Evaluation of the effect of image noise on CT perfusion measurements using digital perfusion phantoms.

OBJECTIVES: To assess the influence of image noise on computed tomography (CT) perfusion studies, CT perfusion software algorithms were evaluated for susceptibility to image noise and results applied to clinical perfusion studies. METHODS: Digital perfusion phantoms were generated using a published deconvolution model to create time-attenuation curves (TACs) for 16 different combinations of blood flow (BF; 30/60/90/120 ml/100 ml/min) and flow extraction product (FEP; 10/20/30/40 ml/100 ml/min) corresponding to values encountered in clinical studies. TACs were distorted with Gaussian noise at 50 different strengths to approximate image noise, performing 200 repetitions for each noise level. A total of 160,000 TACs were evaluated by measuring BF and FEP with CT perfusion software, comparing results for the maximum slope and Patlak models with those obtained with a deconvolution model. To translate results to clinical practice, data of 23 patients from a CT perfusion study were assessed for image noise, and the accuracy of reported CT perfusion measurements was estimated. RESULTS: Perfusion measurements depend on image noise as means and standard deviations of BF and FEP over repetitions increase with increasing image noise, especially for low BF and FEP values. BF measurements derived by deconvolution show larger standard deviations than those performed with the maximum slope model. Image noise in the evaluated CT perfusion study was 26.46 ± 3.52 HU, indicating possible overestimation of BF by up to 85% in a clinical setting. CONCLUSIONS: Measurements of perfusion parameters depend heavily upon the magnitude of image noise, which has to be taken into account during selection of acquisition parameters and interpretation of results, e.g., as a quantitative imaging biomarker. KEY POINTS: • CT perfusion results depend heavily upon the magnitude of image noise. • Different CT perfusion models react differently to the presence of image noise. • Blood flow may be overestimated by 85% in clinical CT perfusion studies.

Investigation into causes of abnormal cerebral MRI findings following PVAC duty-cycled, phased RF ablation of atrial fibrillation.

INTRODUCTION: Left atrial catheter ablation of the pulmonary veins (PVs) is an established option for patients with atrial fibrillation (AF). Asymptomatic cerebral emboli (ACE) detected by diffusion weighted MRI (DW-MRI) following AF ablation has been reported at varying rates. This variability may be linked to procedural variables and demographic risk factors. Animal studies with the multielectrode pulmonary vein ablation catheter (PVAC) have identified potential sources of emboli, including air introduced during PVAC introduction, inadequate anticoagulation, and high current densities when the distal (E1) and proximal (E10) electrodes are in contact. We sought to evaluate the incidence, size, and number of DW-MRI findings with procedural modifications that potentially reduce the embolic load. METHODS: Thirty-seven AF patients (59 ± 10 years, 73% male, all with paroxysmal AF, left atrial [LA] diameter 44 ± 7 mm, left ventricular ejection fraction 57 ± 7%) underwent MRI sequences preceding ablation, within 24 hours postablation, and at 4-6 weeks. During the procedure all patients were on uninterrupted phenprocoumon, an attempted activated clotting time (ACT) level >300 seconds, had the PVAC introduced under saline, and antral ablation was started with a 2:1 bipolar/unipolar mode. Files from the ablation unit (GENius v14.4) were retrospectively analyzed to determine the relationship between E1 and E10 in close proximity and DW-MRI findings. RESULTS: Post procedure, 10/37 patients (27%) were positive for new DWI cerebral lesions. Nine of 10 patients had a single lesion, and 1/10 patient had 2 lesions. Average lesion size was 3.1 ± 3.9 mm (2-14 mm). One of 10 (10%) had lesions at MRI follow-up. No neurological symptoms were observed. Eighteen of 37 (49%) of procedures had evidence of E1/E10 interaction. In the subgroup of patients with and without E1 and E10 in close proximity, the DW-MRI rate was 8/18 (44%) and 2/19 (11%), respectively (P = 0.029). CONCLUSIONS: The source of positive DW-MRI findings in LA ablation involves several factors. Controlling anticoagulation and careful sheath management helps to reduce the number and size of DW-MRI lesions. With the PVAC catheter, an ablation with the E1 and E10 in close proximity increases the risk of a DW-MRI finding. In the future, electrodes E1 and E10 should be kept apart to help reduce the incidence of acute ACE.

The kinetics of αIIbß3 activation determines the size and stability of thrombi in mice: implications for antiplatelet therapy.

Two major pathways contribute to Ras-proximate-1-mediated integrin activation in stimulated platelets. Calcium and diacyglycerol-regulated guanine nucleotide exchange factor I (CalDAG-GEFI, RasGRP2) mediates the rapid but reversible activation of integrin αIIbß3, while the adenosine diphosphate receptor P2Y12, the target for antiplatelet drugs like clopidogrel, facilitates delayed but sustained integrin activation. To establish CalDAG-GEFI as a target for antiplatelet therapy, we compared how each pathway contributes to thrombosis and hemostasis in mice. Ex vivo, thrombus formation at arterial or venous shear rates was markedly reduced in CalDAG-GEFI(-/-) blood, even in the presence of exogenous adenosine diphosphate and thromboxane A(2). In vivo, thrombosis was virtually abolished in arterioles and arteries of CalDAG-GEFI(-/-) mice, while small, hemostatically active thrombi formed in venules. Specific deletion of the C1-like domain of CalDAG-GEFI in circulating platelets also led to protection from thrombus formation at arterial flow conditions, while it only marginally increased blood loss in mice. In comparison, thrombi in the micro- and macrovasculature of clopidogrel-treated wild-type mice grew rapidly and frequently embolized but were hemostatically inactive. Together, these data suggest that inhibition of the catalytic or the C1 regulatory domain in CalDAG-GEFI will provide strong protection from athero-thrombotic complications while maintaining a better safety profile than P2Y12 inhibitors like clopidogrel.

Oxycodone Extended-Release Capsule Utilization for Pain Management in a Cancer Palliative Care Clinic: A Retrospective Review.

Xtampza ER™, an oxycodone extended-release capsule (OERC), was the first long-acting opioid to feature abuse-deterrent properties and various routes of administration without pharmacokinetic alterations. The primary objective of this study was to evaluate changes in reported pain scores after initiation of or rotation to OERC from a previous opioid.  Baseline scores were from patients' outpatient visits immediately before starting OERC and were compared to those at the next two follow-up visits. Secondary objectives identified variables that influenced pain scores. Methods included screening for cancer patients with outpatient OERC prescriptions seen in the palliative care clinic. Eighty-two charts were reviewed with 66 included. Overall mean pain scores at both follow-ups were lower than those at baseline (-0.7 ± 2.1; -1.1 ± 2.4). Results were statistically significant between first and second-reported pain scores versus baseline (p = 0.009; 0.012) but clinically insignificant, defined as a ≥ 2-point change in numeric pain scores. Most patients discontinued OERC at the first or second follow-up (35; 53%), and 12.1% of patients who started OERC were prescribed OERC at the end of the study. There were no significant variables identified to influence pain scores either statistically or clinically. Further studies are needed to determine the long-term efficacy and safety in cancer palliative-care patients.

Patient values and preferences regarding prognostic counseling in isolated REM sleep behavior disorder.

STUDY OBJECTIVES: Isolated REM sleep behavior disorder (iRBD) carries a high lifetime risk for phenoconversion to a defined neurodegenerative disease (NDD) including Parkinson disease, dementia with Lewy bodies, and multiple system atrophy. We aimed to examine iRBD patient values and preferences regarding prognostic counseling. METHODS: One hundred thirteen iRBD patient participants enrolled in the Mayo Clinic iRBD Patient Registry were sent an email survey concerning their values and preferences concerning NDD prognostic counseling and their experiences following diagnosis with iRBD. RESULTS: Of 81 respondents (71.7% response rate), the majority were men (74.0%) with an average age of 65.7 (±9.7) years. Responses indicated a strong preference toward receiving prognostic information about possible future NDD development. 92.5% of respondents felt knowledge concerning personal NDD risk was important, while 87.6% indicated prognostic discussions were important to maintaining trust in their physician. 95.7% indicated a desire for more information, while only 4.3% desired less information regarding their NDD prognostic risk. Most respondents strongly agreed that prognostic information was important to discuss with their family and friends and inform future life planning, and most expressed interest in learning more about future neuroprotective therapies and symptomatic treatments for parkinsonism and dementia. CONCLUSIONS: Most iRBD patients indicated strong preferences for disclosure of NDD prognostic risk and indicated that prognostic information was important for family discussions and future life planning. Future broader surveys and qualitative studies of clinic-based and ultimately community dwelling iRBD patients' values and preferences are needed to guide appropriately tailored and individualized prognostic counseling approaches following iRBD diagnosis.

Monocyte-bound PF4 in the pathogenesis of heparin-induced thrombocytopenia.

Heparin-induced thrombocytopenia (HIT) is a life- and limb-threatening thrombotic disorder that develops after exposure to heparin, often in the setting of inflammation. We have shown previously that HIT is associated with antibodies to complexes that form between platelet factor 4 and glycosaminoglycan (GAG) side chains on the surface of platelets. However, thrombosis can occur in the absence of thrombocytopenia. We now show that platelet factor 4 binds to monocytes and forms antigenic complexes with their surface GAG side chains more efficiently than on platelets likely due to differences in GAG composition. Binding to monocytes is enhanced when the cells are activated by endotoxin. Monocyte accumulation within developing arteriolar thrombi was visualized by situ microscopy. Monocyte depletion or inactivation in vivo attenuates thrombus formation induced by photochemical injury of the carotid artery in a modified murine model of HIT while paradoxically exacerbating thrombocytopenia. These studies demonstrate a previously unappreciated role for monocytes in the pathogenesis of arterial thrombosis in HIT and suggest that therapies targeting these cells might provide an alternative approach to help limit thrombosis in this and possibly other thrombotic disorders that occur in the setting of inflammation.

In vivo efficacy of platelet-delivered, high specific activity factor VIII variants.

Ectopically expressed, human B-domainless (hB) factor 8 (F8) in platelets improves hemostasis in hemophilia A mice in several injury models. However, in both a cuticular bleeding model and a cremaster laser arteriole/venule injury model, there were limitations to platelet-derived (p) hBF8 efficacy, including increased clot embolization. We now address whether variants of F8 with enhanced activity, inactivation resistant F8 (IR8) and canine (c) BF8, would improve clotting efficacy. In both transgenic and lentiviral murine model approaches, pIR8 expressed at comparable levels to phBF8, but pcBF8 expressed at only approximately 30%. Both variants were more effective than hBF8 in cuticular bleeding and FeCl(3) carotid artery models. However, in the cremaster injury model, only pcBF8 was more effective, markedly decreasing clot embolization. Because inhibitors of F8 are stored in platelet granules and IR8 is not protected by binding to von Willebrand factor, we also tested whether pIR8 was effective in the face of inhibitors and found that pIR8 is protected from the inhibitors. In summary, pF8 variants with high specific activity are more effective in controlling bleeding, but this improved efficacy was inconsistent between bleeding models, perhaps reflecting the underlying mechanism(s) for the increased specific activity of the studied F8 variants.

Structural and therapeutic insights from the species specificity and in vivo antithrombotic activity of a novel alphaIIb-specific alphaIIbbeta3 antagonist.

We previously reported on a novel compound (Compound 1; RUC-1) identified by high-throughput screening that inhibits human alphaIIbbeta3. RUC-1 did not inhibit alphaVbeta3, suggesting that it interacts with alphaIIb, and flexible ligand/rigid protein molecular docking studies supported this speculation. We have now studied RUC-1's effects on murine and rat platelets, which are less sensitive than human to inhibition by Arg-Gly-Asp (RGD) peptides due to differences in the alphaIIb sequences contributing to the binding pocket. We found that RUC-1 was much less potent in inhibiting aggregation of murine and rat platelets. Moreover, RUC-1 potently inhibited fibrinogen binding to murine platelets expressing a hybrid alphaIIbbeta3 receptor composed of human alphaIIb and murine beta3, but not a hybrid receptor composed of murine alphaIIb and human beta3. Molecular docking studies of RUC-1 were consistent with the functional data. In vivo studies of RUC-1 administered intraperitoneally at a dose of 26.5 mg/kg demonstrated antithrombotic effects in both ferric chloride carotid artery and laser-induced microvascular injury models in mice with hybrid halphaIIb/mbeta3 receptors. Collectively, these data support RUC-1's specificity for alphaIIb, provide new insights into the alphaIIb binding pocket, and establish RUC-1's antithrombotic effects in vivo.

Transdermal Buprenorphine Use for Pain Management in Palliative Care.

Cancer related pain is prevalent among patients with a cancer diagnosis, occurring from the tumor itself or as a result of treatment. Many patients require opioid therapy to manage pain and providers must balance efficacy with side effects. Transdermal buprenorphine (TDB) has shown promise for pain management, however, the maximum dose available in the US is considered low, resulting in doubts of efficacy. This study set out to assess if the patch strengths available in the US (5-20 mcg/hour) are able to provide analgesia for patients with cancer in a palliative medicine clinic. This retrospective chart review analyzed patient charts for outpatient TDB use within a palliative medicine clinic in the United States. Patients had to have a follow up visit with the clinic in order to be included. Sixty-eight patients were included for analysis with 54 (79%) continuing at least 28 days and 37 (54%) continuing for at least 84 days. The median change in pain score was 0, though 25 (46%) of patients reported a decrease of 1 or more points at the first follow up. TDB is a viable option for cancer related pain for select patients, demonstrated by duration of use and stable reporting of pain.

Specialist approaches to prognostic counseling in isolated REM sleep behavior disorder.

OBJECTIVES/BACKGROUND: Most middle-aged and older adult patients with isolated (idiopathic) REM sleep behavior disorder (RBD) eventually develop parkinsonism, dementia with Lewy bodies, or multiple system atrophy. We aimed to describe the current sleep medicine specialist approach toward RBD prognostic counseling, and to determine physician beliefs and characteristics that impact provision of counseling. PATIENTS/METHODS: We surveyed 70 sleep medicine physicians with RBD expertise for demographic information, counseling practices, and their beliefs and understandings concerning the association between RBD and synucleinopathies, among other questions. Responses were summarized by descriptive statistics. RESULTS: Among the 44 respondents (63% response rate), 41 (93.2%) regularly provided prognostic counseling for most RBD patients, but only 31.8% routinely asked about patient preferences on receiving counseling. 41.8% believed that the risk for developing overt synucleinopathy following RBD diagnosis was >80%, but only 15.9% routinely provided this detailed phenoconversion risk estimate to their patients. Most respondents were concerned that RBD prognostic counseling could adversely impact on the patient's and family's mental health. CONCLUSIONS: Most expert RBD sleep clinicians routinely counsel their patients regarding the high risk for phenoconversion to parkinsonism or dementia, yet relatively few routinely ask patients about their preferences for receiving this information, and fewer provide details concerning the known high risk estimates for developing a synucleinopathy. Future research should analyze patients' values and preferences in RBD populations to inform approaches toward shared decision making for RBD prognostic counseling.

Ethical Tensions Resulting from Interpreter Involvement in the Consent Process.

We describe how our institution responded when an interpreter who participated in the consent process involving an individual with limited English proficiency refused to cosign consent documents attesting that the individual enrolling in the study understood the consent information and that her consent to enroll was voluntary. In developing our approach, our institution took into account ethical tensions between the Belmont principles of respect for persons, beneficence, and justice that apply to the protection of research participants and the professional principles of beneficence, fidelity, and respect for the importance of culture that are outlined in ethical guidelines for medical interpreters.

Inpatient-based intensive interdisciplinary pain treatment for highly impaired children with severe chronic pain: randomized controlled trial of efficacy and economic effects.

Pediatric chronic pain, which can result in deleterious effects for the child, bears the risk of aggravation into adulthood. Intensive interdisciplinary pain treatment (IIPT) might be an effective treatment, given the advantage of consulting with multiple professionals on a daily basis. Evidence for the effectiveness of IIPT is scarce. We investigated the efficacy of an IIPT within a randomized controlled trial by comparing an intervention group (IG) (n=52) to a waiting-list control group (WCG) (n=52). We made assessments before treatment (PRE), immediately after treatment (POST), as well as at short-term (POST6MONTHS) and long-term (POST12MONTHS) follow-up. We determined a combined endpoint, improvement (pain intensity, disability, school absence), and investigated 3 additional outcome domains (anxiety, depression, catastrophizing). We also investigated changes in economic parameters (health care use, parental work absenteeism, subjective financial burden) and their relationship to the child's improvement. Results at POST showed that significantly more children in the IG than in the WCG were assigned to improvement (55% compared to 14%; Fisher P<.001; 95% confidence interval for incidence difference: 0.21% to 0.60%). Although immediate effects were achieved for disability, school absence, depression, and catastrophizing, pain intensity and anxiety did not change until short-term follow-up. More than 60% of the children in both groups were improved long-term. The parents reported significant reductions in all economic parameters. The results from the present study support the efficacy of the IIPT. Future research is warranted to investigate differences in treatment response and to understand the changes in economic parameters in nonimproved children.

Infusion of mature megakaryocytes into mice yields functional platelets.

Thrombopoiesis, the process by which circulating platelets arise from megakaryocytes, remains incompletely understood. Prior studies suggest that megakaryocytes shed platelets in the pulmonary vasculature. To better understand thrombopoiesis and to develop a potential platelet transfusion strategy that is not dependent upon donors, of which there remains a shortage, we examined whether megakaryocytes infused into mice shed platelets. Infused megakaryocytes led to clinically relevant increases in platelet numbers. The released platelets were normal in size, displayed appropriate surface markers, and had a near-normal circulating half-life. The functionality of the donor-derived platelets was also demonstrated in vivo. The infused megakaryocytes mostly localized to the pulmonary vasculature, where they appeared to shed platelets. These data suggest that it may be unnecessary to generate platelets from ex vivo grown megakaryocytes to achieve clinically relevant increases in platelet numbers.