Citations

ABSTRACT Objective Hypertension is a key risk factor for aortic dissection (AD). AD, if left untreated, carries significant mortality rates. Our aim is to analyse trends in mortality due to AD in adults with primary hypertension in the United States (US). Methods We used the CDC WONDER database to extract mortality data for patients with primary hypertension who died due to AD. Age‐adjusted mortality rates (AAMRs) and crude mortality rates (CMRs) were extracted per 100 000 persons. Annual percentage changes (APCs) and average APCs (AAPCs) in AAMRs and CMRs were calculated using Joinpoint regression. Results From 1999 to 2020, a total of 13 128 deaths due to AD were reported in patients with primary hypertension in the US. Males displayed a higher overall AAMR (0.3) than females (0.2) throughout the study period. Slight regional variations were observed, with the West showing the highest overall AAMR (0.4), followed by the Midwest (0.3), and the Northeast and South (0.2). In urban areas, AAMRs were higher than in rural areas until 2008. From 2009 to 2020, AAMRs remained stable in urban areas (0.3) but increased in rural areas from 2010 to 2020 (4.7). The highest state‐level AAMRs were observed in Hawaii, Oregon, and Oklahoma. Conclusion Significant differences were observed in AAPCs compared to AD‐related mortality trends in the general population. Mortality trends revealed an initial decline followed by a gradual rise. Clinicians should focus on high‐risk groups and raise awareness about the disease in these populations.

Autism is a heritable neurodevelopmental condition marked by impaired social interaction, repetitive behavior, and co-occurring conditions. Sleep disturbances are common in autism. This study uses low-cost wearable devices to compare sleep, physical activity, and circadian behavior in autistic adults and their non-autistic relatives. We recruited 318 autistic individuals and 130 family members, collecting accelerometer data over 3 weeks (8249 days). Using a data-driven approach, we identified actimetry-derived features associated with autism. We examined 308 traits using the elastic net algorithm and linear mixed effects regressions. We identified 52 actimetry measures associated with autism (area under the curve: 0.812; confidence interval: 0.761–0.862), validated in a test set (area under the curve: 0.756; confidence interval: 0.700–0.813). Both mean and day-to-day variability in several measures (e.g., time spent sedentary, total light physical activity) were associated with autism. In autistic individuals, reduced physical activity during wake was more strongly associated with shorter sleep time than in non-autistic relatives (likelihood ratio: 41.6; p = 1.13e−10). Reduced physical activity in autistic individuals was linked to increased social impairment, as measured by the Social Responsiveness Scale. Long inactivity periods and lower physical activity levels were associated with autism, correlating with less sleep and later sleep onset. Interventional studies are needed to explore if improving sleep and physical activity can improve the quality of life for autistic individuals. Lay Abstract Autistic individuals frequently report problems with their sleep, though what aspects of sleep are most affected is not well understood. In this study, we recruited 318 adult autistic participants without intellectual disability and 130 of their non-autistic family members to measure their sleep, physical activity, and daily routines. Study participants wore accelerometer-based wrist-worn devices over 3 consecutive weeks to record their movement and activity. In total, 154 distinct physical activity, sleep, and behavioral traits were identified from the recordings, 52 of which were found to associate with autism. Many of these traits were related to physical activity, where autistic individuals were more likely to be less active for longer periods and have lower overall physical activity levels. Long periods of inactivity also associated with less sleep, with a stronger association in those with autism. For example, for every hour of inactivity, autistic participants had on average ~23 min less of sleep compared to ~17 min in their family members. Autistic individuals with lower levels of physical activity showed higher social impairment as measured by the Social Responsiveness Scale. Overall, lower physical activity may impair sleep and worsen the core features of autism. Interventional studies aimed to increase physical activity may improve the quality of life of autistic individuals.

This cohort study evaluates the reduction in risk of high-grade serous carcinoma among women undergoing opportunistic bilateral salpingectomy in Canada.

INTRODUCTION Recent work has identified unique cognitive profiles for early‐onset Alzheimer's disease (EOAD) relative to late‐onset Alzheimer's disease (LOAD), however, examination has been limited in determining whether the association between age and cognitive severity at presentation also differs across conditions. METHODS A series of linear spline regression models was conducted across baseline cognitive data from 325 EOAD and 314 LOAD participants, after accounting for education, sex, and apolipoprotein ε4 status. RESULTS Significant differences existed in the relationship between baseline age and cognitive performance between EOAD and LOAD samples for Processing Speed/Attention, Executive Functioning, and Episodic Immediate Memory. Younger participants from both EOAD and LOAD groups performed disproportionately worse on non‐amnestic cognitive domains, with this occurring to a greater extent in EOAD than LOAD. DISCUSSION In the age of disease‐modifying treatments, results highlight the importance of assessing for cognitive declines in individuals starting much earlier than age 65. Highlights Early‐onset Alzheimer's disease (EOAD) and late‐onset Alzheimer's disease (LOAD) participants each displayed cognitive impairments relative to same‐aged peers across most domains. Both groups displayed positive relationships between impairment among non‐amnestic cognitive domains and baseline age. This relationship displayed a significantly greater effect in EOAD than LOAD, with domains of Processing Speed/Attention and Executive Functioning skills being the most pronounced. Of those participants developing AD, age displayed a disproportionate impact on their symptom onset.

Objective Age of symptom onset is highly variable in familial frontotemporal lobar degeneration (f‐FTLD). Accurate prediction of onset would inform clinical management and trial enrollment. Prior studies indicate that individualized maps of brain atrophy can predict conversion to dementia in f‐FTLD. We used a Bayesian linear mixed‐effect (BLME) prediction method for identifying accelerated brain volume loss to predict conversion to dementia. Methods Participants included 234 asymptomatic or prodromal carriers of C9orf72 , GRN , or MAPT mutations (including 21 dementia converters) with ≥3 longitudinal magnetic resonance imaging (MRI) T1‐weighted scans. The BLME models established individual voxel‐wise gray matter trajectories using the first 2 scans. Person‐specific clusters of accelerated volume loss were estimated in subsequent scans and tested as predictors of dementia conversion compared with other approaches in time‐varying Cox proportional hazard models covarying for age. Receiver‐operating characteristic (ROC) curves estimated utility of cluster volume in discriminating which participants converted to dementia within 24 months. Results The BLME cluster volume predicted conversion to dementia in f‐FTLD mutation carriers overall and separately in C9orf72 , GRN , and MAPT , with comparable hazard ratios observed for atrophy W‐maps and regional volumes. Within a 24‐month timeframe, BLME cluster volume discriminated dementia converters from non‐converters with larger areas under the curve (AUCs) than other approaches. Interpretation Bayesian‐modeled individualized atrophy scores predict dementia progression among asymptomatic f‐FTLD mutation carriers and may have increased utility compared with other structural imaging methods when studying individuals over shorter timeframes that align with clinical trial design. ANN NEUROL 20269999:n/a–n/a

Biologic augmentation, using substances like bone marrow aspirate concentrate (BMAC) and platelet-rich plasma (PRP), shows promise for improving outcomes in foot and ankle surgery, particularly in high-risk patients. Historically, autologous bone graft is the benchmark due to its trifecta of osteogenic, osteoinductive, and osteoconductive properties, despite its associated donor site morbidity. Current evidence supporting orthobiologics remains fragmented and inconclusive, with a lack of high-level randomized controlled trials (RCTs). BMAC shows fusion rates comparable to autograft in some foot and ankle applications, but PRP evidence is often conflicting due to a lack of preparation standardization. The regulatory environment is complex. The Food and Drug Administration (FDA) oversees human cells and tissues (HCT/Ps) through a tiered system: high-risk §351 products (eg, cultured stem cells) require rigorous premarket approval, whereas §361 products (eg, allograft bone) have minimal oversight. BMAC and PRP often bypass this through the Same Surgical Procedure Exemption or are regulated through their processing devices, meaning the biologics themselves are not FDA-approved therapeutics. This regulatory gap and direct-to-consumer marketing necessitate meticulous informed consent, transparently discussing the lack of specific FDA approval, limited evidence, and high out-of-pocket costs. Future success depends on standardized, prospective RCTs and a collaborative “middle-ground pathway” for regulatory approval.

Background While delivery of supplemental oxygen is a life-saving therapy, exposure to high oxygen, called hyperoxia, leads to increased intensive care unit mortality. Hyperoxia induces oxidant-mediated acute lung injury (ALI) and pulmonary cell death, called hyperoxic ALI (HALI). Elucidating molecular mechanisms in HALI could identify therapeutic targets in ALI. Methods In the current study, we examined in vivo effects of HALI on Beclin-1 (BCN1), which regulates autophagy, and modulation of BCN1 by epidermal growth factor receptor (EGFR). Effects of HALI on BCN1 and autophagy were examined in mice with genetically decreased EGFR (EGFR Wa5/+ ). Wildtype (WT) and EGFR Wa5/+ mice were exposed to 100% oxygen for 24–72 hours along with normoxia controls (eight groups; n=4–6/group), and analysis of pulmonary BCN1 and autophagy was completed. Results In WT, HALI led to increased BCN1 (59% increased total BCN1/β-Actin; p<0.01) in lung and alveolar epithelium (484% increased H-score; p<0.001). HALI led to decreased microtubule-associated protein 1B-light chain (LC3B)-II/-I ratios (43% decrease; p<0.05) and increased p62 (93% increase; p<0.05), suggesting reduced autophagic flux. In human alveolar type-II cells derived from induced pluripotent stem cells (AT2s iPSC ), HALI caused increased LDH release (130% increase; p<0.0001) and decreased LC3B-II/-I ratios (32% decrease; p<0.05). We previously showed that EGFR Wa5/+ mice are protected in HALI. In the current study, EGFR Wa5/+ mice showed increased pulmonary BCN1 (122% increase; p<0.05), reduced phosphorylated-(p-)/total BCN1 (47% decrease; p<0.05) and decreased LC3B-II/-I ratios (70% decrease; p<0.01) in HALI compared with WT. In addition, wortmannin (1 mg/kg), which decreases BCN1-mediated autophagy, increased mortality in HALI compared with vehicle control (n=10/group; 18% decreased hours survived; p<0.001). Conclusions These data delineate a novel cell death pathway in HALI involving BCN1 and EGFR with therapeutic potential.

ABSTRACT Background Previous studies have shown an increased prevalence of eosinophilic gastrointestinal disease (EGID) in pediatric liver and heart transplant recipients. However, EGID after other solid organ and bone marrow transplantations has not been extensively evaluated. Aims The purpose of this study is to determine relationships between subsets of EGID with different solid organ and bone marrow transplants in pediatric patients. Methods We performed a single‐center retrospective chart review of pediatric patients with transplant and EGID between 2007 and 2023. For comparison between transplant groups, ANOVA was used for statistical analysis of continuous variables, and Fisher's exact test was used for categorical variables. Results There were 30 patients with EGID (eosinophilic esophagitis [EoE] = 21; eosinophilic gastritis [EoG] = 4; EoE + EoG = 3; EoE + eosinophilic colitis [EoC] = 1; eosinophilic duodenitis [EoD] = 1) and history of transplant (liver = 15; heart = 9; bone marrow = 3; multivisceral liver + small bowel + pancreas = 2; kidney = 1). When comparing the transplant groups, there was a significant difference in EoE + EoG incidence ( p = 0.011), specifically, EoE + EoG was present in 2 (100%) multivisceral and in 1/15 (7%) liver transplant patients. A statistically significant difference in the presence of gastroesophageal reflux (GER) and oral allergy syndrome between groups was noted ( p = 0.036, p = 0.033). There was no significant difference in the symptoms leading to EGID work‐up: incidence; morphologic features; achievement of histologic remission; medications; or family history of atopy between groups. Conclusion This retrospective biopsy‐confirmed cohort demonstrates that EGID subtype varies by transplant type, with higher rates of EoE + EoG in multivisceral recipients. Findings are exploratory and hypothesis‐generating; larger multicenter studies including more non‐liver and non‐heart transplant patients are needed.

Abstract Objective Despite being safe and effective, surgery for pediatric epilepsy is underutilized. Social determinants of health (SDoH) are important to consider when examining this treatment gap. This study examined the potential systemic inequities at three different stages in the journey toward epilepsy surgery across the Pediatric Epilepsy Research Consortium (PERC). Methods Any youth in the PERC prospective surgery database (≤18 years) was eligible and included if sociodemographic factors were also available. We examined if there were differences in disparity factors in: (1) referral to Phase I evaluation, (2) offering of surgery, and (3) completion of surgery. Results Of 1309 patients, the majority were male (53%, p = .04), White (82.2%, p < .001), not Hispanic or Latino (84.3%, p < .001), and privately insured (56.3%, p < .001). Of the youth who were offered surgical treatment ( n = 1103, 84.3%), there were no significant differences in race/ethnicity or sex. Those with a structural lesion were more likely to be offered surgery, and historically marginalized youth were more likely to have a lesion. Of patients who completed surgery ( n = 927, 84.0%), White patients were 1.88 times (95% confidence interval [CI]: 1.14–3.04) more likely than Black patients to complete surgery ( p = .01). Significance Youth who began surgery evaluation are not representative of the demographics of those with epilepsy in the United States, with greater representation of White, non‐Hispanic male individuals. In addition, youth who began surgery evaluation disproportionally have private insurance. At the next stage of offering surgery, there were no differences based on SDoH. However, there is evidence that underrepresented youth that were magnetic resonance negative were less likely to be referred for surgical workup and that Black youth were less likely to undergo surgery. Therefore, efforts to provide equitable opportunity for all youth with refractory epilepsy should be concentrated at the referral for surgery evaluation point of care; however, additional efforts are also needed at later stages.

Abstract Objective To measure the relative levels of signal and noise in expert diagnosis of epilepsy. Methods Twenty multinational epileptologists independently reviewed 50 vignettes of adult and pediatric patients presenting with suspected seizure(s) on two separate occasions with a ≥30‐day washout period. Experts provided a diagnosis of epilepsy or non‐epilepsy based on clinical information and, if requested, routine EEG and neuroimaging data. Cases had an established clinical diagnosis of epilepsy or non‐epilepsy based on capture of habitual paroxysmal events on video‐EEG or long‐term clinical follow‐up. Experts' judgments were analyzed to decompose variability into different sources: signal (objective differences between cases), level noise (experts' bias toward over/under‐diagnosis), pattern noise (experts' idiosyncratic reactions to specific case features), and occasion noise (inconsistency across occasions). Results The probability of an expert making a different diagnosis for a given case on two different occasions was 16%. The probability of two different experts making a different diagnosis for the same case was 26%. Signal (case “difficulty”) accounted for 66–69% of total variation, with 31–34% attributable to noise. Level noise was the largest contributor in the absence of EEG/neuroimaging results (23%), while pattern noise dominated when test results were available (24%). Occasion noise contributed relatively little (1%) but was still sufficient to cause diagnostic reversals in 16–22% between occasions. Significance The degree of noise in expert diagnosis of epilepsy is substantial, stemming primarily from physicians' idiosyncratic interpretations of case features and variable dispositions toward over‐ or under‐diagnosis. Strategies to improve reliability are needed, including standardized data collection protocols and structured decision algorithms. For “difficult cases,” where expert reliability and accuracy are lowest, our findings support current clinical practice which favors early referral for video‐EEG monitoring over reliance on diagnostic anchoring. This diagnostic pathway may become more accessible with advances in EEG technology (e.g., wearable devices) and artificial intelligence.