Predictors of heart failure symptoms in hereditary hemorrhagic telangiectasia patients with hepatic arteriovenous malformations.

BACKGROUND: Hepatic arteriovenous malformations (AVMs) in hereditary hemorrhagic telangiectasia (HHT) patients are most commonly hepatic artery to hepatic venous shunts which can result in high-output heart failure. This condition can be debilitating and is a leading cause of liver transplantation in HHT patients. However, it is not known what characteristics can discriminate between asymptomatic patients and those who will develop heart failure symptoms. RESULTS: 176 patients with HHT were evaluated with computed tomography angiography (CTA) between April 2004 and February 2019 at our HHT Center of Excellence. 63/176 (35.8%) patients were found to have hepatic AVMs on CTA. 18 of these patients were excluded because of the presence of another condition which could confound evaluation of heart failure symptoms. In the remaining 45 patients included in our cohort, 25/45 (55.6%) patients were classified as asymptomatic and 20/45 (44.4%) were classified as symptomatic, and these groups were compared. In symptomatic patients, mean common hepatic artery (CHA) diameter was significantly higher (11.1 versus 8.4 mm) and mean hemoglobin levels were significantly lower (10.7 vs 12.6 g/dL). A stepwise multiple logistic regression analysis demonstrated that both CHA diameter and hemoglobin level were independent predictors of heart failure symptoms with ORs of 2.554 (95% CI 1.372-4.754) and 0.489 (95% CI 0.299-0.799), respectively. The receiver operator characteristic (ROC) curve of our analysis demonstrated an AUC of 0.906 (95% CI 0.816-0.996), sensitivity 80.0% (95% CI 55.7-93.4%), and specificity 75.0% (95% CI 52.9-89.4%). CONCLUSIONS: CTA is an effective and easily reproducible method to evaluate hepatic involvement of HHT. Utilizing CTA, clinical, and laboratory data we determined CHA diameter and hemoglobin level were independent predictors of heart failure symptoms.

Transformation of Australian Community Pharmacies Into Good Clinical Practice Compliant Trial Pharmacies for HIV Pre-Exposure Prophylaxis.

Background: In Australia, clinical trial drugs are conventionally dispensed through clinical trial pharmacies only, while community pharmacies dispense drugs approved by Australia's regulatory body. A large HIV pre-exposure prophylaxis study aimed to deliver clinical trial drug through community pharmacies to improve convenience and mimic real world prescribing. This paper describes the process of making community trials compliant with good clinical practice and reports outcomes of delivering clinical trial drug through community pharmacies. Methods: Eight community and four clinical trial pharmacies across three Australian states were approached to participate. A good clinical practice checklist was generated and pharmacies underwent a number of changes to meet clinical trial pharmacy requirements prior to study opening. Changes were made to community pharmacies to make them compliant with good clinical trial practice including; staff training, structural changes, and implementing monitoring of study drug and prescribing practices. Study drug was ordered through standard clinical trial processes and dispensed from study pharmacies by accredited pharmacists. Throughout the trial, record logs for training, prescriber signature and delegation, temperature, participant, and drug accountability were maintained at each pharmacy. The study team monitored each log and delivered on-site training to correct protocol variations. Results: Each pharmacy that was approached agreed to participate. All community pharmacies achieved good clinical practice compliance prior to dispensing study drug. Over the course of the study, 20,152 dispensations of study drug occurred, 83% of these occurred at community pharmacies. Only 2.0% of dispensations had an error, and errors were predominantly minor. On five occasions a pharmacist who was not accredited dispensed study drug. Conclusions: Community based pharmacies can undergo training and modifications to achieve good clinical practice compliance and dispense clinical trial study drug. Community based pharmacies recorded few variations from study protocol. Community based pharmacies offer a useful alternative to clinical trial pharmacies to increase convenience for study participants and expanded use of these pharmacies should be considered for large clinical trials, including HIV prevention trials.

PACS used while on-call: a national survey of radiology program directors and chief residents.

The aim of this study was to determine the prevalence of different diagnostic image viewing platforms used by radiologists while on-call, and to assess the opinions and preferences of radiology program directors and chief residents regarding their use. An online survey was sent electronically to radiology residency program directors and chief residents via the Association of University Radiologists. Forty-two radiology program directors and 25 chief residents completed the survey, yielding response rates of 24.9 and 8.5 %, respectively. From the survey results, 10 different Picture Archiving Communications Systems (PACS) were identified; GE (25 %), Philips (17 %), and Agfa Impax (15 %) were the most prevalent. Interestingly, only 5 % of all respondents use a secondary "Digital Imaging and Communications in Medicine" viewer for on-call studies. Perceptions of PACS functionality were generally neutral to weakly positive. Most respondents strongly agreed that it is important to have a single integrated PACS for viewing on-call studies and agreed that the PACS should be integrated into the Electronic Medical Records (EMR). The overwhelming majority of respondents use their institution's PACS while on-call. The results show there is still a wide variety of PACS platforms used by different institutions; however, GE, Phillips, and Agfa were some of the most prevalent. Most radiologists surveyed have neutral to slightly positive perceptions about the functionality and ease of use of their PACS. Finally, while radiologists agree that PACS should be integrated with EMR, only 53 % of respondents currently have this arrangement.

ApoE mimetic peptide decreases Abeta production in vitro and in vivo.

BACKGROUND: Apolipoprotein E (apoE) is postulated to affect brain Abeta levels through multiple mechanisms--by altering amyloid precursor protein (APP) processing, Abeta degradation, and Abeta clearance. We previously showed that an apoE-derived peptide containing a double repeat of the receptor-binding region was similarly effective in increasing APP processing in vivo. Here, we further examined whether peptides containing tandem repeats of the apoE receptor-binding region (amino acids 141-149) affected APP trafficking, APP processing, and Abeta production. RESULTS: We found that peptides containing a double or triple tandem repeat of the apoE receptor-binding region, LRKLRKRLL, increased cell surface APP and decreased Abeta levels in PS1-overexpressing PS70 cells and in primary neurons. This effect was potentiated by a sequential increase in the number of apoE receptor-binding domain repeats (trimer > dimer > monomer). We previously showed that the apoE dimer increased APP CTF in vivo; to determine whether the dimer also affected secreted APP or Abeta levels, we performed a single hippocampal injection of the apoE dimer in wild-type mice and analyzed its effect on APP processing. We found increased sAPPalpha and decreased Abeta levels at 24 hrs after treatment, suggesting that the apoE dimer may increase alpha-secretase cleavage. CONCLUSIONS: These data suggest that small peptides consisting of tandem repeats of the apoE receptor-binding region are sufficient to alter APP trafficking and processing. The potency of these peptides increased with increasing repeats of the receptor binding domain of apoE. In addition, in vivo administration of the apoE peptide (dimer) increased sAPPalpha and decreased Abeta levels in wild-type mice. Overall, these findings contribute to our understanding of the effects of apoE on APP processing and Abeta production both in vitro and in vivo.

ApoE4 decreases spine density and dendritic complexity in cortical neurons in vivo.

The three human alleles of apolipoprotein E (APOE) differentially influence outcome after CNS injury and affect one's risk of developing Alzheimer's disease (AD). It remains unclear how ApoE isoforms contribute to various AD-related pathological changes (e.g., amyloid plaques and synaptic and neuron loss). Here, we systematically examined whether apoE isoforms (E2, E3, E4) exhibit differential effects on dendritic spine density and morphology in APOE targeted replacement (TR) mice, which lack AD pathological changes. Using Golgi staining, we found age-dependent effects of APOE4 on spine density in the cortex. The APOE4 TR mice had significantly reduced spine density at three independent time points (4 weeks, 3 months, and 1 year, 27.7% +/- 7.4%, 24.4% +/- 8.6%, and 55.6% +/- 10.5%, respectively) compared with APOE3 TR mice and APOE2 TR mice. Additionally, in APOE4 TR mice, shorter spines were evident compared with other APOE TR mice at 1 year. APOE2 TR mice exhibited longer spines as well as significantly increased apical dendritic arborization in the cortex compared with APOE4 and APOE3 TR mice at 4 weeks. However, there were no differences in spine density across APOE genotypes in hippocampus. These findings demonstrate that apoE isoforms differentially affect dendritic complexity and spine formation, suggesting a role for APOE genotypes not only in acute and chronic brain injuries including AD, but also in normal brain functions.