👤 Sarah Gonzales

Alzheimer disease neuropathologic change (ADNC) is the most common pathology underlying cognitive impairment and dementia in the aging population, but there is significant variation in outcome between affected individuals. Moreover, other common neurodegenerative processes are often concurrent and may significantly worsen cognition, but the degree to which these processes interact and affect the We performed a cross-sectional cohort study of 586 participants from the National Alzheimer’s Coordinating Center (NACC) database, who were ≥ 65 years of age and displayed high-level ADNC at autopsy, and who had available longitudinal cognitive data and Clinical Dementia Rating (CDR) performed within the final 24 months of life. This cohort was subdivided into “resilient” individuals/those with minimal progression of cognitive decline (MinP; Individuals with rapid progression were more likely to have at least one These data suggest that resilience and progression in ADNC are impacted by AD-relevant genetics and the severity of late-stage ADNC (even within the narrow range of values compatible with high-level ADNC), additional pathologic features, and potentially the clinical management of underlying systemic disorders. The online version contains supplementary material available at 10.1186/s13195-025-01904-6. Show less

Electronic health record (EHR)-integrated digital personal health records (PHRs) via Fast Healthcare Interoperability Resources (FHIR) are promising digital health tools to support care coordination (CC) for children and youth with special health care needs but remain widely unadopted; as their adoption grows, mixed methods and implementation research could guide real-world implementation and evaluation. This study (1) evaluates the feasibility of an FHIR-enabled digital PHR app for CC for children and youth with special health care needs, (2) characterizes determinants of implementation, and (3) explores associations between adoption and patient- or family-reported outcomes. This nonrandomized, single-arm, prospective feasibility trial will test an FHIR-enabled digital PHR app's use among families of children and youth with special health care needs in primary care settings. Key app features are FHIR-enabled access to structured data from the child's medical record, families' abilities to longitudinally track patient- or family-centered care goals, and sharing progress toward care goals with the child's primary care provider via a clinician dashboard. We shall enroll 40 parents or caregivers of children and youth with special health care needs to use the app for 6 months. Inclusion criteria for children and youth with special health care needs are age 0-16 years; primary care at a participating site; complex needs benefiting from CC; high hospitalization risk in the next 6 months; English speaking; having requisite technology at home (internet access, Apple iOS mobile device); and an active web-based EHR patient portal account to which a parent or caregiver has full proxy access. Digital prescriptions will be used to disseminate study recruitment materials directly to eligible participants via their existing EHR patient portal accounts. We will apply an intervention mixed methods design to link quantitative and qualitative (semistructured interviews and family engagement panels with parents of children and youth with special health care needs) data and characterize implementation determinants. Two CC frameworks (Pediatric Care Coordination Framework; Patient-Centered Medical Home) and 2 evaluation frameworks (Consolidated Framework for Implementation Research; Technology Acceptance Model) provide theoretical foundations for this study. Participant recruitment began in fall 2022, before which we identified >300 potentially eligible patients in EHR data. A family engagement panel in fall 2021 generated formative feedback from family partners. Integrated analysis of pretrial quantitative and qualitative data informed family-centered enhancements to study procedures. Our findings will inform how to integrate an FHIR-enabled digital PHR app for children and youth with special health care needs into clinical care. Mixed methods and implementation research will help strengthen implementation in diverse clinical settings. The study is positioned to advance knowledge of how to use digital health innovations for improving care and outcomes for children and youth with special health care needs and their families. ClinicalTrials.gov NCT05513235; https://clinicaltrials.gov/study/NCT05513235. DERR1-10.2196/46847. Show less

Pulmonary hypertension in sickle cell disease is an independent predictor of mortality, yet the pathogenesis of pulmonary vascular disease in chronic hemolytic disorders remains incompletely understood and treatment options are limited primarily to supportive care. The release of extracellular hemoglobin has been implicated in the development of pulmonary hypertension, and in this study we explored the direct effects of hemin, the oxidized moiety of heme, on the pulmonary artery endothelium. We found that low dose hemin exposure leads to significantly increased endothelial cell proliferation, migration, and cytokine release as markers of endothelial dysfunction. Protein expression changes in our pulmonary artery endothelial cells showed upregulation of mesenchymal markers after hemin treatment in conjunction with a decrease in endothelial markers. Endothelial to mesenchymal transition (EndoMT) resulting from hemin exposure was further confirmed by showing upregulation of the transcription factors SNAI1 and SLUG, known to regulate EndoMT. Lastly, given the endothelial dysfunction and phenotypic transition observed, the endothelial cytoskeleton was considered a potential novel target. Inhibiting myosin light chain kinase, to prevent phosphorylation of myosin light chain and cytoskeletal contraction, attenuated hemin-induced endothelial hyper-proliferation, migration, and cytokine release. The findings in this study implicate hemin as a key inducer of endothelial dysfunction through EndoMT, which may play an important role in pulmonary vascular remodeling during the development of pulmonary hypertension in chronic hemolytic states. Show less

The role of omega-3 fatty acid in multiple sclerosis (MS) susceptibility is unclear. To determine whether fish/seafood intake or genetic factors that regulate omega-3 fatty acids levels are associated with MS risk. We examined the association of fish and shrimp consumption and 13 tag single nucleotide polymorphisms (SNPs) in Consuming fish/seafood at least once a week or at least once a month with regular fish oil use was associated with 44% reduced odds of MS/CIS (adjusted OR = 0.56; 95% CI = 0.41-0.76; These findings suggest that omega-3 fatty acid intake may be an important modifiable risk factor for MS. This is consistent with the other known health benefits of fish consumption and complementary genetic studies supporting a key role for omega-3 regulation. Show less

Tubulinopathies are increasingly emerging major causes underlying complex cerebral malformations, particularly in case of microlissencephaly often associated with hypoplastic or absent corticospinal tracts. Fetal akinesia deformation sequence (FADS) refers to a clinically and genetically heterogeneous group of disorders with congenital malformations related to impaired fetal movement. We report on an early foetal case with FADS and microlissencephaly due to TUBB2B mutation. Neuropathological examination disclosed virtually absent cortical lamination, foci of neuronal overmigration into the leptomeningeal spaces, corpus callosum agenesis, cerebellar and brainstem hypoplasia and extremely severe hypoplasia of the spinal cord with no anterior and posterior horns and almost no motoneurons. At the cellular level, the p.Cys239Phe TUBB2B mutant leads to tubulin heterodimerization impairment, decreased ability to incorporate into the cytoskeleton, microtubule dynamics alteration, with an accelerated rate of depolymerization. To our knowledge, this is the first case of microlissencephaly to be reported presenting with a so severe and early form of FADS, highlighting the importance of tubulin mutation screening in the context of FADS with microlissencephaly. Show less

The heparan sulfate proteoglycan (HSPG) syndecan-1 (SDC1) acts as a major receptor for triglyceride-rich lipoprotein (TRL) clearance in the liver. We sought to identify the relevant apolipoproteins on TRLs that mediate binding to SDC1 and determine their clinical relevance. Evidence supporting ApoE as a major determinant arose from its enrichment in TRLs from mice defective in hepatic heparan sulfate (Ndst1f/fAlbCre⁺ mice), decreased binding of ApoE-deficient TRLs to HSPGs on human hepatoma cells, and decreased clearance of ApoE-deficient [³H]TRLs in vivo. Evidence for a second ligand was suggested by the faster clearance of ApoE-deficient TRLs after injection into WT Ndst1f/fAlbCre⁻ versus mutant Ndst1f/fAlbCre⁺ mice and elevated fasting and postprandial plasma triglycerides in compound Apoe⁻/⁻Ndst1f/fAlbCre⁺ mice compared with either single mutant. ApoAV emerged as a candidate based on 6-fold enrichment of ApoAV in TRLs accumulating in Ndst1f/fAlbCre⁺ mice, decreased binding of TRLs to proteoglycans after depletion of ApoAV or addition of anti-ApoAV mAb, and decreased heparan sulfate-dependent binding of ApoAV-deficient particles to hepatocytes. Importantly, disruption of hepatic heparan sulfate-mediated clearance increased atherosclerosis. We conclude that clearance of TRLs by hepatic HSPGs is atheroprotective and mediated by multivalent binding to ApoE and ApoAV. Show less

Bardet-Biedl syndrome (BBS) is a multisystemic disorder characterized by postaxial polydactyly, progressive retinal dystrophy, obesity, hypogonadism, renal dysfunction, and learning difficulty. Other manifestations include diabetes mellitus, heart disease, hepatic fibrosis, and neurological features. The condition is genetically heterogeneous, and eight genes (BBS1-BBS8) have been identified to date. A mutation of the BBS1 gene on chromosome 11q13 is observed in 30%-40% of BBS cases. In addition, a complex triallelic inheritance has been established in this disorder--that is, in some families, three mutations at two BBS loci are necessary for the disease to be expressed. The clinical features of BBS that can be observed at birth are polydactyly, kidney anomaly, hepatic fibrosis, and genital and heart malformations. Interestingly, polydactyly, cystic kidneys, and liver anomalies (hepatic fibrosis with bile-duct proliferation) are also observed in Meckel syndrome, along with occipital encephalocele. Therefore, we decided to sequence the eight BBS genes in a series of 13 antenatal cases presenting with cystic kidneys and polydactyly and/or hepatic fibrosis but no encephalocele. These fetuses were mostly diagnosed as having Meckel or "Meckel-like" syndrome. In six cases, we identified a recessive mutation in a BBS gene (three in BBS2, two in BBS4, and one in BBS6). We found a heterozygous BBS6 mutation in three additional cases. No BBS1, BBS3, BBS5, BBS7, or BBS8 mutations were identified in our series. These results suggest that the antenatal presentation of BBS may mimic Meckel syndrome. Show less