Epileptic seizures are refractory to treatment in approximately one‐third of patients despite the recent introduction of many newer antiepileptic drugs (AEDs). Development of novel AEDs therefore ...remains a high priority. Perampanel is a first‐in‐class non‐competitive selective AMPA receptor antagonist with a unique mechanism of action. Clinical efficacy and safety of perampanel as adjunctive treatment for focal seizures with/without secondary generalization (±SG) and primary generalized tonic‐clonic (PGTC) seizures have been established in five phase 3 randomized controlled trials (RCTs), and a long‐term extension study, and perampanel is approved as monotherapy for focal seizures ±SG in the USA. In patients with focal seizures ±SG, add‐on perampanel resulted in median percent reduction in seizure frequency 23.3%‐34.5% and ≥50% responder rate 28.5%‐37.6%; in PGTC seizures, these results were 76.5% and 64.2%, respectively. Efficacy among adolescents (reduction in seizure frequency 34.8%‐35.6%; ≥50% responder rate 40.9%‐45.0%) and elderly people (reduction in seizure frequency 12.5%‐16.9%; ≥50% responder rate 22.2%‐42.9%) is similar to those in adults, and results remain comparable between Asian (reduction in seizure frequency 17.3%‐38.0%) and global populations. Perampanel has been extensively studied in real‐world clinical practice, with similar efficacy and safety results to the RCTs (≥50% responder rate 12.8%‐75.0%; adverse events of somnolence/sedation, dizziness, ataxia, and behavioral changes). Real‐world observational studies suggest that perampanel tolerability can be improved by slow titration (2 mg every 2‐4 weeks), and bedtime administration can mitigate somnolence and dizziness. Counseling about the potential for behavioral changes and close monitoring are recommended.
Summary
Background
Aspirin increases the risk of gastrointestinal bleeding.
Aim
To investigate the risk of lower gastrointestinal bleeding (LGIB) in aspirin users.
Methods
Low‐dose (75‐325 mg daily) ...aspirin users and controls matched by age, gender and enrollment time in a 1:5 ratio were selected from 1 million randomly sampled subjects in the National Health Insurance Research Database of Taiwan. Cox proportional hazard regression models were developed to evaluate the predictors of LGIB with adjustments for age, gender, comorbidities including coronary artery disease, ischaemic stroke, diabetes, hypertension, chronic kidney disease, liver cirrhosis, chronic obstructive pulmonary disease, dyslipidemia, uncomplicated peptic ulcer disease, history of peptic ulcer bleeding, and concomitant use of clopidogrel, ticlopidine, warfarin, nonsteroidal anti‐inflammatory drugs (NSAIDs), cyclooxygenase‐2 inhibitors, steroids, proton pump inhibitors (PPIs), histamine‐2 receptor antagonists (H2RAs), nitrates, alendronate, selective serotonin reuptake inhibitors (SSRIs) and calcium channel blockers.
Results
A total of 53 805 aspirin users and 269 025 controls were included. Aspirin group had a higher incidence of LGIB within 1 year than control group (0.20% vs 0.06%, P<.0001). Aspirin (hazard ratio HR: 2.75, 95% confidence interval CI: 2.06‐3.65), NSAIDs (HR: 8.61, 95% CI: 3.28‐22.58), steroids (HR: 10.50, 95% CI: 1.98‐55.57), SSRIs (HR: 11.71, 95% CI: 1.40‐97.94), PPIs (HR: 8.47, 95% CI: 2.26‐31.71), and H2RAs (HR: 10.83, 95% CI: 2.98‐39.33) were significantly associated with LGIB.
Conclusions
The risk of LGIB was higher in low‐dose aspirin users than in aspirin nonusers in this nationwide cohort. Low‐dose aspirin, NSAIDs, steroids, SSRIs, PPIs and H2RAs were independent risk factors for LGIB.
Linked ContentThis article is linked to Taha and Chen et al papers. To view these articles visit https://doi.org/10.1111/apt.14114 and https://doi.org/10.1111/apt.14138.
A repeat expansion mutation in the C9orf72 gene is the leading known genetic cause of FTD and ALS. The C9orf72-ALS/FTD field has been plagued by a lack of reliable tools to monitor this genomic locus ...and its RNA and protein products. We have validated assays that quantify C9orf72 pathobiology at the DNA, RNA and protein levels using knock-out human iPSC lines as controls. Here we show that single-molecule sequencing can accurately measure the repeat expansion and faithfully report on changes to the C9orf72 locus in what has been a traditionally hard to sequence genomic region. This is of particular value to sizing and phasing the repeat expansion and determining changes to the gene locus after gene editing. We developed ddPCR assays to quantify two major C9orf72 transcript variants, which we validated by selective excision of their distinct transcriptional start sites. Using validated knock-out human iPSC lines, we validated 4 commercially available antibodies (of 9 tested) that were specific for C9orf72 protein quantification by Western blot, but none were specific for immunocytochemistry. We tested 15 combinations of antibodies against dipeptide repeat proteins (DPRs) across 66 concentrations using MSD immunoassay, and found two (against poly-GA and poly-GP) that yielded a 1.5-fold or greater signal increase in patient iPSC-motor neurons compared to knock-out control, and validated them in human postmortem and transgenic mouse brain tissue. Our validated DNA, RNA and protein assays are applicable to discovery research as well as clinical trials.
We demonstrate synthetic azimuthal gauge potentials for Bose-Einstein condensates from engineering atom-light couplings. The gauge potential is created by adiabatically loading the condensate into ...the lowest energy Raman-dressed state, achieving a coreless vortex state. The azimuthal gauge potentials act as effective rotations and are tunable by the Raman coupling and detuning. We characterize the spin textures of the dressed states, in agreements with the theory. The lowest energy dressed state is stable with a 4.5-s half-atom-number-fraction lifetime. In addition, we exploit the azimuthal gauge potential to demonstrate the Hess-Fairbank effect, the analogue of Meissner effect in superconductors. The atoms in the absolute ground state has a zero quasiangular momentum and transits into a polar-core vortex when the synthetic magnetic flux is tuned to exceed a critical value. Our demonstration serves as a paradigm to create topological excitations by tailoring atom-light interactions where both types of SO(3) vortices in the |⟨Fover →⟩|=1 manifold, coreless vortices and polar-core vortices, are created in our experiment. The gauge field in the stationary Hamiltonian opens a path to investigating rotation properties of atomic superfluids under thermal equilibrium.
Though the early integration of mesenchymal stem cells (MSCs) into tumor-associated stroma of cancer has been demonstrated, the functional contributions and underlying mechanisms of these cells to ...tumor growth and angiogenesis remain to be clarified. Using a xenograft model, human colorectal cancer cells, MSCs, and their cell mixture were introduced to a subcutaneous site of immunodeficient mice. The tumor growth rate and angiogenesis of each transplantation was then compared. We demonstrate that a variety of colorectal cancer cells, when mixed with otherwise non-tumorigenic MSCs, increase the tumor growth rate and angiogenesis more than that when mixed with carcinoma-associated fibroblasts or normal colonic fibroblasts. The secretion of interleukin-6 (IL-6) from MSCs increases the secretion of endothelin-1 (ET-1) in cancer cells, which induces the activation of Akt and ERK in endothelial cells, thereby enhancing their capacities for recruitment and angiogenesis to tumor. The IL-6/ET-1/Akt or ERK pathway of tumor-stroma interaction can be targeted by an antibody against IL-6 or Lentiviral-mediated RNAi against IL-6 in MSCs, by inhibition or knockdown of ET-1 in cancer cells, or by inhibition of ERK and Akt in host endothelial cells. These demonstrate that attempts to interrupt the interaction of MSCs and cancer cells help to abrogate angiogenesis and inhibit tumor growth in tumors formed by cancer cells admixed with MSCs. These data demonstrate that the tumor microenvironment, namely, MSCs-secreted IL-6, may enrich the proangiognic factors secreted by cancer cells to increase angiogenesis and tumor growth and that targeting this interaction may lead to novel therapeutic and preventive strategies.
The dispersive sweep of fast radio bursts (FRBs) has been used to probe the ionized baryon content of the intergalactic medium
, which is assumed to dominate the total extragalactic dispersion. ...Although the host-galaxy contributions to the dispersion measure appear to be small for most FRBs
, in at least one case there is evidence for an extreme magneto-ionic local environment
and a compact persistent radio source
. Here we report the detection and localization of the repeating FRB 20190520B, which is co-located with a compact, persistent radio source and associated with a dwarf host galaxy of high specific-star-formation rate at a redshift of 0.241 ± 0.001. The estimated host-galaxy dispersion measure of approximately Formula: see text parsecs per cubic centimetre, which is nearly an order of magnitude higher than the average of FRB host galaxies
, far exceeds the dispersion-measure contribution of the intergalactic medium. Caution is thus warranted in inferring redshifts for FRBs without accurate host-galaxy identifications.
Summary
Due to the huge gap in the care of patients with osteoporosis and fragility fractures, we aimed to explore the effectiveness of the osteoporosis liaison service (OLS) in osteoporosis care. We ...found that OLS can improve osteoporosis care, including increasing medication compliance, increasing calcium/vitamin D/protein intake, and reducing fall rate.
Introduction
A significant gap exists in the care of patients with osteoporosis and fragility fractures. This study aimed to evaluate 1-year outcomes of an osteoporosis liaison service (OLS) program that includes two independent components: medication management services (MMS) to improve medication adherence and fracture liaison services (FLS) for secondary prevention.
Methods
Patients with new hip fracture or untreated vertebral fractures enrolled in the FLS program (
n
= 600), and those with osteoporosis medication management issues but not necessarily fragility fractures enrolled in the MMS program (
n
= 499) were included. To evaluate outcomes, care coordinators assessed baseline items adapted from the 13 Best Practices Framework (BPF) standards of the International Osteoporosis Foundation, with telephone follow-up every 4 months for 1 year.
Results
Mean age of this cohort was 76.2 ± 10.3 years, 78.8% were female. After 1-year participation in the program, all patients had received bone mineral density tests, and medication adherence for the entire cohort at 12 months was 91.9 ± 19.6%, with significant improvement in fall rates (23.4% reduction), exercise rates (16.8% increase), calcium intake (26.5% increase), vitamin D intake (26.4% increase), and adequate protein intake (17.3% increase) (all
p
< 0.05). After 1-year OLS program, the overall rates of mortality, incident fracture, and falls were 6.6%, 4.0%, and 24.3%, respectively.
Conclusions
The OLS program is associated with improved osteoporosis care, including increased medication adherence, calcium/vitamin D and protein intake, and reduced fall rate.
Anti-PD-1 antibodies (anti-PD-1) have clinical activity in a number of malignancies. All clinical trials have excluded patients with significant preexisting autoimmune disorders (ADs) and only one ...has included patients with immune-related adverse events (irAEs) with ipilimumab. We sought to explore the safety and efficacy of anti-PD-1 in such patients.
Patients with advanced melanoma and preexisting ADs and/or major immune-related adverse events (irAEs) with ipilimumab (requiring systemic immunosuppression) that were treated with anti-PD-1 between 1 July 2012 and 30 September 2015 were retrospectively identified.
One hundred and nineteen patients from 13 academic tertiary referral centers were treated with anti-PD-1. In patients with preexisting AD (N=52), the response rate was 33%. 20 (38%) patients had a flare of AD requiring immunosuppression, including 7/13 with rheumatoid arthritis, 3/3 with polymyalgia rheumatica, 2/2 with Sjogren’s syndrome, 2/2 with immune thrombocytopaenic purpura and 3/8 with psoriasis. No patients with gastrointestinal (N=6) or neurological disorders (N=5) flared. Only 2 (4%) patients discontinued treatment due to flare, but 15 (29%) developed other irAEs and 4 (8%) discontinued treatment. In patients with prior ipilimumab irAEs requiring immunosuppression (N=67) the response rate was 40%. Two (3%) patients had a recurrence of the same ipilimumab irAEs, but 23 (34%) developed new irAEs (14, 21% grade 3–4) and 8 (12%) discontinued treatment. There were no treatment-related deaths.
In melanoma patients with preexisting ADs or major irAEs with ipilimumab, anti-PD-1 induced relatively frequent immune toxicities, but these were often mild, easily managed and did not necessitate discontinuation of therapy, and a significant proportion of patients achieved clinical responses. The results support that anti-PD-1 can be administered safely and can achieve clinical benefit in patients with preexisting ADs or prior major irAEs with ipilimumab.
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