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Objective: To test whether anti-inflammatory and antioxidant drugs that inhibit the nuclear factor kappa light chain enhancer of activated B cells (NF-kB), celastrol and edaravone, suppress spasms and improve developmental outcomes in the multiple-hit rat model of refractory infantile spasms (IS) due to structural lesions., Methods: Postnatal day 3 (PN3) Sprague-Dawley rats were treated according to the multiple-hit IS model protocol. Using a randomized, blinded, vehicle-controlled, dose- and time-response study design, we tested the effects of single celastrol [1, 2, or 4 mg/kg intraperitoneally (i.p.), 10-14 rats/group] or edaravone (1, 10 or 30 mg/kg i.p., 14-17 rats/group) injections vs their vehicles on behavioral and electroclinical spasms and developmental milestones. Video-EEG monitoring was done on PN6-7 (n = 11-12 rats/group). Pulse celastrol treatment effects (PN4: 4 mg/kg, PN5-6: 2 mg/kg/day i.p.) were determined on spasms, developmental milestones and Barnes maze. Celastrol and edaravone pharmacokinetics in plasma and neocortex were assessed. Linear mixed model analysis of raw or normalized log-transformed spasm frequencies, considering repeated observations was used., Results: Single (2-4 mg/kg i.p) or pulse celastrol, but not edaravone, reduced behavioral and electroclinical spasms frequencies within 5hrs. Pulse celastrol did not affect spasm-freedom, survival, developmental milestones or Barnes maze performance. Celastrol had erratic i.p. absorption with maximum concentrations observed between 2-4 h, when effects on spasms were seen. Edaravone had low blood-to-brain permeability., Conclusions: Celastrol's efficacy on spasms is partially explained by its better brain penetration than edaravone's. NFkB inhibitors may be useful in treating drug-resistant IS but delivery methods with improved bioavailability and brain permeability are needed., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: S.L.M. was associate editor of Neurobiology of Disease until December 2021. He is on the editorial board of Brain and Development, Pediatric Neurology, Annals of Neurology, MedLink, and Physiological Research. He has previously received compensation from Elsevier for his work as associate editor for Neurobiology of Disease and currently from MedLink for his work as associate editor, and royalties from two books he coedited. SLM holds a US patent for the multiple hit rat model (#7863499); no financial profits or conflicts have ensued as a resultof this patent. He has no conflicts of interest in regards to this study. A.S.G. was editor-in-chief of Epilepsia Open until August 2024 and is associate editor for Neurobiology of Disease and has received royalties from Elsevier and Wolters Kluwer for publications. She has no conflicts of interest in regards to this study. None of the other authors have competing interests to declare., (Copyright © 2024 Elsevier Inc. All rights reserved.)

A growing body of empirical literature connects anxiety symptoms and high-risk suicidal and self-harming behaviors in youth. Emotion regulation (ER) processes and deficits have been identified as important factors in the etiology, maintenance, and treatment of both youth anxiety and high-risk behaviors. The present study assessed the association between these variables using an acute, socio-demographically diverse clinical sample of youth presenting to an outpatient mental health clinic. Ninety-nine youth aged 12-20 years old completed measures of anxiety symptoms, ER difficulties, and lifetime history of high-risk behaviors including non-suicidal self-injury (NSSI) and suicide attempts. Unadjusted analyses show that more severe anxiety symptoms were associated with more ER difficulties and history of risk behavior. Multivariate linear regression models considering age, sex, race/ethnicity, and risk history show that more severe anxiety symptoms remained significantly associated with more ER difficulties (p < 0.0001) and positive suicide attempt history (p < 0.01). Findings highlight the importance of integrating considerations of ER into the case conceptualization and treatment planning of high-risk, anxious youth to inform evidenced-based care with this population. The need for targeted, ongoing risk assessment with anxious youth to identify and mitigate risk is also demonstrated., Competing Interests: Declaration of Competing Interest None. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Objective: To determine whether hydroxychloroquine (HCQ) dose is associated with adverse cardiac outcomes in patients with systemic lupus erythematosus (SLE)., Methods: Patients with SLE taking HCQ and with ≥1 echocardiogram followed at a tertiary care center in the Bronx, New York between 2005 and 2021 were included. The HCQ weight-based dose at the HCQ start date was the main exposure of interest. The outcome was incident all-cause heart failure with reduced ejection fraction (HFrEF), life-threatening arrhythmia, or cardiac death. We used Fine-Gray regression models with death as a competing event to study the association of HCQ dose with the outcome. Due to a significant interaction between smoking and HCQ exposure, models were stratified by smoking status. Propensity score analysis was performed as a secondary analysis., Results: Of 294 patients, 37 (13%) developed the outcome over a median follow-up time of 7.9 years (interquartile range [IQR] 4.2-12.3 years). In nonsmokers (n = 226), multivariable analysis adjusted for age, body mass index, hypertension, chronic kidney disease, diabetes mellitus, and thromboembolism showed that higher HCQ weight-based doses were not associated with an increased risk of the outcome (subdistribution hazard ratio [HR] 0.62 [IQR 0.41-0.92], P = 0.02). Similarly, higher baseline HCQ doses were not associated with a higher risk of the outcome among smokers (n = 68) (subdistribution HR 0.85 [IQR 0.53-1.34] per mg/kg, P = 0.48). Propensity score analysis showed comparable results., Conclusion: Higher HCQ doses were not associated with an increased risk of HFrEF, life-threatening arrhythmia, or cardiac death among patients with SLE and may decrease the risk among nonsmokers., (© 2022 American College of Rheumatology.)

Objective: We used the lateral fluid percussion injury (LFPI) model of moderate-to-severe traumatic brain injury (TBI) to identify early plasma biomarkers predicting injury, early post-traumatic seizures or neuromotor functional recovery (neuroscores), considering the effect of levetiracetam, which is commonly given after severe TBI., Methods: Adult male Sprague-Dawley rats underwent left parietal LFPI, received levetiracetam (200 mg/kg bolus, 200 mg/kg/day subcutaneously for 7 days [7d]) or vehicle post-LFPI, and were continuously video-EEG recorded (n = 14/group). Sham (craniotomy only, n = 6), and naïve controls (n = 10) were also used. Neuroscores and plasma collection were done at 2d or 7d post-LFPI or equivalent timepoints in sham/naïve. Plasma protein biomarker levels were determined by reverse phase protein microarray and classified according to injury severity (LFPI vs. sham/control), levetiracetam treatment, early seizures, and 2d-to-7d neuroscore recovery, using machine learning., Results: Low 2d plasma levels of Thr 231 -phosphorylated tau protein (pTAU-Thr 231 ) and S100B combined (ROC AUC = 0.7790) predicted prior craniotomy surgery (diagnostic biomarker). Levetiracetam-treated LFPI rats were differentiated from vehicle treated by the 2d-HMGB1, 2d-pTAU-Thr 231 , and 2d-UCHL1 plasma levels combined (ROC AUC = 0.9394) (pharmacodynamic biomarker). Levetiracetam prevented the seizure effects on two biomarkers that predicted early seizures only among vehicle-treated LFPI rats: pTAU-Thr 231 (ROC AUC = 1) and UCHL1 (ROC AUC = 0.8333) (prognostic biomarker of early seizures among vehicle-treated LFPI rats). Levetiracetam-resistant early seizures were predicted by high 2d-IFNγ plasma levels (ROC AUC = 0.8750) (response biomarker). 2d-to-7d neuroscore recovery was best predicted by higher 2d-S100B, lower 2d-HMGB1, and 2d-to-7d increase in HMGB1 or decrease in TNF (P < 0.05) (prognostic biomarkers)., Significance: Antiseizure medications and early seizures need to be considered in the interpretation of early post-traumatic biomarkers., (© 2023 The Authors. Epilepsia Open published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Background: End-stage kidney disease (ESKD) from lupus nephritis (LN) is a major cause of morbidity and mortality in patients with systemic lupus erythematosus (SLE). Kidney biopsy is the gold standard for diagnosis and prognostication of LN. While interstitial fibrosis and tubular atrophy (IFTA) predict progression to ESKD, the National Institutes of Health (NIH) classification of interstitial inflammation in unscarred cortical parenchyma is not predictive of chronic kidney disease (CKD) progression. The objective of this study was to determine whether total cortical interstitial inflammation that accounts for inflammation in the entire cortical parenchyma could predict CKD progression in patients with LN. Early identification of at-risk patients may improve outcomes., Methods: This retrospective cohort study included 125 SLE patients with LN class III, IV, V or mixed (III/V, IV/V) on the index biopsy (2005-2018). Kidney biopsies were reviewed and assigned based on the 2018 NIH Activity Index (AI) and tubulointerstitial lesion categories. Total interstitial inflammation in the entire cortical parenchyma was graded as 0, 1, 2 or 3, corresponding to <10%, 10-25%, 26-50% and >50%, respectively, of the total cortical parenchyma containing an inflammatory infiltrate (similar to the definition used in the Banff total inflammation score). CKD progression was defined as an estimated glomerular filtration rate decrease of ≥30% within 5 years after the index biopsy. Kaplan-Meier survival curves and Cox proportional hazards models were performed to compare the two scoring systems, the total cortical intestinal inflammation score and the NIH interstitial inflammation score as predictors of CKD progression., Results: Of 125 patients, 46 experienced CKD progression; 21 of 46 subsequently developed ESKD, 28 (22.4%) had moderate-severe total cortical interstitial inflammation and 8 (6.4%) had moderate-severe NIH interstitial inflammation. There were no differences in baseline characteristics between progressors and nonprogressors. Total cortical interstitial inflammation was associated with CKD progression in time-dependent analyses [hazard ratio 2.45 (95% confidence interval 1.2-4.97)] adjusted for age at biopsy, race, sex, LN class and hypertensive vascular change on kidney biopsy. The NIH interstitial inflammation was not associated with CKD progression., Conclusions: In contrast to the current NIH interstitial inflammation classification, accounting for interstitial inflammation in the entire cortical parenchyma allows identification of patients at risk for CKD progression in LN., (© The Author(s) 2022. Published by Oxford University Press on behalf of the ERA.)

Objective: Optimal strategies for managing lupus medications after end-stage renal disease (ESRD) have not been addressed. The objective was to identify the current US-wide prescribing patterns of hydroxychloroquine (HCQ) and oral glucocorticoids (GS) among systemic lupus erythematosus (SLE) patients with incident ESRD enrolled in the US Renal Data System (USRDS) registry., Methods: We identified incident ESRD patients age ≥18 years with SLE as a primary cause of ESRD between January 2006 and June 2013. Patients who were started on dialysis at ESRD onset and enrolled in Medicare Part D within 93 days as required by Medicare were included., Results: Among the 2,654 new-onset ESRD patients with Part D, the median duration of follow-up was 761 days (interquartile range [IQR] 374-1,375). At baseline, 1,076 patients (41%) were not receiving HCQ or GS, 220 (8%) were prescribed HCQ alone, 509 (19%) were prescribed both HCQ and GS, and 849 (32%) were prescribed GS alone. Of the 1,983 patients who either never received or discontinued HCQ after ESRD onset, 667 (34%) continued GS to the end of the follow-up period. The median GS dose was lower for patients taking HCQ (14 mg [IQR 9-21]) compared to patients who were never prescribed HCQ (15 mg [IQR 9-27]) or patients who discontinued HCQ after ESRD (17 mg [IQR 10-27]; P = 0.001)., Conclusion: Approximately one-third of patients with lupus nephritis and new-onset ESRD received GS monotherapy at high doses. As GS-related complications contribute to hospitalizations and deaths in SLE ESRD, changing these prescribing practices may improve morbidity and mortality outcomes., (© 2021 American College of Rheumatology.)

Fetal hemoglobin (HbF) is known to lessen the severity of sickle cell disease (SCD), through reductions in peripheral vaso-occlusive disease and reduced risk for cerebrovascular events. However, the influence of HbF on oxygen delivery to high metabolism tissues like the brain, or its influence on cerebral perfusion, metabolism, inflammation or function have not been widely studied. We employed a Berkley mouse model (BERK) of SCD with gamma transgenes q3 expressing exclusively human α- and β S -globins with varying levels of γ globin expression to investigate the effect of HbF expression on the brain using magnetic resonance imaging (MRI), MRI diffusion tensor imaging (DTI) and spectroscopy (MRS) and hematological parameters. Hematological parameters improved with increasing γ level expression, as did markers for brain metabolism, perfusion and inflammation. Brain microstructure assessed by DTI fractional anisotropy improved, while myo-inositol levels increased, suggesting improved microstructural integrity and reduced cell loss. Our results suggest that increasing γ levels not only improves sickle peripheral disease, but also improves brain perfusion and oxygen delivery while reducing brain inflammation while protecting brain microstructural integrity., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Chronic back and leg pain are leading causes of disability worldwide. The purpose of this study was to compare the care in a unidisciplinary (USC) versus multidisciplinary (MSC) spine clinic, where patients are evaluated by different specialists during the same office visit. Adult patients presenting with a chief complaint of back and/or leg pain between June 2018 and July 2019 were assessed for eligibility. The main outcome measures included the first treatment recommendations, the time to treatment order, and the time to treatment occurrence. A 1:1 propensity score-matched analysis was performed on 874 patients (437 in each group). For all patients, the most common recommendation was physical therapy (41.4%), followed by injection (14.6%), and surgery (9.7%). Patients seen in the MSC were more likely to be recommended injection (p < 0.001) and less likely to be recommended surgery as first treatment (p = 0.001). They also had significantly shorter times to the injection order (log-rank test, p = 0.004) and the injection occurrence (log-rank test, p < 0.001). In this study, more efficient care for patients with back and/or leg pain was delivered in the MSC setting, which was evidenced by the shorter times to the injection order and occurrence. The impact of the MSC approach on patient satisfaction and health-related quality-of-life outcome measures warrants further investigation.

Objectives: Children presenting to the emergency department (ED) requiring psychiatric admission often undergo screening electrocardiograms (ECG) as part of the medical clearance process. The diagnostic yield of screening ECGs for this purpose has not been reported. The purpose of this study was to determine the clinical utility of screening ECGs in children and adolescents requiring acute inpatient psychiatric admission., Methods: A single-center retrospective study of patients aged 5 to 18 years who did not have documented indications for ECG and underwent screening ECG before psychiatric inpatient admission over a 2-year period was conducted. Abnormal ECGs were identified via chart review and were reinterpreted by a pediatric cardiologist to determine potential significance to psychiatric care. Impact on treatment and disposition was examined., Results: From January 2018 through December 2019, 252 eligible pediatric patients had a screening ECG in the ED before psychiatric admission. Twenty-one (8.3%) of these ECGs were interpreted as abnormal, and 6 (2.4%) were determined to be potentially relevant to psychiatric care in the setting of specific medication use. The abnormal ECG interpretations resulted in additional workup and/or cardiology consultation for 7 (2.7%) patients but had no impact on psychiatric admission., Conclusions: In the absence of concerning individual or family history or cardiac symptoms, routine screening ECGs as part of medical clearance for psychiatric admission are not warranted given the low yield of meaningful findings. The decision to obtain an ECG should be made with careful consideration of medical history and in the presence of specific indications., Competing Interests: Disclosure: The authors declare no conflict of interest., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Study Design: Retrospective single-institution study., Objective: The aim of this study was to determine the relationship between patients' insurance status and the likelihood for them to be recommended various spine interventions upon evaluation in our neurosurgical clinics., Summary of Background Data: Socioeconomically disadvantaged populations have worse outcomes after spine surgery. No studies have looked at the differential rates of recommendation for surgery for patients presenting to spine surgeons based on socioeconomic status., Methods: We studied patients initially seeking spine care from spine-fellowship trained neurosurgeons at our institution from July 1, 2018 to June 30, 2019. Multivariable logistic regression was used to assess the association between insurance status and the recommended patient treatment., Results: Overall, 663 consecutive outpatients met inclusion criteria. Univariate analysis revealed a statistically significant association between insurance status and treatment recommendations for surgery (P < 0.001). Multivariate logistic regression demonstrated that compared with private insurance, Medicare (odds ratio [OR] 3.54, 95% confidence interval [CI] 1.21-7.53, P = 0.001) and Medicaid patients (OR 2.46, 95% CI 1.21-5.17, P = 0.014) were more likely to be recommended for surgery. Uninsured patients did not receive recommendations for surgery at significantly different rates than patients with private insurance., Conclusion: Medicare and Medicaid patients are more likely to be recommended for spine surgery when initially seeking spine care from a neurosurgeon. These findings may stem from a number of factors, including differential severity of the patient's condition at presentation, disparities in access to care, and differences in shared decision making between surgeons and patients.Level of Evidence: 3., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: Infantile spasms may evolve into persistent epilepsies including Lennox-Gastaut syndrome. We compared adult epilepsy outcomes in models of infantile spasms due to structural etiology (multiple-hit model) or focal cortical inflammation and determined the anti-epileptogenic effects of pulse-rapamycin, previously shown to stop spasms in multiple-hit rats., Methods: Spasms were induced in 3-day-old male rats via right intracerebral doxorubicin/lipopolysaccharide (multiple-hit model) infusions. Controls and sham rats were used. Separate multiple-hit rats received pulse-rapamycin or vehicle intraperitoneally between postnatal days 4 and 6. In adult mice, video-EEG (electroencephalography) scoring for seizures and sleep and histology were done blinded to treatment., Results: Motor-type seizures developed in 66.7% of multiple-hit rats, usually from sleep, but were reduced in the pulse-rapamycin-treated group (20%, p = .043 vs multiple-hit) and rare in other groups (0-9.1%, p < .05 vs multiple-hit). Spike-and-wave bursts had a slower frequency in multiple-hit rats (5.4-5.8Hz) than in the other groups (7.6-8.3Hz) (p < .05); pulse rapamycin had no effect on the hourly spike-and-wave burst rates in adulthood. Rapamycin, however, reduced the time spent in slow-wave-sleep (17.2%), which was increased in multiple-hit rats (71.6%, p = .003). Sham rats spent more time in wakefulness (43.7%) compared to controls (30.6%, p = .043). Multiple-hit rats, with or without rapamycin treatment, had right more than left corticohippocampal, basal ganglia lesions. There was no macroscopic pathology in the other groups., Significance: Structural corticohippocampal/basal ganglia lesions increase the risk for post-infantile spasms epilepsy, Lennox-Gastaut syndrome features, and sleep dysregulation. Pulse rapamycin treatment for infantile spasms has anti-epileptogenic effects, despite the structural lesions, and decreases the time spent in slow wave sleep., (© 2021 International League Against Epilepsy.)

Study Design: Case series., Objective: To evaluate the impact of a multidisciplinary spine surgery indications conference (MSSIC) on surgical planning for elective spine surgeries., Summary of Background Data: Identifying methods for pairing the proper patient with the optimal intervention is of the utmost importance for improving spine care and patient outcomes. Prior studies have evaluated the utility of multidisciplinary spine conferences for patient management, but none have evaluated the impact of a MSSIC on surgical planning and decision making., Methods: We implemented a mandatory weekly MSSIC with all spine surgeons at our institution. Each elective spine surgery in the upcoming week is presented. Subsequently, a group consensus decision is achieved regarding the best treatment option based on the expertise and opinions of the participating surgeons. We reviewed cases presented at the MSSIC from September 2019 to December 2019. We compared the surgeon's initial proposed surgery for a patient with the conference attendees' consensus decision on the best treatment and measured compliance rates with the group's recommended treatment., Results: The conference reviewed 100 patients scheduled for elective spine surgery at our indications conference during the study period. Surgical plans were recommended for alteration in 19 cases (19%) with the proportion statistically significant from zero indicated by a binomial test (P < 0.001). The median absolute change in the invasiveness index of the altered procedures was 3 (interquartile range [IQR] 1-4). Participating surgeons complied with the group's recommendation in 96.5% of cases., Conclusion: In conjunction with other multidisciplinary methods, MSSICs can lead to surgical planning alterations in a significant number of cases. This could potentially result in better selection of surgical candidates and procedures for particular patients. Although long-term patient outcomes remain to be evaluated, this care model will likely play an integral role in optimizing the care spine surgeons provide patients., Level of Evidence: 4.

Objectives: To determine whether there is an association between adverse childhood experiences (ACEs) and childhood-onset arthritis, comparing youth with arthritis to both healthy youth and youth with other acquired chronic physical diseases (OCPD); and to examine whether ACEs are associated with disease-related characteristics among children with arthritis., Study Design: In a cross-sectional analysis of data from the 2016 National Survey of Children's Health we examined whether ACEs were associated with having arthritis vs either being healthy or having a nonrheumatologic OCPD. ACE scores were categorized as 0, 1, 2-3, ≥4 ACEs. Multinomial logistic regression models examined associations between ACEs and health status while adjusting for age, sex, race/ethnicity, and poverty status. Among children with arthritis, associations between ACEs and disease-related characteristics were assessed by Pearson χ 2 analyses., Results: Compared with children with no ACEs, children with 1, 2-3, and ≥4 ACEs had an increased odds of having arthritis vs being healthy (adjusted OR for ≥4 ACEs, 9.4; 95% CI, 4.0-22.1) and vs OCPD (adjusted OR for ≥4 ACEs, 3.7; 95% CI-1.7, 8.1). Among children with arthritis, ACEs were associated with worse physical impairment., Conclusions: Children with higher numbers of ACEs are more likely to have arthritis, when arthritis status is compared either with being healthy or with having OCPD. Further studies are needed to determine the direction of the association between ACEs and childhood arthritis, its impact on disease course, and potential intervention targets that might mitigate these effects., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: The ASTHMAXcel mobile application has been linked to favorable outcomes among adult patients with asthma., Objective: To assess the impact of ASTHMAXcel Adventures, a gamified, guideline-based, pediatric version on asthma control, knowledge, health care utilization, and patient satisfaction., Methods: Pediatric patients with asthma received the ASTHMAXcel Adventures mobile intervention on-site only at baseline (visit 1), 4 months (visit 2), and 6 months (visit 3). The asthma control test, asthma illness representation scale-self-administered, pediatric asthma impact survey, and Client Satisfaction Questionnaire-8 were used to assess asthma control, knowledge, and patient satisfaction. Patients reported the number of asthma-related emergency department (ED) visits, hospitalizations, and oral prednisone use., Results: A total of 39 patients completed the study. The proportion of controlled asthma increased from visit 1 to visits 2 and 3 (30.8% vs 53.9%, P = .04; 30.8% vs 59.0%, P = .02), and largely seen in boys. The mean asthma illness representation scale-self-administered scores increased from baseline pre- to postintervention, with sustained improvements at visits 2 and 3 (3.55 vs 3.76, P < .001; 3.55 vs 3.80, P = .001; 3.55 vs 3.99, P < .001). The pediatric asthma impact survey scores improved from baseline to visits 2 and 3 (43.33 vs 34.08, P < .001; 43.33 vs 31.74, P < .001). ED visits and prednisone use significantly decreased from baseline to visits 2 and 3 (ED: 0.46 vs 0.13, P = .03; 0.46 vs 0.02, P = .02; prednisone use, 0.49 vs 0.13, P = .02; 0.49 vs 0.03, P = .003. Satisfaction was high with mean client satisfaction questionnaire score of approximately 30 (out of 32) at all visits., Conclusion: ASTHMAXcel Adventures improved asthma control, knowledge, and quality of life, and reduced ED visits and prednisone use with high satisfaction scores., (Copyright © 2020 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: SLE manifestations after ESRD may be underdiagnosed and undertreated, contributing to increased morbidity and mortality. Whether specific symptoms persist after ESRD or a shift towards new manifestations occurs has not been extensively studied, especially in the non-Caucasian patients in the United States. In addition, hydroxychloroquine (HCQ) prescribing patterns post-ESRD have not been described. The objective of this study was to assess lupus activity and HCQ prescribing before and after ESRD development. Knowledge gained from this study may aid in the identification of SLE manifestations and improve medication management post-ESRD., Methods: We performed a retrospective cohort study of SLE patients with incident ESRD between 2010 and 2017. SLE-related symptoms, serologic markers of disease activity, and medication use were collected from medical records before and after ESRD development., Results: Fifty-nine patients were included in the study. Twenty-five (43%) patients had at least one clinical (non-renal) SLE manifestation documented within 12 months before ESRD. Of them, 11/25 (44%) continued to experience lupus symptoms post-ESRD; 9 patients without clinical or serological activity pre-ESRD developed new symptoms of active SLE. At the last documented visit post-ESRD, 42/59 (71%) patients had one or more clinical or serological markers of lupus activity; only 17/59 (29%) patients achieved clinical and serological remission. Thirty-three of 59 (56%) patients had an active HCQ prescription at the time of ESRD. Twenty-six of the 42 (62%) patients with active SLE manifestations post-ESRD were on HCQ. Patients who continued HCQ post-ESRD were more likely to be followed by a rheumatologist (26 [87%] vs 17 [61%], p = 0.024), had a higher frequency of documented arthritis (10 [32%] vs 1 [4%], p = 0.005), CNS manifestations (6 [20%] vs 1 [4%], p = 0.055), and concurrent immunosuppressive medication use (22 [71%] vs 12 [43%], p = 0.029)., Conclusions: Lupus activity may persist after the development of ESRD. New onset arthritis, lupus-related rash, CNS manifestations, low complement and elevated anti-dsDNA may develop. HCQ may be underutilized in patients with evidence of active disease pre- and post ESRD. Careful clinical and serological monitoring for signs of active disease and frequent rheumatology follow up is advised in SLE patients both, pre and post-ESRD.

The aim of this study is to validate the Attention, Memory, and Frontal Abilities Screening Test (AMFAST), a novel, 10-minute, paper-and-pencil measure developed to identify attention, processing speed, memory, and executive functioning deficits in children and adults with various conditions characterized by frontal-subcortical dysfunction. We administered the AMFAST to 186 English-speaking healthy control participants (aged 8-88 years) without reported cognitive impairment. The AMFAST was also administered to a mixed clinical sample that included 114 English-speaking individuals (aged 8-84 years) who also received comprehensive neuropsychological testing. Results indicated that total AMFAST scores in the healthy control sample were not significantly affected by education or gender. There was, however, a significant effect of age, as the 8- to 10-year-old group scored significantly lower than other age groups. Thus, only participants 11+ years were included in further analyses. The AMFAST demonstrated high test-retest and interrater reliabilities, good construct validity, and the identified optimal cutoff score of 70 had excellent sensitivity and specificity for differentiating between cognitively intact and cognitively impaired individuals. These findings demonstrate that the AMFAST is a highly effective screening test that can be used to identify attention, memory, processing speed, and executive functioning deficits in individuals from middle childhood through older adulthood.

Background: We sought to longitudinally assess the efficacy of the patient-facing ASTHMAXcel mobile application in improving asthma knowledge and outcomes in adults with asthma., Methods: ASTHMAXcel is a novel smartphone application consistent with the National Asthma Education and Prevention Program, Global Initiative for Asthma, and British Thoracic Society/Scottish Intercollegiate Guidelines Network guidelines. The intervention was provided for 1-time use at baseline only. The Asthma Knowledge Questionnaire (AKQ), the Asthma Control Test (ACT), and the mini-Asthma Quality of Life Questionnaire (mini-AQLQ) were administered at baseline and at 2, 4, and 6 months thereafter. Rates of asthma-related emergency department visits, hospitalizations, and prednisone use were also evaluated., Results: ACT scores increased significantly at 2, 4, and 6 months (mean scores: 15.1 vs 16.9, P = .038; 15.1 vs 17.2, P = .02; 15.1 vs 17.9, P = .003) after baseline. There were significant increases in AKQ scores at 4 and 6 months (11.7 vs 12.6, P = .02; 11.7 vs 13.1, P = .005) and in mini-AQLQ scores at 6 months (55.5 vs 64.2, P = .02). There were significant decreases in asthma-related emergency department visits at 6 months (0.6 vs 0, P < .001) and in hospitalizations at 4 and 6 months (0.3 vs 0.1, P = .02; 0.3 vs 0, P = .002). Prednisone use decreased at 4 and 6 months (1.2 vs 0.6, P = .01; 1.2 vs 0.3, P < .001)., Conclusions: ASTHMAXcel contributes to improved asthma knowledge and outcomes and to decreased health care utilization. ASTHMAXcel is an inexpensive, scalable aid for out-patient asthma management., Competing Interests: This work was supported by an American Lung Association/American Academy of Allergy, Asthma & Immunology Foundation Allergic Respiratory Diseases Research Award, a Stony Wold-Herbert Fund Community Service Grant, and a Genentech Research Grant [grant number G27639]. The authors have disclosed no conflicts of interest., (Copyright © 2020 by Daedalus Enterprises.)

Aims: Little is known about glycemic management, particularly with novel cardio-nephroprotecive agents, in underserved minority kidney transplant recipients with pre-transplant type 2 (T2DM) and posttransplantation diabetes mellitus (PTDM). We assessed glycemic management and outcomes in this high-risk population., Methods: We reviewed records of patients who received kidney transplants between June 2012 and December 2014 at a single center. Hemoglobin A1c (HbA1c) and prescribed glucose-lowering medications were examined, and mortality was compared between T2DM, PTDM, and no diabetes (NoDM) patients., Results: We followed 302 patient records (41.1% Hispanic, 41.1% non-Hispanic black) for a median (IQR) of 45.5 (37.0, 53.0) months post-transplant. Pre-transplant T2DM was present in 152 (50.3%), while 58 (19.2%) developed PTDM and 92 (30.4%) remained NoDM. At 1-year post-transplant, the average HbA1c was 8.1 ± 1.8% in T2DM and 6.6 ± 1.3% in PTDM. No glucose-lowering agents were prescribed in 3.4% of T2DM and 44.8% of PTDM. When treated, both received mostly insulin and metformin. Diabetes, HbA1c and insulin therapy were not independently associated with risk of mortality., Conclusions: Glycemic management was suboptimal and relied on older medications. Further studies are needed to assess longer-term outcomes of more rigorous glycemic management, and the value of novel cardio-nephroprotective agents in kidney transplant recipients., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: In animal studies, zinc supplementation inhibited phosphate-induced arterial calcification. We tested the hypothesis that higher intake of dietary zinc was associated with lower abdominal aortic calcification (AAC) among adults in the USA. We also explored the associations of AAC with supplemental zinc intake, total zinc intake and serum zinc level., Methods: We performed cross-sectional analyses of 2535 participants from the National Health and Nutrition Examination Survey 2013-14. Dietary and supplemental zinc intakes were obtained from two 24-h dietary recall interviews. Total zinc intake was the sum of dietary and supplemental zinc. AAC was measured using dual-energy X-ray absorptiometry in adults ≥40 years of age and quantified using the Kauppila score system. AAC scores were categorized into three groups: no AAC (AAC = 0, reference group), mild-moderate (AAC >0-≤6) and severe AAC (AAC >6)., Results: Dietary zinc intake (mean ± SE) was 10.5 ± 0.1 mg/day; 28% had AAC (20% mild-moderate and 8% severe), 17% had diabetes mellitus and 51% had hypertension. Higher intake of dietary zinc was associated with lower odds of having severe AAC. Per 1 mg/day higher intake of dietary zinc, the odds of having severe AAC were 8% lower [adjusted odds ratio 0.92 (95% confidence interval 0.86-0.98), P = 0.01] compared with those without AAC, after adjusting for demographics, comorbidities and laboratory measurements. Supplemental zinc intake, total zinc intake and serum zinc level were not associated with AAC., Conclusions: Higher intake of dietary zinc was independently associated with lower odds of having severe AAC among noninstitutionalized US adults., (© The Author(s) 2019. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.)

Objective: Individuals with a diagnosis of multiple sclerosis (MS) often present with cognitive and motor deficits, and thus the ability to perform tasks that rely on both domains may be particularly impaired. Yet, dual-task walking studies yield mixed results. Individual variance in the ability to cope with brain insult and mobilize additional brain resources may contribute to mixed findings., Methods: To test this hypothesis, we acquired event-related potentials (ERP) in individuals with MS and healthy controls (HCs) performing a Go/NoGo task while sitting (i.e., single task) or walking (i.e., dual-task) and looked at the relationship between task related modulation of the brain response and performance., Results: On the Go/NoGo task the MS group showed dual-task costs when walking, whereas HCs showed a dual-task benefit. Further, whereas the HC group showed modulation of the brain response as a function of task load, this was not the case in the MS group. Analysis for the pooled sample revealed a positive correlation between load-related ERP effects and dual-task performance., Conclusions: These data suggest a neurophysiological marker of cognitive-motor dysfunction in MS., Significance: Understanding neural processes underlying dual-task walking will help identify objective brain measurements of real-world issues and may improve assessment of MS., Competing Interests: Declaration of Competing Interest All authors declare no conflicts of interest, financial or otherwise., (Copyright © 2020 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

Advancements in acquisition technology and signal-processing techniques have spurred numerous recent investigations on the electro-cortical signals generated during whole-body motion. This approach, termed Mobile Brain/Body Imaging (MoBI), has the potential to elucidate the neural correlates of perceptual and cognitive processes during real-life activities, such as locomotion. However, as of yet, no one has assessed the long-term stability of event-related potentials (ERPs) recorded under these conditions. Therefore, the objective of the current study was to evaluate the test-retest reliability of cognitive ERPs recorded while walking. High-density EEG was acquired from 12 young adults on two occasions, separated by an average of 2.3years, as they performed a Go/No-Go response inhibition paradigm. During each testing session, participants performed the task while walking on a treadmill and seated. Using the intraclass correlation coefficient (ICC) as a measure of agreement, we focused on two well-established neurophysiological correlates of cognitive control, the N2 and P3 ERPs. Following ICA-based artifact rejection, the earlier N2 yielded good to excellent levels of reliability for both amplitude and latency, while measurements for the later P3 component were generally less robust but still indicative of adequate to good levels of stability. Interestingly, the N2 was more consistent between walking sessions, compared to sitting, for both hits and correct rejection trials. In contrast, the P3 waveform tended to have a higher degree of consistency during sitting conditions. Overall, these results suggest that the electro-cortical signals obtained during active walking are representative of stable indices of neurophysiological function., (Copyright © 2017. Published by Elsevier B.V.)

Background: Patients with alcohol use disorder (AUD) are at an increased risk of developing Wernicke's encephalopathy (WE), a devastating and difficult diagnosis caused by thiamine deficiency. Even as AUD is present in up to 25% of hospitalized patients on medical floors, appropriate thiamine supplementation in the hospital setting remains inadequate. These patients are particularly susceptible to thiamine deficiency and subsequent WE due to both their alcohol use and active medical illnesses. The electronic medical record (EMR) has become ubiquitous in health care systems and can be used as a tool to improve the care of hospitalized patients., Methods: As a quality improvement initiative, we implemented a medication order panel in the EMR with autopopulated orders for thiamine dosing to increase the appropriate use of high-dose parenteral thiamine (HPT) for hospitalized patients with AUD. We conducted a retrospective cohort study of all inpatients with AUD who received an Addiction Psychiatry Consult Service consult three months before and after the EMR change. We compared the proportion of patients receiving HPT prior to consultation (primary outcome) and the length of stay (secondary outcome) between the historical control group and the EMR intervention group., Results: Patients in the EMR intervention group were significantly more likely to receive HPT than the historical control group (20.2% vs. 2.7%, p < 0.0001). This difference remained statistically significant when adjusted for potential confounders (OR: 9.89, 95% CI: [2.77, 35.34], p = 0.0004). There was a trend towards statistical significance that the intervention group had a higher likelihood of being prescribed any thiamine (76.6% vs. 64.6%, p = 0.06) and had a shorter length of stay (median (IQR): 3.8 (2.4, 7.0) vs. 4.6 (2.9, 7.8) days, p = 0.06)., Conclusion: These results indicate that providing autopopulated thiamine order panels for patients with AUD can be an effective method for specialty services to increase appropriate care practices without additional education or training for providers. Further research should consider the clinical outcomes of increasing HPT for patients with AUD., (Published by Elsevier Inc.)

Background: We compared pre-emptive transplant rates between SLE and non-SLE end-stage renal disease (ESRD) from the U.S. Renal Data System (USRDS) and investigated the potential influence of frequency matching and primary ESRD causes in the non-SLE group., Methods: 4830 adult SLE patients with incident ESRD from USRDS 2005-2009 were frequency matched by age, sex and race to 4830 patients with incident non-SLE ESRD. Multivariable logistic regression models were used to estimate the odds of pre-emptive transplantation in SLE and non-SLE, and with the non-SLE subgroups by primary ESRD cause., Results: The odds ratios (OR) of receiving a pre-emptive transplant were similar among non-SLE and SLE (referent group): OR = 1.18 (95% CI: 0.92, 1.50; p = 0.20). However, the ORs for receiving a pre-emptive transplant were 0.19 (95% CI: 0.08, 0.42) in type 2 diabetes ESRD, 0.42 (95% CI: 0.23, 0.75) for hypertension-associated ESRD, 1.67 (95% CI: 1.10, 2.54) in type 1 diabetes ESRD, and 2.06 (95% CI: 1.55, 2.73) for "other" ESRD. In contrast to non-SLE, younger SLE patients were less likely to receive a pre-emptive transplant than older SLE patients., Conclusion: The results of this study provide compelling evidence that major improvements need to be made in optimizing access to pre-emptive transplantation in SLE by addressing sociodemographic disparities and the unique challenges faced by SLE patients. Applying careful matching and selecting appropriate comparison groups in future studies may facilitate the development of effective strategies to address these barriers and to increase the number of pre-emptive renal transplants among SLE patients., (Copyright © 2018 Elsevier Inc. All rights reserved.)

OBJECTIVEThe object of this study was to use diffusion tensor imaging (DTI) and tract-based spatial statistics (TBSS) to characterize the long-term effects of hydrocephalus and shunting on white matter integrity and to investigate the relationship of ventricular size and alterations in white matter integrity with headache and quality-of-life outcome measures.METHODSPatients with shunt-treated hydrocephalus and age- and sex-matched healthy controls were recruited into the study and underwent anatomical and DTI imaging on a 3-T MRI scanner. All patients were clinically stable, had undergone CSF shunt placement before 2 years of age, and had a documented history of complaints of headaches. Outcome was scored based on the Headache Disability Inventory and the Hydrocephalus Outcome Questionnaire. Fractional anisotropy (FA) and other DTI-based measures (axial, radial, and mean diffusivity; AD, RD, and MD, respectively) were extracted in the corpus callosum and internal capsule with manual region-of-interest delineation and in other regions with TBSS. Paired t-tests, corrected with a 5% false discovery rate, were used to identify regions with significant differences between patients and controls. Within the patient group, linear regression models were used to investigate the relationship between FA or ventricular volume and outcome, as well as the effect of shunt-related covariates.RESULTSTwenty-one hydrocephalus patients and 21 matched controls completed the study, and their data were used in the final analysis. The authors found significantly lower FA for patients than for controls in 20 of the 48 regions, mostly posterior white matter structures, in periventricular as well as more distal tracts. Of these 20 regions, 17 demonstrated increased RD, while only 5 showed increased MD and 3 showed decreased AD. No areas of increased FA were observed. Higher FA in specific periventricular white matter tracts, tending toward FA in controls, was associated with increased ventricular size, as well as improved clinical outcome.CONCLUSIONSThe study shows that TBSS-based DTI is a sensitive technique for elucidating changes in white matter structures due to hydrocephalus and chronic CSF shunting and provides preliminary evidence that DTI may be a valuable tool for tailoring shunt procedures to monitor ventricular size following shunting and achieve optimal outcome, as well as for guiding the development of alternate therapies for hydrocephalus.

Objective: To characterize and compare the factors associated with tubulointerstitial inflammation (TII) and tubulointerstitial scarring, defined as interstitial fibrosis and/or tubular atrophy (IF/TA), in patients with lupus nephritis (LN)., Methods: We identified systemic lupus erythematosus patients who had renal biopsy results consistent with LN between 2005 and 2017. Clinical data were collected from medical records. Multivariable logistic regression models were fitted to assess factors associated with TII and with IF/TA (moderate-to-severe versus none/mild)., Results: Of 203 LN patients included, 41 (20%) had moderate-to-severe TII, 45 (22%) had moderate-to-severe IF/TA, and 21 (10%) had both. Multivariable logistic regression models showed that moderate-to-severe TII was associated with a shorter disease duration, African American race, proliferative LN, and an estimated glomerular filtration rate (eGFR) of <60 ml/minute/1.73 m 2 at the time of biopsy. Hydroxychloroquine use was associated with significantly lower odds of moderate-to-severe TII (odds ratio 0.27 [95% confidence interval 0.10-0.70], P = 0.008). Similar to TII, factors associated with moderate-to-severe IF/TA included proliferative LN and eGFR <60 ml/minute/1.73 m 2 at the time of biopsy. In addition, the presence of moderate-to-severe TII and older age was associated with moderate-to-severe IF/TA. None of the routinely available serologic markers-including anti-double-stranded DNA antibodies, anti-Ro/La antibodies, and low complement-were associated with tubulointerstitial damage., Conclusion: The use of hydroxychloroquine was strongly associated with less inflammation, while the presence of TII, proliferative LN, and low eGFR were major determinants of tubulointerstitial scarring. Identifying modifiable factors is critical for the development of better preventive and therapeutic strategies with the goal of improving survival in patients with lupus-related kidney disease., (© 2018, American College of Rheumatology.)

Background: Antibody immunity is thought to be essential to prevent severe Plasmodium falciparum infection, but the exact correlates of protection are unknown. Over time, children in endemic areas acquire non-sterile immunity to malaria that correlates with development of antibodies to merozoite invasion proteins and parasite proteins expressed on the surface of infected erythrocytes., Results: A 1000 feature P. falciparum 3D7 protein microarray was used to compare P. falciparum-specific seroreactivity during acute infection and 30 days after infection in 23 children with uncomplicated malaria (UM) and 25 children with retinopathy-positive cerebral malaria (CM). All children had broad P. falciparum antibody reactivity during acute disease. IgM reactivity decreased and IgG reactivity increased in convalescence. Antibody reactivity to CIDR domains of "virulent" PfEMP1 proteins was low with robust reactivity to the highly conserved, intracellular ATS domain of PfEMP1 in both groups. Although children with UM and CM differed markedly in parasite burden and PfEMP1 exposure during acute disease, neither acute nor convalescent PfEMP1 seroreactivity differed between groups. Greater seroprevalence to a conserved Group A-associated ICAM binding extracellular domain was observed relative to linked extracellular CIDRα1 domains in both case groups. Pooled immune IgG from Malawian adults revealed greater reactivity to PfEMP1 than observed in children., Conclusions: Children with uncomplicated and cerebral malaria have similar breadth and magnitude of P. falciparum antibody reactivity. The utility of protein microarrays to measure serological recognition of polymorphic PfEMP1 antigens needs to be studied further, but the study findings support the hypothesis that conserved domains of PfEMP1 are more prominent targets of cross reactive antibodies than variable domains in children with symptomatic malaria. Protein microarrays represent an additional tool to identify cross-reactive Plasmodium antigens including PfEMP1 domains that can be investigated as strain-transcendent vaccine candidates.

Objective: Prompt treatment for lupus is important to prevent morbidity. A potential barrier to early treatment of pediatric lupus is delayed presentation to a pediatric rheumatologist. To better understand factors contributing to delayed presentation among pediatric lupus patients, we examined differences in demographic and clinical characteristics of lupus patients within the Childhood Arthritis and Rheumatology Research Alliance (CARRA) Legacy Registry with regard to time between symptom onset and presentation to a pediatric rheumatologist., Methods: We analyzed data from 598 CARRA Legacy Registry participants for differences between those who presented early (within <1 month of symptom onset), between 1-3 months (typical presentation), with moderate delays (3-12 months), and with severe delays (≥1 year). Factors associated with early presentation, moderate delay, and severe delay were determined by multinomial logistic regression., Results: Forty-four percent of patients presented early, while 23% had moderate delays and 9% had severe delays. Family history of lupus, absence of discoid rash, and location in a state with a higher density of pediatric rheumatologists were associated with earlier presentation. Younger age, low household income (<$25,000 per year), and a family history of lupus were associated with severe delay., Conclusion: Delays to care ≥1 year exist in a notable minority of pediatric lupus patients from the CARRA Legacy Registry. In this large and diverse sample of patients, access to care and family resources played an important role in predicting time to presentation to a pediatric rheumatologist., (© 2017, American College of Rheumatology.)

Objectives Although non-O blood type is an established risk factor for venous thromboembolism in the general population, the impact of ABO blood type (ABO) on venous thromboembolism risk in individuals with persistent antiphospholipid antibodies (aPL) has not been studied. We sought to investigate the relationship between ABO and venous thromboembolism in aPL-positive individuals. We also sought to explore potential interactions between ABO and sex or race to determine whether ABO contributes to race or sex differences with respect to the development of venous thromboembolism. Methods We identified all patients over 18 years old followed at a tertiary medical center between January 2000 and January 2015 with serological aPL criteria and ABO data. Episodes of venous thromboembolism were recorded. Logistic regression models were fitted to estimate odds ratios (ORs) of venous thromboembolism for non-O (A, B, or AB blood types) versus O blood type. Results There were 226 patients included in the final analysis, of whom 75 (33%) had reported venous thromboembolism. In the overall sample, there was a non-significant difference between venous thromboembolism in patients with non-O blood type compared to O blood type (OR 1.64, 95% confidence interval (CI) 0.94, 2.88; P = 0.08). Men with non-O blood type had a significantly higher risk of venous thromboembolism as compared to men with O-type blood (OR 4.94, 95% CI 1.37, 17.85; P = 0.02), but there was no significant association between ABO and venous thromboembolism among women (OR 0.96, 95% CI 0.50, 1.83; P = 0.52). Conclusions Non-O blood type may be an under-recognized risk factor for venous thromboembolism among men with persistent aPL antibodies, whereas the risk associated with non-O blood type seen in the general population may be attenuated in aPL-positive women.

Objectives: The presence of tubulointerstitial damage (TID) on renal biopsy is considered to be a late sequela of lupus nephritis (LN). The objective of this study was to determine if TID predicts progression to end stage renal disease (ESRD) in LN patients without advanced kidney disease., Methods: All SLE patients with an index biopsy consistent with LN between January 2005 and July 2015, and eGFR ≥ 30mL/min/1.73m 2 were included. Moderate-to-severe TID was defined as the presence of moderate-to-severe tubular atrophy and/or interstitial fibrosis. Time to ESRD was defined as time from the index biopsy date to incident ESRD date; non-ESRD patients were censored at the time of death or the last visit before December 2015. Time-dependent analyses were conducted to evaluate whether moderate-to-severe TID was predictive of ESRD progression., Results: Of the 131 LN patients with eGFR ≥ 30mL/min/1.73m 2 , 17 (13%) patients progressed to ESRD. Moderate-to-severe TID was present in 13% of biopsies with eGFR ≥ 60mL/min/1.73m 2 and in 33% of biopsies with eGFR between 30 and 60mL/min/1.73m 2 . Moderate-to-severe TID was associated with a higher risk of ESRD progression: adjusted hazard ratio (HR) = 4.1, 95% CI: 1.4-12.1, p = 0.01 for eGFR ≥ 30mL/min/1.73m 2 ; HR = 6.2, 95% CI: 1.7-23.2, p = 0.008 for eGFR ≥ 60mL/min/1.73m 2 . There was no association between tubulointerstitial inflammation (TII) and ESRD progression., Conclusions: Moderate-to-severe TID, but not TII, was a strong predictor of ESRD progression independent of eGFR or glomerular findings, therefore, providing an important window for potential early interventions., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: The Memory Binding Test (MBT) demonstrated good cross-sectional discriminative validity and predicted incident aMCI., Objective: To assess whether the MBT predicts incident dementia better than a conventional list learning test in a longitudinal community-based study., Methods: As a sub-study in the Einstein Aging Study, 309 participants age≥70 initially free of dementia were administered the MBT and followed annually for incident dementia for up to 13 years. Based on previous work, poor memory binding was defined using an optimal empirical cut-score of≤17 on the binding measure of the MBT, Total Items in the Paired condition (TIP). Cox proportional hazards models were used to assess predictive validity adjusting for covariates. We compared the predictive validity of MBT TIP to that of the free and cued selective reminding test free recall score (FCSRT-FR; cut-score:≤24) and the single list recall measure of the MBT, Cued Recalled from List 1 (CR-L1; cut-score:≤12)., Results: Thirty-five of 309 participants developed incident dementia. When assessing each test alone, the hazard ratio (HR) for dementia was significant for MBT TIP (HR = 8.58, 95% CI: (3.58, 20.58), p < 0.0001), FCSRT-FR (HR = 4.19, 95% CI: (1.94, 9.04), p = 0.0003) and MBT CR-L1 (HR = 2.91, 95% CI: (1.37, 6.18), p = 0.006). MBT TIP remained a significant predictor of dementia (p = 0.0002) when adjusting for FCSRT-FR or CR-L1., Conclusions: Older adults with poor memory binding as measured by the MBT TIP were at increased risk for incident dementia. This measure outperforms conventional episodic memory measures of free and cued recall, supporting the memory binding hypothesis.

Recent World Health Organization (WHO) guidelines recommend antiretroviral therapy (ART) for all HIV-infected people; previously CD4+ T lymphocyte quantification (CD4 count) or clinical staging determined eligibility for children ≥ 5 years old in low- and middle-income countries. We examined positive predictive value (PPV) of a rapid diagnostic test (RDT) algorithm and ART eligibility for hospitalized children with newly diagnosed HIV infection. We enrolled 363 hospitalized Malawian children age 2 months to 16 years with two serial positive HIV RDT from 2013 to 2015. Children aged ≤ 18 months whose nucleic acid testing was negative or unavailable were later excluded from the analysis ( N = 16). If RNA PCR was undetectable, human immunodeficiency virus (HIV) enzyme immunoassay (EIA) and western blot (WB) were performed. Those with negative or discordant EIA and WB were considered HIV negative and excluded from further analysis ( N = 6). ART eligibility was assessed using age, CD4 count, and clinical HIV stage. Among 150 patients with HIV RNA PCR results, 15 had undetectable HIV RNA. Of those, EIA and WB were positive in nine patients and negative or discordant in six patients. PPV of serial RDT was 90% versus RNA PCR alone and 96% versus combined RNA PCR, EIA, and WB. Of all patients aged ≥ 5 years, 8.9% were ineligible for ART under previous WHO guidelines. Improved HIV testing algorithms are needed for accurate diagnosis of HIV infection in children as prevalence of pediatric HIV declines. Universal treatment will significantly increase the numbers of older children who qualify for ART.

Brain swelling is a major predictor of mortality in pediatric cerebral malaria (CM). However, the mechanisms leading to swelling remain poorly defined. Here, we combined neuroimaging, parasite transcript profiling, and laboratory blood profiles to develop machine-learning models of malarial retinopathy and brain swelling. We found that parasite var transcripts encoding endothelial protein C receptor (EPCR)-binding domains, in combination with high parasite biomass and low platelet levels, are strong indicators of CM cases with malarial retinopathy. Swelling cases presented low platelet levels and increased transcript abundance of parasite PfEMP1 DC8 and group A EPCR-binding domains. Remarkably, the dominant transcript in 50% of swelling cases encoded PfEMP1 group A CIDRα1.7 domains. Furthermore, a recombinant CIDRα1.7 domain from a pediatric CM brain autopsy inhibited the barrier-protective properties of EPCR in human brain endothelial cells in vitro. Together, these findings suggest a detrimental role for EPCR-binding CIDRα1 domains in brain swelling., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Infantile spasms are the typical seizures of West syndrome, an infantile epileptic encephalopathy with poor outcomes. There is an increasing need to identify more effective and better tolerated treatments for infantile spasms. We have optimized the rat model of infantile spasms due to structural etiology, the multiple-hit rat model, for therapy discovery. Here, we test three compounds administered after spasms induction in the multiple hit model for efficacy and tolerability. Specifically, postnatal day 3 (PN3) male Sprague-Dawley rats were induced by right intracerebral injections of doxorubicin and lipopolysaccharide. On PN5 p-chlorophenylalanine was given intraperitoneally (i.p.). Daily monitoring of weights and developmental milestones was done and rats were intermittently video monitored. A blinded, randomized, vehicle-controlled study design was followed. The caspase 1 inhibitor VX-765 (50-200 mg/kg i.p.) and the GABA B receptor inhibitor CGP35348 (12.5-100 mg/kg i.p.) each was administered in different cohorts as single intraperitoneal injections on PN4, using a dose- and time-response design with intermittent monitoring till PN5. 17β-estradiol (40 ng/g/day subcutaneously) was given daily between PN3-10 and intermittent monitoring was done till PN12. None of the treatments demonstrated acute or delayed effects on spasms, yet all were well tolerated. We discuss the implications for therapy discovery and challenges of replication trials.

Objective: Although cardiovascular disease (CVD) is the leading cause of death among individuals with rheumatoid arthritis (RA), CVD risks are not being assessed frequently and systematically in RA. We implemented an electronic medical record (EMR)-based reminder in a tertiary care center and assessed the effects of this intervention on CVD risk screening by rheumatologists and primary care providers., Methods: The EMR reminder was implemented in December 2013 and included the most recent value and target ranges for body mass index, blood pressure (BP), and lipid profiles. It was displayed for every rheumatology and primary care visit for all patients with the International Classification of Diseases, Ninth Revision code for RA (714.0). Lipid screening rates, as well as changes in BP and obesity rates were compared pre- and postimplementation. Factors associated with lipid screening postimplementation were assessed using multivariate logistic regression., Results: A total of 138 and 112 RA patients were seen in the outpatient clinics pre- and postimplementation, respectively. The demographic characteristics were similar in the pre- and postimplementation groups. Lipid screening rates were 50% preimplementation and 46% postimplementation (P = 0.58). There were no significant improvements in BP or obesity rates postimplementation. Factors associated with the higher odds of lipid screening included older age and history of diabetes mellitus., Conclusion: Implementing an EMR reminder did not improve CVD risk screening among RA patients. Future research is needed to identify and address barriers to CVD screening, and to educate patients and providers about RA-related risks., (© 2016, American College of Rheumatology.)

Objective: We investigated temporal and spatial characteristics of ictal gamma and beta activity on scalp EEG during spasms in patients with West syndrome (WS) to evaluate potential focal cortical onset., Methods: A total of 1,033 spasms from 34 patients with WS of various etiologies were analyzed on video-electroencephalography (EEG) using time-frequency analysis. Ictal gamma (35-90 Hz) and beta (15-30 Hz) activities were correlated with visual symmetry of spasms, objective EMG (electromyography) analysis, and etiology of WS., Results: Prior to the ictal motor manifestation, focal ictal gamma activity emerged from one hemisphere (71%, 24/34) or from midline (26%, 9/34), and was rarely simultaneously bilateral (3%, 1/34). Focal ictal beta activity emerged from either one hemisphere (68%, 23/34) or from midline (32%, 11/34). Onsets of focal ictal gamma and beta activity were most commonly observed around the parietal areas. Focal ictal gamma activity propagated faster than ictal beta activity to adjacent electrodes (median: 65 vs. 170 msec, p < 0.01), and to contralateral hemisphere (median: 100 vs. 170 msec, p = 0.01). Asymmetric peak amplitude of ictal gamma activity in the centroparietal areas (C3-P3 vs. C4-P4) correlated with asymmetric semiology. On the other hand, most of the visually symmetric spasms showed asymmetry in peak amplitude and interhemispheric onset latency difference in both ictal gamma and beta activity., Significance: Spasms may be a seizure with focal electrographic onset regardless of visual symmetry. Asymmetric involvement of ictal gamma activity to the centroparietal areas may determine the motor manifestations in WS. Scalp EEG ictal gamma and beta activity may be useful to demonstrate localized seizure onset in infants with WS., (Wiley Periodicals, Inc. © 2017 International League Against Epilepsy.)

Objective: Using American College of Rheumatology (ACR) and Systemic Lupus International Collaborating Clinics (SLICC) criteria for systemic lupus erythematosus (SLE) classification as gold standards, we determined sensitivity, specificity, positive and negative predictive values (PPV and NPV) of having SLE denoted as the primary cause of end-stage renal disease (ESRD) in the US Renal Data System (USRDS)., Methods: ESRD patients were identified by International Classification of Diseases, Ninth Revision codes in electronic medical records of 1 large tertiary care center, Montefiore Hospital, from 2006 to 2012. Clinical data were extracted and reviewed to establish SLE diagnosis. Data were linked by social security number, name, and date of birth to the USRDS, where primary causes of ESRD were ascertained., Results: Of 7,396 ESRD patients at Montefiore, 97 met ACR/SLICC SLE criteria, and 86 had SLE by record only. Among the 97 SLE patients, the attributed causes of ESRD in the USRDS were 77 SLE and 12 with other causes (unspecified glomerulonephritis, hypertension, scleroderma), and 8 missing. Sensitivity, specificity, PPV, and NPV for SLE in the USRDS were 79%, 99.9%, 93%, and 99.7%, respectively. Of the 60 patients with biopsy-proven lupus nephritis, 44 (73%) had SLE as primary ESRD cause in the USRDS. Attribution of the primary ESRD causes among SLE patients with ACR/SLICC criteria differed by race, ethnicity, and transplant status., Conclusion: The diagnosis of SLE as the primary cause of ESRD in the USRDS has good sensitivity, and excellent specificity, PPV, and NPV. Nationwide access to medical records and biopsy reports may significantly improve sensitivity of SLE diagnosis., (© 2016, American College of Rheumatology.)

Preclinical studies have produced numerous drugs with antiseizure properties which currently are the standard of care in clinical care. A third of the human population with epilepsy still continues having seizures despite the ongoing discoveries. The recognized clinical gaps of care that need to be addressed are the identification of antiepileptogenic and disease modifying treatments, treatments for refractory seizures or for seizures and epilepsies with limited or unsatisfactory treatments, such as early life epileptic encephalopathies. In this invited review, we provide a historical summary of the international efforts to re-evaluate the strategies adopted in preclinical epilepsy therapy discovery studies. We discuss issues that may impact the quality, interpretation and validation of preclinical studies and their translation to successful therapies for humans affected with epilepsy. These include the selection of animal models and the study design, research practices that affect rigor, such as appropriate use of statistics and reporting of study methods and results, their validation across models, labs and preclinical-clinical studies, the need to harmonize research methods and outcome assessment, and the importance to improve translation to clinically appropriate situations. The epilepsy research community is incrementally adopting collaborative research, including consortia or multicenter studies to meet these needs. Improving the infrastructure that can support these efforts will be instrumental in the future success., Competing Interests: We have no conflicts of interest in regards to this manuscript.

Objective: The objective was to compare two screening strategies for dementia in an urban primary care clinic, serving a low-education, minority community composed largely of Latino and African American patients., Method: Two hundred and fifty-seven patients underwent two-stage patient-based screening (PBS) and informant-based screening (IBS) followed by a diagnostic evaluation. In the first stage, PBS included brief tests of episodic memory (Memory Impairment Screen), semantic memory (Animal Fluency), and executive function (Reciting Months Backwards). For IBS, the first stage consisted of the short Informant Questionnaire on Cognitive Decline in the Elderly, administered to a family member or friend. Patients who screened positive in the first stage of either strategy underwent testing with the picture version of the Free and Cued Selective Reminding Test with Immediate Recall to identify memory impairment. Sensitivity, specificity, and positive and negative predictive values were computed for various cutoffs of each test and combination of tests. Dementia was diagnosed using Diagnostic and Statistical Manual of Mental Disorders-Fourth Edition (DSM-IV) criteria without access to the screening test results., Results: We identified 66 patients (25.7%) with previously undiagnosed dementia. Sensitivity was the same (77%) for both strategies but specificity was higher for IBS than for PBS (92% versus 83%). IBS's higher specificity makes it the preferred strategy if a knowledgeable informant is available., Conclusion: Unrecognized dementia is common in primary care. Case-finding can be improved using either PBS or IBS two-stage screening strategies.

Background: The Memory Binding Test (MBT), previously known as Memory Capacity Test, has demonstrated discriminative validity for distinguishing persons with amnestic mild cognitive impairment (aMCI) and dementia from cognitively normal elderly., Objective: We aimed to assess the predictive validity of the MBT for incident aMCI., Methods: In a longitudinal, community-based study of adults aged 70+, we administered the MBT to 246 cognitively normal elderly adults at baseline and followed them annually. Based on previous work, a subtle reduction in memory binding at baseline was defined by a Total Items in the Paired (TIP) condition score of ≤22 on the MBT. Cox proportional hazards models were used to assess the predictive validity of the MBT for incident aMCI accounting for the effects of covariates. The hazard ratio of incident aMCI was also assessed for different prediction time windows ranging from 4 to 7 years of follow-up, separately., Results: Among 246 controls who were cognitively normal at baseline, 48 developed incident aMCI during follow-up. A baseline MBT reduction was associated with an increased risk for developing incident aMCI (hazard ratio (HR) = 2.44, 95% confidence interval: 1.30-4.56, p = 0.005). When varying the prediction window from 4-7 years, the MBT reduction remained significant for predicting incident aMCI (HR range: 2.33-3.12, p: 0.0007-0.04)., Conclusion: Persons with poor performance on the MBT are at significantly greater risk for developing incident aMCI. High hazard ratios up to seven years of follow-up suggest that the MBT is sensitive to early disease.

Objective: To investigate the association between the presence of aPL and/or LA and all-cause mortality among end-stage renal disease (ESRD) patients with and without SLE., Methods: We included ESRD patients >18 years old followed at an urban tertiary care centre between 1 January 2006 and 31 January 2014 who had aPL measured at least once after initiating haemodialysis. All SLE patients met ACR/SLICC criteria. APL/LA+ was defined as aCL IgG or IgM >40 IU, anti-β2glycoprotein1 IgG or IgM >40 IU or LA+. Deaths as at 31 January 2014 were captured in the linked National Death Index data. Time to death was defined from the first aPL measurement., Results: We included 34 SLE ESRD and 64 non-SLE ESRD patients; 30 patients died during the study period. SLE ESRD patients were younger [40.4 (12.5) vs 51.9 (18.1) years, P = 0.001] and more were women (88.2% vs 54.7%, P < 0.001) vs non-SLE ESRD patients. The frequency of aPL/LA+ was 24% in SLE and 13% in non-SLE ESRD (P = 0.16). Median (inter-quartile range) follow-up time was 1.6 (0.3-3.5) years in SLE and 1.4 (0.4-3.2) years in non-SLE, P = 0.74. The adjusted hazard ratio (HR) for all-cause mortality for SLE patients who were aPL/LA+ vs aPL/LA- was 9.93 (95% CI 1.33, 74.19); the adjusted HR for non-SLE aPL/LA+ vs aPL/LA- was 0.77 (95% CI 0.14, 4.29)., Conclusion: SLE ESRD patients with aPL/LA+ had higher all-cause mortality risk than SLE ESRD patients without these antibodies, while the effects of aPL/LA on mortality were comparable among non-SLE ESRD patients., (© The Author 2015. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)