The complexity of CRISPR machinery is a challenge to its application for nonviral in vivo therapeutic gene editing. Here, we demonstrate that proteins, regardless of size or charge, efficiently load ...into porous silicon nanoparticles (PSiNPs). Optimizing the loading strategy yields formulations that are ultrahigh loading>40% cargo by volumeand highly active. Further tuning of a polymeric coating on the loaded PSiNPs yields nanocomposites that achieve colloidal stability under cryopreservation, endosome escape, and gene editing efficiencies twice that of the commercial standard Lipofectamine CRISPRMAX. In a mouse model of arthritis, PSiNPs edit cells in both the cartilage and synovium of knee joints, and achieve 60% reduction in expression of the therapeutically relevant MMP13 gene. Administered intramuscularly, they are active over a broad dose range, with the highest tested dose yielding nearly 100% muscle fiber editing at the injection site. The nanocomposite PSiNPs are also amenable to systemic delivery. Administered intravenously in a model that mimics muscular dystrophy, they edit sites of inflamed muscle. Collectively, the results demonstrate that the PSiNP nanocomposites are a versatile system that can achieve high loading of diverse cargoes and can be applied for gene editing in both local and systemic delivery applications.
We perform an analysis of ∼80 000 photometric measurements for the following 10 stars hosting transiting planets: WASP-2, -4, -5, -52, Kelt-1, CoRoT-2, XO-2, TrES-1, HD 189733, GJ 436. Our analysis ...includes mainly transit light curves from the Exoplanet Transit Database, public photometry from the literature, and some proprietary photometry privately supplied by other authors. Half of these light curves were obtained by amateurs. From this photometry we derive 306 transit timing measurements, as well as improved planetary transit parameters. Additionally, for 6 of these 10 stars we present a set of radial velocity measurements obtained from the spectra stored in the HARPS, HARPS-N and SOPHIE archives using the HARPS–TERRA pipeline. Our analysis of these transit timing and radial velocity data did not reveal significant hints of additional orbiting bodies in almost all of the cases. In the WASP-4 case, we found hints of marginally significant TTV signals having amplitude 10–20 s, although their parameters are model dependent and uncertain, while radial velocities did not reveal statistically significant Doppler signals.
The existence of asteroid pairs, two bodies on similar heliocentric orbits, reveals an ongoing process of rotational fission among asteroids. This newly found class of objects has not been studied in ...detail yet. Here we choose asteroids (6070) Rheinland and (54827) 2001 NQ8, the most suitable pair for an in-depth analysis. First, we use available optical photometry to determine their rotational state and convex shapes. Rotational pole of Rheinland is very near the south ecliptic pole with a latitude uncertainty of about 10°. There are two equivalent solutions for the pole of 2001 NQ8, either (72°, −49°) or (242°, −46°) (ecliptic longitude and latitude). In both cases, the longitude values have about 10° uncertainty and the latitude values have about 15° uncertainty (both uncertainties). The sidereal rotation period of 2001 NQ8 is 5.877186 0.000002 hr. Second, we construct a precise numerical integrator to determine the past state vectors of the pair's components, namely their heliocentric positions and velocities, and orientation of their spin vectors. Using this new tool, we investigate the origin of the (6070) Rheinland and (54827) 2001 NQ8 pair. We find a formal age solution of 16.34 0.04 kyr. This includes effects of the most massive objects in the asteroid belt (Ceres, Pallas, and Vesta), but the unaccounted gravitational perturbations from other asteroids may imply that the realistic age uncertainty is slightly larger than its formal value. Analyzing results from our numerical simulation to 250 kya, we argue against a possibility that this pair would allow an older age. Initial spin vectors of the two asteroids, at the moment of their separation, were not collinear, but tilted by .
The asteroid (2121) Sevastopol is a binary asteroid from the main belt. The duplicity of the asteroid was discovered based on photometric observations of mutual phenomena (eclipses and occultations) ...that were detected in its light curves (Higgins et al., 2010).
We organized a photometrical observational campaign for the observations of mutual phenomena in binary system of the asteroid (2121) Sevastopol and an investigation of the properties of the asteroid's satellite. The observations allowed us to define mass, density, taxonomical class and preliminary orbit of the satellite of the asteroid (2121) Sevastopol.
•The asteroid (2121) Sevastopol is a binary asteroid from the main belt. The duplicity of the asteroid was discovered based on photometric observations of mutual phenomena (eclipses and occultations) that were detected in its light curves (Higgins et al, 2010).•We organized a photometrical observational campaign for the observations of mutual phenomena in binary system of the asteroid (2121) Sevastopol asteroid and investigation of properties of the asteroid satellite. The observations allowed us to define mass, density, taxonomical class and preliminary orbit of the satellite of the asteroid (2121) Sevastopol.
The objectives of this study were to assess the discontinuation of biologic therapy in patients who achieve remission and identify predictors of discontinuation of biologics in patients with ...inflammatory arthritis in remission.
An observational retrospective study from the BIOBADASER registry comprising adult patients diagnosed with rheumatoid arthritis (RA), ankylosing spondylitis (AS), or psoriatic arthritis (PsA) and receiving 1 or 2 biological disease-modifying drugs (bDMARDs) between October 1999 and April 2021. Patients were followed yearly after initiation of therapy or until discontinuation of treatment. Reasons for discontinuation were collected. Patients who discontinued bDMARDs because of remission as defined by the attending clinician were studied. Predictors of discontinuation were explored using multivariable regression models.
The study population comprised 3,366 patients taking 1 or 2 bDMARDs. Biologics were discontinued owing to remission by 80 patients (2.4%): 30 with RA (1.7%), 18 with AS (2.4%), and 32 with PsA (3.9%). The factors associated with a higher probability of discontinuation on remission were shorter disease duration (OR: 0.95; 95% CI: 0.91-0.99), no concomitant use of classic DMARDs (OR: 0.56; 95% CI: 0.34-0.92), and shorter usage of the previous bDMARD (before the decision to discontinue biological therapy) (OR: 1.01; 95% CI: 1.01-1.02); in contrast, smoking status (OR: 2.48; 95% CI: 1.21-5.08) was associated with a lower probability. In patients with RA, positive ACPA was associated with a lower probability of discontinuation (OR: 0.11; 95% CI: 0.02-0.53).
Discontinuation of bDMARDs in patients who achieve remission is uncommon in routine clinical care. Smoking and positive ACPA in RA patients were associated with a lower probability of treatment discontinuation because of clinical remission.
Background
Retention of biological treatment provides a marker of drug effectiveness and patient satisfaction. Retention of golimumab was high in clinical trial extensions and real-world studies up ...to 5 years in patients with immune-mediated rheumatic diseases.
Objective
To assess the probability of real-world long-term retention of treatment with golimumab up to 7 years after treatment initiation.
Methods
This retrospective noninterventional study involved analysis of the Spanish biological drugs registry, BIOBADASER. Adults who had ever received golimumab for rheumatoid arthritis (RA), axial spondyloarthritis (SpA), or psoriatic arthritis (PsA), and had initiated it > 6 months before the analysis date, were included.
Results
Among 685 patients (28.5% RA, 42.9% SpA, 28.6% PsA), the overall probability of retention of golimumab treatment since initiation was 71.7% (95% confidence interval 68.1–74.9) at year 1, 60.5% (56.5–64.2%) at year 2, 55.6% (51.5–59.5%) at year 3, 50.6% (46.2–54.8%) at year 4, 45.1% (40.1–50.0%) at year 5, 44.2% (39.0–49.3) at year 6, and 39.5% (32.8–46.2) at year 7. Retention was greater in patients with axial SpA or PsA versus RA (
p
< 0.001) and when golimumab was used as first-line treatment versus third or later lines (
p
< 0.001). Factors associated with greater golimumab retention in Cox regression included use as first-line biological therapy, having axial SpA or PsA rather than RA, and concomitant methotrexate therapy. Steroids were associated with lower retention.
Conclusion
In this real-world study of RA, axial SpA, and PsA patients, the retention rate of golimumab was 39.5% at year 7.
Key Points
• Retention of biological treatment provides a marker of drug effectiveness and patient satisfaction.
• This real-world study of 685 patients with rheumatoid arthritis (RA), axial spondyloarthritis (SpA), or psoriatic arthritis (PsA) showed that golimumab treatment had a retention rate up to 39.5% at year 7.
• Greater golimumab retention was associated with use as first-line biological therapy, having axial SpA or PsA rather than RA, and concomitant methotrexate therapy
A 74-year-old man with a medical history significant for papillary thyroid cancer (PTC) presented with a rapidly enlarging grape-sized mass in his right medial arm with paresthesia in the ulnar nerve ...distribution. Imaging was suspicious for a peripheral nerve sheath tumor (PNST), but an ultrasound-guided biopsy was equivocal. The mass was excised with final histopathology demonstrating a benign neurofibroma/schwannoma hybrid nerve sheath tumor (N/S HNST) harboring a metastatic PTC deposit, ultimately mimicking the rare glandular schwannoma subtype. Next-generation sequencing (NGS) of the lesion demonstrated somatic variants in BRAF and TERT (common in PTC) and NF2 (common in PNSTs). After excision, the patient’s nerve symptoms improved. A postsurgical PET/CT scan also showed progression in the lungs/mediastinum. Due to the metastatic nature of his PTC, he was treated with 14 mg of Lenvima (lenvatinib) daily, and his PET/CT surveillance was performed at more frequent intervals. Tumor-to-tumor metastasis (TTM) is a rare occurrence. To our knowledge, this is the first case reported on PTC metastasizing into a benign (hybrid) PNST, which mimicked glandular schwannoma. Symptomatology, imaging characteristics, NGS, and histopathological characteristics that can decipher between different benign PNST subtypes (schwannoma, neurofibroma, glandular, hybrid, etc.), malignant PNSTs (MPNSTs), and TTM are described.
•The critical relative soil water content (HRc) depends on soil type and wind velocity.•HRc values were lower in fine than in coarse textured soils.•Sandy loam soils with different organic matter ...contents present different HRc value.•HRc was negatively related to micro-aggregation.
The soil water content is one of the main factors influencing the beginning of soil particle movement by the wind. Although, some authors studied the effect of soil water content on threshold wind velocity and have defined a value to prevent wind erosion, the critical relative soil water content (HRc), most of them used disturbed and/or sieved soil samples. Under these conditions, the effect of aggregation, i.e. the natural state of the soil, cannot be evaluated. So, our objective was to determine HRc in soils with different textures in Semiarid Argentinian Pampas Region (SAPR) using uncrushed soil samples under variable wind velocities. Wind tunnel simulations were performed at three wind speeds (2.1, 8.0 and 10.5 m s−1) during 3 min in each case. Results indicated that the quantity of collected soil (Q) decreased with increasing relative soil water contents (HR) up to a HRc value at which it became negligible. HRc values were lower in fine textured soils than in coarse soils. All soils showed increasing HRc values as wind velocity increased from 2.1 to 10.5 m s−1, while the wind velocity effect is more important in coarse textured soils. HRc was negatively related to micro-aggregation in a linear way. For that reason, soils with high fine silt and clay content need lower HRc values to inhibit wind erosion. In conclusion, not only texture is important factor in defining the HRc value at a specific wind velocity but also the micro and macro-aggregation of the soils.
Objective
To assess the efficacy and safety of combination therapy with chondroitin sulfate (CS) and glucosamine sulfate (GS) compared to placebo in patients with symptomatic knee osteoarthritis ...(OA).
Methods
A multicenter, randomized, double‐blind, placebo‐controlled study was performed in 164 patients with Kellgren/Lawrence grade 2 or grade 3 radiographic knee OA and moderate‐to‐severe knee pain (mean ± SD global pain score 62.1 ± 11.3 mm on a 100‐mm visual analog scale VAS). Patients were randomized to receive either combined treatment with CS (1,200 mg) plus GS (1,500 mg) or placebo in a single oral daily dose for 6 months. The mean change from baseline in the VAS global pain score was set as the primary end point. Secondary outcomes included the mean change in the investigator's global assessment of disease activity, total Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), pain and function subscale scores on the WOMAC, responder rates based on the Outcome Measures in Rheumatology (OMERACT)–Osteoarthritis Research Society International (OARSI) 2004 response criteria, and rescue medication use. Adverse events were also recorded. A Data and Safety Monitoring Board was instituted to ensure patient safety and data accuracy.
Results
Intriguingly, in the modified intent‐to‐treat (mITT) population, CS/GS combination therapy was inferior to placebo in the reduction of joint pain (mean ± SD change in VAS global pain score over 6 months −11.8 ± 2.4 mm 19% reduction in patients receiving CS plus GS versus −20.5 ± 2.4 mm 33% reduction in patients receiving placebo; peak between‐group difference in global pain score at 6 months 8.7 mm 14.2%, P < 0.03), but no between‐group differences were seen in the per‐protocol completers. Both placebo treatment and CS/GS combination treatment improved to a similar extent the total WOMAC score as well as the pain and function WOMAC subscale scores, both in the mITT population and in the per‐protocol completers. Neither the OMERACT–OARSI responder rate nor the frequency of rescue medication use differed between the treatment groups. Severe adverse events were uncommon and equally distributed.
Conclusion
The results of this trial demonstrate a lack of superiority of CS/GS combination therapy over placebo in terms of reducing joint pain and functional impairment in patients with symptomatic knee OA over 6 months. Further research might fully elucidate the suitability of CS/GS combination therapy in patients with OA.
PDF
