Citations

Background and Purpose— We aimed at providing estimates of mortality associated with cardiometabolic comorbidity and incident readmission from cardiometabolic as compared with noncardiometabolic conditions after a first transient ischemic attack. Methods— Between 2000 and 2015, patients hospitalized for a first transient ischemic attack were examined for cardiometabolic comorbidities (diabetes mellitus, coronary artery disease, heart failure, and atrial fibrillation), 5-year incident hospitalization, and time to death. Results— Of 251 patients with transient ischemic attack, 134 (53%) had at least 1 and 55 (22%) had at least 2 cardiometabolic conditions. By 5 years, 491 readmissions (134 [27%] cardiometabolic and 357 [73%] noncardiometabolic) and 75 deaths (27 [36%] cardiometabolic and 47 [64%] noncardiometabolic) were observed. Mortality was increased with any concurrent cardiometabolic comorbidity (hazard ratio, 1.89; 95% confidence interval, 1.17–3.03; P =0.0089) with multiplicative mortality risk from a combination of coronary artery disease and heart failure. Each hospitalization was associated with a 1.5-fold risk of death (95% confidence interval, 1.37–1.64; P <0.0001). Risk of cardiometabolic and noncardiometabolic mortality was correlated with the corresponding category-specific readmission. Conclusions— Among patients hospitalized for first transient ischemic attack, 5-year mortality is associated with concurrent cardiometabolic comorbidity and rates of subsequent hospitalization.

Objective The type I interferon pathway is activated in many patients with systemic lupus erythematosus (SLE), and anti-double-stranded DNA (dsDNA) and anti-RNA binding protein autoantibodies are correlated with high interferon-α (IFNα) activity. We studied whether antiphospholipid (APL) antibodies, which should not stimulate Toll-like receptors, are also associated with high levels of IFNα activity. Methods Serum IFNα activity was measured in patients with SLE using the WISH cell bioassay. IgG APL, anti-RBP and anti-dsDNA antibodies were measured in the clinical laboratory, and standard clinical cut-offs were used to define the positive results. Results High IFNα activity was associated with anti-RBP and anti-dsDNA antibodies in all three ancestral backgrounds. Strikingly, African-American subjects with a positive APL antibody test had higher IFNα activity than those without IgG APL antibodies. This was not shared with other ancestral backgrounds. This finding was independent of other autoantibody profiles, and clinical features did not differ between IgG APL antibody positive versus negative African-American patients. Conclusion The difference in association between IFNα activity and IgG APL status between ancestral backgrounds supports differences in molecular pathogenesis. This may suggest B cell hyperactivity in the setting of type I IFN in African-Americans and could suggest ways to individualise therapy.

AbstractThe Melatonin Osteoporosis Prevention Study (MOPS) demonstrated that nightly melatonin resulted in a time‐dependent decrease in equilibrium ratios of serum osteoclasts and osteoblasts in perimenopausal women. This study examines mechanisms related to the ratios of osteoblasts and osteoclasts using coculture models (transwell or layered) of human mesenchymal stem cell (MSC) and human peripheral blood monocytes (PBMCs). Human MSC/PBMC cocultures exposed to melatonin in osteogenic (OS+) medium for 21 days induced osteoblast differentiation and mineralization; however, only in layered cocultures did melatonin inhibit osteoclastogenesis. Melatonin effects were mediated through MT2 melatonin receptors, MEK1/2, and MEK5. In layered but not transwell cocultures, melatonin increased OPG:RANKL ratios by inhibiting RANKL, suggesting that contact with osteoclasts during osteoblastogenesis inhibits RANKL secretion. Melatonin modulated expression of ERK1/2, ERK5, β1 integrin, GLUT4, and IRβ that was dependent upon the type of coculture; however, in both cultures, melatonin increased RUNX2 and decreased PPARγ expression, indicating a role for metabolic processes that control osteogenic vs adipogenic cell fates of MSCs. Furthermore, melatonin also has osteoblast‐inducing effects on human adipose‐derived MSCs. In vivo, one‐year nightly melatonin (15 mg/L) given to neu female mice in their drinking water increased pErk1/2, pErk5, Runx2, and Opg and Rankl levels in bone consistent with melatonin's already reported bone‐enhancing effects. Finally, analysis of daily logs from the MOPS demonstrated a significant improvement in mood and perhaps sleep quality in women receiving melatonin vs placebo. The osteoblast‐inducing, bone‐enhancing effects of melatonin and improvement in quality of life suggest that melatonin is a safe and effective bone loss therapy.

Patient-reported outcomes (PROs) provide information on how health care affects patient health and well-being and represent a patient-centered approach. Despite this potential, PROs are not widely used in clinical settings. Semi-structured focus groups were conducted with 3 stakeholder groups (patients, providers, and health care administrators) to determine the top 5 perceived barriers and benefits of PRO implementation. The Delphi technique was employed to obtain consensus and rank order responses. Patients perceived survey length to be important, whereas providers and administrators perceived time to collect data and patient health literacy, respectively, as the greatest barriers to PRO implementation. The greatest perceived benefits were the ability to track changes in clinical symptoms over time, improved quality of care, and better disease control among patients, providers, and administrators, respectively. These results may guide the development of novel frameworks for PRO implementation by addressing perceived barriers and building on the perceived benefits to encourage adoption of PROs.

The scaffold protein synectin plays a critical role in the trafficking and regulation of membrane receptor pathways. As platelet-derived growth factor receptor (PDGFR) is essential for hepatic stellate cell (HSC) activation and liver fibrosis, we sought to determine the role of synectin on the PDGFR pathway and development of liver fibrosis. Mice with deletion of synectin from HSC were found to be protected from liver fibrosis. mRNA sequencing revealed that knockdown of synectin in HSC demonstrated reductions in the fibrosis pathway of genes, including PDGFR-β. Chromatin IP assay of the PDGFR-β promoter upon synectin knockdown revealed a pattern of histone marks associated with decreased transcription, dependent on p300 histone acetyltransferase. Synectin knockdown was found to downregulate PDGFR-α protein levels, as well, but through an alternative mechanism: protection from autophagic degradation. Site-directed mutagenesis revealed that ubiquitination of specific PDGFR-α lysine residues was responsible for its autophagic degradation. Furthermore, functional studies showed decreased PDGF-dependent migration and proliferation of HSC after synectin knockdown. Finally, human cirrhotic livers demonstrated increased synectin protein levels. This work provides insight into differential transcriptional and posttranslational mechanisms of synectin regulation of PDGFRs, which are critical to fibrogenesis.

Brain mutations, young and old Most neurons that make up the human brain are postmitotic, living and functioning for a very long time without renewal (see the Perspective by Lee). Bae et al. examined the genomes of single neurons from the prenatal developing human brain. Both the type of mutation and the rates of accumulation changed between gastrulation and neurogenesis. These early mutations could be generating useful neuronal diversity or could predispose individuals to later dysfunction. Lodato et al. also found that neurons take on somatic mutations as they age by sequencing single neurons from subjects aged 4 months to 82 years. Somatic mutations accumulated with increasing age and accumulated faster in individuals affected by inborn errors in DNA repair. Postmitotic mutations might only affect one neuron, but the accumulated divergence of genomes across the brain could affect function. Science , this issue p. 550 , p. 555 ; see also p. 521