe, especially in the UK, more research is required to tackle this potential public health threat., (© Royal College of Physicians 2015. All rights reserved.)

In medical negligence litigation expert evidence has long played a dominant role. The trend towards the use of concurrent expert evidence is now well underway. However, for the lawyers and the doctors involved, the pathway is not yet familiar. Disputes have frequently arisen in the context of pre-hearing expert conclaves, given the adversarial nature of litigation and perhaps fuelled by fears of a less transparent process at this increasingly important stage. This article explains the concurrent expert evidence framework and examines areas of common dispute both in the conclaves and at trial, with a view to providing assistance to legal practitioners working in this area and the medical practitioners called upon to provide expert evidence in such litigation.

Computed tomography (CT) is routinely used in the evaluation of patients with pulmonary hypertension (PH) to assess vascular anatomy and parenchymal morphology. The introduction of dual-energy CT (DECT) enables additional qualitative and quantitative insights into pulmonary hemodynamics and the extent and variability of parenchymal enhancement. Lung perfusion assessed at pulmonary blood volume imaging correlates well with findings at scintigraphy, and pulmonary blood volume defects seen in pulmonary embolism studies infer occlusive disease with increased risk of right heart dysfunction. Similarly, perfusion inhomogeneities seen in patients with PH closely reflect mosaic lung changes and may be useful for severity assessment and prognostication. The use of DECT may increase detection of peripheral thromboembolic disease, which is of particular prognostic importance in patients with chronic thromboembolic PH with microvascular involvement. Other DECT applications for imaging of PH include low-kilovoltage images with greater inherent iodine conspicuity and iodine-selective color-coded maps of vascular perfusion (both of which can improve visualization of vascular enhancement), virtual nonenhanced imaging (which better depicts vascular calcification), and, potentially, ventricular perfusion maps (to assess myocardial ischemia). In addition, quantitative assessment of central vascular and parenchymal enhancement can be used to evaluate pulmonary hemodynamics in patients with PH. The current status and potential advantages and limitations of DECT for imaging of PH are reviewed, and current evidence is supplemented with data from a tertiary referral center for PH., (©RSNA, 2014.)

Objectives: To investigate the acute cardiovascular effects of smoking shisha., Design: A cross-sectional study was carried out in six shisha cafes. Participants smoked shisha for a period between 45 min (minimum) and 90 min (maximum). The same brand of tobacco and coal was used., Setting: London, UK., Participants: Participants were those who had ordered a shisha to smoke and consented to have their blood pressure, heart rate and carbon monoxide levels measured. Excluded subjects were those who had smoked shisha in the previous 24 h, who smoke cigarettes or who suffered from cardiorespiratory problems., Main Outcome Measures: Blood pressure was measured using a sphygmomanometer. Pulse was measured by palpation of the radial artery. Carbon monoxide levels were obtained via a carbon monoxide monitor. These indices were measured before the participants began to smoke shisha and after they finished or when the maximum 90 min time period was reached., Results: Mean arterial blood pressure increased from 96 mmHg to 108 mmHg (p < 0.001). Heart rate increased from 77 to 91 bpm (p < 0.001). Carbon monoxide increased from an average of 3 to 35 ppm (p < 0.001). A correlation analysis showed no relationship between carbon monoxide and the other indices measured., Conclusion: The acute heart rate, blood pressure and carbon monoxide levels were seen to rise significantly after smoking shisha. The weak correlation between carbon monoxide levels and the other variables suggests that carbon monoxide levels had not contributed to their significant increase.

Individuals carrying DRB1*0401 who smoke cigarettes are at an increased risk of developing severe seropositive RA. To determine how cigarette smoke (CS) interacts with host genetic factors in the induction of RA-associated autoimmunity, we used transgenic mice carrying the RA-susceptible HLA genes DR4 and DQ8, but lacking all endogenous murine class II molecules. Cigarette smoke exposure augmented peptidylarginine deiminase (PAD) enzyme expression, and enhanced immune responses to citrullinated collagen and vimentin. Here we show for the first time that DQ molecules can present citrullinated peptides much more efficiently than native peptides. Interestingly, CS exposure suppressed collagen-induced arthritis (CIA) in DRB1*0401 mice although innate immune response was enhanced. On the other hand, CS exposure exacerbated CIA in DQ8 mice, which was accompanied by an increased expression of Th17 gene transcripts in lungs. These observations suggest that cigarette smoke promotes antigen-specific autoimmunity that is profoundly influenced by host genetic factors., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Purpose: To evaluate quantitative differences in central pulmonary artery (PA) and pulmonary global and regional enhancement in patients with and without pulmonary hypertension (PH) using dual-energy computed tomography (DECT)., Materials and Methods: We retrospectively studied 391 thoracic DECT studies and identified 89 patients with PA pressure (PAP) data and a pulmonary angiogram. PH was defined as a mean PAP of ≥25 mm Hg on right heart catheterization (RHC) (n=19) or a systolic PAP of ≥40 mm Hg on echocardiography (n=20). PH absence was defined by entirely normal echocardiography or RHC (n=50). PA enhancement (PAenh) was calculated from DECT iodine images. Volumetric enhancement of each whole lung (WLenh), 6 standard lung regions (RLenh), and 24 two-dimensional standardized regions of interest (ROIenh) was performed in each patient using pulmonary blood volume analysis., Results: Mean PAenh was greater in PH patients compared with controls (272 vs. 252 HU, P<0.05), with a reciprocal reduction in mean WLenh (27 vs. 32 HU, P<0.01). Mean ROIenh (n=2058) confirmed lower parenchymal enhancement in PH (27 vs. 32 HU, P<0.001), with greater mean ROIenh standard deviation (10.5 vs. 9.3, P<0.001). Mean intrapatient pulmonary enhancement variability was greater in PH patients than in controls for 6 RLenh (variance 37 vs. 22, P=0.02) and 24 ROIenh measures (variance 188 vs. 130, P=0.04). RLenh and ROIenh variance correlated with RHC pulmonary vascular resistance (PVR) (r=0.44, 0.48; P=0.04, 0.03, respectively). A ratio of PAenh/WLenh distinguished PH from non-PH patients (10.9 vs. 8.4, P<0.001) and correlated best with PVR (r=0.59, P=0.004)., Conclusions: PH patients demonstrate increased PAenh with a reciprocal reduction and greater variation in parenchymal enhancement; a DECT ratio of central to parenchymal enhancement correlates with PVR and may help identify PH.

Aims: Pre-participation cardiovascular screening of young athletes may prevent sports-related sudden cardiac deaths. Recognition of physiological electrocardiography (ECG) changes in healthy athletes has improved the specificity of screening while maintaining sensitivity for disease. The study objective was to determine the clinical significance of electrocardiographic right ventricular hypertrophy (RVH) in athletes., Methods and Results: Between 2010 and 2012, 868 subjects aged 14-35 years (68.8% male) were assessed using ECG and echocardiography (athletes; n = 627, sedentary controls; n = 241). Results were compared against patients with established right ventricular (RV) pathology (arrhythmogenic right ventricular cardiomyopathy, n = 68; pulmonary hypertension, n = 30). Sokolow-Lyon RVH (R[V1]+S[V5orV6] > 1.05 mV) was more prevalent in athletes than controls (11.8 vs. 6.2%, P = 0.017), although RV wall thickness (RVWT) was similar (4.0 ± 1.0 vs. 3.9 ± 0.9 mm, P = 0.18). Athletes exhibiting electrocardiographic RVH were predominantly male (95.9%), and demonstrated similar RV dimensions and function to athletes with normal electrocardiograms (RVWT; 4.0 ± 1.1 vs. 4.0 ± 0.9 mm, P = 0.95, RV basal dimension; 42.7 ± 5.2 vs. 42.1 ± 5.9 mm, P = 0.43, RV fractional area change; 40.6 ± 7.6 vs. 42.2 ± 8.1%, P = 0.14). Sensitivity and specificity of Sokolow-Lyon RVH for echocardiographic RVH (>5 mm) were 14.3 and 88.2%, respectively. Further evaluation including cardiac magnetic resonance imaging did not diagnose right ventricular pathology in any athlete. None of the cardiomyopathic or pulmonary hypertensive patients exhibited voltage RVH without additional ECG abnormalities., Conclusion: Electrocardiographic voltage criteria for RVH are frequently fulfilled in healthy athletes without underlying RV pathology, and should not prompt further evaluation if observed in isolation. Recognition of this phenomenon should reduce the burden of investigations after pre-participation ECG screening without compromising sensitivity for disease.

Background: Mitochondrial short and long-range movements are necessary to generate the energy needed for synaptic signaling and plasticity. Therefore, an effective mechanism to transport and anchor mitochondria to pre- and post-synaptic terminals is as important as functional mitochondria in neuronal firing. Mitochondrial movement range is regulated by phosphorylation of cytoskeletal and motor proteins in addition to changes in mitochondrial membrane potential. Movement direction is regulated by serotonin and dopamine levels. However, data on mitochondrial movement defects and their involvement in defective signaling and neuroplasticity in relationship with mood disorders is scarce. We have previously reported the effects of lithium, valproate and a new antipsychotic, paliperidone on protein expression levels at the synaptic level., Hypothesis: Mitochondrial function defects have recently been implicated in schizophrenia and bipolar disorder. We postulate that mood stabilizer treatment has a profound effect on mitochondrial function, synaptic plasticity, mitochondrial migration and direction of movement., Methods: Synaptoneurosomal preparations from rat pre-frontal cortex were obtained after 28 daily intraperitoneal injections of lithium, valproate and paliperidone. Phosphorylated proteins were identified using 2D-DIGE and nano LC-ESI tandem mass spectrometry., Results: Lithium, valproate and paliperidone had a substantial and common effect on the phosphorylation state of specific actin, tubulin and myosin isoforms as well as other proteins associated with neurofilaments. Furthermore, different subunits from complex III and V of the electron transfer chain were heavily phosphorylated by treatment with these drugs indicating selective phosphorylation., Conclusions: Mood stabilizers have an effect on mitochondrial function, mitochondrial movement and the direction of this movement. The implications of these findings will contribute to novel insights regarding clinical treatment and the mode of action of these drugs.

Background: We introduce a promising methodology to identify new therapeutic targets in cancer. Proteins bind to nanoparticles to form a protein corona. We modulate this corona by using surface-engineered nanoparticles, and identify protein composition to provide insight into disease development., Methods/principal Findings: Using a family of structurally homologous nanoparticles we have investigated the changes in the protein corona around surface-functionalized gold nanoparticles (AuNPs) from normal and malignant ovarian cell lysates. Proteomics analysis using mass spectrometry identified hepatoma-derived growth factor (HDGF) that is found exclusively on positively charged AuNPs ((+)AuNPs) after incubation with the lysates. We confirmed expression of HDGF in various ovarian cancer cells and validated binding selectivity to (+)AuNPs by Western blot analysis. Silencing of HDGF by siRNA resulted s inhibition in proliferation of ovarian cancer cells., Conclusion: We investigated the modulation of protein corona around surface-functionalized gold nanoparticles as a promising approach to identify new therapeutic targets. The potential of our method for identifying therapeutic targets was demonstrated through silencing of HDGF by siRNA, which inhibited proliferation of ovarian cancer cells. This integrated proteomics, bioinformatics, and nanotechnology strategy demonstrates that protein corona identification can be used to discover novel therapeutic targets in cancer.

Pulmonary function tests are valuable investigations in the management of patients with suspected or previously diagnosed respiratory disease. They aid diagnosis, help monitor response to treatment and can guide decisions regarding further treatment and intervention. The interpretation of pulmonary functions tests requires knowledge of respiratory physiology. In this review we describe investigations routinely used and discuss their clinical implications.