The Collaborative Approach to Reach Everyone with Familial Hypercholesterolemia (CARE-FH) study aims to improve diagnostic evaluation rates for FH at Geisinger, an integrated health delivery system. This clinical trial relies upon implementation science to transition the initial evaluation for FH into primary care, attempting to identify individuals prior to the onset of atherosclerotic cardiovascular disease events. This paper provides the protocol for the CARE-FH study (Registered with ClinicalTrials.gov, number NCT05284513). The first phase of the project focuses on trial design, including the development of implementation strategies to deploy evidence-based guidelines. The second phase will study the intervention, rolled out regionally to internal medicine, community medicine, and pediatric care clinicians using a stepped-wedge design, and analyzing data on diagnostic evaluation rates, and implementation, service, and health outcomes.
Introduction:Postural tachycardia syndrome is more frequently being recognised in adolescents and adults. However, its pathophysiology remains undefined. We evaluated our database for patterns in family history of clinical symptoms and associated disorders in these patients.Materials and methods:Patients with postural tachycardia syndrome diagnosed in our clinic between 2014 and 2018 and who were less than 19 years at diagnosis were included. The history was reviewed for family members with postural tachycardia syndrome, dizziness and/or syncope, joint hypermobility with or without hypermobile Ehlers–Danlos syndrome, and autoimmune disorders. Statistical analysis assessed the entire cohort plus differences in gender, presence or absence of joint hypermobility, and presence or absence of familial autoimmune disease.Results:A total of 579 patients met inclusion criteria. We found that 14.2% of patients had a family member with postural tachycardia syndrome, with male patients more likely to have an affected family member (20% versus 12.7%, p = 0.04). If the patient also had joint hypermobility, male patients were more likely to have a family member with postural tachycardia syndrome (25% versus 12.6%, p = 0.017), more than one affected family member (7.1% versus 0.74%, p = 0.001), and a family member with joint hypermobility (37.5% versus 23.7%, p = 0.032). Autoimmune disease was seen in 45.1% of family members, but more likely in female patients with concurrent hypermobility (21.1% versus 8.9%, p = 0.035).Discussion:This in-depth analysis of associated familial disorders in patients with postural tachycardia syndrome offers further insight into the pathophysiology of the disorder, and informs further screening of family members in these patients.
While Gram‐positive organisms are the most common causative agent of initial bone infections, the percentage of Gram‐negative species increases in reoccurring bone infections. As bacterial internalization has been suggested as one cause of reoccurring bone infection, we tested the hypothesis that Gram‐negative species of bacteria can be internalized into bone cells. Using the MLO‐A5 and the MLO‐Y4 cell lines as our cell models, we demonstrated that the Gram‐negative species, Proteus mirabilis and Serratia marcescens, can be internalized in these cells using an internalization assay. This rate at which these two species were internalized was both time‐ and initial concentration‐dependent. Confocal analysis demonstrated the presence of internalized bacteria within both cell types. Inhibition of the cellular uptake with methyl‐β‐cyclodextrin and chloroquine both reduced internalized bacteria, indicating that this process is, at least in part, cell mediated. Finally, we demonstrated that the presence of internalized P. mirabilis did not impact cell viability, measured either by lactate dehydrogenase (LDH) release or 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide (MTT) activity, while the presence of S. marcescens, on the other hand, both increased LDH release and reduced MTT activity, indicating a loss of cell viability in response to the organism. These results indicated that both species of Gram‐negative bacteria can be internalized by bone cells and that these internalized bacteria could potentially result in reoccurring bone infections. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 38:861‐870, 2020
Background Data mining of electronic health records to identify patients suspected of familial hypercholesterolemia (FH) has been limited by absence of both phenotypic and genomic data in the same cohort. Methods and Results Using the Geisinger MyCode Community Health Initiative cohort (n=130 257), we ran 2 screening algorithms (Mayo Clinic [Mayo] and flag, identify, network, deliver [FIND] FH) to determine FH genetic and phenotypic diagnostic yields. With 29 243 excluded by Mayo (for secondary causes of hypercholesterolemia, no lipid value in electronic health records), 52 034 excluded by FIND FH (insufficient data to run the model), and 187 excluded for prior FH diagnosis, a final cohort of 59 729 participants was created. Genetic diagnosis was based on presence of a pathogenic or likely pathogenic variant in FH genes. Charts from 180 variant‐negative participants (60 controls, 120 identified by FIND FH and Mayo) were reviewed to calculate Dutch Lipid Clinic Network scores; a score ≥5 defined probable phenotypic FH. Mayo flagged 10 415 subjects; 194 (1.9%) had a pathogenic or likely pathogenic FH variant. FIND FH flagged 573; 34 (5.9%) had a pathogenic or likely pathogenic variant, giving a net yield from both of 197 out of 280 (70%). Confirmation of a phenotypic diagnosis was constrained by lack of electronic health record data on physical findings or family history. Phenotypic FH by chart review was present by Mayo and/or FIND FH in 13 out of 120 versus 2 out of 60 not flagged by either ( P <0.09). Conclusions Applying 2 recognized FH screening algorithms to the Geisinger MyCode Community Health Initiative identified 70% of those with a pathogenic or likely pathogenic FH variant. Phenotypic diagnosis was rarely achievable due to missing data.
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