Untreated brain arteriovenous malformation Patient-level meta-analysis of hemorrhage predictors

ABSTRACT Objective: To identify risk factors for intracranial hemorrhage in the natural history course of brain arteriovenous malformations (AVMs) using individual patient data meta-analysis of 4 existing cohorts. Methods: We harmonized data from Kaiser Permanente of Northern California (n 5 856), University of California San Francisco (n 5 787), Columbia University (n 5 672), and the Scottish Intracranial Vascular Malformation Study (n 5 210). We censored patients at first treatment, death, last visit, or 10-year follow-up, and performed stratified Cox regression analysis of timeto-hemorrhage after evaluating hemorrhagic presentation, sex, age at diagnosis, deep venous drainage, and AVM size as predictors. Multiple imputation was performed to assess impact of missing data. Results: A total of 141 hemorrhage events occurred during 6,074 patient-years of follow-up (annual rate of 2.3%, 95% confidence interval [CI] 2.0%-2.7%), higher for ruptured (4.8%, 3.9%-5.9%) than unruptured (1.3%, 1.0%-1.7%) AVMs at presentation. Hemorrhagic presentation (hazard ratio 3.86, 95% CI 2.42-6.14) and increasing age (1.34 per decade, 1.17-1.53) independently predicted hemorrhage and remained significant predictors in the imputed dataset. Female sex (1.49, 95% CI 0.96-2.30) and exclusively deep venous drainage (1.60, 0.95-2.68, p 5 0.02 in imputed dataset) may be additional predictors. AVM size was not associated with intracerebral hemorrhage in multivariable models (p . 0.5). Conclusion: This large, individual patient data meta-analysis identified hemorrhagic presentation and increasing age as independent predictors of hemorrhage during follow-up. Additional AVM cohort data may further improve precision of estimates, identify new risk factors, and allow validation of prediction models. Brain arteriovenous malformations (BAVMs) are the most common cause of intracranial hemorrhage in younger people, who are at risk of long-term morbidity and mortality. The most common presentation is hemorrhage (approximately 50%), followed by seizures and neurologic deficits. Understanding hemorrhage risk in the natural history course of BAVM is crucial when making treatment decisions. However, obtaining accurate estimates is challenging because of short follow-up times from censoring by treatment, low event rates, and low prevalence of disease, which are major limitations of all BAVM longitudinal studies. Current BAVM annual hemorrhage rates range from 2%-4% overall 1-9 to 1%-3% among unruptured patients, 1,4,6,9 but vary †Deceased

Seizures and Reproductive Function: Insights From Female Rats With Epilepsy," Annals of Neurology 64

Abstract OBJECTIVE-Chronic seizures in women can have adverse effects on reproductive function, such as polycystic ovarian syndrome (PCOS), but it has been difficult to dissociate the effects of epilepsy per se from the role of antiepileptic drugs (AEDs). To distinguish the effects of chronic seizures from AEDs, we used the laboratory rat, where an epileptic condition can be induced without concomitant AED treatment. METHODS-Adult female rats were administered the chemoconvulsant pilocarpine to initiate status epilepticus (SE), which was decreased in severity by the anticonvulsant diazepam. These rats developed spontaneous seizures in the ensuing weeks, and are therefore termed "epileptic." Controls were saline-treated rats, or animals that were injected with pilocarpine but did not develop SE. Ovarian cyclicity and weight gain were evaluated for 2-3 months. Serum hormone levels were assayed from trunk blood, collected at the time of death. Paraformaldehyde-fixed ovaries were evaluated quantitatively. RESULTS-Rats that had pilocarpine-induced seizures had an increased incidence of acyclicity by the end of the study, even if SE did not occur. Ovarian cysts and weight gain were significantly greater in epileptic rats than controls, whether rats maintained cyclicity or not. Serum testosterone was elevated in epileptic rats, but estradiol, progesterone and prolactin were not. INTERPRETATIONS- The results suggest that an epileptic condition in the rat leads to increased body weight, cystic ovaries and elevated testosterone levels. Although caution is required when comparing female rats to women, the data suggest that epilepsy per se may be sufficient to induce abnormalities in the control of the ovary

Coordinated Health Care Interventions for Childhood Asthma Gaps in Outcomes (CHICAGO) plan

Background: Evidence-based strategies to improve outcomes in minority children with uncontrolled asthma discharged from the emergency department (ED) are needed. Objectives: This multicenter pragmatic clinical trial was designed to compare an ED-only intervention (decision support tool), an ED-only intervention and home visits by community health workers for 6 months (ED-plus-home), and enhanced usual care (UC). Methods: Children aged 5 to 11 years with uncontrolled asthma were enrolled. The change over 6 months in the Patient-Reported Outcomes Measurement Information System Asthma Impact Scale score in children and Satisfaction with Participation in Social Roles score in caregivers were the primary outcomes. The secondary outcomes included guideline-recommended ED discharge care and self-management. Results: Recruitment was significantly lower than expected (373 vs 640 expected). Of the 373 children (64% Black and 31% Latino children), only 63% completed the 6-month follow-up visit. In multivariable analyses that accounted for missing data, the adjusted odds ratios and 98% CIs for differences in Asthma Impact Scores or caregivers’ Satisfaction with Participation in Social Roles scores were not significant. However, guideline-recommended ED discharge care was significantly improved in the intervention groups versus in the UC group, and self-management behaviors were significantly improved in the ED-plus-home group versus in the ED-only and UC groups. Conclusions: The ED-based interventions did not significantly improve the primary clinical outcomes, although the study was likely underpowered. Although guideline-recommended ED discharge care and self-management did improve, their effect on clinical outcomes needs further study

Sparsentan in patients with IgA nephropathy: a prespecified interim analysis from a randomised, double-blind, active-controlled clinical trial

Background: Sparsentan is a novel, non-immunosuppressive, single-molecule, dual endothelin and angiotensin receptor antagonist being examined in an ongoing phase 3 trial in adults with IgA nephropathy. We report the prespecified interim analysis of the primary proteinuria efficacy endpoint, and safety. Methods: PROTECT is an international, randomised, double-blind, active-controlled study, being conducted in 134 clinical practice sites in 18 countries. The study examines sparsentan versus irbesartan in adults (aged ≥18 years) with biopsy-proven IgA nephropathy and proteinuria of 1·0 g/day or higher despite maximised renin-angiotensin system inhibitor treatment for at least 12 weeks. Participants were randomly assigned in a 1:1 ratio to receive sparsentan 400 mg once daily or irbesartan 300 mg once daily, stratified by estimated glomerular filtration rate at screening (30 to 1·75 g/day). The primary efficacy endpoint was change from baseline to week 36 in urine protein-creatinine ratio based on a 24-h urine sample, assessed using mixed model repeated measures. Treatment-emergent adverse events (TEAEs) were safety endpoints. All endpoints were examined in all participants who received at least one dose of randomised treatment. The study is ongoing and is registered with ClinicalTrials.gov, NCT03762850. Findings: Between Dec 20, 2018, and May 26, 2021, 404 participants were randomly assigned to sparsentan (n=202) or irbesartan (n=202) and received treatment. At week 36, the geometric least squares mean percent change from baseline in urine protein-creatinine ratio was statistically significantly greater in the sparsentan group (-49·8%) than the irbesartan group (-15·1%), resulting in a between-group relative reduction of 41% (least squares mean ratio=0·59; 95% CI 0·51-0·69; p<0·0001). TEAEs with sparsentan were similar to irbesartan. There were no cases of severe oedema, heart failure, hepatotoxicity, or oedema-related discontinuations. Bodyweight changes from baseline were not different between the sparsentan and irbesartan groups. Interpretation: Once-daily treatment with sparsentan produced meaningful reduction in proteinuria compared with irbesartan in adults with IgA nephropathy. Safety of sparsentan was similar to irbesartan. Future analyses after completion of the 2-year double-blind period will show whether these beneficial effects translate into a long-term nephroprotective potential of sparsentan. Funding: Travere Therapeutics