ASTHMAXcel PRO patient satisfaction and usability field testing.

Background: ASTHMAXcel PRO, an enhanced version of the ASTHMAXcel mobile application, has been developed to deliver comprehensive, guideline-based asthma education while also facilitating the collection of patient-reported outcomes (PROs) and enhancing user experience.Objective: To perform field testing and conduct formative and summative evaluation of the ASTHMAXcel PRO application to assess its impact on patient satisfaction, usability, and usage.Methods: Twenty-eight adult patients completed a baseline visit during which ASTHMAXcel PRO was introduced, health literacy was assessed, and demographic data were collected. They were instructed to use the app for 4 weeks. The Questionnaire for User Interface Satisfaction (QUIS) and the Unified Theory of Acceptance and Use of Technology (UTAUT) questionnaire were administered at baseline and 4 weeks to assess user satisfaction and technology acceptance, respectively. Semi-structured interviews were conducted to gather feedback regarding the application from patients.Results: The baseline total scores were high for both UTAUT and QUIS (mean (SD): 64.2 (10.1), 6.8 (2.2) respectively) indicating that user satisfaction and acceptance began at high levels. UTAUT total score, as well as all domain scores, improved significantly from baseline to 4 weeks (p < 0.02). QUIS total score along with several domain scores (screen, system capabilities, usability) also increased from baseline to 4-weeks (p = 0.03, 0.01, 0.03, 0.01, respectively). These improvements remained significant when adjusting for age, gender, education, and health literacy. Patients reported that the application was helpful, informative, and easy to understand and use.Conclusion: The significant increases in satisfaction and technology adoption observed among ASTHMAXcel PRO users demonstrate that the application is viable and has the potential to improve upon usability challenges faced by existing mobile health applications.

Developing and Evaluating the DiabetesXcel Mobile Application for Adult Patients With Type 2 Diabetes.

The authors trialed a mobile application, DiabetesXcel, which included type 2 diabetes-focused educational videos and modules, in 50 adults of Bronx, NY, a region with a high prevalence of diabetes and diabetes complications. From baseline to 4 months and from baseline to 6 months, there was significantly improved quality of life, self-management, knowledge, self-efficacy, depression, A1C, and LDL cholesterol among those who used DiabetesXcel. There was also a significant decrease in diabetes-related emergency department visits and hospital admissions from baseline to 6 months. This study demonstrates that DiabetesXcel could be beneficial for type 2 diabetes management.

Total cortical interstitial inflammation predicts chronic kidney disease progression in patients with lupus nephritis.

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.

Susceptibility to epilepsy after traumatic brain injury is associated with preexistent gut microbiome profile.

OBJECTIVE: We examined whether posttraumatic epilepsy (PTE) is associated with measurable perturbations in gut microbiome. METHODS: Adult Sprague Dawley rats were subjected to lateral fluid percussion injury (LFPI). PTE was examined 7 months after LFPI, during 4-week continuous video-electroencephalographic monitoring. 16S ribosomal RNA gene sequencing was performed in fecal samples collected before LFPI/sham-LFPI and 1 week, 1 month, and 7 months thereafter. Longitudinal analyses of alpha diversity, beta diversity, and differential microbial abundance were performed. Short-chain fatty acids (SCFAs) were measured in fecal samples collected before LFPI by liquid chromatography with tandem mass spectrometry. RESULTS: Alpha diversity changed over time in both LFPI and sham-LFPI subjects; no association was observed between alpha diversity and LFPI, the severity of post-LFPI neuromotor impairments, and PTE. LFPI produced significant changes in beta diversity and selective changes in microbial abundances associated with the severity of neuromotor impairments. No association between LFPI-dependent microbial perturbations and PTE was detected. PTE was associated with beta diversity irrespective of timepoint vis-à-vis LFPI, including at baseline. Preexistent fecal microbial abundances of four amplicon sequence variants belonging to the Lachnospiraceae family (three enriched and one depleted) predicted the risk of PTE, with area under the curve (AUC) of .73. Global SCFA content was associated with the increased risk of PTE, with AUC of .722, and with 2-methylbutyric (depleted), valeric (depleted), isobutyric (enriched), and isovaleric (enriched) acids being the most important factors (AUC = .717). When the analyses of baseline microbial and SCFA compositions were combined, AUC to predict PTE increased to .78. SIGNIFICANCE: Whereas LFPI produces no perturbations in the gut microbiome that are associated with PTE, the risk of PTE can be stratified based on preexistent microbial abundances and SCFA content.

Screening Electrocardiograms Have Low Utility in Medical Clearance Before Pediatric Inpatient Psychiatric Admission.

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.

Antiepileptogenic effects of rapamycin in a model of infantile spasms due to structural lesions.

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.

Developing and pilot testing ASTHMAXcel, a mobile app for adults with asthma.

Objective: We sought to compare the impact of ASTHMAXcel, a novel, guideline-based, patient-facing mobile app to human-delivered asthma education.Methods: We conducted a focus group with asthma patients in the Bronx to identify desired mobile app features. ASTHMAXcel was designed based on patient feedback and consistent with NAEPP, BTS/SIGN, and GINA guidelines. The app was reviewed by internists, allergist/immunologists, and pulmonologists specializing in asthma treatment, asthma educators, and a behavioral scientist, and iteratively refined. The refined version of ASTHMAXcel was administered once via tablet at our outpatient Montefiore Asthma Center (MAC). Asthma knowledge was measured through the Asthma Knowledge Questionnaire (AKQ) pre and post-intervention. We also recorded process outcomes including completion time and patient satisfaction. In parallel, human-delivered education was delivered once at MAC. These outcomes were similarly collected.Results: 60 patients were enrolled with 30 in the ASTHMAXcel and 30 in the human-educator group. Mean AKQ in the ASTHMAXcel group vs human-educator group pre-intervention was 9.9 vs 10.5, p = 0.27. Mean AKQ post-intervention in the ASTHMAXcel group vs human-educator group was 12.3 vs 14.4, p = 0.0002. The mean AKQ improvement for both groups were 2.4 vs 3.9, p = 0.007. Patients were highly satisfied in the ASTHMAXcel group scoring on average 27.9 out of 30 maximum points on the satisfaction survey. There was no difference in satisfaction scores or completion times (minutes) of either intervention.Conclusion: ASTHMAXcel was associated with an increase in AKQ, but the human-educator group experienced a greater improvement. ASTHMAXcel demonstrated no differences in process outcomes vs human-delivered education.

Adverse Childhood Experiences Are Associated with Childhood-Onset Arthritis in a National Sample of US Youth: An Analysis of the 2016 National Survey of Children's Health.

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 χ2 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.

Association between dietary zinc intake and abdominal aortic calcification in US adults.

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.

Developing and evaluating ASTHMAXcel adventures: A novel gamified mobile application for pediatric patients with asthma.

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.

Systemic lupus Erythematosus activity and Hydroxychloroquine use before and after end-stage renal disease.

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.

Child and Adolescent Psychiatry Trainees' Attitudes Toward Prescribing and Managing Psychotropic Medications.

OBJECTIVE: There has been a recent concern about the overuse of psychotropic medications in children. This study was designed to assess the attitudes held by child and adolescent psychiatry trainees toward the prescription and management of medications in the pediatric population. METHODS: An online survey was sent to all Accreditation Council for Graduate Medical Education (ACGME)-accredited child and adolescent psychiatry training programs across the USA with the goal of assessing trainee comfort and confidence with prescribing skills and concepts. RESULTS: About 63 trainees (7.2% of the targeted population) were included in the analyses. While most participants reported confidence in basic prescribing skills, areas of lower confidence included cross-tapering medications, managing side effects, knowledge of the evidence base, drug-drug interactions, and de-prescribing. Advanced year in training was associated with higher confidence overall but failed to reach significance with some complex concepts such as polypharmacy (p = 0.27) and de-prescribing (p = 0.10). In contrast, increased supervision had a significant impact on confidence regarding complex concepts (p = 0.04) but not basic skills (p = 0.51). Supervision was also associated with higher training satisfaction (p = 0.001). CONCLUSIONS: Though the study was limited by a low response rate, these preliminary findings suggest potential areas for targeted psychopharmacology training. The findings also support how the important role supervision plays in the development of more complex skills. Further studies are needed to better understand these potential areas of curricula development and to explore the most effective training modalities.

The association between pollutant levels and asthma-related emergency department visits in the Bronx after the World Trade Center attacks.

Objective: To examine the potential impact of the World Trade Center (WTC) attacks on asthma-related emergency department visits (AREDV) in the New York City borough of the Bronx. Methods: We obtained daily nitrogen dioxide (NO2), sulfur dioxide (SO2) and ozone (O3) values from the National Climatic Data Center's collection station in the Bronx from 1999 and 2002, a year before and after the WTC attacks. We compared daily AREDV and pollutant levels between 1999 and 2002 using the Wilcoxon signed rank sum test. We considered each season separately due to seasonal variations of AREDV and pollutants. We then used multiple linear regression models to assess the relationships between the changes in AREDV and the changes in pollutants from 1999 to 2002 in each season. Results: There were statistically significant increases from 1999 to 2002 in the daily NO2 in the summer. Significant increases for daily SO2 and O3 values from 1999 to 2002 occurred in all seasons. Significant increases occurred in daily AREDV values in the spring and fall. Multiple linear regression analyses showed that increases in the daily O3 values were significantly associated with increases in AREDV from 1999 to 2002 in the summer season. Conclusion: We observed a possible association between the WTC attacks and significant increases in O3 and SO2 for all seasons, and NO2 for the summer. AREDV significantly increased following the WTC attacks. Increases in daily O3 values were significantly associated with increases in AREDV in the summer season.

Convalescent Plasmodium falciparum-specific seroreactivity does not correlate with paediatric malaria severity or Plasmodium antigen exposure.

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.

Scalp EEG Ictal gamma and beta activity during infantile spasms: Evidence of focality.

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.

Preclinical Screening for Treatments for Infantile Spasms in the Multiple Hit Rat Model of Infantile Spasms: An Update.

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 GABAB 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. 17ß-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.

Association between antiphospholipid antibodies and all-cause mortality among end-stage renal disease patients with and without SLE: a retrospective cohort study.

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-ß2glycoprotein1 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.

CPP-115, a vigabatrin analogue, decreases spasms in the multiple-hit rat model of infantile spasms.

OBJECTIVE: Infantile spasms (IS) have poor outcomes and limited treatment options, including vigabatrin, a γ-aminobutyric acid (GABA) aminotransferase inactivator. Vigabatrin has been associated with retinal toxicity. A high affinity vigabatrin analogue (CPP-115; Catalyst Pharmaceutical Partners, Inc., Coral Gables, FL, U.S.A.) has shown lower risk of retinal toxicity. Here, we test the efficacy of CPP-115 in reducing spasms and its tolerability in the multiple-hit rat model of IS, in which daily vigabatrin reduced spasms for only one day, but was not well tolerated. METHODS: Male rats were treated with the protocol of the multiple-hit model of IS on postnatal day 3 (PN3). Using a randomized, blinded, vehicle-controlled, dose-response study design, CPP-115 (0.1, 1, or 5 mg/kg intraperitoneally [i.p.]) or vehicle was given daily (PN4-12) or as a single injection (PN7) after spasm onset. Intermittent video- or video-electroencephalography (EEG) monitoring was done. Secondary end points included the following: daily weights, survival, performance on open field activity, surface righting time, and negative geotaxis (PN3-20), horizontal bar (PN13-20), and Barnes maze (PN16-19). Statistics used a linear mixed model of raw or normalized log-transformed data, taking into account the repeated observations on each animal. RESULTS: The lower CPP-115 doses (0.1-1 mg/kg/day, PN4-12) reduced spasms between PN6 and 7 without increasing mortality. CPP-115 at 5 mg/kg/day (PN4-12) reduced spasms earlier (PN5), but was eventually lethal. A single CPP-115 injection (1 mg/kg, i.p.) decreased electroclinical spasms acutely but transiently. CPP-115 transiently improved the probability to >50% reduction of spasms, but did not accelerate spasm cessation. CPP-115 did not alter neurodevelopmental outcomes or visuospatial learning. SIGNIFICANCE: We provide proof-of-concept evidence that CPP-115, a vigabatrin analogue, decreases spasms in the multiple-hit rat model of IS at considerably lower and better tolerated doses than vigabatrin did in our previous studies. Further optimization of the treatment protocol is needed. CPP-115 may be a promising new candidate treatment for IS with better tolerability than vigabatrin.

Linking Dementia Pathology and Alteration in Brain Activation to Complex Daily Functional Decline During the Preclinical Dementia Stages: Protocol for a Prospective Observational Cohort Study.

BACKGROUND: Progressive difficulty in performing everyday functional activities is a key diagnostic feature of dementia syndromes. However, not much is known about the neural signature of functional decline, particularly during the very early stages of dementia. Early intervention before overt impairment is observed offers the best hope of reducing the burdens of Alzheimer disease (AD) and other dementias. However, to justify early intervention, those at risk need to be detected earlier and more accurately. The decline in complex daily function (CdF) such as managing medications has been reported to precede impairment in basic activities of daily living (eg, eating and dressing). OBJECTIVE: Our goal is to establish the neural signature of decline in CdF during the preclinical dementia period. METHODS: Gait is central to many CdF and community-based activities. Hence, to elucidate the neural signature of CdF, we validated a novel electroencephalographic approach to measuring gait-related brain activation while participants perform complex gait-based functional tasks. We hypothesize that dementia-related pathology during the preclinical period activates a unique gait-related electroencephalographic (grEEG) pattern that predicts a subsequent decline in CdF. RESULTS: We provide preliminary findings showing that older adults reporting CdF limitations can be characterized by a unique gait-related neural signature: weaker sensorimotor and stronger motor control activation. This subsample also had smaller brain volume and white matter hyperintensities in regions affected early by dementia and engaged in less physical exercise. We propose a prospective observational cohort study in cognitively unimpaired older adults with and without subclinical AD (plasma amyloid-ß) and vascular (white matter hyperintensities) pathologies. We aim to (1) establish the unique grEEG activation as the neural signature and predictor of decline in CdF during the preclinical dementia period; (2) determine associations between dementia-related pathologies and incidence of the neural signature of CdF; and (3) establish associations between a dementia risk factor, physical inactivity, and the neural signature of CdF. CONCLUSIONS: By establishing the clinical relevance and biological basis of the neural signature of CdF decline, we aim to improve prediction during the preclinical stages of ADs and other dementias. Our approach has important research and translational implications because grEEG protocols are relatively inexpensive and portable, and predicting CdF decline may have real-world benefits. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/56726.

Tau Phosphorylation Patterns in the Rat Cerebral Cortex After Traumatic Brain Injury and Sodium Selenate Effects: An Epibios4rx Project 2 Study.

Sodium selenate (SS) activates protein phosphatase 2 (PP2A) and reduces phosphorylated tau (pTAU) and late post-traumatic seizures after lateral fluid percussion injury (LFPI). In EpiBioS4Rx Project 2, a multi-center international study for post-traumatic targets, biomarkers, and treatments, we tested the target relevance and modification by SS of pTAU forms and PP2A and in the LFPI model, at two sites: Einstein and Melbourne. In Experiment 1, adult male rats were assigned to LFPI and sham (both sites) and naïve controls (Einstein). Motor function was monitored by neuroscores. Brains were studied with immunohistochemistry (IHC), Western blots (WBs), or PP2A activity assay, from 2 days to 8 weeks post-operatively. In Experiment 2, LFPI rats received SS for 7 days (SS0.33: 0.33 mg/kg/day; SS1: 1 mg/kg/day, subcutaneously) or vehicle (Veh) post-LFPI and pTAU, PR55 expression, or PP2A activity were studied at 2 days and 1 week (on treatment), or 2 weeks (1 week off treatment). Plasma selenium and SS levels were measured. In Experiment 1 IHC, LFPI rats had higher cortical pTAU-Ser202/Thr205-immunoreactivity (AT8-ir) and pTAU-Ser199/202-ir at 2 days, and pTAU-Thr231-ir (AT180-ir) at 2 days, 2 weeks, and 8 weeks, ipsilaterally to LFPI, than controls. LFPI-2d rats also had higher AT8/total-TAU5-ir in cortical extracts ipsilateral to the lesion (WB). PP2A (PR55-ir) showed time- and region-dependent changes in IHC, but not in WB. PP2A activity was lower in LFPI-1wk than in sham rats. In Experiment 2, SS did not affect neuroscores or cellular AT8-ir, AT180-ir, or PR55-ir in IHC. In WB, total cortical AT8/total-TAU-ir was lower in SS0.33 and SS1 LFPI rats than in Veh rats (2 days, 1 week); total cortical PR55-ir (WB) and PP2A activity were higher in SS1 than Veh rats (2 days). SS dose dependently increased plasma selenium and SS levels. Concordant across-sites data confirm time and pTAU form-specific cortical increases ipsilateral to LFPI. The discordant SS effects may either suggest SS-induced reduction in the numbers of cells with increased pTAU-ir, need for longer treatment, or the involvement of other mechanisms of action.