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OBJECTIVE Patients with unruptured brain arteriovenous malformations (AVMs) may present with headaches, seizures, and/or neurological deficits. A smaller number of cases may be discovered incidentally. These lesions remain incompletely understood due to their sparse reporting. Herein, the authors describe the largest series to date comparing the presentation, angioarchitecture, and management of incidental versus symptomatic unruptured AVMs in children. METHODS The authors performed a retrospective analysis of patients who presented with brain AVMs from 1998 to 2022 at the University of California, San Francisco. Inclusion criteria were age ≤ 18 years at the time of presentation and an angiographically proven unruptured AVM that had been diagnosed postnatally. RESULTS Of 76 children with unruptured AVMs, 66 (86.8%) presented with headaches, seizures, and/or neurological deficit. Ten AVMs (13.1%) were incidentally discovered through unrelated disease workup (50%), cranial trauma (40%), or research study participation (10%). Compared with patients with symptomatic unruptured AVMs, patients with incidental unruptured AVMs had a smaller mean ± SD maximum nidus diameter (2.82 ± 1.1 vs 3.98 ± 1.52 cm, p = 0.025) and fewer had deep venous drainage (20% of patients vs 61%, p = 0.036). They also presented at an earlier age (10 ± 5.2 vs 13.5 ± 4 years, p = 0.043) and with longer duration to first treatment (541 ± 922 vs 196 ± 448 days, p = 0.005). During the observation period, 1 patient developed recurring headaches and demonstrated AVM nidus growth. Four AVMs greater than 3 cm in size or in a deep location were treated with radiosurgery. Six other AVMs were treated with resection, with 2 receiving preoperative embolization. Eight AVMs (80%) were obliterated on last follow-up. Postprocedural complications included 2 transient neurological deficits after resection and 1 case of delayed seizure development after radiosurgery. The mean follow-up period was 5.7 ± 5.7 years without any hemorrhage episodes. CONCLUSIONS A substantial proportion of pediatric patients with unruptured AVMs are discovered incidentally. With earlier presentation and more elementary angioarchitecture than symptomatic unruptured AVMs, these incidental lesions provide a snapshot into the natural history of AVM before symptom development or rupture.

Background: Data from the early pandemic revealed that 0.62% of children hospitalized with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) had an acute arterial ischemic stroke (AIS). In a larger cohort from June 2020 to December 2020, we sought to determine whether our initial point estimate was stable as the pandemic continued and to understand radiographic and laboratory data that may clarify mechanisms of pediatric AIS in the setting of SARS-CoV-2. Methods: We surveyed international sites with pediatric stroke expertise to determine numbers of hospitalized SARS-CoV-2 patients Results: Sixty-one centers from 21 countries provided AIS data. Forty-eight centers (78.7%) provided SARS-CoV-2 hospitalization data. SARS-CoV-2 testing was performed in 335/373 acute AIS cases (89.8%) compared with 99/166 (59.6%) in March to May 2020, P P =0.78. Of the 22 of 23 AIS cases with SARS-CoV-2 in whom we could collect additional data, SARS-CoV-2 was the main stroke risk factor in 6 (3 with arteritis/vasculitis, 3 with focal cerebral arteriopathy), a contributory factor in 13, and incidental in 3. Elevated inflammatory markers were common, occurring in 17 (77.3%). From centers with SARS-CoV-2 hospitalization data, of 7231 pediatric patients hospitalized with SARS-CoV-2, 23 had AIS (0.32%) compared with 6/971 (0.62%) from March to May 2020, P =0.14. Conclusions: The risk of AIS among children hospitalized with SARS-CoV-2 appeared stable compared with our earlier estimate. Among children in whom SARS-CoV-2 was considered the main stroke risk factor, inflammatory arteriopathies were the stroke mechanism.

Background Hypertrophic cardiomyopathy (HCM) is the most common heritable cardiac disease. In small studies, sociodemographic factors have been associated with disparities in septal reduction therapy, but little is known about the association of sociodemographic factors with HCM treatments and outcomes more broadly. Methods and Results Using the National Inpatient Survey from 2012 to 2018, HCM diagnoses and procedures were identified by International Classification of Diseases, Ninth/Tenth Revision, Clinical Modification ( ICD‐9‐CM and ICD‐10‐CM ) codes. Logistic regression was used to determine the association of sociodemographic risk factors with HCM procedures and in‐hospital death, adjusting for clinical comorbidities and hospital characteristics. Of 53 117 patients hospitalized with HCM, 57.7% were women, 20.5% were Black individuals, 27.7% lived in the lowest zip income quartile, and 14.7% lived in rural areas. Among those with obstruction (45.2%), compared with White patients, Black patients were less likely to undergo septal myectomy (adjusted odds ratio [aOR], 0.52 [95% CI, 0.40–0.68]), or alcohol septal ablation (aOR, 0.60 [95% CI, 0.42–0.86]). Patients with Medicaid were less likely to undergo each procedure (aOR, 0.78 [95% CI, 0.61–0.99] for myectomy; aOR, 0.54 [95% CI, 0.36–0.83] for ablation). Women (aOR, 0.66 [95% CI, 0.58–0.74]), patients with Medicaid (aOR, 0.78 [95% CI, 0.65–0.93]), and patients from low‐income areas (aOR, 0.77 [95% CI, 0.65–0.93]) were less likely to receive implantable cardioverter‐defibrillators. Women (aOR, 1.23 [95% CI, 1.10–1.37]) and patients from towns (aOR, 1.16 [95% CI, 1.03–1.31]) or rural areas (aOR, 1.57 [95% CI, 1.30–1.89]) had higher odds of in‐hospital death. Conclusions Among 53 117 patients hospitalized with HCM, race, sex, social, and geographic risk factors were associated with disparities in HCM outcomes and treatment. Further research is required to identify and address the sources of these inequities.

OBJECTIVE Pediatric brain arteriovenous malformations (AVMs) are the leading cause of spontaneous intracranial hemorrhage (SICH) in children. Although the incidence of SICH is low in pediatric populations, such events cause substantial morbidity. The recently created Ruptured Arteriovenous Malformation Grading Scale (RAGS) is proposed as a reliable and novel grading system to specifically serve as a predictor of clinical outcomes in patients following AVM rupture, similar to the Hunt and Hess (HH) grade for ruptured aneurysms. While these data are promising, pediatric patients were notably absent from the original study validating the RAGS. Therefore, correlation of the RAGS score with clinical outcomes following AVM rupture in individuals younger than 18 years of age using the RAGS score is needed. The objective of this study was to validate the RAGS in a cohort of pediatric patients with AVMs who presented with hemorrhage, thereby demonstrating the score’s generalizability, and expanding its external validity. METHODS A cohort of children with ruptured AVMs were retrospectively reviewed. Using disability, measured by the modified Rankin Scale (mRS), as the response variable, the area under the receiver operating characteristic curve (AUROC) was calculated for patients based on their RAGS scores for three time periods. The AUROC values were then compared with those generated by two commonly used clinical grading systems, the HH classification and Glasgow Coma Scale. RESULTS A total of 81 children who presented with ruptured AVMs were included in the study, with a mean follow-up duration of 4 years. The RAGS score outperformed other clinical grading scales in predicting mRS scores, with AUROC values of 0.81, 0.82, and 0.81 at three distinct follow-up periods. CONCLUSIONS The RAGS score correlated well with the clinical outcome after AVM rupture in pediatric patients. Additional validation studies across multiple treatment centers are needed to further demonstrate the generalizability of the scoring system.

BackgroundPrimary care providers (PCPs) face increasing numbers of patients at risk for NAFLD and are responsible for the detection of NAFLD and the decision on referral to specialists. We conducted a PCP needs assessment to ascertain the barriers and desired supports for NAFLD in primary care.MethodsWe designed a cross-sectional study of PCPs at a large diverse health system and surveyed faculty, residents, and nurse practitioners. Questions assessed NAFLD knowledge, approach to diagnosis and fibrosis testing including use of FIB-4, and attitudes toward support tools.ResultsThe survey was sent to 115 PCPs with an 80% (n = 92) response rate. Respondents were 52% faculty and 48% residents. Over 40% were unsure of which diagnostic tests to order and which data constituted a diagnosis. PCPs were aware of the importance of fibrosis, yet few knew the components of FIB-4, few used FIB-4 in practice, and yet the most common reason for referral was to obtain fibrosis staging. The majority showed high levels of interest toward possible tools to improve NAFLD management, and only 5% perceived lack of time to be a barrier.DiscussionOur survey revealed PCPs need and want strategic approaches to NAFLD. We found PCPs lack confidence in diagnosing NAFLD and are inconsistent in management strategies. PCPs had high awareness of the importance of fibrosis, but not of the FIB-4. It was encouraging that PCPs reported that time was not a major barrier and had positive attitudes toward potential practice support tools, indicating that practice guidelines designed for primary care should be created.

Introduction: Brain arteriovenous malformations (bAVMs) are the leading cause of pediatric hemorrhagic stroke. Prior studies have implicated inflammation as a major contributor to bAVM pathogenesis, with increased inflammatory cell infiltration and IL-6 protein levels reported in bAVM tissue. However, few studies have evaluated circulating inflammatory proteins as biomarkers for bAVM or intracranial hemorrhage (ICH). Hypothesis: We hypothesized that higher plasma levels of interleukin (IL)-1B and IL-6 would be associated with bAVM ICH at initial presentation. Methods: Pediatric bAVM cases (2 -transformed for analysis. Multivariable regression analysis compared plasma protein levels between cases with and without ICH presentation, adjusting for sex, race, ethnicity, age, and time between initial presentation and first plasma collection. Exponentiated coefficients are presented as proportional increase (PI). Results: Samples were collected a median of 23.5 days after presentation in the ICH group and 140 days in the non-ICH group. Plasma levels of IL-6 were higher in bAVM patients with ICH vs. those without ICH (PI=3.22, 95% CI=1.32-7.85, p=0.011), adjusting for age, sex, race and Hispanic ethnicity. After further adjustment for time to sample collection, the association between IL-6 levels and ICH was no longer significant. (PI =1.36, CI=0.57-3.29, p=0.478). There was no difference in plasma levels of IL-1B between groups (PI=0.85, 95% CI=0.65-1.12, p=0.26). Conclusion: Plasma levels of IL-6 were associated with ICH presentation in this pediatric bAVM cohort; however, this association may reflect downstream effects of the hemorrhage. Further studies are needed to help clarify whether plasma IL-6 levels can be used to predict hemorrhage risk in patients with unruptured bAVMs.

Introduction: Sporadic brain arteriovenous malformations (bAVMs) are a potentially treatable cause of stroke disproportionately affecting young people. Non-inherited somatic activating mutations in KRAS have been reported in ~50% of bAVM specimens primarily from adults. We hypothesized that KRAS mutations would be associated with an earlier age at diagnosis, larger bAVM size, or earlier time to hemorrhage. Methods: Sporadic bAVM tissue and clinical data were collected from patients seen at our institution. Genotyping was performed by digital droplet polymerase chain reaction to detect KRAS mutations (p.G12D, p.G12V or p.Q61H) in three batches and coded as presence/absence of any KRAS mutation (primary predictor). Age at diagnosis was dichotomized into adults (18 years) or children (KRAS mutations between children and adults (logistic), with bAVM size (linear), or with time from diagnosis to hemorrhage (survival), censoring at treatment or last follow-up. Results: We analyzed data from 221 patients: median age at bAVM diagnosis was 20 years; 44% were diagnosed as children; 53% were female; and 56% were ruptured on presentation. Median bAVM diameter was 2.1 cm (IQR: 1.4 - 3.0). KRAS mutations were detected in 53% of samples. Childhood bAVMs were significantly more likely to harbor KRAS mutations than those diagnosed in adulthood (OR=2.20, 95% CI: 1.24 - 3.91, p=0.007). KRAS -mutant bAVMs tended to be larger than KRAS -wildtype bAVMs, but this did not reach significance (+0.29 cm, 95% CI: -0.03 - 0.62, p=0.08). No association was observed for time to hemorrhage (HR=1.31, 95% CI: 0.91 - 1.88, p=0.15). Conclusions: Somatic activating KRAS mutations are more prevalent in bAVMs diagnosed in childhood than adulthood. Further work is required to elucidate mechanisms of mutagenesis and bAVM progression, which may differ in children and adults.

Studies have linked childhood anxiety and depression with parenting characterized by high control and low warmth. However, few studies have examined how control and warmth may work together to influence internalizing symptoms in children. Therefore, the goal of this study was to examine the moderating effect of warmth on the relationship between overcontrol and anxiety and depressive symptoms, as well as whether negative thoughts serve as a mediator of these pathways. A total of 182 fourth and fifth grade children completed measures of maternal parenting behavior, negative thoughts, and anxiety and depressive symptoms. Results showed an interaction between overcontrol and warmth for depressive but not anxiety symptoms. Furthermore, low warmth increased the strength of the mediating relationship between overcontrol and depression via thoughts of personal failure. Findings may signal a need for early interventions to address parenting behaviors, such as controlling behaviors, in parents of children at risk for internalizing difficulties.

Obesity is a multifactorial chronic disease for which treatment remains challenging. While the cornerstone treatment is lifestyle modification, the addition of anti-obesity medications leads to greater weight reduction. In cases where monotherapy with a single anti-obesity medication results in either weight stabilization or only modest weight reduction, combination regimens can be highly effective, especially those including glucagon-like peptide-1 receptor agonists. We report the case of a 23-year-old male initially presenting with a body mass index of 84.3 kg/m2. In addition to lifestyle modification therapy, he was started on phentermine, topiramate, and metformin, which only resulted in weight stabilization after 1 year. Subsequently, semaglutide (a glucagon-like peptide-1 receptor agonist) was added, along with a lower calorie diet, which resulted in a 32.5% total body weight reduction, approximating that which can be achieved following metabolic/bariatric surgery. This case highlights the potential benefit of combination anti-obesity medication regimens including glucagon-like peptide-1 receptor agonists, as such regimens may provide a synergistic effect by targeting multiple eating behavior pathways simultaneously. Further studies are needed to evaluate the efficacy of combination anti-obesity medication regimens, especially among those achieving suboptimal response to monotherapies.

Background Microparticles and endothelial microparticles (EMPs) are implicated in accelerating cardiovascular disease (CVD); however, data in pediatrics are limited. We examined the relationship of microparticles and EMPs with adiposity and subclinical CVD risk measures in a pediatric population to determine their potential as biomarkers of CVD risk. Methods and Results A cross‐sectional study of youth (n=280; ages 8–20 years) with a range of body mass index categories was used. Microparticles, EMPs, and activated EMPs were measured by flow cytometry. %Body fat and %visceral adipose tissue were measured by dual X‐ray absorptiometry. Measures of arterial stiffness and vascular wall structure were obtained. Linear regression (with log‐transformed outcomes) and logistic regression were used to evaluate associations and all results were exponentiated. Youth with overweight/obesity and severe obesity had 2.50 (95% CI, 1.56–4.01) and 3.42 (95% CI, 2.15–5.43) times the geometric means of the total number of microparticles, respectively, compared with those with normal weight. Youth with overweight/obesity and severe obesity had 1.97 (95% CI, 1.09–3.55) and 2.34 (95% CI, 1.31–4.19) times the geometric means of the total number of EMPs, respectively, compared with those with normal weight. There were positive associations between the levels of both microparticles and EMPs with higher adiposity measures and poor CVD risk measures. Youth with higher adiposity showed 1.84 times the odds of having high levels of activated EMPs (%) (odds ratio, 1.84; 95% CI, 1.08–3.14) compared with those with normal weight. Conclusions Levels of microparticles, EMPs, and activated EMPs were positively associated with adiposity and poor subclinical CVD risk in a pediatric population.

Meal replacement therapy (MRT) is a structured treatment that is effective for short-term weight reduction in adolescents with severe obesity. However, like other interventions, MRT response is variable.The goal of the current study was to characterize the experience of adolescents with severe obesity participating in MRT.Seventeen adolescents with severe obesity participated in semi-structured, individual interviews about their experience participating in MRT. The authors used a biopsychosocial model as the theoretical framework and data was analysed using Interpretive Phenomenological Analysis. A biopsychosocial model views an individual's health as a blend of biological characteristics, behavioural factors, and social conditions.Results showed that adolescents with severe obesity described three biopsychosocial factors that were central to their experience with MRT: (1) scheduling and planning, (2) social support and pressure, and (3) intrapersonal factors. Specifically, adolescents with severe obesity identified that planning ahead, social support, and intrapersonal changes (e.g. self-confidence) can promote engagement in MRT. On the other hand, unplanned schedule changes, social pressures, and different intrapersonal factors (e.g., taste preference) can make engagement challenging.Adolescents provided information on factors that supported or hindered their engagement in MRT, and themes were consistent with prior literature on health behaviour change. Overall, adolescents would recommend MRT to other teenagers who carry extra weight. Future research can use the rich information provided by adolescents with severe obesity to enhance and individualize treatment options.

Purpose To study the effects of a perindopril-based regimen on cardiovascular (CV) outcomes in patients with vascular disease in relation to background statin therapy. Methods A pooled analysis of the randomized ADVANCE, EUROPA, and PROGRESS trials was performed to evaluate CV outcomes in 29,463 patients with vascular disease treated with perindopril-based regimens versus placebo. The primary endpoint was a composite of CV mortality, nonfatal myocardial infarction, and stroke. Multivariable Cox regression analyses were performed to assess the effects of a perindopril-based regimen versus placebo in relation to statin use. Results At randomization, 39.5% of the overall combined study population used statins. After a mean follow-up of 4.0 years (SD 1.0), the cumulative event-free survival was highest in the statin/perindopril group and lowest in the no statin/placebo group (91.2% vs. 85.6%, respectively, log-rank p Conclusion Our data suggest that the treatment benefits of a perindopril-based regimen in patients with vascular disease are independent of statin use.

Background Statins are cornerstone in the management of atherosclerotic cardiovascular disease. If a patient has experienced clinically significant adverse drug reactions (ADRs), representing an unacceptable risk or may result in adherence issues, we would consider them intolerant. The prevalence is lower in randomised trials than cohort observational studies, 5% vs. 17%. Purpose To assess how many people we reviewed in clinic were able to be re-challenged and successfully continued on a statin, free from side effects. Methods Over 6 months we reviewed all patients referred to our innovative clinic for lipid optimisation labelled as “statin intolerant”. Initially, as per our protocol, we adopted a person-centred approach and explored this label (actual vs. potential concerns, any previous issues, symptoms experienced and timings, statins tried (if any), and patient's feelings on re-challenge). A statin re-challenge was offered if not contraindicated. If agreed, based on shared-decision making, we offered patients a once weekly statin (usually rosuvastatin 5mg) with a clear self-management plan to up/down-titrate frequency and dose, until they identify a tolerated regimen. We measured LDL-C at baseline and every 3 months thereafter until satisfactory. Results Of 207 patients referred 152 (73%) were labelled as “statin intolerant”. Average age was 62 (±11), 51% females. 78% for secondary prevention and 37% had familial hypercholesterolaemia. The average baseline LDL-C was 4.4mmol/L. 108 (71%) qualified for PCSK9 inhibitors therapy (PCSK9i) as per UK NICE guidance. The top 3 reported ADRs were musculoskeletal side effects (48%), GI upsets (13%) and deranged LFTs (7%). 25 (58%) of those “intolerant” who did not qualify for PCSK9i attempted a re-challenge with statins vs. 44 (41%) among those who qualified. Of the 69 patients, who accepted a re-challenge, 43 (62%) were successfully restarted on a statin. At an average of 14 months post re-challenge, LDL-C (available for >80% of the sample) was reduced by an average of 31% in those not on PCSK9i, compared to a 62% reduction (sustained over an average of 40 months) in those on combination therapy with PCSK9i. The top 3 rosuvastatin regimens established were 5mg OD (29%), 5mg weekly (24%) and 10mg OD (15%). Approximately 80% of patients were on rosuvastatin, and the rest accepted atorvastatin, pravastatin or simvastatin. There was no attempt to re-challenge in 77 (51%) patients, mostly due to choice (45%) or statins re-challenged prior to referral (44%). We stopped statins in 6 cases due to intolerable ADRs. Conclusion(s) By using a person-centred approach, and a variety of strategies to tackle “statin intolerance” we have successfully re-established over 60% of patients with very high CVD risk on statins. While patients who qualified for PCSK9i therapy were less likely to consider re-challenge with statins (41% v 58%), combination lipid-lowering therapies produced better reduction in LDL-C. Funding Acknowledgement Type of funding sources: None.

Background Various BP characteristics, e.g., systolic blood pressure (SBP), diastolic blood pressure (DBP), and pulse pressure (PP), as well as heart rate (HR) may affect the risk of both cardiovascular events and bleeding events. However, the exact way in which these characteristics and outcomes are associated among patients with diabetes and stable coronary artery disease (CAD) remains debated. Moreover, it is unknown whether the risks and benefits of intensified antiplatelet therapy in this patient population are affected by their baseline BP and HR. Purpose To assess the relationship between BP components (including HR) and cardiovascular and bleeding events, and to determine if the effects of ticagrelor vs. placebo varied across the BP and HR spectrum, in patients with diabetes and stable CAD. Methods THEMIS was a randomized, controlled trial in which 19,220 individuals ≥50 years of age with stable CAD and type 2 diabetes were randomized to receive either ticagrelor plus aspirin or placebo plus aspirin. Patients with a prior myocardial infarction or stroke, or already on dual antiplatelet therapy, were excluded. The primary efficacy outcome was a composite of cardiovascular death, myocardial infarction, or stroke. The primary safety outcome was TIMI major bleeding. We examined prognostic implications of BP components using 1) restricted cubic splines for the overall trends with outcomes; 2) Cox proportional-hazards regression models with predefined BP component intervals adjusted for demographic, clinical, and laboratory variables; and 3) Cox regression models for the effects of ticagrelor vs. placebo on outcomes across the spectrum of BP component values (test for interaction). THEMIS is registered at ClinicalTrials.gov (NCT01991795). Results Mean values of baseline BP components were similar between the two study groups. Median follow-up duration was 39.9 months (range 0–57), with 1554 primary efficacy events and 306 primary safety events occurring over the course of the study. All BP components (including HR) displayed various, independent relationships with the tested outcomes. For example, in adjusted spline models, SBP displayed non-linear relationships with the primary outcome, all-cause death, any bleeding, serious adverse events, and intracranial bleeding, and linear relationships with the remaining outcomes. Figure 1 shows the associations of each BP component with the primary efficacy outcome. BP components did not substantially modify the risks and benefits of ticagrelor vs. placebo for the tested outcomes. Conclusions BP components were independently associated with efficacy and safety outcomes in patients with stable CAD and type 2 diabetes. However, no important modification of BP components on the effect of ticagrelor vs. placebo was detected. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): AstraZeneca