Congenital complete heart block (CCHB) is seen in 1:15,000-1:20,000 live births, with risk of left ventricular (LV) dysfunction or dilated cardiomyopathy in 7%-23% of subjects.
The purpose of this ...study was to investigate serial changes in LV size and systolic function in paced CCHB subjects to examine the effect of time from pacemaker on echocardiographic parameters.
Single-center retrospective cohort analysis of paced CCHB subjects was performed. Echocardiographic data were collected before and after pacemaker placement. Linear mixed effect regression of left ventricular end-diastolic dimension (LVEDD) z-score, left ventricular shortening fraction (LVSF), and left ventricular ejection fraction (LVEF) was performed, with slopes compared before and after pacemaker placement.
Of 114 CCHB subjects, 52 had echocardiographic data before and after pacemaker placement. Median age at CCHB diagnosis was 0.6 interquartile range 0.0-3.5 years; age at pacemaker placement 3.4 0.5-9.0 years; and pacing duration 10.8 5.2-13.7 years. Estimated LVEDD z-score was 1.4 at pacemaker placement and decreased -0.08 per year (95% confidence interval CI -0.12 to -0.04; P = .002) to 0.2 (95% CI -0.3 to +0.3) 15 years postplacement. Estimated LVSF decreased -1.1% per year (95% CI -1.7% to -0.6%; P <.001) from 6 months prepacemaker placement to 34% (95% CI 32%-37%) 4 years postplacement. There was no significant change in LVSF between 4 and 15 years postplacement. Estimated LVEF did not change significantly after pacemaker placement, with estimated LVEF 59% (95% CI 55%-62%) 15 years postplacement.
In 52 paced CCHB subjects, estimated LVEDD z-score decreased significantly after pacemaker placement, and estimated LVSF and LVEF remained within normal limits at 15 years postpacemaker placement.
•Investigated 2 year efficacy and safety of CBD for epilepsy in open label study.•Seizure frequency and severity decreased from baseline and sustained for 2 years.•One time point noted lower seizure ...severity in adults compared to children.•Adverse Events Profile decreased from baseline and reductions stable for 2 years.•CBD appears to have durable efficacy and tolerance in treatment resistant epilepsy.
To evaluate the safety, efficacy, and tolerability of highly purified cannabidiol (CBD) for the treatment of seizures in children and adults with treatment-resistant epilepsy (TRE) in an open-label, expanded access program (EAP).
One hundred sixty-nine participants (89 children and 80 adults) with TRE received plant-derived highly purified CBD (Epidiolex® in the U.S.; 100 mg/mL oral solution) with a starting dose of 5 mg/kg/day divided twice per day and titrated to a maximum dose of 50 mg/kg/day over the study period to seizure control and tolerability and followed for up to 2 years. Seizure frequency (calendars) and severity (Chalfont Seizure Severity Score; CSSS) were collected at every study visit. Adverse Events were reported at/between study visits as required, and participants also completed Adverse Events Profile (AEP) which generates a numerical representation of AEs. Response to CBD was defined as ≥50% reduction in seizure frequency. Given non-normal distribution of seizure frequency, a log transformation was applied after which the generalized least squares regression model for longitudinal data was used.
Evidence from the adjusted model revealed a significant mean reduction in seizure frequency compared to baseline in children and adults at all time points (1 month and 1 and 2 years). Percentage of children achieving ≥50% seizure frequency reduction was 44% at month 1, and 41% at year 1, and 61% reduction at year 2, while adult responder rates were 34% at month 1, 53% at year 1, and 71% at year 2 (all P < 0.0001). CSSS showed a sustained reduction from baseline to all 3 time points. Children displayed 52% seizure reduction at month 1, a 51% reduction at year 1, and 75% reduction at year 2. Seizure reductions in adults were 60%, 81%, and 85%, respectively (all P < 0.0001). While there were no significant differences between seizure frequency reduction between children and adults at all time points, there was a significant difference in seizure severity reduction at year 1, with adults reporting greater improvement in seizure severity (P < 0.001). The most commonly reported adverse events in the study period were diarrhea, sedation, and decreased appetite. AEP revealed significant improvement from baseline at multiple time points in adults and children, and the mean AEP scores were always lower compared to baseline over the duration of the study.
Our study provides further evidence of sustained seizure frequency and severity reduction over two years of treatment with highly purified CBD in TRE. In addition, CBD was generally well tolerated with minority of participants experiencing adverse events resulting in stopping CBD.
Ketorolac-refractory pain behavior following bilateral myringotomy and pressure equalization tube placement (BMT) is associated with the absence of middle ear fluid. Intraoperative fentanyl/ketorolac ...affords more reliable pain control than ketorolac alone. We hypothesized that middle ear condition would correlate with postoperative pain despite such combination therapy. We further sought to demonstrate seasonal variation in ear condition and its influence on pain.
We conducted a single-institution retrospective cohort study of healthy children (9 months-7 years), who underwent BMT by a single surgeon from 2015 to 2020. Anesthetic care included sevoflurane/nitrous oxide/oxygen/air by mask and intramuscular fentanyl/ketorolac. Left/right middle ear fluid status was recorded at the time of BMT, and ear condition (primary exposure) was dichotomized as bilateral infected (mucoid or purulent) or normal/unilateral infected. The primary outcome was maximum postanesthesia care unit Face, Legs, Activity, Cry, and Consolability (FLACC) score: 4-10 (moderate-to-severe pain) versus 0-3 (no-to-low pain). Rescue oxycodone, acetaminophen administration, and emergence agitation were secondary outcomes. Statistical analysis incorporated generalized linear mixed-effect models (GLMMs) with random intercepts to account for clustering by anesthesia provider. A year-over-year monthly time-series analysis was conducted using an autoregressive integrated moving average (ARIMA) regression model.
Excluding recurrent cases, 1149 unique evaluable subjects remained. Bilateral infection prevalence was 39.8% (457/1149; 95% confidence interval CI, 37.0-42.6). Probability of moderate-to-severe pain behavior was 23.5% (270/1149; 95% CI, 21.1-26.0) overall. Compared to patients with bilateral infected middle ears, those with normal/unilateral infected ears were more likely to have a FLACC score ≥4 (26.7% 185/692 versus 18.6% 85/457; odds ratio 95% CI, 1.7 1.2-2.3; P = .002). Variability in pain outcome explained by the multivariable GLMM was 4.7%. Fentanyl dose response was evidenced by oxycodone administration differences ( P ≤ 0.002). Moderate-to-severe pain and emergence agitation were more likely with reduced fentanyl dosing. Bilateral infection prevalence exhibited seasonality, peaking in March and nadiring in July. However, pain outcomes did not vary by season.
Normal/unilateral infected ears at time of pediatric BMT are associated with higher incidence of moderate-to-severe postoperative pain following intraoperative fentanyl/ketorolac administration, but the predictive value of ear condition on pain is limited. Infections were less common in the summer.
Cannabidiol (CBD) is a nonpsychoactive derivative of cannabis. Studies indicate that it is safe and effective in treating certain types of epilepsy. The present study examined the presence of adverse ...or beneficial cognitive or functional adaptive effects associated with CBD in the treatment of children, adolescents, and teenagers with treatment-resistant epilepsy (TRE) as part of an ongoing prospective, open-label safety study.
Participants (N = 38) between the age of 3 and 19 years with TRE were enrolled in an open-label study of a pharmaceutical formulation of CBD (Epidiolex®; GW Research Ltd.) as an add-on treatment. In addition to baseline physical, neurological, and laboratory testing, cognitive assessment was completed prior to initiating CBD and after one year, both using the NIH Toolbox Cognition Battery (NIHTB-CB). Many participants were unable to complete the NIHTB-CB because of the magnitude of their cognitive impairment (n = 24), and in these cases, the participant's caregiver was asked to complete the Adaptive Behavior Assessment System – Second Edition (ABAS-II) as a measure of functional adaptive skills.
There were no statistically significant changes in cognitive function, as measured by the NIHTB-CB, in those participants who were able to complete such testing, but there was a nonsignificant trend toward improvement in some cognitive domains. For participants who were unable to complete formal standardized cognitive testing because of the magnitude of their cognitive impairment, their functional adaptive skills, as measured by the ABAS-II, were unchanged after a one-year trial of CBD.
Our findings suggest that CBD, as an add-on drug for TRE in a pediatric sample, does not appear to cause adverse effects (AEs) involving cognition or adaptive function over one year of treatment.
•Cannabidiol (CBD) was cognitively and functionally well tolerated after one year.•There were no significant changes in cognitive test scores or functional adaptive scores after one year.•Neither CBD dose after one year nor seizure control were associated with scores on the cognitive and functional measures.
Cognitive dysfunction is a common comorbidity in adults with treatment-resistant epilepsy (TRE). Recently, cannabidiol (CBD) has demonstrated efficacy in epilepsy treatment. However, our ...understanding of CBD's cognitive effects in epilepsy is limited. We examined long-term cognitive effects of CBD in adults with TRE as part of an ongoing prospective, open-label safety study. Twenty-sevenadults with TRE (mean age: 34SD +14, female 52%) enrolled in the UAB CBD program completed standardized cognitive testing (NIH Toolbox Cognition Battery (NIHTB-CB)) at pre-CBD administration baseline and at one-yearfollow-up. Participants were receiving stable CBD dose at the time of one-year testing (mean=36.5mg/kg/day). The NIHTB-CB consisted of two global composite scales (Fluid and Crystallized) and seven individual tests measuring aspects of working memory, episodic memory, executive function, processing speed, and language. All participants had recorded Chalfont Seizure Severity Scale (CSSS) scores at each visit. Statistical analyses consisted of t-test, Pearson correlation coefficient, and linear regression. At baseline, cognitive test performance was below average for both global composite scales (Fluid: 71 ±18 range: 46–117) and Crystallized (76 ±15 range: 59–112). Longitudinal analysis revealed no significant group change across the two global composite scales. Of the seven individual cognitive tests, none changed significantly over time. No correlation was found between the cognitive change scores and CBD dose (all P's≥0.21). Change in cognitive test performance was not associated change in seizure severity rating. These findings are encouraging and indicate that long-term administration of pharmaceutical grade CBD is overall cognitively well-tolerated in adults with TRE.
•Overall, cannabidiol (CBD) was cognitively well tolerated at time of one-year study visit.•Modest cognitive change occurred on two of seven individual cognitive tasks (one modest improvement, one modest decline).•Neither CBD dose at time of one-year visit nor seizure severity change was significantly associated with one-year performance across the cognitive measures.
We have previously shown that cannabidiol (CBD; Epidiolex®) significantly affects levels of clobazam/N-desmethylclobazam, rufinamide, topiramate, zonisamide, and eslicarbazepine. In the present ...study, we tested whether the presence of concomitant clobazam affected seizure frequency and severity (treatment response) 12 weeks after initiation of therapy with CBD in patients with treatment-resistant epilepsy (TRE). The secondary questions were whether the presence of any of the other antiepileptic drugs (AEDs) had an effect on seizure frequency or severity at 12, 24, or 48 weeks after therapy initiation.
One hundred and thirty-two adults and children with TRE receiving CBD were studied prospectively. Participants were separated into two groups — either taking (CBD + clobazam) or not taking concomitant clobazam (CBD − clobazam). In the secondary analyses, participants were divided into groups depending on whether they were taking at least 1/4 of the other AEDs shown to interact with CBD (iAED). Seizure counts and Chalfont Seizure Severity Scale (CSSS) were obtained at baseline, 12, 24, and 48 weeks. Groups were compared at each respective time point in the study using generalized estimating equations (GEE) analyses.
All groups demonstrated statistically significant reductions in seizure frequency and severity from baseline (all P < 0.05). When participants on CBD + clobazam were compared with CBD − clobazam, there were no significant differences in seizure frequency and severity reduction between the groups at 12 weeks (both P > 0.05). When comparing groups with iAEDs vs. group without iAEDs, independent of coadministration of clobazam, no differences in treatment response were observed (all P > 0.05). Longitudinal analyses up to 48 weeks after therapy initiation did not reveal any differences in treatment response between groups.
These analyses suggest that concomitant to CBD, AEDs may not have an effect on reducing seizure frequency and severity in patients with TRE.
•No study addresses if drug interactions with cannabidiol influence seizure control.•Analyzed if certain AEDs changed seizure frequency or severity in open-label CBD study•At 12 weeks, no change to frequency or severity with CBD + clobazam.•No difference in seizure frequency/severity at 48 weeks with other interacting drugs.•CBD drug interactions did not appear to affect seizure control in our study.
The objective of this study was to determine the relationship between cannabidiol (CBD) dose, CBD plasma level, and seizure control in a large open-label single-center study.
All participants with ...treatment-refractory epilepsy participating in our expanded access program (EAP) were approached for participation. Highly purified grade CBD (Epidiolex®) dosing was weight-based and could be increased every 2 weeks by 5 mg/kg/day up to a maximum dosage of 50 mg/kg/day depending on tolerance and seizure control. Seizure counts were obtained at each visit with frequency calculated per 2-week periods. Cross-sectional plasma peak levels of CBD were obtained ~4 h after dosing in consecutively presenting patients.
We evaluated 56 adults and 44 children (100 total; 54 female) at two time points — one before initiating CBD and one at the time of CBD plasma level testing. There was a positive linear correlation between CBD dosage (range from 5 to 50 mg/kg/day) and level (range from 7.1–1200 ng/mL) in all participants (r = 0.640; p < 0.001). The quantile regression model supported the notion of increased CBD levels being associated with improvement in seizure frequency after adjusting for age — specifically, a 100 ng/mL increase in CBD level was associated with approximately two counts reduction in seizure frequency per time period (1.87 96% confidence interval CI 0.34–3.39; p = 0.018). In participants with the same CBD level, differences in seizure improvement did not depend on age (p = 0.318).
In this open-label study, we found evidence of a linear correlation between CBD dosage and plasma levels, and that higher dose/levels are associated with a higher response rate for seizure improvement. Children and adults responded to CBD similarly. However, seizure control response rates suggest children may respond to lower dosages/plasma levels than adults. Findings reported in this study are specific to Epidiolex® and should not be extrapolated to other CBD products.
•Relationship between CBD dosing and plasma level is not clear.•CBD level–seizure control relationship has not been investigated to date.•Results show linear relationship between dosage and level of CBD.•Seizure control is proportional to CBD plasma level.
Fish oil (FO) is a commonly used supplemental source of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), 2 n-3 (ω-3) polyunsaturated fatty acids (PUFAs) that have been shown to have a ...variety of health benefits considered to be protective against cardiometabolic diseases. Although the effects of EPA and DHA on lipid metabolism have been extensively studied, not all of the metabolic effects of FO-derived n-3 PUFAs have been characterized. Our laboratory recently showed that a high-fructose diet in rhesus monkeys induces the features of metabolic syndrome (MetS) similar to those observed in humans. Thus, we specifically wanted to evaluate the effects of FO in rhesus monkeys fed a high-fructose diet and hypothesized that FO supplementation would mitigate the development of fructose-induced insulin resistance, dyslipidemia, and other cardiometabolic risk factors. In this study, adult monkeys (aged 12-20 y) received either a standard unpurified diet plus 75 g fructose/d (control group; n = 9) or a standard unpurified diet, 75 g fructose/d, and 4 g FO (16% EPA + 11% DHA)/d (treatment group; n = 10) for 6 mo. Importantly, our results showed that daily FO supplementation in the monkeys prevented fructose-induced hypertriglyceridemia and insulin resistance as assessed by intravenous-glucose-tolerance testing (P ≤ 0.05). Moreover, FO administration in the monkeys prevented fructose-induced increases in plasma apolipoprotein (Apo)C3, ApoE, and leptin concentrations and attenuated decreases in circulating adropin concentrations (P ≤ 0.05). No differences between the control and FO-treated monkeys were observed in body weight, lean mass, fat mass, or fasting glucose, insulin, and adiponectin concentrations. In conclusion, FO administration in a nonhuman primate model of diet-induced MetS ameliorates many of the adverse changes in lipid and glucose metabolism induced by chronic fructose consumption.
There are no consensus guidelines defining optimal timing for the Fontan operation, the last planned surgery in staged palliation for single-ventricle heart disease.
Identify patient-level ...characteristics, center-level variation, and secular trends driving Fontan timing.
A retrospective observational study of subjects who underwent Fontan from 2007 to 2021 at centers in the Pediatric Health Information Systems database was performed using linear mixed-effects modeling in which age at Fontan was regressed on patient characteristics and date of operation with center as random effect.
We included 10,305 subjects (40.4% female, 44% non-white) at 47 centers. Median age at Fontan was 3.4 years (IQR 2.6-4.4). Hypoplastic left heart syndrome (-4.4 months, 95%CI -5.5 to -3.3) and concomitant conditions (-2.6 months, 95%CI -4.1 to -1.1) were associated with younger age at Fontan. Subjects with technology-dependence (+4.6 months, 95%CI 3.1-6.1) were older at Fontan. Black (+4.1 months, 95%CI 2.5-5.7) and Asian (+8.3 months, 95%CI 5.4-11.2) race were associated with older age at Fontan. There was significant variation in Fontan timing between centers. Center accounted for 10% of variation (ICC 0.10, 95%CI 0.07-0.14). Center surgical volume was not associated with Fontan timing (P = .21). Operation year was associated with age at Fontan, with a 3.1 month increase in age for every 5 years (+0.61 months, 95%CI 0.48-0.75).
After adjusting for patient-level characteristics there remains significant inter-center variation in Fontan timing. Age at Fontan has increased. Future studies addressing optimal Fontan timing are warranted.
To evaluate factors associated with discontinuation of pulmonary vasodilator therapy in bronchopulmonary dysplasia-related pulmonary hypertension (BPD-PH).
Retrospective study of neonatal, ...echocardiographic, and cardiac catheterization data in 121 infants with BPD-PH discharged on pulmonary vasodilator therapy from 2009-2020 and followed into childhood.
After median 4.4 years, medications were discontinued in 58%. Those in whom medications were discontinued had fewer days of invasive support, less severe BPD, lower incidence of PDA closure or cardiac catheterization, and higher incidence of fundoplication or tracheostomy decannulation (p < 0.05). On multivariable analysis, likelihood of medication discontinuation was lower with longer period of invasive respiratory support HR 0.95 (CI:0.91-0.99), p = 0.01 and worse RV dilation on pre-discharge echocardiogram HR 0.13 (CI:0.03-0.70), p = 0.017. In those with tracheostomy, likelihood of medication discontinuation was higher with decannulation HR 10.78 (CI:1.98-58.59), p < 0.001.
In BPD-PH, childhood discontinuation of pulmonary vasodilator therapy is associated with markers of disease severity.
PDF
