Respiratory Syncytial Virus (RSV) causes lower respiratory tract infections that can be severe and sometimes fatal. The risk for severe RSV infection is highest in infants and older adults. A safe ...and effective RSV vaccine for older adults represents a serious unmet medical need due to higher morbidity and mortality in this age group. In this randomized, partially double-blind, placebo-controlled, phase 1 dose-escalation study, we evaluated the safety, tolerability and immunogenicity of an investigational messenger ribonucleic acid (mRNA) vaccine encoding the RSV fusion protein (F) stabilized in the prefusion conformation. The study was conducted in healthy younger adults (ages ≥18 and ≤49 years) and healthy older adults (ages ≥60 and ≤79 years). Participants received mRNA-1777 (V171) or placebo as a single intramuscular dose. For each dose level, three sentinel participants were administered open-label mRNA-1777 (V171). Seventy-two younger adults were randomized and administered 25, 100, or 200 µg mRNA-1777 (V171) or placebo, and 107 older adults were randomized and administered 25, 100, 200 or 300 µg mRNA-1777 (V171) or placebo. Primary objectives were safety and tolerability and secondary objectives included humoral and cell-mediated immunogenicity. All dose levels of mRNA-1777 (V171) were generally well tolerated and no serious adverse events related to the vaccine were reported. Immunization with mRNA-1777 (V171) elicited a humoral immune response as measured by increases in RSV neutralizing antibody titers, serum antibody titers to RSV prefusion F protein, D25 competing antibody titers to RSV prefusion F protein, and cell-mediated immune responses to RSV-F peptides.
Proteasome substrate receptor hRpn13 is a promising anti-cancer target. By integrated in silico and biophysical screening, we identified a chemical scaffold that binds hRpn13 with non-covalent ...interactions that mimic the proteasome and a weak electrophile for Michael addition. hRpn13 Pru domain binds proteasomes and ubiquitin whereas its DEUBAD domain binds deubiquitinating enzyme UCHL5. NMR revealed lead compound XL5 to interdigitate into a hydrophobic pocket created by lateral movement of a Pru β-hairpin with an exposed end for Proteolysis Targeting Chimeras (PROTACs). Implementing XL5-PROTACs as chemical probes identified a DEUBAD-lacking hRpn13 species (hRpn13
) present naturally with cell type-dependent abundance. XL5-PROTACs preferentially target hRpn13
, causing its ubiquitination. Gene-editing and rescue experiments established hRpn13 requirement for XL5-PROTAC-triggered apoptosis. These data establish hRpn13 as an anti-cancer target for multiple myeloma and introduce an hRpn13-targeting scaffold that can be optimized for preclinical trials against hRpn13
-producing cancer types.
This phase I dose-escalation trial was performed to determine the maximum-tolerated dose, dose-limiting toxicities, and pharmacokinetics of CPX-351.
CPX-351 induction was administered on days 1, 3, ...and 5 by 90-minute infusion to 48 relapsed or refractory patients with acute myeloid leukemia (AML) or high-risk myelodysplasia. Doses started at 3 units/m(2) with dose doublings in single-patient cohorts until a pharmacodynamic effect (treatment-related adverse events or reduction in bone marrow cellularity or blast count) was observed, followed by 33% escalations in three patient cohorts until dose-limiting toxicity (DLT) occurred.
The maximum-tolerated dose was 101 units/m(2). DLTs consisted of hypertensive crisis, congestive heart failure, and prolonged cytopenias. Adverse events were consistent with cytarabine and daunorubicin treatment. Response occurred at doses as low as 32 units/m(2). Of 43 patients with AML, nine had complete response (CR) and one had CR with incomplete platelet recovery; of patients with acute lymphoblastic leukemia, one of three had CR. Eight CRs were achieved among the 31 patients with prior cytarabine and daunorubicin treatment. CR in AML occurred in five of 26 patients age ≥ 60 years and in five of 17 patients younger than age 60 years. Median half-life was 31.1 hours (cytarabine) and 21.9 hours (daunorubicin), with both drugs and their metabolites detectable > 7 days after the last dose. The targeted 5:1 molar ratio was maintained at all dose levels for up to 24 hours.
The recommended dose of CPX-351 for phase II study is 101 units/m(2). Further exploration of efficacy and safety is ongoing in phase II trials in newly diagnosed and first-relapse patients with AML.
Background Patients undergoing tricuspid valve surgery have a mortality of 9.8%, which is higher than expected given the complexity of the procedure. Despite liver dysfunction seen in many patients ...with tricuspid disease, no existing risk model accounts for this. The Model for End-Stage Liver Disease (MELD) score accurately predicts mortality for abdominal surgery. The objective of this study was to determine if MELD could accurately predict mortality after tricuspid valve surgery and compare it to existing risk models. Methods From 1994 to 2008, 168 patients (mean age, 61 ± 14 years; male = 72, female = 96) underwent tricuspid repair (n = 156) or replacement (n = 12). Concomitant operations were performed in 87% (146 of 168). Patients with history of cirrhosis or MELD score 15 or greater (MELD = 3.8*LN total bilirubin + 11.2*log normal international normalized ratio + 9.6*log normal creatinine + 6.4) were compared with patients without liver disease or MELD score less than 15. Preoperative risk, intraoperative findings, and complications including operative mortality were evaluated. Statistical analyses were performed using χ2 , Fisher's exact test, and area under the curve (AUC) analyses. Results Patients with a history of liver disease or MELD score of 15 or greater had significantly higher mortality (18.9% 7 of 37 versus 6.1% 8 of 131, p = 0.024). To further characterize the effect of MELD, patients were stratified by MELD alone. No major differences in demographics or operation were identified between groups. Mortality increased as MELD score increased, especially when MELD score of 15 or greater ( p = 0.0015). A MELD score less than 10, 10 to 14.9, 15 to 19.9, and more than 20 was associated with operative mortality of 1.9%, 6.8%, 27.3%, and 30.8%, respectively. By multivariate analysis, MELD score of 15 or greater remained strongly associated with mortality ( p = 0.0021). The MELD score predicted mortality (AUC = 0.78) as well as the European System for Cardiac Operative Risk Evaluation logistic risk calculator (AUC = 0.78, p = 0.96). Conclusions The MELD score predicts mortality in patients undergoing tricuspid valve surgery and offers a simple and effective method of risk stratification in these patients.
Data on the amount and type of small debris items deposited on the beaches of the Hawaiian Islands National Wildlife Refuge Tern Island station, French Frigate Shoals were collected over 16 years. We ...calculated deposition rates and investigated the relationship among deposition and year, season, El Niño and La Niña events from 1990 to 2006. In total 52,442 debris items were collected with plastic comprising 71% of all items collected. Annual debris deposition varied significantly (range 1116–5195 items) but was not influenced by season. Debris deposition was significantly greater during El Niño events as compared to La Niña events. Although often deduced to influence floating marine pollution, this study provides the first quantitative evidence of the influence of El Niño/La Niña cycles on marine debris deposition.
OBJECTIVE:To determine the steroid-sparing effect of methotrexate (MTX) in patients with symptomatic generalized myasthenia gravis (MG).
METHODS:We performed a 12-month multicenter, randomized, ...double-blind, placebo-controlled trial of MTX 20 mg orally every week vs placebo in 50 acetylcholine receptor antibody–positive patients with MG between April 2009 and August 2014. The primary outcome measure was the prednisone area under the dose-time curve (AUDTC) from months 4 to 12. Secondary outcome measures included 12-month changes of the Quantitative Myasthenia Gravis Score, the Myasthenia Gravis Composite Score, Manual Muscle Testing, the Myasthenia Gravis Quality of Life, and the Myasthenia Gravis Activities of Daily Living.
RESULTS:Fifty-eight patients were screened and 50 enrolled. MTX did not reduce the month 4–12 prednisone AUDTC when compared to placebo (difference MTX − placebo−488.0 mg, 95% confidence interval −2,443.4 to 1,467.3, p = 0.26); however, the average daily prednisone dose decreased in both groups. MTX did not improve secondary measures of MG compared to placebo over 12 months. Eight participants withdrew during the course of the study (1 MTX, 7 placebo). There were no serious MTX-related adverse events. The most common adverse event was nonspecific pain (19%).
CONCLUSIONS:We found no steroid-sparing benefit of MTX in MG over 12 months of treatment, despite being well-tolerated. This study demonstrates the challenges of conducting clinical trials in MG, including difficulties with recruitment, participants improving on prednisone alone, and the need for a better understanding of outcome measure variability for future clinical trials.
CLASSIFICATION OF EVIDENCE:This study provides Class I evidence that for patients with generalized MG MTX does not significantly reduce the prednisone AUDTC over 12 months of therapy.
Abstract Objective The purpose of this study was to determine whether use of chiropractic manipulative treatment (CMT) was associated with lower healthcare costs among multiply-comorbid Medicare ...beneficiaries with an episode of chronic low back pain (cLBP). Methods We conducted an observational, retrospective study of 2006 to 2012 Medicare fee-for-service reimbursements for 72 326 multiply-comorbid patients aged 66 and older with cLBP episodes and 1 of 4 treatment exposures: chiropractic manipulative treatment (CMT) alone, CMT followed or preceded by conventional medical care, or conventional medical care alone. We used propensity score weighting to address selection bias. Results After propensity score weighting, total and per-episode day Part A, Part B, and Part D Medicare reimbursements during the cLBP treatment episode were lowest for patients who used CMT alone; these patients had higher rates of healthcare use for low back pain but lower rates of back surgery in the year following the treatment episode. Expenditures were greatest for patients receiving medical care alone; order was irrelevant when both CMT and medical treatment were provided. Patients who used only CMT had the lowest annual growth rates in almost all Medicare expenditure categories. While patients who used only CMT had the lowest Part A and Part B expenditures per episode day, we found no indication of lower psychiatric or pain medication expenditures associated with CMT. Conclusions This study found that older multiply-comorbid patients who used only CMT during their cLBP episodes had lower overall costs of care, shorter episodes, and lower cost of care per episode day than patients in the other treatment groups. Further, costs of care for the episode and per episode day were lower for patients who used a combination of CMT and conventional medical care than for patients who did not use any CMT. These findings support initial CMT use in the treatment of, and possibly broader chiropractic management of, older multiply-comorbid cLBP patients.
Objectives Severe reperfusion injury after lung transplantation has mortality rates approaching 40%. The purpose of this investigation was to identify whether our improved 1-year survival after lung ...transplantation is related to a change in reperfusion injury. Methods We reported in March 2000 that early institution of extracorporeal membrane oxygenation can improve lung transplantation survival. The records of consecutive lung transplant recipients from 1990 to March 2000 (early era, n = 136) were compared with those of recipients from March 2000 to August 2006 (current era, n = 155). Reperfusion injury was defined by an oxygenation index of greater than 7 (where oxygenation index = Percentage inspired oxygen × Mean airway pressure/Partial pressure of oxygen). Risk factors for reperfusion injury, treatment of reperfusion injury, and 30-day mortality were compared between eras by using χ2 , Fisher's, or Student's t tests where appropriate. Results Although the incidence of reperfusion injury did not change between the eras, 30-day mortality after lung transplantation improved from 11.8% in the early era to 3.9% in the current era ( P = .003). In patients without reperfusion injury, mortality was low in both eras. Patients with reperfusion injury had less severe reperfusion injury ( P = .01) and less mortality in the current era (11.4% vs 38.2%, P = .01). Primary pulmonary hypertension was more common in the early era (10% 14/136 vs 3.2% 5/155, P = .02). Graft ischemic time increased from 223.3 ± 78.5 to 286.32 ± 88.3 minutes in the current era ( P = .0001). The mortality of patients with reperfusion injury requiring extracorporeal membrane oxygenation improved in the current era (80.0% 8/10 vs 25.0% 3/12, P = .01). Conclusion Improved early survival after lung transplantation is due to less severe reperfusion injury, as well as improvements in survival with extracorporeal membrane oxygenation.
Liposomal encapsulation of doxorubicin is designed to increase safety and tolerability by decreasing cardiac and gastrointestinal toxicity through decreased exposure of these tissues to doxorubicin, ...while effectively delivering drug to the tumor. We conducted an open-label phase I study to determine the pharmacokinetic profile of a single dose of liposome-encapsulated doxorubicin (Myocet) in patients with various solid tumors. Safety and tolerability were monitored.
Patients received a single intravenous infusion of Myocet 75 mg/m2. Plasma samples were analyzed for concentration of liposome-encapsulated doxorubicin, total doxorubicin, and doxorubicinol.
A total of 18 patients aged 20-73 years (median 60 years) participated; 17 were evaluable for pharmacokinetic analysis. The most common primary tumor was soft tissue sarcoma (22%). Total body clearance for total doxorubicin was 5.6 l/h/m2 while the volume (Vss) was 82 l/m2. The terminal half-life was 52.6 h. Based on the AUC and Cmax values for total doxorubicin and encapsulated doxorubicin, an estimated 85% of circulating doxorubicin was encapsulated. Doxorubicinol was detected in all patients; the mean AUC was 2.03+/-1.10 micromol/l/h. The mean 48-h urinary excretion of doxorubicin was 6.44% of the dose. The most common adverse events were nausea (94%), fatigue (78%) and vomiting (67%). Cardiotoxicity (measured as ten-point fall in LVEF to <50%) was observed in one patient. Pharmacokinetic values did not correlate with hematological, laboratory or demographic variables.
The pharmacokinetic profile of Myocet suggests that the liposomal formulation results in a longer half-life with less free drug available for tissue distribution than conventional doxorubicin, consistent with the enhanced therapeutic index observed in clinical studies.
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