The cascading origin of the 2018 Kilauea eruption and implications for future forecasting.

The 2018 summit and flank eruption of Kilauea Volcano was one of the largest volcanic events in Hawai'i in 200 years. Data suggest that a backup in the magma plumbing system at the long-lived Pu'u 'O'o eruption site caused widespread pressurization in the volcano, driving magma into the lower flank. The eruption evolved, and its impact expanded, as a sequence of cascading events, allowing relatively minor changes at Pu'u 'O'o to cause major destruction and historic changes across the volcano. Eruption forecasting is inherently challenging in cascading scenarios where magmatic systems may prime gradually and trigger on small events.

The 2017-19 activity at Mount Agung in Bali (Indonesia): Intense unrest, monitoring, crisis response, evacuation, and eruption.

After 53 years of quiescence, Mount Agung awoke in August 2017, with intense seismicity, measurable ground deformation, and thermal anomalies in the summit crater. Although the seismic unrest peaked in late September and early October, the volcano did not start erupting until 21 November. The most intense explosive eruptions with accompanying rapid lava effusion occurred between 25 and 29 November. Smaller infrequent explosions and extrusions continue through the present (June 2019). The delay between intense unrest and eruption caused considerable challenges to emergency responders, local and national governmental agencies, and the population of Bali near the volcano, including over 140,000 evacuees. This paper provides an overview of the volcanic activity at Mount Agung from the viewpoint of the volcano observatory and other scientists responding to the volcanic crisis. We discuss the volcanic activity as well as key data streams used to track it. We provide evidence that magma intruded into the mid-crust in early 2017, and again in August of that year, prior to intrusion of an inferred dike between Mount Agung and Batur Caldera that initiated an earthquake swarm in late September. We summarize efforts to forecast the behavior of the volcano, to quantify exclusion zones for evacuations, and to work with emergency responders and other government agencies to make decisions during a complex and tense volcanic crisis.

The 2018 rift eruption and summit collapse of Kilauea Volcano.

In 2018, Kilauea Volcano experienced its largest lower East Rift Zone (LERZ) eruption and caldera collapse in at least 200 years. After collapse of the Pu'u 'O'o vent on 30 April, magma propagated downrift. Eruptive fissures opened in the LERZ on 3 May, eventually extending ~6.8 kilometers. A 4 May earthquake [moment magnitude (M w) 6.9] produced ~5 meters of fault slip. Lava erupted at rates exceeding 100 cubic meters per second, eventually covering 35.5 square kilometers. The summit magma system partially drained, producing minor explosions and near-daily collapses releasing energy equivalent to M w 4.7 to 5.4 earthquakes. Activity declined rapidly on 4 August. Summit collapse and lava flow volume estimates are roughly equivalent-about 0.8 cubic kilometers. Careful historical observation and monitoring of Kilauea enabled successful forecasting of hazardous events.

Adalimumab for refractory pulmonary sarcoidosis.

BACKGROUND: Ireland has one of the highest prevalence of sarcoidosis globally. Currently anti-TNF treatment in sarcoidosis is considered on a case-by-case basis particularly in patients who have a sub-optimal response to corticosteroid therapy. AIMS: We report our experience of Adalimumab in a series of refractory pulmonary sarcoidosis and discuss implications for treatment. CONCLUSION: Symptomatic improvement was found in all patients as well as stabilisation or improvement in DLCO sb. Improvements in pulmonary function tests correlated well to radiological stage and length of disease.

Single microbubble response using pulse sequences: initial results.

The study of acoustic scattering by single microbubbles has the potential to offer improved signal processing techniques. A microacoustic system that employs a hydrodynamically-focused flow was used to detect radiofrequency (RF) backscatter from single microbubbles. RF data were collected using a commercial scanner. Results are presented for two agents, namely Definity (Lantheus Medical Imaging, N. Billerica, MA, USA) and biSphere (Point Biomedical Corp, San Carlos, CA, USA). The agents were insonified with amplitude-modulated pulses, and it was observed in both agents that a subpopulation of microbubbles did not produce a measurable echo from the first-half amplitude pulse, but did produce a response from the full amplitude pulse and from a subsequent half amplitude pulse. The number of microbubbles in this subpopulation was seen to increase with increasing transmit amplitude. These results do not bear out the simple theory of microbubble-pulse sequence interaction and invite a reassessment of signal processing approaches.

Randomized comparison of the efficacy and safety of cerivastatin and pravastatin in 1,030 hypercholesterolemic patients. The Cerivastatin Study Group.

OBJECTIVE: To determine the relative efficacy and safety of cerivastatin and pravastatin in patients with type II hypercholesterolemia. PATIENTS AND METHODS: In this prospective, double-blind, parallel-group study, hypercholesterolemic patients were randomized to treatment with cerivastatin, 0.3 mg (n=250) or 0.4 mg (n=258), or pravastatin, 20 mg (n=266) or 40 mg (n=256), for 8 weeks. RESULTS: Cerivastatin, 0.3 mg, was significantly more effective than pravastatin, 20 mg, in reducing low-density lipoprotein (LDL) cholesterol from baseline (-29.6% vs -26.8%; P=.008). Cerivastatin, 0.4 mg, was significantly more effective than pravastatin, 40 mg, in reducing LDL cholesterol (-34.2% vs -30.3%; P<.001). A larger proportion of cerivastatin-treated patients had greater than 40% reductions in LDL cholesterol than those receiving pravastatin (11.1% vs 6.0%). The percentage of patients who achieved the National Cholesterol Education Program (NCEP) target was 71.3% with cerivastatin, 0.3 mg, compared with 67.5% with pravastatin, 20 mg, and 74.0% with cerivastatin, 0.4 mg, compared with 71.1% with pravastatin, 40 mg (no significant difference). Cerivastatin, 0.3 mg, reduced total cholesterol to a greater extent than did pravastatin, 20 mg (P<.03). Both agents reduced triglycerides and increased high-density lipoprotein cholesterol to a similar degree (no significant differences). Cerivastatin and pravastatin were well tolerated. CONCLUSIONS: Cerivastatin, 0.3 mg and 0.4 mg, showed greater efficacy than pravastatin, 20 mg and 40 mg, respectively, in lowering LDL cholesterol. Cerivastatin is safe and effective for patients with hypercholesterolemia who require aggressive LDL cholesterol lowering to achieve NCEP-recommended targets.

Efficacy and safety of cerivastatin and pravastatin in the treatment of primary hypercholesterolemia.

In this randomized, double-blind, parallel group study, the efficacy and safety of cerivastatin (0.3 mg) and pravastatin (20 mg) were compared in 402 patients with primary hypercholesterolemia with and without documented coronary heart disease or peripheral vascular disease. After 8 weeks of treatment, cerivastatin provided significantly greater reductions than pravastatin in low-density lipoprotein (LDL)-cholesterol (31.1% vs. 26.0%; p < 0.0001) and total cholesterol (21.1% vs. 17.8%; p < 0.0001). A greater proportion of patients treated with cerivastatin than pravastatin achieved > 30% and > 40% reductions from baseline in LDL-cholesterol. Both agents also increased high density lipoprotein-cholesterol and reduced triglycerides. Overall, 65.1% of patients treated with cerivastatin and 63.3% of patients with pravastatin achieved LDL-cholesterol goals defined by the National Cholesterol Education Program. Both drugs were well tolerated, with most adverse events being mild. These results demonstrate that cerivastatin (0.3 mg) is a highly effective 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor, which enables a large proportion of patients to achieve clinically meaningful reductions in LDL-cholesterol.

The PRESTO (Prevention of restenosis with tranilast and its outcomes) protocol: a double-blind, placebo-controlled trial.

BACKGROUND: Tranilast is a unique drug in clinical development for the prevention of restenosis after percutaneous transluminal coronary revascularization (PTCR). Tranilast interferes with proliferation and migration of vascular medial smooth muscle cells induced by platelet-derived growth factor and transforming growth factor beta1. Collagen synthesis in vascular medial smooth muscle cells is inhibited by tranilast, which also inhibits the release or production of cyclooxygenase-2 and restores cytokine-induced nitric oxide production. These mechanisms may contribute to the reduction of angiographic restenosis after coronary intervention previously reported in clinical studies. METHODS: The primary objective of this multicenter study of 11,500 patients is to compare the composite clinical event rate of death, myocardial infarction, or the need for ischemia-driven target vessel revascularization of tranilast (300 and 450 mg twice daily) for 1 or 3 months with that of placebo in patients undergoing PTCR with or without stenting for single or multiple vessels over a 9-month period. The lesions can be de novo or restenotic. All revascularization procedures and the use of glycoprotein IIb/IIIa agents are permitted. The inclusion criteria are meant to allow an "all comer" approach for generalization of results to the broadest possible PTCR population. A subset population (n = 2000) will undergo 9-month follow-up angiography, 1000 of which will also undergo intravascular ultrasound (n = 1000). This study is the first tranilast trial to be conducted in a Western population to confirm the improved angiographic findings reported in Japanese patients and to determine if the clinical sequelae of restenosis are also reduced. CONCLUSION: This multicenter study is the largest restenosis trial planned to date. It will test whether tranilast, a drug with multiple actions aimed at affecting proliferation and migration of vascular smooth muscle cells, can reduce clinical, angiographic, and intravascular ultrasound assessments of restenosis.

Activation of RhoA by lysophosphatidic acid and Galpha12/13 subunits in neuronal cells: induction of neurite retraction.

Neuronal cells undergo rapid growth cone collapse, neurite retraction, and cell rounding in response to certain G protein-coupled receptor agonists such as lysophosphatidic acid (LPA). These shape changes are driven by Rho-mediated contraction of the actomyosin-based cytoskeleton. To date, however, detection of Rho activation has been hampered by the lack of a suitable assay. Furthermore, the nature of the G protein(s) mediating LPA-induced neurite retraction remains unknown. We have developed a Rho activation assay that is based on the specific binding of active RhoA to its downstream effector Rho-kinase (ROK). A fusion protein of GST and the Rho-binding domain of ROK pulls down activated but not inactive RhoA from cell lysates. Using GST-ROK, we show that in N1E-115 neuronal cells LPA activates endogenous RhoA within 30 s, concomitant with growth cone collapse. Maximal activation occurs after 3 min when neurite retraction is complete and the actin cytoskeleton is fully contracted. LPA-induced RhoA activation is completely inhibited by tyrosine kinase inhibitors (tyrphostin 47 and genistein). Activated Galpha12 and Galpha13 subunits mimic LPA both in activating RhoA and in inducing RhoA-mediated cytoskeletal contraction, thereby preventing neurite outgrowth. We conclude that in neuronal cells, LPA activates RhoA to induce growth cone collapse and neurite retraction through a G12/13-initiated pathway that involves protein-tyrosine kinase activity.

Effect of nabumetone on hemostasis during arthroscopic knee surgery.

The known effects of commonly used nonsteroidal anti-inflammatory drugs (NSAIDs) on hemostatic parameters have led to concern over their use in the perioperative period. Nabumetone, unlike other NSAIDs, has little effect on collagen-induced platelet aggregation. To evaluate the effect of nabumetone 2000 mg daily on other hemostatic parameters (e.g., bleeding time, prothrombin time, and partial thromboplastin time) in the clinical setting, this double-masked study was conducted in patients with osteoarthritis undergoing arthroscopic knee surgery. After a 1-week placebo washout period, 58 patients were randomized to receive nabumetone and 53 were randomized to receive placebo. They were assessed before surgery (after 1 to 2 weeks of treatment) and again after surgery (after an additional 3 weeks of treatment). The study was designed to have 90% power to show equivalence in bleeding time to within 1.5 minutes, a difference assumed to be of no clinical importance. No meaningful differences were observed between the groups in any of the measured hemostatic parameters. Before surgery, the bleeding time increased by only 0.3 minutes with nabumetone and decreased by 0.2 minutes with placebo. The mean (+/- SD) difference between the groups in change from baseline was 0.5 +/- 0.3 minutes. After surgery, the changes were 0.1 minutes and 0.0 minutes, respectively, and the difference between groups was 0.2 +/- 0.3 minutes. These differences were neither statistically nor clinically significant, and maximum individual increases were similar in each group. Furthermore, there were no reports of abnormal bleeding in the operative knees. The results of this study show that nabumetone had little or no effect on hemostasis and suggest that this drug can be used safely in the perioperative period.

Dissociation of LPA-induced cytoskeletal contraction from stress fiber formation by differential localization of RhoA.

Addition of lysophosphatidic acid (LPA) to serum-deprived N1E-115 neuronal cells results in rapid f-actin assembly accompanied by neurite retraction and rounding of the cell body due to contraction of the cortical actin cytoskeleton. LPA action is mimicked by activated RhoA, while it is blocked by dominant-negative RhoA (N19RhoA) and the Rho-inactivating C3 toxin. Using immunofluorescence analysis and high speed centrifugation we show that activated RhoA is localized to the plasma membrane. Wild-type RhoA and N19RhoA, however, are mainly cytosolic. We find that LPA-induced shape changes are preceded by translocation of RhoA from the cytosol to the cell periphery. LPA also stimulates translocation of inactive N19RhoA in the absence of ensuing shape changes. When membrane localization of RhoA is prevented by lovastatin, an inhibitor of protein isoprenylation, or by CAAX motif mutation, cytoskeletal contraction is blocked. However, the assembly of f-actin into stress fibers is not affected under these conditions. The effects of both LPA and activated RhoA are blocked by tyrosine kinase inhibitors (herbimycin, genistein, tyrphostin), but not by dominant-negative Src. We conclude that: (1) LPA-induced cytoskeletal contraction, but not stress fiber formation, requires translocation of RhoA from the cytosol to the plasma membrane; (2) translocation of RhoA occurs independently of its activation; and (3), a non-Src tyrosine kinase is involved in RhoA-stimulated contractility.

Comparative effects of nabumetone, sulindac, and ibuprofen on renal function.

OBJECTIVE: Nonsteroidal antiinflammatory drugs (NSAID) have been associated with hemodynamically mediated acute renal failure. There appear to be differences among NSAID in producing this effect. We compare renal effects of ibuprofen, sulindac, and nabumetone. METHODS: Seventeen women over age 56 receiving hydrochlorothiazide and fosinopril for hypertension who had osteoarthritis requiring NSAID received 3 different NSAID to evaluate potential varying renal effects. In an investigator blinded randomized study, patients received nabumetone, sulindac, or ibuprofen for 1 month with intervening 2 week control periods. After each period renal function was assessed by inulin and para-aminohippurate clearances and urinary prostaglandins were measured. RESULTS: No overall statistical differences among the NSAID were observed. However, there were clinically meaningful differences during ibuprofen therapy: 4 patients developed a clinically significant decrease in renal function; during sulindac therapy one of these also developed a clinically significant decrease in renal function. During nabumetone there were 0 episodes of clinically significant decrease in renal function. Using Gomez equations, glomerular hydrostatic pressure and afferent and efferent arteriolar resistances were estimated. None changed overall during any intervention. However, the 4 patients who developed decreased renal function while taking ibuprofen were analyzed separately. Glomerular hydrostatic pressure decreased 15%; afferent arteriolar resistance increased 85%. These changes were associated with marked decreases in vasodilatory prostaglandins compared to patients receiving ibuprofen who did not develop decreases in renal function. CONCLUSION: There are differences in effect on renal function among NSAID. These can be correlated with specific alterations in suppression of the cyclooxygenase system cascade and related to changes in the hemodynamic control of glomerular filtration.

Identification of a novel, putative Rho-specific GDP/GTP exchange factor and a RhoA-binding protein: control of neuronal morphology.

The small GTP-binding protein Rho has been implicated in the control of neuronal morphology. In N1E-115 neuronal cells, the Rho-inactivating C3 toxin stimulates neurite outgrowth and prevents actomyosin-based neurite retraction and cell rounding induced by lysophosphatidic acid (LPA), sphingosine-1-phosphate, or thrombin acting on their cognate G protein-coupled receptors. We have identified a novel putative GDP/GTP exchange factor, RhoGEF (190 kD), that interacts with both wild-type and activated RhoA, but not with Rac or Cdc42. RhoGEF, like activated RhoA, mimics receptor stimulation in inducing cell rounding and in preventing neurite outgrowth. Furthermore, we have identified a 116-kD protein, p116(Rip), that interacts with both the GDP- and GTP-bound forms of RhoA in N1E-115 cells. Overexpression of p116(Rip) stimulates cell flattening and neurite outgrowth in a similar way to dominant-negative RhoA and C3 toxin. Cells overexpressing p116(Rip) fail to change their shape in response to LPA, as is observed after Rho inactivation. Our results indicate that (a) RhoGEF may link G protein-coupled receptors to RhoA activation and ensuing neurite retraction and cell rounding; and (b) p116(Rip) inhibits RhoA-stimulated contractility and promotes neurite outgrowth.

Safety experience with nabumetone versus diclofenac, naproxen, ibuprofen, and piroxicam in osteoarthritis and rheumatoid arthritis.

The comparative safety of nabumetone (1,000-2,000 mg/day) versus diclofenac (100-200 mg/day), naproxen (500-1,500 mg/day), piroxicam (10-20 mg/day), and ibuprofen (1,200-3,200 mg/day) was evaluated in a 12-week, randomized, open-label, multicenter study. Patients with osteoarthritis (OA) or rheumatoid arthritis (RA) were enrolled in a 3:1 ratio (nabumetone:one of the four comparator NSAIDs). The incidence of > or = 1 adverse event considered by the investigator to be related or probably related to therapy was similar in all groups. However, significantly (p < 0.02) more diclofenac-treated patients experienced abdominal pain and/or gastritis than nabumetone-treated patients. Naproxen-treated patients experienced significantly (p < 0.002) more dyspepsia as compared with patients treated with nabumetone or ibuprofen and significantly (p < or = 0.001) more nabumetone-treated patients experienced diarrhea than patients treated with naproxen, ibuprofen, or piroxicam. Ulcers occurred in one (0.03%) nabumetone-treated patient versus six (0.5%) patients treated with one of the comparator NSAIDs (p = 0.001). A decrease in hemoglobin > or = 1.5 g/dL occurred in fewer nabumetone-treated patients than in patients treated with diclofenac (p < 0.04), ibuprofen (p < or = 0.04), or piroxicam (p = 0.055). Finally, a similar percentage of patients in all treatment groups withdrew from the study because of adverse events related or probably related to treatment. More (p < 0.001) diclofenac-treated patients withdrew because of elevated hepatic transaminases than patients treated with the other agents. Withdrawal because of gastritis was also noted for more diclofenac-treated patients than nabumetone-treated patients (p < 0.04). In conclusion, nabumetone was demonstrated to be at least as safe as diclofenac, piroxicam, ibuprofen, and naproxen as related to subjective complaints, such as dyspepsia or gastritis. However, more serious events, such as ulcers or meaningful decreases in hemoglobin, seem to occur less often with nabumetone.

Efficacy and safety of nabumetone versus diclofenac, naproxen, ibuprofen, and piroxicam in the elderly.

In a randomized, open-label, controlled, multicenter, 12-week study, the efficacy and safety of nabumetone (1,000-2,000 mg/day) versus diclofenac (100-200 mg/day), naproxen (500-1,500 mg/day), ibuprofen (1,200-3,200 mg/day), or piroxicam (10-20 mg/day) were evaluated in patients with osteoarthritis (OA) or rheumatoid arthritis (RA). The results in elderly patients (> or = 65 years of age) are presented. Nabumetone was as effective as the comparator nonsteroidal antiinflammatory drugs (NSAIDs) in the treatment of elderly OA and RA patients. Ibuprofen and diclofenac caused significantly (p < 0.05) more abdominal pain than nabumetone (8.5%, 13.1%, and 4.1%, respectively). The frequency of abdominal pain was dose related for all NSAIDs except nabumetone. Diarrhea was reported by significantly (p < 0.02) more nabumetone-treated (6.6%) than ibuprofen-treated (0.9%) elderly patients, but the incidence of diarrhea was not dose related. There were no clinically significant changes in renal function with nabumetone or the comparator NSAIDs. A significant change in hepatic enzymes occurred in elderly patients treated with diclofenac (3.3%), which was different than for patients treated with nabumetone (p < 0.04), naproxen (p < 0.06), or ibuprofen (p < 0.06). With regard to withdrawals for adverse events, more (p < 0.04) piroxicam-treated patients (4.9%) withdrew than nabumetone-treated patients (1%). In addition, doubling the dose of nabumetone from 1,000 mg/day to 2,000 mg/day did not result in a proportional increase in adverse events. However, with the comparator NSAIDs, proportional increases in adverse events occurred with increased dose. Finally, the efficacy and safety of nabumetone in elderly patients were similar to the efficacy and safety observed in nonelderly patients.

Efficacy of nabumetone versus diclofenac, naproxen, ibuprofen, and piroxicam in osteoarthritis and rheumatoid arthritis.

The efficacy of nabumetone was compared with that of diclofenac, naproxen, ibuprofen, and piroxicam in patients with osteoarthritis (OA) or rheumatoid arthritis (RA) in a randomized, controlled, open-label, multicenter trial. Patients > or = 18 years with clinical and radiographic evidence of OA or RA (functional class I, II, or III), who provided written informed consent, were eligible. To mimic real-life therapy, no washout phase preceded randomization. Eligible patients were assigned in a 3:1 ratio to receive nabumetone or a comparator NSAID for 12 weeks. Thus a total of 4,411 eligible patients were randomized to receive nabumetone (N = 3,315) or one of the comparator NSAIDs (N = 1,096). Initial daily doses were: nabumetone, 1,000 mg; diclofenac, 100 mg; naproxen, 500 mg; ibuprofen, 1,200 mg; piroxicam, 10 mg. Dosage increases were permitted after a 2-week trial period. All patients were evaluated at baseline, and at 4 and 12 weeks. Of all patients randomized, approximately 46% had RA and approximately 54% had OA. Demographic characteristics were similar for the nabumetone and comparator NSAID treatment groups. In OA, nabumetone was as effective as the comparator NSAIDs in the physician and patient global assessments of disease activity, in improving the Activities and Lifestyle Index, and in decreasing the degree of pain. There was no significant difference in the percentage of patients withdrawn for lack of efficacy when treated with nabumetone or one of the comparator NSAIDs. In contrast, nabumetone was significantly (p < or = 0.02) more effective than the comparator NSAIDs in RA patients for the global assessments of disease activity, pain relief, and improving the Activities and Lifestyle Index, primarily due to the poor response in the ibuprofen and piroxicam treatment groups. Furthermore, fewer nabumetone-treated RA patients (8.8%) withdrew for lack of efficacy than those treated with diclofenac (10.3%), naproxen (11%), piroxicam (13.5%), or ibuprofen (13.2%). In conclusion, in a large, randomized, open-label trial that mimicked real-life therapy, nabumetone was as effective as diclofenac, naproxen, piroxicam, and ibuprofen for the treatment of patients with OA. However, in RA, nabumetone was significantly more effective than the comparator NSAIDs, and fewer patients were withdrawn because of lack of efficacy.

Punishing pregnant drug users: enhancing the flight from care.

One hundred forty-two low income women were interviewed postpartum to determine their attitudes regarding the potential effects of a punitive law on the behavior of substance-using pregnant women. The convenience sample was primarily black (85.2%) and single (81%) and 14.8% admitted use of illicit drugs during pregnancy. A goodness-of-fit chi-square analysis revealed that subjects believed a punitive law would be a significant deterrent to substance-using gravida seeking prenatal care, drug testing or drug treatment (P < 0.01). Comments indicated that substance-using pregnant women would 'go underground' to avoid detection and treatment for fear of incarceration and loss of their children.