Prescription factors influencing baloxavir prescription during the 2018/2019 and 2019/2020 seasons: a administrative database study in Japan.

BACKGROUND: We aimed to evaluate the factors associated with baloxavir prescription in Japanese hospitals using a health insurance claim-based database (MDV analyzer), during the 2018/2019 and 2019/2020 influenza seasons. The MDV analyzer contains anonymized claims data from approximately 420 Diagnosis Procedure Combination hospitals, and does not contain data from clinics. METHODS: Data were collected for influenza patients treated with anti-influenza drugs during the 2018/2019 and 2019/2020 influenza seasons. Multivariate analysis was used to identify factors associated with baloxavir prescription. RESULTS: During the study period, 322,063 influenza patients were included for analyses. In multivariate analysis, children, female sex, inpatient, hospital bed capacity, and private hospitals were negatively associated with baloxavir prescription. Compared to elderly patients, the adjusted odds ratio (OR) for baloxavir prescription was 0.612 (95% confidence interval (CI), 0.587-0.637) in children aged 6-11 years, and 0.119 (95% CI, 0.111-0.128) in children aged 0-5 years. Compared to small hospitals (bed capacity, 20-299), the adjusted OR for baloxavir prescription was 0.559 (95% CI, 0.540-0.578) in large hospitals (bed capacity, ≥ 500). CONCLUSION: Children, female sex, inpatient, hospital bed capacity, and private hospitals were negatively associated with baloxavir prescription.

MR diagnosis of a pulmonary embolism: comparison of P792 and Gd-DOTA for first-pass perfusion MRI and contrast-enhanced 3D MRA in a rabbit model.

OBJECTIVE: To compare P792 (gadomelitol, a rapid clearance blood pool MR contrast agent) with gadolinium-tetraazacyclododecanetetraacetic acid (Gd-DOTA), a standard extracellular agent, for their suitability to diagnose a pulmonary embolism (PE) during a first-pass perfusion MRI and 3D contrast-enhanced (CE) MR angiography (MRA). MATERIALS AND METHODS: A perfusion MRI or CE-MRA was performed in a rabbit PE model following the intravenous injection of a single dose of contrast agent. The time course of the pulmonary vascular and parenchymal enhancement was assessed by measuring the signal in the aorta, pulmonary artery, and lung parenchyma as a function of time to determine whether there is a significant difference between the techniques. CE-MRA studies were evaluated by their ability to depict the pulmonary vasculature and following defects between 3 seconds and 15 minutes after a triple dose intravenous injection of the contrast agents. RESULTS: The P792 and Gd-DOTA were equivalent in their ability to demonstrate PE as perfusion defects on first pass imaging. The signal from P792 was significantly higher in vasculature than that from Gd-DOTA between the first and the tenth minutes after injection. The results suggest that a CE-MRA PE could be reliably diagnosed up to 15 minutes after injection. CONCLUSION: P792 is superior to Gd-DOTA for the MR diagnosis of PE.

Type 1 collagen as an endovascular stent-graft material for small-diameter vessels: a biocompatibility study.

PURPOSE: To compare patency rates and degrees of neointimal hyperplasia between bovine type 1 collagen stent-grafts and uncovered control stents in small-diameter vessels (< or =4 mm). MATERIALS AND METHODS: Uncovered stainless-steel, balloon-expandable stents (n = 5) and type 1 collagen stent-grafts (n = 6) were implanted via the femoral arteries with use of 4-mm balloon catheters into the abdominal aorta of New Zealand White rabbits. Ten animals were available for follow-up. Subjects were followed for 1 month (three uncovered stents; three collagen stent-grafts) or 4 months (two uncovered stents; two collagen stent-grafts). Angiography was performed before animal sacrifice and luminal compromise was compared between groups. Histologic and immunohistochemical analysis was performed to determine presence of neointima and neointimal thickness and area; these parameters were also compared between groups. RESULTS: All stents and stent-grafts remained patent at both time points. Luminal compromise was not detectable angiographically in any subject. Maximum neointimal thickness was less than 5 mum for all subjects. Neointimal thickness and area were not statistically significantly different between groups. CONCLUSIONS: Type 1 collagen stent-grafts demonstrate excellent hemocompatibility and biocompatibility in small-diameter vessels in rabbits.

Na-K-2Cl cotransporter inhibition impairs human lung cellular proliferation.

The widespread presence of the Na-K-2Cl (NKCC) cotransporter protein suggests that chronic administration of inhibitors may result in adverse effects. Inhibition of the NKCC cotransporter by loop diuretics is felt to underlie the diuretic and the pulmonary smooth muscle relaxant effects of this drug class. However, the fundamental regulation of salt and water movement by this cotransporter suggests that it may also mediate cell volume changes occurring during cell cycle progression. Thus we hypothesized that NKCC cotransporter inhibition by loop diuretics would decrease cellular proliferation. Normal human bronchial smooth muscle cells (BSMC) showed a significant concentration-dependent decrease in cell counts after 7 days of exposure to both bumetanide (n=5-10) and furosemide (n=6-16) compared with controls. Proliferation was similarly inhibited in normal human lung fibroblasts (n=5-9). To determine whether this was due to loss of cells, we performed apoptosis assays on BSMC. Both annexin V-propidium iodide staining (n=5-10) and single cell gel electrophoresis assays (n=4) were negative for necrosis and apoptosis in BSMC exposed to 10 microM bumetanide. Subsequent analysis of the cell cycle by flow cytometry showed that bumetanide-exposed BSMC were delayed in G1 phase compared with controls (n=4-8). This is the first evidence for loop diuretic inhibition of airway smooth muscle cell proliferation. NKCC cotransporter inhibition impeded G1-S phase transition without facilitating cell death. Thus although inhibition by loop diuretics relaxes airway smooth muscle, the NKCC cotransporter may have a more important role in cell proliferation regulation.

Aneurysm growth, elastinolysis, and attempted doxycycline inhibition of elastase-induced aneurysms in rabbits.

PURPOSE: To establish the relationship between elastin degradation and aneurysm growth in New Zealand white rabbit model aneurysms, and to explore the potential for pharmacologic inhibition of elastinolysis and aneurysm growth with use of the matrix metalloproteinase (MMP) inhibitor doxycycline. MATERIALS AND METHODS: Elastase-induced, saccular aneurysms created in the right common carotid artery in 30 animals randomly divided into controls (n = 16) and doxycycline treated (n = 14) were studied. Aneurysm growth was determined by angiography and aneurysm specimens were collected at 7 and 14 days for histologic and immunohistochemical analysis. RESULTS: Aneurysms were characterized by marked elastin degradation and thickening of the arterial wall media in the absence of inflammatory cell markers. There was no evidence for expression of MMPs in the aneurysm wall at any time point. Aneurysm formation and growth were not prevented by the systemic administration of doxycycline. Mean aneurysm width increased from 3.1 +/- 0.7 mm at 3 days to 3.7 +/- 0.8 mm at 7 days and 4.2 +/- 0.8 mm at 14 days (P =.012 and P =.017, respectively). There was no statistically significant difference in aneurysm size and elastin content at any time point between doxycycline treated and control animals. CONCLUSION: Elastase-induced rabbit aneurysm formation is accompanied by total elastin destruction that was not inhibited by the administration of doxycycline. Aneurysms in this model may be caused by the initial infusion of elastase, rather than by ongoing degradation from endogenous proteases released by inflammatory cells.

A collagen-based coil for embolization of saccular aneurysms in a New Zealand White rabbit model.

BACKGROUND AND PURPOSE: In the treatment of cerebral aneurysms, platinum coils often fail to elicit a fibrotic response. We tested the hypothesis that a new, collagen-based endovascular coil would improve angiographic and histologic outcomes as compared with those achieved with platinum coils in a rabbit model of saccular aneurysms. METHODS: Elastase-induced aneurysms were created in 12 New Zealand White rabbits (body weight, 3-4 kg). Embolization was performed either by use of collagen-based coils (n = 6) or platinum coils (n = 6). In both coil groups, subjects were kept alive for either 2 weeks (n = 3 [collagen], n = 3 [platinum]) or 10 weeks (n = 3 [collagen], n = 3 [platinum]) after embolization and then were sacrificed. Digital subtraction angiography (DSA) was performed immediately after embolization and immediately before sacrifice. Postmortem histologic analysis of all coils was performed. RESULTS: Collagen-based coils were loosely packed in all cases because of limitations in size of coils available for embolization. In all six aneurysms packed with collagen-based coils, progressive thrombosis was noted at follow-up (DSA). Platinum coil samples were densely packed in all six cases. Progressive thrombosis was seen in one case, and interval regrowth was present in one case. Two weeks after embolization, collagen-based coil samples showed a marked peri-coil cellular response. Ten weeks after embolization, collagen-based samples had dense connective tissue matrix deposition in two of three cases. Platinum coils had unorganized thrombus at 2 weeks; loose-matrix deposition was only seen in the 10-week samples. Smooth muscle actin-positive cells were seen across the neck of the aneurysm in four of six collagen-based coil cases. CONCLUSION: Collagen-based coils show a marked cellular response in animal-model aneurysms, with resultant high rates of progressive occlusion after embolization. Dense matrix deposition is commonly seen with collagen-based coils. This contrasts with low rates of progressive thrombosis and high rates of loose matrix deposition seen with platinum coils.

New expandable hydrogel-platinum coil hybrid device for aneurysm embolization.

This study introduces a new, hybrid embolic device that in addition to offering all the important attributes of existing detachable platinum coils also shows an enhanced ability to fill aneurysm cavities. The device consists of a carrier platinum coil coupled to an expandable hydrogel material, which undergoes a ninefold increase in volume when placed into a physiological environment. Distinct from previous devices aimed at speeding the organization of thrombus, the new device has been designed to entirely fill the aneurysm cavity, with complete or near-complete exclusion of thrombus. Unlike thrombus, the hydrogel material is stable and unaffected by natural thrombolytic processes and thus may diminish observed rates of aneurysm recanalization. We report the angiographic and histologic findings of the new, hybrid device used to treat experimental aneurysms in rabbits.

Comparison of first-pass Gd-DOTA and FAIRER MR perfusion imaging in a rabbit model of pulmonary embolism.

PURPOSE: To compare the sensitivity of contrast-enhanced magnetic resonance imaging (MRI) and arterial spin labeling to perfusion deficits in the lung. MATERIALS AND METHODS: A rabbit model of pulmonary embolism was imaged with both flow-sensitive alternating inversion recovery with an extra radiofrequency pulse (FAIRER) arterial spin labeling and Gd-DOTA enhanced MRI. The signal-to-noise ratio (SNR) was measured in the area of the perfusion deficit and the normal lung for both techniques. RESULTS: The defect was readily visible in all images. The normal lung had an average of 3.8 +/- 1.2 times the SNR of the unperfused lung with the arterial spin labeling technique, and approximately 13.7 +/- 3.3 times the SNR with the contrast-enhanced technique. CONCLUSION: Gd-DOTA enhanced MRI provides higher SNR in pulmonary perfusion imaging; however, arterial spin labeling is also adequate and may be used when repeated studies are indicated.

Healing response in elastase-induced rabbit aneurysms after embolization with a new platinum coil system.

BACKGROUND AND PURPOSE: Elastase-induced rabbit aneurysms offer promise in preclinical testing, but their radiographic and histologic features after dense packing with platinum coils are unknown. We evaluated these features by using a new platinum coil system. METHODS: Right common carotid arterial (CCA) aneurysms were created in 17 rabbits by distal ligation and intraluminal elastase incubation. At least 3 weeks later, aneurysms were packed with detachable platinum coils. Animals were sacrificed at 2 (group 1, n=4), 4 (group 2, n=5), 12 (group 3, n=4), or 24 (group 4, n=4) weeks. Aneurysmal occlusion and coil compaction were angiographically assessed. Histologic features of tissue covering the coils and the aneurysmal dome were assessed and semiquantitatively compared across groups. RESULTS: No notable tracking, deployment, or detachment problems occurred. Volumetric occlusion was 5-49% (mean, 26.8% +/- 11%). Angiographic occlusion was 100% in six cases, 95% in four, and 90% in seven; occlusion scores remained unchanged in 13 cases, decreased in one, and increased in two (one case excluded from angiographic follow-up). Histologic findings were concordant within groups. Group 1 had coverage with thin fibrin layers and scattered leukocytes; group 2, some spindle-cell coverage; group 3, spindle-cell coverage. In groups 1 and 2, dome findings included only unorganized blood products. In group 3, blood products had been replaced with a hypocellular, poorly staining matrix. Some group 4 subjects had variably aged blood products, with tissue of limited organization. CONCLUSION: The platinum coil system performed well in experimental aneurysmal embolization. Densely packed rabbit aneurysms demonstrate reproducible histologic evolution: early fibrin coverage, delayed spindle-cell coverage, delayed intraaneurysmal thrombus resorption, and occasional coil compaction.

Elastase-induced saccular aneurysms in rabbits: a dose-escalation study.

BACKGROUND AND PURPOSE: Reproducible animal models facilitate preclinical assessment of aneurysm therapies. Our purpose was to determine if increased elastase doses enlarge aneurysms and parent arteries. METHODS: Rabbit right common carotid artery (CCA) aneurysms were created with distal ligation and intraluminal elastase incubation. Groups were 1) sham (no elastase, n = 3), 2) 25% elastase (10 minutes, n = 9), 3) 50% elastase (10 minutes, n = 7), and 4) 50% elastase (20 minutes, n = 41). Angiography was performed after 14 days. Resultant aneurysm width and height and parent artery diameters were measured and compared with the Student t or Mann-Whitney (Wilcoxon rank sum) test. RESULTS: Proximal segments were enlarged in all elastase subjects and no sham subjects. Mean measurements were significantly smaller in the sham group than in other groups. Aneurysm widths and heights, respectively, were 3.8 mm +/- 0.8 and 7.4 mm +/- 2.0 in the low-dose group; 3.9 mm +/- 1.3 and 8.5 mm +/- 3.8, medium-dose group; and 4.1 mm +/- 1.1 and 8.7 mm +/- 2.6, high-dose group. Differences were not significant. Parent artery widths were 3.5 mm +/- 0.7, 3.8 mm +/- 0.7, and 4.3 mm +/- 1.4 in the low-, medium-, and high-dose groups, respectively; the high-dose group had larger arteries (P =.07). CONCLUSION: Aneurysms were reliably created and were sized similar to human intracranial aneurysms. Elastase concentration and incubation duration did not affect resultant size. Relatively short incubation (eg, 10 minutes) and 25% elastase can be used to create rabbit aneurysms, especially if dilatation of adjacent parent arteries is to be avoided.