Complement peptide C3a receptor 1 promotes optic nerve degeneration in DBA/2J mice.

BACKGROUND: The risk of glaucoma increases significantly with age and exposure to elevated intraocular pressure, two factors linked with neuroinflammation. The complement cascade is a complex immune process with many bioactive end-products, including mediators of inflammation. Complement cascade activation has been shown in glaucoma patients and models of glaucoma. However, the function of complement-mediated inflammation in glaucoma is largely untested. Here, the complement peptide C3a receptor 1 was genetically disrupted in DBA/2J mice, an ocular hypertensive model of glaucoma, to test its contribution to neurodegeneration. METHODS: A null allele of C3ar1 was backcrossed into DBA/2J mice. Development of iris disease, ocular hypertension, optic nerve degeneration, retinal ganglion cell activity, loss of RGCs, and myeloid cell infiltration in C3ar1-deficient and sufficient DBA/2J mice were compared across multiple ages. RNA sequencing was performed on microglia from primary culture to determine global effects of C3ar1 on microglia gene expression. RESULTS: Deficiency in C3ar1 lowered the risk of degeneration in ocular hypertensive mice without affecting intraocular pressure elevation at 10.5 months of age. Differences were found in the percentage of mice affected, but not in individual characteristics of disease progression. The protective effect of C3ar1 deficiency was then overcome by additional aging and ocular hypertensive injury. Microglia and other myeloid-derived cells were the primary cells identified that express C3ar1. In the absence of C3ar1, microglial expression of genes associated with neuroinflammation and other immune functions were differentially expressed compared to WT. A network analysis of these data suggested that the IL10 signaling pathway is a major interaction partner of C3AR1 signaling in microglia. CONCLUSIONS: C3AR1 was identified as a damaging neuroinflammatory factor. These data help suggest complement activation causes glaucomatous neurodegeneration through multiple mechanisms, including inflammation. Microglia and infiltrating myeloid cells expressed high levels of C3ar1 and are the primary candidates to mediate its effects. C3AR1 appeared to be a major regulator of microglia reactivity and neuroinflammatory function due to its interaction with IL10 signaling and other immune related pathways. Targeting myeloid-derived cells and C3AR1 signaling with therapies is expected to add to or improve neuroprotective therapeutic strategies.

Sleep is an eye-opener: Behavioral causes and consequences of hypersomnolence in children.

The most common behavioral cause of hypersomnia in children is insufficient sleep. Behavioral causes of insufficient sleep for children, ages six months through 12 years, include inadequate sleep hygiene, bedtime struggles, prolonged sleep onset latency, nighttime fears, and nightmares. Behavioral interventions are efficacious and should be individualized to meet the needs of the child and family. Insufficient sleep affects many areas of child development, including academic, cognitive, and psychosocial, as well as parents and caregivers. Behavioral causes of sleepiness in children are best identified through a clinical interview, sleep diary, and actigraphy.

Impact of Point-of-Care Implementation in Pharmacist-Run Anticoagulation Clinics Within a Community-Owned Health System: A Two-Year Retrospective Analysis.

BACKGROUND: Point-of-care (POC) testing devices allow laboratory monitoring to be performed in various settings and accessed immediately. OBJECTIVE: To evaluate the outcomes of monitoring anticoagulation patients in pharmacistmanaged, multicenter clinics utilizing i-STAT POC machines. METHODS: This study was a retrospective, multicenter chart review of 150 patients before and after implementation of the POC intervention for anticoagulation monitoring. Data collected included international normalized ratio (INR) results, indication for warfarin, minor and major bleeds, thromboembolic events, emergency room (ER) visits, and hospitalizations before and after i-STAT POC implementation. RESULTS: The time in therapeutic INR range (TTR) was significantly higher after i-STAT POC implementation than before implementation (60.4% ± 21.2% and 52.5% ± 21.5%, respectively; P = .0001). There were no reports of major bleeding during the study period. Twenty-three minor bleeds were reported after i-STAT POC implementation compared to 19 events before implementation (P < .0001). One thromboembolic event was reported after i-STAT POC implementation. There was a significant difference in the number of hospitalizations before i-STAT POC implementation as opposed to after implementation (2 and 0, respectively; P < .0001). There was also a significant increase in ER visits after i-STAT POC implementation (P < .0001). CONCLUSION: The results of the study indicate improvement in TTR in pharmacist-managed anticoagulation clinics by 7.8%. Although the use of the i-STAT POC machine detected an increase in minor bleeds, thromboembolic events, and ER visits, there was a decrease in hospitalization. The outcomes of this multicenter study indicate that implementation on this scale provides improvement in regard to safety and cost.

Personalized medicine in rheumatoid arthritis: Combining biomarkers and patient preferences to guide therapeutic decisions.

The last few decades have seen major therapeutic advancements in rheumatoid arthritis (RA) therapeutics. New disease-modifying antirheumatic drugs (DMARDs) have continued to emerge, creating more choices for people. However, no therapeutic works for all patients. Each has its own inherent benefits, risks, costs, dosing, and monitoring considerations. In parallel, there has been a focus on personalized medicine initiatives that tailor therapeutic decisions to patients based on their unique characteristics or biomarkers. Personalized effect estimates require an understanding of a patient's baseline probability of response to treatment and data on the comparative effectiveness of the available treatments. However, even if accurate risk prediction models are available, trade-offs often still need to be made between treatments. In this paper, we review the history of RA therapeutics and progress that has been made toward personalized risk predictive models for DMARDs, outlining where knowledge gaps still exist. We further review why patient preferences play a key role in a holistic view of personalized medicine and how this links with shared decision-making. We argue that a "preference misdiagnosis" may be equally important as a medical misdiagnosis but is often overlooked.

Sleep problems and sleep disorders in pediatric primary care: treatment recommendations, persistence, and health care utilization.

STUDY OBJECTIVE: This study examined documented treatment recommendations provided for sleep disorders and sleep problems in pediatric primary care, the persistence of sleep problems and sleep disorders in children and adolescents, and the relationship between sleep issues and health care utilization. METHODS: In-depth chart review of pediatric primary care patient visits (n = 750 patients) from 2007 through 2010. RESULTS: Only 26 children (5.2% of those with a sleep disorder/ problem) received a treatment recommendation, with half of these recommendations behavioral in nature. Sleep disorders and sleep problems were highly persistent across time for up to a third of children. Children with sleep disorders had significantly more sick visits/calls (mean = 8.84, 95% CI 7.77-9.90) than children without a sleep disorder (mean = 6.34, 95% CI 5.56-7.12). CONCLUSIONS: Very few children or adolescents were found to have documented treatment recommendations or referrals for diagnosed sleep disorders or sleep problems. In addition, given that sleep disorders and sleep problems are highly persistent, as well as result in more sick visits/calls, it is important that pediatric primary care providers screen for and identify these issues across development. Furthermore, it is essential to provide health care providers with more education and support on sleep disorders and sleep problems in pediatric primary care.