Agreement between attended home and ambulatory blood pressure measurements in adolescents with chronic kidney disease.

BACKGROUND: This study aimed to compare attended home blood pressure (BP) measurements (HBPM) with ambulatory BP monitor (ABPM) readings and examine if level of agreement between measurement modalities differs overall and by subgroup. METHODS: This was a secondary analysis of data from a 2-year, multicenter observational study of children 11-19 years (mean 15, SD = 2.7) with chronic kidney disease. Participants had 3 standardized resting oscillometric home BPs taken by staff followed by 24-h ABPM within 2 weeks of home BP. BP indices (measured BP/95%ile BP) were calculated for mean triplicate attended HBPM and mean ABPM measurements. Paired HBPM and ABPM measurements taken during any of 5 study visits were compared using linear regression with robust standard errors. Generalized estimating equation-based logistic regression determined sensitivity, specificity, negative, and positive predictive values with ABPM as the gold standard. Analyses were conducted for the group overall and by subgroup. RESULTS: A total of 103 participants contributed 251 paired measurements. Indexed systolic BP did not differ between HBPM and daytime APBM (mean difference - 0.002; 95% CI: - 0.006, 0.003); the difference in indexed diastolic BP was minimal (mean difference - 0.033; 95% CI: - 0.040, - 0.025). Overall agreement between HBPM and 24-h ABPM in identifying abnormal BP was high (81.8%). HBPM had higher sensitivity (87.5%) than specificity (77.4%) and greater negative (89.8%) than positive (73.3%) predictive value, and findings were consistent in subgroups. CONCLUSIONS: Attended HBPM may be reasonable for monitoring BP when ABPM is unavailable. The greater accessibility and feasibility of attended HBPM may potentially help improve BP control among at-risk youth. A higher resolution version of the Graphical abstract is available as Supplementary information.

Variant-specific changes in persistent or resurgent sodium current in SCN8A-related epilepsy patient-derived neurons.

Missense variants in the SCN8A voltage-gated sodium channel gene are linked to early-infantile epileptic encephalopathy type 13, also known as SCN8A-related epilepsy. These patients exhibit a wide spectrum of intractable seizure types, severe developmental delay, movement disorders, and elevated risk of sudden unexpected death in epilepsy. The mechanisms by which SCN8A variants lead to epilepsy are poorly understood, although heterologous expression systems and mouse models have demonstrated altered sodium current properties. To investigate these mechanisms using a patient-specific model, we generated induced pluripotent stem cells from three patients with missense variants in SCN8A: p.R1872>L (Patient 1); p.V1592>L (Patient 2); and p.N1759>S (Patient 3). Using small molecule differentiation into excitatory neurons, induced pluripotent stem cell-derived neurons from all three patients displayed altered sodium currents. Patients 1 and 2 had elevated persistent current, while Patient 3 had increased resurgent current compared to controls. Neurons from all three patients displayed shorter axon initial segment lengths compared to controls. Further analyses focused on one of the patients with increased persistent sodium current (Patient 1) and the patient with increased resurgent current (Patient 3). Excitatory cortical neurons from both patients had prolonged action potential repolarization. Using doxycycline-inducible expression of the neuronal transcription factors neurogenin 1 and 2 to synchronize differentiation of induced excitatory cortical-like neurons, we investigated network activity and response to pharmacotherapies. Both small molecule differentiated and induced patient neurons displayed similar abnormalities in action potential repolarization. Patient induced neurons showed increased burstiness that was sensitive to phenytoin, currently a standard treatment for SCN8A-related epilepsy patients, or riluzole, an FDA-approved drug used in amyotrophic lateral sclerosis and known to block persistent and resurgent sodium currents, at pharmacologically relevant concentrations. Patch-clamp recordings showed that riluzole suppressed spontaneous firing and increased the action potential firing threshold of patient-derived neurons to more depolarized potentials. Two of the patients in this study were prescribed riluzole off-label. Patient 1 had a 50% reduction in seizure frequency. Patient 3 experienced an immediate and dramatic seizure reduction with months of seizure freedom. An additional patient with a SCN8A variant in domain IV of Nav1.6 (p.V1757>I) had a dramatic reduction in seizure frequency for several months after starting riluzole treatment, but then seizures recurred. Our results indicate that patient-specific neurons are useful for modelling SCN8A-related epilepsy and demonstrate SCN8A variant-specific mechanisms. Moreover, these findings suggest that patient-specific neuronal disease modelling offers a useful platform for discovering precision epilepsy therapies.

Engagement and Affective Communication During Pediatric Nephrology Clinic Visits: Associations with Medication Adherence.

OBJECTIVE: To evaluate whether engagement and affective communication among adolescents and young adults (AYAs) with chronic kidney disease (CKD), caregivers, and pediatric nephrology providers during outpatient clinic visits predicts antihypertensive medication adherence. METHODS: AYAs (n = 60, M age = 15.4 years, SD = 2.7, 40% female, 43% African American/Black) and caregivers (n = 60, 73% female) attended audio-recorded clinic visits with pediatric nephrologists (n = 12, 75% female). Recordings were analyzed using global affect ratings of the Roter Interactional Analysis System. Antihypertensive medication adherence was monitored electronically before and after clinic visits. A linear regression model evaluated associations between affect ratings and post-visit adherence. RESULTS: AYAs took 84% of doses (SD = 20%) pre-visit and 82% of doses (SD = 24%) post-visit. Higher AYA engagement (ß = 0.03, p = .01) and the absence of provider negative affect (ß=-0.15, p = .04) were associated with higher post-visit adherence, controlling for pre-visit adherence, AYA sex, age, and race, and clustered by provider. CONCLUSIONS: Post-visit adherence was higher when AYAs were rated as more engaged and providers as less negative. PRACTICE IMPLICATIONS: AYAs with lower engagement may benefit from further adherence assessment. Communication strategies designed to more actively engage AYAs in their care and diminish provider conveyance of negative affect during clinic visits may positively influence adherence among AYAs with CKD.

Looking at education through the microscope.

Advanced research microscopes in universities can be used to enhance the education of STEM students, as demonstrated by initiatives at Johns Hopkins University that give students the opportunity to get hands-on experience with sophisticated microscopes.

Rapid Generation of Human Genetic Loss-of-Function iPSC Lines by Simultaneous Reprogramming and Gene Editing.

Specifically ablating genes in human induced pluripotent stem cells (iPSCs) allows for studies of gene function as well as disease mechanisms in disorders caused by loss-of-function (LOF) mutations. While techniques exist for engineering such lines, we have developed and rigorously validated a method of simultaneous iPSC reprogramming while generating CRISPR/Cas9-dependent insertions/deletions (indels). This approach allows for the efficient and rapid formation of genetic LOF human disease cell models with isogenic controls. The rate of mutagenized lines was strikingly consistent across experiments targeting four different human epileptic encephalopathy genes and a metabolic enzyme-encoding gene, and was more efficient and consistent than using CRISPR gene editing of established iPSC lines. The ability of our streamlined method to reproducibly generate heterozygous and homozygous LOF iPSC lines with passage-matched isogenic controls in a single step provides for the rapid development of LOF disease models with ideal control lines, even in the absence of patient tissue.