Targeting Enclysis in Liver Autoimmunity, Transplantation, Viral Infection and Cancer.

Persistent liver inflammation can lead to cirrhosis, which associates with significant morbidity and mortality worldwide. There are no curative treatments beyond transplantation, followed by long-term immunosuppression. The global burden of end stage liver disease has been increasing and there is a shortage of donor organs, therefore new therapies are desperately needed. Harnessing the power of the immune system has shown promise in certain autoimmunity and cancer settings. In the context of the liver, regulatory T cell (Treg) therapies are in development. The hypothesis is that these specialized lymphocytes that dampen inflammation may reduce liver injury in patients with chronic, progressive diseases, and promote transplant tolerance. Various strategies including intrinsic and extracorporeal expansion of Treg cells, aim to increase their abundance to suppress immune responses. We recently discovered that hepatocytes engulf and delete Treg cells by enclysis. Herein, we propose that inhibition of enclysis may potentiate existing regulatory T cell therapeutic approaches in patients with autoimmune liver diseases and in patients receiving a transplant. Moreover, in settings where the abundance of Treg cells could hinder beneficial immunity, such us in chronic viral infection or liver cancer, enhancement of enclysis could result in transient, localized reduction of Treg cell numbers and tip the balance towards antiviral and anti-tumor immunity. We describe enclysis as is a natural process of liver immune regulation that lends itself to therapeutic targeting, particularly in combination with current Treg cell approaches.

Repeated Endovascular Interventions Are Worthwhile, Even After Thrombosis, to Maintain Long-Term Use of Autogenous Dialysis Fistulas.

OBJECTIVES: Patients often require multiple access re-interventions to improve fistula patency and the overall usable lifespan of autogenous arteriovenous fistula (aAVF). There is no consensus on the appropriate number of re-interventions after which an access should be abandoned and new access placed. We evaluated whether repeated endovascular interventions for failing/failed aAVF are worthwhile or futile. METHODS: A retrospective review was performed on aAVFs created between 2009-2014. Fistula function was evaluated until January 2017. Functional fistula patency (FFP) was defined as the total time of functional fistula use for hemodialysis, from time of cannulation to time of measurement or fistula abandonment, including all interventions performed to maintain/reestablish patency. Primary outcomes were FFP duration and number of post-dialysis interventions. RESULTS: The study included 163 patients. Mean age was 67 (SD = 15.03). The only variable statistically different between functional fistulas and abandoned fistulas was obesity (p = 0.03). At the end of the study period, 145 (89.0%) patients continued to have functional fistulas, and 73 (44.8%) patients died, but had functional fistulas at time of death. Median FFP for the functional group was 3.18 years (range 0.01-7.01 years) and median number of interventions was 1 (range 0-13). In 18 patients (11%), the fistula was abandoned, most commonly due to thrombosis (47.1%), followed by infection (23.5%). No fistula was abandoned because of an unacceptable rate of reintervention. Median FFP in the abandoned group was 0.91 years (range 0.03-5.30 years), and median number of interventions was 0 (range of 0-5). CONCLUSIONS: Through repeated interventions on aAVFs, none of the patients in our study exhausted all hemodialysis access options prior to transplantation, death or loss to follow-up. These results may indicate repeated and/or more frequent revisions do not negatively affect the FFP nor do they increase the overall risk for abandonment of aAVFs.

Use of a tick-borne disease manual increases accuracy of tick identification among primary care providers in Lyme disease endemic areas.

Given the high incidence of tick bites and tick-borne diseases in the United States, it is important for primary care providers to recognize common ticks and the pathogens they may transmit. If a patient has removed and saved an attached tick, identifying the tick helps guide clinical management and determine whether antibiotic prophylaxis for Lyme disease is appropriate. To investigate providers' ability to recognize common ticks and the pathogens they may transmit, we asked 76 primary care providers from Lyme disease endemic areas to identify the common name or genus of preserved ticks found in their area. At baseline, 10.5%, 46.1%, and 57.9% of participants correctly identified an adult female blacklegged tick (engorged), dog tick, and lone star tick, respectively. Less than half of participants identified the three pathogens most frequently transmitted by blacklegged ticks. Use of a reference manual with tick photographs and drawings substantially improved identification of ticks and associated pathogens and therefore should be encouraged in clinical practice.

Tick-borne disease preventive practices and perceptions in an endemic area.

Lyme disease is the most commonly reported vector-borne illness in the United States. Since the institution of Nationally Notifiable surveillance efforts for Lyme disease in the United States in 1991, there has been a consistent increase in the number of reported cases. Thus, the need for targeted prevention strategies is underscored. The purpose of this study was to investigate knowledge about tick-borne diseases as well as beliefs and practices related to a variety of personal tick-borne disease prevention methods among individuals in southwestern Connecticut, a Lyme disease-endemic area. Between June and September 2014, an anonymous questionnaire was administered to 275 participants through a point-of-contact convenience sample obtained at community events in southwestern Connecticut. The questionnaire assessed individuals' general knowledge about tick-borne diseases, performance of four selected tick-borne disease prevention methods, and perceived effectiveness and burdensomeness of those four behaviors. Some 80% of participants were female; median age was 55 years (IQR 45-64 years); 30% reported having been treated for a tick-borne illness and 50% reported a family member having been treated for a tick-borne illness. Overall, participants' knowledge of tick-borne diseases was poor; the average knowledge score was only 57% (SD 22.6%). The reported frequency of performing preventive behaviors was variable. The most commonly reported behavior was performing a tick check (68%); use of tick repellent was the least commonly reported behavior (38%). Those who were more knowledgeable about Lyme disease were more likely to perform tick checks but knowledge score was not significantly associated with any of the other three behaviors studied. Respondents largely believed preventive behaviors to be effective at reducing the risk of tick-borne diseases. Belief that a prevention behavior is effective was highly correlated with performing that behavior but perceived burdensomeness does not appear to influence behavior performance. The reasons for differential uptake of preventive behaviors remains unknown; further study of barriers to performance of personal preventive behaviors is needed to better target public health interventions.

Effects of krill oil on endothelial function and other cardiovascular risk factors in participants with type 2 diabetes, a randomized controlled trial.

OBJECTIVE: The purpose of this trial was to evaluate the effect of krill oil supplementation, a source of ω-3 fatty acids, on cardiovascular disease risk factors and blood glucose control among participants with type 2 diabetes. RESEARCH DESIGN AND METHODS: A randomized, double-blind controlled cross-over trial was employed. Outcomes assessed were: endothelial function, blood lipids, glucose, glycated hemoglobin, serum antioxidant level, C peptide, and calculated Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) scores. Participants were randomized to either krill oil or olive oil supplementation for 4 weeks, underwent a 2-week washout period, and then crossed to the other supplementation for 4 weeks. All participants were then offered an additional 17 weeks of krill supplementation. Testing occurred at 3 time points: baseline, after first supplementation, and after second supplementation. Testing also occurred after an optional 17 weeks of krill oil supplementation. Difference scores were calculated for each participant in both sequences (ie, differences in outcome measures in the first and second period of the sequence). The mean and SD of the scores in the 2 sequence groups were used to test for differences between treatment effects at a significance level of p<0.05. RESULTS: A total of 47 participants were included in the initial cross-over study. Participants who received krill oil for 4 weeks had an improvement in their endothelial function and a reduction in blood C peptide levels and HOMA scores as compared with the olive oil. A total of 34 participants completed the additional 17-week supplementation period. When compared with their respective baseline measures, these participants had a statistically significant improvement in endothelial function and blood high-density lipoprotein (HDL). CONCLUSIONS: Krill oil may lead to moderate improvement of cardiovascular risks, specifically endothelial dysfunction and HDL in patients with type 2 diabetes. TRIAL REGISTRATION NUMBER: Registered with ClinicalTrials.gov: NCT02091193.

Effect of obstructive sleep apnea on frequency of stroke in patients with atrial fibrillation.

Obstructive sleep apnea (OSA) is an independent risk factor for ischemic stroke that is not included in the usual cardioembolic risk assessments for patients with atrial fibrillation (AF). The aim of this study was to investigate the impact of OSA on stroke rate in patients with AF. Patients with AF and new diagnoses of OSA were identified from retrospective chart review. Those with histories of stroke at the time of the sleep study were excluded. The primary outcome was the incidence of stroke, determined by a physician investigator blinded to the results of polysomnography. Subgroup analysis was performed among different CHADS2 and CHA2DS2-VASc scores. Of 5,138 patients screened for OSA, 402 (7.7%) had AF and 332 (6.4%) met the inclusion criteria. Among the study population, the occurrence of first-time stroke was 22.9%. Ischemic stroke was more common in patients with OSA compared with patients without (25.4% vs 8.2% respectively, p = 0.006). After controlling for age, male gender, and coronary artery disease, the association between OSA and stroke remained statistically significant, with an adjusted odds ratio of 3.65 (95% confidence interval 1.252 to 10.623). A positive dose effect of the apnea-hypopnea index on the rate of stroke was observed (p = 0.0045). Subgroup analysis showed significantly higher rates of stroke in patients with CHADS2 scores of 0 and CHA2DS2-VASc scores of 0 and 1 and co-morbid OSA. In conclusion, OSA in patients with AF is an independent predictor of stroke. This association may have important clinical implications in ischemic stroke risk stratification.

New insights into stages of lyme disease symptoms from a novel hospital-based registry.

BACKGROUND: Western Connecticut Health Network created the Lyme Disease Registry in response to the community's request and clinical need for more Lyme disease research. The registry includes acute, recovered, and persistently symptomatic patients to better define the different stages of the disease. The design of the registry was guided by community and clinician input through a community-based participatory research process. METHODS: Registry participants are asked questions regarding their diagnosis, symptoms, treatments, recovery, and satisfaction with the Registry. A blood specimen is also collected and stored at the initial appointment. RESULTS: The Lyme Disease Registry has enrolled 256 participants, 24% are acute cases, 45% are persistently symptomatic cases, and 31% are recovered cases. The symptoms experienced by the group of patients with persistent symptoms had unexpectedly strong overlap with those experienced by acutely infected patients. CONCLUSION: The difference between symptoms in the acutely infected patients and those experiencing persistent symptoms is not as large as initially thought.