Postinfectious Inflammation, Autoimmunity, and Obsessive-Compulsive Disorder: Sydenham Chorea, Pediatric Autoimmune Neuropsychiatric Disorder Associated with Streptococcal Infection, and Pediatric Acute-Onset Neuropsychiatric Disorder.

Postinfectious neuroinflammation has been implicated in multiple models of acute-onset obsessive-compulsive disorder including Sydenham chorea (SC), pediatric acute-onset neuropsychiatric syndrome (PANS), and pediatric autoimmune neuropsychiatric disorders associated with streptococcal infection (PANDAS). These conditions are associated with a range of autoantibodies which are thought to be triggered by infections, most notably group A streptococci (GAS). Based on animal models using huma sera, these autoantibodies are thought to cross-react with neural antigens in the basal ganglia and modulate neuronal activity and behavior. As is true for many childhood neuroinflammatory diseases and rheumatological diseases, SC, PANS, and PANDAS lack clinically available, rigorous diagnostic biomarkers and randomized clinical trials. In this review article, we outline the accumulating evidence supporting the role neuroinflammation plays in these disorders. We describe work with animal models including patient-derived anti-neuronal autoantibodies, and we outline imaging studies that show alterations in the basal ganglia. In addition, we present research on metabolites, which are helpful in deciphering functional phenotypes, and on the implication of sleep in these disorders. Finally, we encourage future researchers to collaborate across medical specialties (e.g., pediatrics, psychiatry, rheumatology, immunology, and infectious disease) in order to further research on clinical syndromes presenting with neuropsychiatric manifestations.

Assessing medical student satisfaction with rural placement: The Australian Rural Clinical School Support Survey.

INTRODUCTION: Australia has a doctor shortage in rural settings, and rural placements for medical students have an important role in increasing the likelihood of students staying in rural settings throughout their careers. However, to date there is limited research regarding medical student perceptions of rural placement quality. OBJECTIVE: We aimed to determine factors that impact the overall medical student experience during rural placements. DESIGN: Cross-sectional survey. SETTING: Rural/remote clinical schools across Australia. PARTICIPANTS: Medical students on rural/remote clinical placements for at least 6 months. MAIN OUTCOME MEASURES: To assess factors impacting student experience on rural placements, we conducted a cross-sectional survey, known as the Australian Rural Clinical School Support Survey (ARCSSS) which was completed online by medical students across Australia. Demographic data were collected in addition to responses regarding academic teaching, extracurricular activities, and support services. Multiple choice and Likert scale questions were utilised. RESULTS: A total of 107 responses to our survey were analysed. The majority of participants were female (66.4%), and in their middle years of clinical education (55.1%). Overall, respondents showed high levels of satisfaction with clinical school supervisors, and clinical education. A high proportion of respondents indicated minimal accessibility of health and other support services. While a large proportion of participants indicated satisfaction with the rural placements, it was demonstrated that students were generally dissatisfied with school wellness activities and extracurricular activities. Financial insecurity was noted. CONCLUSION: The findings from our survey indicate there are numerous areas in which rural placements have been effective for medical students, and others in which improvement is needed. Furthermore, more research is required to better develop well-being initiatives that are effective in improving overall experience.

Severe Pancreatitis Multidisciplinary Working Group: Exploratory Analysis to Optimize Care and Cost.

INTRODUCTION: The minimally invasive step-up approach to pancreatitis improves outcomes. Multidisciplinary working groups may best facilitate this approach. However, support for these working groups requires funding. We hypothesize that patients requiring surgical debridement generate sufficient revenue to sustain these working groups. Furthermore, patients selected for surgical debridement by the working group will have a higher rate of percutaneous and endoscopic intervention in adherence to the step-up approach. METHODS: We conducted an observational cohort study of all patients with severe acute and/or necrotizing pancreatitis whose care was overseen by our multidisciplinary working group (October 2015 through January 2019). Patient demographics, hospital treatments, and outcomes data were compared between those who underwent surgical debridement and those who did not. Hospital billing data were also collected from those who are undergoing surgical debridement and compared to institutional benchmarks for financial sustainability. RESULTS: A total of 108 patients received care overseen by the working group, 10 of which progressed to surgical debridement. The mean contribution margin percentages for each patient in the surgical debridement group were higher than the threshold value for financial sustainability, 39% (60.34% ± 16.66%; P = 0.004). Patients in the surgical debridement group were more likely to undergo intervention by interventional radiologist (odds ratio, 1.58; P = 0.005). The mortality was higher in the nonsurgical debridement group (odds ratio, 15; P = 0.008). CONCLUSIONS: Our multidisciplinary working group delivered step-up care to patients with pancreatitis. Patients requiring surgical debridement generated a significantly positive contribution margin that could be used to help support the costs associated with providing multidisciplinary care.

Health-related quality of life and economic burden of prurigo nodularis.

BACKGROUND: Prurigo nodularis (PN) is an understudied, pruritic inflammatory skin disease. Little is known about the effect of PN on quality of life and its associated economic burden. OBJECTIVE: To quantify the impact of PN on quality of life and its economic implications. METHODS: A cohort study of PN patients (n = 36) was conducted using the Health Utilities Index Mark 3 questionnaire. Control data from US adults (n = 4187) were obtained from the 2002-2003 Joint Canada/United States Survey of Health. Quality-adjusted life year loss and economic costs were estimated by comparing the Health Utilities Index Mark 3 scores of the PN patients with those of the controls. RESULTS: The PN patients had lower overall health performance compared to the controls, (mean ± SE, 0.52 ± 0.06 vs 0.86 ± 0.003, respectively, P < .001). In multivariable regression, PN was found to be associated with worse health performance (coefficient -0.34, 95% CI [-0.46 to -0.23]), most prominent in the pain subdomain (coefficient -0.24, 95% CI [-0.35 to -0.13]). This correlated to an average of 6.5 lifetime quality-adjusted life years lost per patient, translating to an individual lifetime economic burden of $323,292 and a societal burden of $38.8 billion. CONCLUSION: These results demonstrate that PN is associated with significant quality-of-life impairment, similar to the level of other chronic systemic conditions. PN is also associated with a substantial individual economic burden, emphasizing the necessity of research on effective treatment options.

Real-world comorbidities of atopic dermatitis in the pediatric ambulatory population in the United States.

BACKGROUND: Increasing evidence has suggested the systemic nature of atopic dermatitis (AD), a common inflammatory skin condition in children. However, comprehensive analyses of real-world comorbidities in pediatric AD are limited. OBJECTIVE: To characterize comorbidity burden in patients with AD aged <18 years old. METHODS: The MarketScan commercial claims database was queried from January 1, 2017, to December 31, 2017. Age- and sex-matched analyses were used to compare patients with AD with general population controls. RESULTS: A total of 86,969 pediatric patients with AD and 116,564 matched controls were identified. Increased anxiety (odds ratio [OR], 1.20) and attention-deficit hyperactivity disorder (OR, 1.11) were noted in patients with AD. In addition to dermatologic/allergic diseases, AD was also associated with infections, including methicillin-resistant Staphylococcus aureus (OR, 3.76), and autoimmune conditions, including vitiligo (OR, 2.98) and alopecia areata (OR, 4.32). Pediatric patients with AD had higher likelihoods of lymphoid/hematologic malignancies (OR, 1.94), ocular disorders (OR, 1.37-2.02), metabolic syndrome (OR, 1.61), and obesity (OR, 1.81). For all the ORs mentioned above, P was <.001. LIMITATIONS: Retrospective analysis of health care claims data. CONCLUSIONS: AD in pediatric patients was associated with a wide range of psychologic and systemic comorbidities. Increased awareness can help minimize its negative effects on the quality of life and prevent long-term health consequences in young patients with AD.

Sleep disturbance in adults with chronic pruritic dermatoses is associated with increased C-reactive protein levels.

BACKGROUND: Pruritus is a common symptom that can significantly reduce quality of life through sleep disruption. OBJECTIVE: To examine features of disturbed sleep in patients with chronic pruritic dermatoses and test the hypothesis that systemic inflammation may serve as a biomarker for impaired sleep in these patients. METHODS: Cross-sectional analysis of the National Health and Nutrition Examination Survey investigating systemic inflammation using C-reactive protein (CRP) levels. Logistic regression was used to compare patients with and without sleep disturbances, adjusting for demographics (model 1) and medical comorbidities (model 2). RESULTS: Chronic pruritic dermatoses were associated with multiple sleep disturbances, including nighttime awakenings (model 1: odds ratio [OR], 1.646; 95% confidence interval [CI], 1.031-2.627; model 2: OR, 1.329; 95% CI, 0.888-1.989) and early morning awakening (model 1: OR, 1.669, 95% CI, 1.118-2.493; model 2: OR, 1.582; 95% CI, 1.008-2.481). Mean CRP levels were 52.8% higher among patients with pruritic dermatoses reporting trouble sleeping compared with those who did not (0.663 vs 0.434 mg/dL; P = .034). Trouble sleeping was also positively correlated with CRP levels (ß = 0.142, P = .025). LIMITATIONS: Potential recall bias among participants. CONCLUSIONS: In addition to confirming sleep disturbances with pruritic dermatoses, we found these disturbances are more likely to present with elevated CRP levels. Clinicians should consider the potential risk for sleep-related and cardiac comorbidities in patients diagnosed with itchy skin conditions.

Cognitive, Graphomotor, and Psychosocial Challenges in Pediatric Autoimmune Neuropsychiatric Disorders Associated With Streptococcal Infections (PANDAS).

OBJECTIVES: Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infection (PANDAS) is characterized by the sudden onset of obsessive-compulsive disorder (OCD) and other neurobehavioral symptoms following group A streptococcal infection. The cardinal neuropsychiatric symptoms are believed to reflect an aberrant autoimmune or inflammatory response that may selectively disrupt basal ganglia function. The investigators examined whether neuropsychological skills associated with frontostriatal networks (executive functions and motor skills) are affected in patients with PANDAS following resolution of acute symptoms and the degree to which there are persistent social, emotional, and academic difficulties. METHODS: Twenty-seven patients ages 6-14 years (mean age=9.63 years [SD=1.78]; male, N=22) completed neuropsychological testing as part of routine clinical care. Performances on measures of intellectual ability, executive function, motor skills, and academic skills are reported, as well as parent-reported emotional, behavioral, and social skills. RESULTS: On neuropsychological measures, patients exhibited average intellectual functioning with relative and mild difficulties in skills supporting cognitive efficiency, including attentional regulation, inhibitory control, and processing speed. Dexterity was normal but graphomotor skills were reduced. Core reading, math, and writing skills were within expectations, but reading and math fluency were reduced, and the majority of patients received special education services or accommodations. Parents reported high levels of concern about anxiety, depression, inattention, hyperactivity, and social skills. CONCLUSIONS: These findings indicated relative difficulties with aspects of executive and motor functions. Although evaluations were performed following the resolution of acute symptoms, ongoing and significant academic difficulties and emotional, behavioral, and social concerns were targets for clinical intervention and support.

Prurigo nodularis: Epidemiology and clinical features.

Prurigo nodularis (PN) is a chronic inflammatory skin disease characterized by intensely pruritic, hyperkeratotic nodules that favor the extensor surfaces of the extremities and the trunk. In addition to its significant impact on quality of life, many patients with PN are recalcitrant to therapy because there are currently no therapies approved by the US Food and Drug Administration. In the first article of this 2-part continuing medical education series, we describe the broader epidemiology, patient demographics, physical examination findings, and symptoms to aid in the timely recognition and diagnosis of PN. Furthermore, we quantify the burden of comorbidities in PN by discussing the broad spectrum of systemic diseases and mental health conditions that have been associated with this condition. The second article of this 2-part series focuses on the pathogenesis of PN and provides detailed algorithms for comprehensive work-up and management.

Prurigo nodularis: Pathogenesis and management.

Prurigo nodularis is a chronic skin condition characterized by severely pruritic nodules that cause a profound negative impact on quality of life. The second article in this 2-part continuing medical education series focuses on reviewing the pathogenesis of prurigo nodularis and exploring management algorithms for this condition. In addition, we discuss some emerging and novel therapies for treating prurigo nodularis. The first article in this 2-part series describes the broader epidemiology, patient demographics, physical examination findings, and symptoms to aid in the timely recognition and diagnosis of prurigo nodularis.

Welding and Additive Manufacturing with Nanoparticle-Enhanced Aluminum 7075 Wire.

Aluminum alloy 7075 (Al 7075) with a T73 heat treatment is commonly used in aerospace applications due to exceptional specific strength properties. Challenges with manufacturing the material from the melt has previously limited the processing of Al 7075 via welding, casting, and additive manufacturing. Recent research has shown the capabilities of nanoparticle additives to control the solidification behavior of high-strength aluminum alloys, showcasing the first Al 7075 components processed via casting, welding, and AM. In this work, the properties of nanoparticle-enhanced aluminum 7075 are investigated on welded parts, overlays and through wire-based additive manufacturing. The hardness and tensile strength of the deposited materials were measured in the as-welded and T73 heat-treated conditions showing that the properties of Al 7075 T73 can be recovered in welded and layer-deposited parts. The work shows that Al 7075 now has the potential to be conventionally welded or additively manufactured from wire into high-strength, crack-free parts.

The Anti-sigma Factor RsiV Is a Bacterial Receptor for Lysozyme: Co-crystal Structure Determination and Demonstration That Binding of Lysozyme to RsiV Is Required for σV Activation.

σ factors provide RNA polymerase with promoter specificity in bacteria. Some σ factors require activation in order to interact with RNA polymerase and transcribe target genes. The Extra-Cytoplasmic Function (ECF) σ factor, σV, is encoded by several Gram-positive bacteria and is specifically activated by lysozyme. This activation requires the proteolytic destruction of the anti-σ factor RsiV via a process of regulated intramembrane proteolysis (RIP). In many cases proteases that cleave at site-1 are thought to directly sense a signal and initiate the RIP process. We previously suggested binding of lysozyme to RsiV initiated the proteolytic destruction of RsiV and activation of σV. Here we determined the X-ray crystal structure of the RsiV-lysozyme complex at 2.3 Å which revealed that RsiV and lysozyme make extensive contacts. We constructed RsiV mutants with altered abilities to bind lysozyme. We find that mutants that are unable to bind lysozyme block site-1 cleavage of RsiV and σV activation in response to lysozyme. Taken together these data demonstrate that RsiV is a receptor for lysozyme and binding of RsiV to lysozyme is required for σV activation. In addition, the co-structure revealed that RsiV binds to the lysozyme active site pocket. We provide evidence that in addition to acting as a sensor for the presence of lysozyme, RsiV also inhibits lysozyme activity. Thus we have demonstrated that RsiV is a protein with multiple functions. RsiV inhibits σV activity in the absence of lysozyme, RsiV binds lysozyme triggering σV activation and RsiV inhibits the enzymatic activity of lysozyme.

Differential binding of antibodies in PANDAS patients to cholinergic interneurons in the striatum.

Pediatric Autoimmune Neuropsychiatric Disorder Associated with Streptococcus, or PANDAS, is a syndrome of acute childhood onset of obsessive-compulsive disorder and other neuropsychiatric symptoms in the aftermath of an infection with Group A beta-hemolytic Streptococcus (GABHS). Its pathophysiology remains unclear. PANDAS has been proposed to result from cross-reactivity of antibodies raised against GABHS with brain antigens, but the targets of these antibodies are unclear and may be heterogeneous. We developed an in vivo assay in mice to characterize the cellular targets of antibodies in serum from individuals with PANDAS. We focus on striatal interneurons, which have been implicated in the pathogenesis of tic disorders. Sera from children with well-characterized PANDAS (n = 5) from a previously described clinical trial (NCT01281969), and matched controls, were infused into the striatum of mice; antibody binding to interneurons was characterized using immunofluorescence and confocal microscopy. Antibodies from children with PANDAS bound to ∼80% of cholinergic interneurons, significantly higher than the <50% binding seen with matched healthy controls. There was no elevated binding to two different populations of GABAergic interneurons (PV and nNOS-positive), confirming the specificity of this phenomenon. Elevated binding to cholinergic interneurons resolved in parallel with symptom improvement after treatment with intravenous immunoglobulin. Antibody-mediated dysregulation of striatal cholinergic interneurons may be a locus of pathology in PANDAS. Future clarification of the functional consequences of this specific binding may identify new opportunities for intervention in children with this condition.

Longitudinal outcomes of children with pediatric autoimmune neuropsychiatric disorder associated with streptococcal infections (PANDAS).

Little is known about the natural history of children with pediatric autoimmune neuropsychiatric disorder associated with streptococcal infections (PANDAS). This study prospectively followed 33 children with PANDAS for up to 4.8 years (mean 3.3 ± 0.7 years) after enrollment in a 24-week randomized, double-blind, placebo-controlled trial of intravenous immunoglobulin (IVIG) (N = 35). Fourteen of eighteen children randomized to placebo received open label IVIG 6 weeks after the blinded infusion, so follow-up results reported below largely reflect outcomes in a population of children who received at least one dose of IVIG. Telephone interviews with the parents of participants found that at the time of phone follow-up, 29 (88%) were not experiencing clinically significant obsessive-compulsive symptoms. During the interim period (6-57 months after entering the clinical trial), 24 (72%) had experienced at least one exacerbation of PANDAS symptoms, with a median of one exacerbation per child (range 1-12; interquartile range 0-3). A variety of treatment modalities, including antibiotics, IVIG, psychiatric medications, cognitive behavioral therapy, and others, were used to treat these exacerbations, and were often used in combination. The outcomes of this cohort are better than those previously reported for childhood-onset OCD, which may support conceptualization of PANDAS as a subacute illness similar to Sydenham chorea. However, some children developed a chronic course of illness, highlighting the need for research that identifies specific symptoms or biomarkers that can be used to predict the longitudinal course of symptoms in PANDAS.

Evidence of a bacterial receptor for lysozyme: binding of lysozyme to the anti-σ factor RsiV controls activation of the ecf σ factor σV.

σ factors endow RNA polymerase with promoter specificity in bacteria. Extra-Cytoplasmic Function (ECF) σ factors represent the largest and most diverse family of σ factors. Most ECF σ factors must be activated in response to an external signal. One mechanism of activation is the stepwise proteolytic destruction of an anti-σ factor via Regulated Intramembrane Proteolysis (RIP). In most cases, the site-1 protease required to initiate the RIP process directly senses the signal. Here we report a new mechanism in which the anti-σ factor rather than the site-1 protease is the sensor. We provide evidence suggesting that the anti-σ factor RsiV is the bacterial receptor for the innate immune defense enzyme, lysozyme. The site-1 cleavage site is similar to the recognition site of signal peptidase and cleavage at this site is required for σV activation in Bacillus subtilis. We reconstitute site-1 cleavage in vitro and demonstrate that it requires both signal peptidase and lysozyme. We demonstrate that the anti-σ factor RsiV directly binds to lysozyme and muramidase activity is not required for σV activation. We propose a model in which the binding of lysozyme to RsiV activates RsiV for signal peptidase cleavage at site-1, initiating proteolytic destruction of RsiV and activation of σV. This suggests a novel mechanism in which conformational change in a substrate controls the cleavage susceptibility for signal peptidase. Thus, unlike other ECF σ factors which require regulated intramembrane proteolysis for activation, the sensor for σV activation is not the site-1 protease but the anti-σ factor.

Advanced practitioners in emergency care: a literature review.

There has been an expansion of advanced practitioner roles, such as advanced clinical practitioners, in emergency departments (EDs) in recent years, with the assumption that they will positively affect the provision and quality of emergency care. This article presents a literature review which aimed to identify the evidence on the effects of advanced practitioners in emergency care. The search revealed only four papers, but these studies did identify a need for the role, and highlighted positive attitudes towards it and its potential to improve patient care. The studies also raised concerns about the lack of clarity about titles, education, skills and competence, issues that must be addressed before implementation of such roles. There is clearly an urgent need for further research, but with careful consideration and implementation, advanced clinical practitioners, like the established emergency nurse practitioner role, can positively affect emergency care provision and help address the challenges faced by EDs across the UK.