Chronic kidney disease is associated with increased mortality and procedural complications in transcatheter aortic valve replacement: a systematic review and meta‐analysis

ObjectiveWe performed a systematic review and meta‐analysis to explore the association between chronic kidney disease (CKD) and mortality and procedural complications in transcatheter aortic valve replacement (TAVR).BackgroundThe impact of varying stages of CKD or end‐stage renal disease (ESRD) on patients receiving TAVR is not clearly identified.MethodsWe searched the databases of MEDLINE and EMBASE from inception to May 2018. Included studies were published TAVR studies that compared the risk of mortality and procedural complications in CKD patients compared to control patients. Data from each study were combined using the random‐effects model.ResultsTwelve studies (42,703 CKD patients and 51,347 controls) were included. Compared with controls, CKD patients had a significantly higher risk of 30‐day overall mortality (risk ratio [RR] = 1.56, 95% confidence interval [CI]: 1.34–1.80, I2 = 60.9), long‐term cardiovascular mortality (RR = 1.44, 95% CI: 1.22–1.70, I2 = 36.2%), and long‐term overall mortality (RR = 1.66, 95% CI: 1.45–1.91, I2 = 80.3), as well as procedural complications including pacemaker requirement (RR = 1.20, 95% CI: 1.03–1.39, I2 = 56.1%) and bleeding (RR = 1.60, 95% CI: 1.26–2.02, I2 = 86.0%). Risk of mortality and procedural complications increased with severity of CKD for stages 3, 4, and 5, respectively, in terms of long‐term overall mortality (RR = 1.28, 1.82, and 2.12), 30‐day overall mortality (RR = 1.26, 1.89, and 1.93), 30‐day cardiovascular mortality (RR = 1.18, 1.75, and 2.50), and 30‐day overall bleeding (RR = 1.19, 1.63, and 2.12).ConclusionsOur meta‐analysis demonstrates a significant increased risk of mortality and procedural complications in patients with CKD who underwent TAVR compared to controls.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/151278/1/ccd28102_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/151278/2/ccd28102.pd

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Not AvailableViperin, also known as radical S-adenosyl methionine domain-containing protein (RSAD2) is a multifunctional interferon-stimulated gene (ISG) that is activated during the viral infections. Viperin belongs to S-adenosyl methionine (SAM) superfamily of enzymes known to catalyze radical-mediated reactions and viperin inhibits a wide range of DNA and RNA viruses through its broad range of activity. The present study reports cloning and expression of bovine viperin in a bacterial expression system. PCR-based site-directed mutagenesis was carried out for deletion of N-terminal 1–70 amino acid containing amphipathic helix of viperin that interferes in protein expression and purification. The resultant truncated viperin protein was expressed in Escherichia coli, BL-21(DE3) competent cells and purified using nickel charged affinity column. The truncated 54 kDa protein was confirmed by western blot using human RSAD2 as a probe. Further, in house, hyperimmune serum was raised against the truncated viperin in the rabbit and the reactivity was confirmed by western blot using mammalian expression vector construct of viperin transfected in Baby Hamster kidney (BHK) cells and in MDBK cells infected with Foot and Mouth disease Asia I virus.Not Availabl

Association for Computational Linguistics: Human Language Technologies

[No abstract available

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Not AvailableFoot and mouth disease virus (FMDV) causes an economically devastating, contagious viral disease in cloven-hoofed animals. Macrophages are potent mediators of innate immune responses against viruses. The macrophage-FMDV interaction is not studied in detail, especially the innate immune responses to the virus. Here, we investigated the effects of experimental infection of FMDV on bovine monocyte-derived macrophages (MDM). The detection of negative-strand FMDV RNA by strand specific RT-PCR and demonstration of viral antigen by immunofluorescence indicated the replication of FMDV RNA and synthesis of viral proteins, respectively in the infected MDM. However, replication kinetic experiments revealed that the copy number of FMDV transcripts and virus titration peaked at 12 hpi with subsequent reduction, indicating non-progressive replication. FMDV infection upregulated the expression of RIG1 and MDA5 in MDM, suggests that the FMDV RNA are sensed by RLRs. In addition, nearly 75% of the infected MDM differentiated into M1 phenotype, characterized by the increased expression of M1-specific markers; CD80, iNOS and proinflammatory cytokines such as TNFα and IL12. The infection induced the expression of Type I IFNs, which coincided with the decline in the viral RNA and progeny virus after 12 hpi. In addition, infected MDM abundantly expressed ISGs such as PKR, OAS1, Mx1 and viperin against FMDV infection at 12 hpi. In conclusion, FMDV underwent a non-progressive replication in the bovine MDM that might be due to induction of M1 polarization and upregulation of antiviral genes.ICAR-IVR

Introduction

ACL HLT 2011 - 49th Annual Meeting of the Association for Computational Linguistics: Human Language Technologies, Proceedings of Student Sessioniii-

Introduction

Peer reviewed: YesNRC publication: Ye

Pembrolizumab plus lenalidomide and dexamethasone for patients with treatment-naive multiple myeloma (KEYNOTE-185): a randomised, open-label, phase 3 trial

BACKGROUND: Lenalidomide and dexamethasone has been a standard of care in transplant-ineligible patients with newly diagnosed multiple myeloma. The addition of a third drug to the combination is likely to improve treatment efficacy. KEYNOTE-185 assessed the efficacy and safety of lenalidomide and dexamethasone with and without pembrolizumab in patients with previously untreated multiple myeloma. Here, we present the results of an unplanned interim analysis done to assess the benefit-risk of the combination at the request of the US Food and Drug Administration (FDA). METHODS: KEYNOTE-185 was a randomised, open-label, phase 3 trial done at 95 medical centres across 15 countries (Australia, Canada, France, Germany, Ireland, Israel, Italy, Japan, New Zealand, Norway, Russia, South Africa, Spain, UK, and USA). Transplantation-ineligible patients aged 18 years and older with newly diagnosed multiple myeloma, Eastern Cooperative Oncology Group performance status of 0 or 1, and who were treatment naive were enrolled, and randomly assigned 1:1 to receive either pembrolizumab plus lenalidomide and dexamethasone or lenalidomide and dexamethasone alone using an interactive voice or integrated web response system. Patients received oral lenalidomide 25 mg on days 1-21 and oral dexamethasone 40 mg on days 1, 8, 15, and 22 of repeated 28-day cycles, with or without intravenous pembrolizumab 200 mg every 3 weeks. The primary endpoint was progression-free survival, which was investigator-assessed because of early trial termination. Efficacy was analysed in all randomly assigned patients and safety was analysed in all patients who received at least one dose of study drug. This trial is registered at ClinicalTrials.gov, number NCT02579863, and it is closed for accrual. FINDINGS: Between Jan 7, 2016, and June 9, 2017, 301 patients were randomly assigned to the pembrolizumab plus lenalidomide and dexamethasone group (n=151) or the lenalidomide and dexamethasone group (n=150). On July 3, 2017, the FDA decided to halt the study because of the imbalance in the proportion of death between groups. At database cutoff (June 2, 2017), with a median follow-up of 6·6 months (IQR 3·4-9·6), 149 patients in the pembrolizumab plus lenalidomide and dexamethasone group and 145 in the lenalidomide and dexamethasone group had received their assigned study drug. Median progression-free survival was not reached in either group; progression-free survival estimates at 6-months were 82·0% (95% CI 73·2-88·1) versus 85·0% (76·8-90·5; hazard ratio [HR] 1·22; 95% CI 0·67-2·22; p=0·75). Serious adverse events were reported in 81 (54%) patients in the pembrolizumab plus lenalidomide and dexamethasone group versus 57 (39%) patients in the lenalidomide and dexamethasone group; the most common serious adverse events were pneumonia (nine [6%]) and pyrexia (seven [5%]) in the pembrolizumab plus lenalidomide and dexamethasone group and pneumonia (eight [6%]) and sepsis (two [1%]) in the lenalidomide and dexamethasone group. Six (4%) treatment-related deaths occurred in the pembrolizumab plus lenalidomide and dexamethasone group (cardiac arrest, cardiac failure, myocarditis, large intestine perforation, pneumonia, and pulmonary embolism) and two (1%) in the lenalidomide and dexamethasone group (upper gastrointestinal haemorrhage and respiratory failure). INTERPRETATION: The results from this unplanned, FDA-requested, interim analysis showed that the benefit-risk profile of pembrolizumab plus lenalidomide and dexamethasone is unfavourable for patients with newly diagnosed, previously untreated multiple myeloma. Long-term safety and survival follow-up is ongoing. FUNDING: Merck Sharp & Dohme, a subsidiary of Merck & Co, Inc (Kenilworth, NJ, USA)

Ziritaxestat, a novel autotaxin inhibitor, and lung function in idiopathic pulmonary fibrosis

Importance There is a major need for effective, well-tolerated treatments for idiopathic pulmonary fibrosis (IPF). Objective To assess the efficacy and safety of the autotaxin inhibitor ziritaxestat in patients with IPF. Design, Setting, and Participants The 2 identically designed, phase 3, randomized clinical trials, ISABELA 1 and ISABELA 2, were conducted in Africa, Asia-Pacific region, Europe, Latin America, the Middle East, and North America (26 countries). A total of 1306 patients with IPF were randomized (525 patients at 106 sites in ISABELA 1 and 781 patients at 121 sites in ISABELA 2). Enrollment began in November 2018 in both trials and follow-up was completed early due to study termination on April 12, 2021, for ISABELA 1 and on March 30, 2021, for ISABELA 2. Interventions Patients were randomized 1:1:1 to receive 600 mg of oral ziritaxestat, 200 mg of ziritaxestat, or placebo once daily in addition to local standard of care (pirfenidone, nintedanib, or neither) for at least 52 weeks. Main Outcomes and Measures The primary outcome was the annual rate of decline for forced vital capacity (FVC) at week 52. The key secondary outcomes were disease progression, time to first respiratory-related hospitalization, and change from baseline in St George’s Respiratory Questionnaire total score (range, 0 to 100; higher scores indicate poorer health-related quality of life). Results At the time of study termination, 525 patients were randomized in ISABELA 1 and 781 patients in ISABELA 2 (mean age: 70.0 [SD, 7.2] years in ISABELA 1 and 69.8 [SD, 7.1] years in ISABELA 2; male: 82.4% and 81.2%, respectively). The trials were terminated early after an independent data and safety monitoring committee concluded that the benefit to risk profile of ziritaxestat no longer supported their continuation. Ziritaxestat did not improve the annual rate of FVC decline vs placebo in either study. In ISABELA 1, the least-squares mean annual rate of FVC decline was –124.6 mL (95% CI, −178.0 to −71.2 mL) with 600 mg of ziritaxestat vs –147.3 mL (95% CI, −199.8 to −94.7 mL) with placebo (between-group difference, 22.7 mL [95% CI, −52.3 to 97.6 mL]), and –173.9 mL (95% CI, −225.7 to −122.2 mL) with 200 mg of ziritaxestat (between-group difference vs placebo, −26.7 mL [95% CI, −100.5 to 47.1 mL]). In ISABELA 2, the least-squares mean annual rate of FVC decline was –173.8 mL (95% CI, −209.2 to −138.4 mL) with 600 mg of ziritaxestat vs –176.6 mL (95% CI, −211.4 to −141.8 mL) with placebo (between-group difference, 2.8 mL [95% CI, −46.9 to 52.4 mL]) and –174.9 mL (95% CI, −209.5 to −140.2 mL) with 200 mg of ziritaxestat (between-group difference vs placebo, 1.7 mL [95% CI, −47.4 to 50.8 mL]). There was no benefit with ziritaxestat vs placebo for the key secondary outcomes. In ISABELA 1, all-cause mortality was 8.0% with 600 mg of ziritaxestat, 4.6% with 200 mg of ziritaxestat, and 6.3% with placebo; in ISABELA 2, it was 9.3% with 600 mg of ziritaxestat, 8.5% with 200 mg of ziritaxestat, and 4.7% with placebo. Conclusions and Relevance Ziritaxestat did not improve clinical outcomes compared with placebo in patients with IPF receiving standard of care treatment with pirfenidone or nintedanib or in those not receiving standard of care treatment. Trial Registration ClinicalTrials.gov Identifiers: NCT03711162 and NCT0373344