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Osteoarthritis is a prevalent and debilitating disease that involves pathological contributions from numerous joint tissues and cells. The joint is a challenging arena for drug ...delivery, since the joint has poor bioavailability for systemically administered drugs and experiences rapid clearance of therapeutics after intra-articular injection. Moreover, each tissue within the joint presents unique barriers to drug localization. In this review, the various applications of nanotechnology to overcome these drug delivery limitations are investigated. Nanomaterials have reliably shown improvements to retention profiles of drugs within the joint space relative to injected free drugs. Additionally, nanomaterials have been modified through active and passive targeting strategies to facilitate interactions with and localization within specific joint tissues such as cartilage and synovium. Last, the limitations of drawing cross-study comparisons, the implications of synovial fluid, and the potential importance of multi-modal therapeutic strategies are discussed. As emerging, cell-specific disease modifying osteoarthritis drugs continue to be developed, the need for targeted nanomaterial delivery will likely become critical for effective clinical translation of therapeutics for osteoarthritis.
Improving drug delivery to the joint is a pressing clinical need. Over 27 million Americans live with osteoarthritis, and this figure is continuously expanding. Numerous drugs have been investigated but have failed in clinical trials, likely related to poor bioavailability to target cells. This article comprehensively reviews the advances in nano-scale delivery vehicles designed to overcome the delivery barriers in the joint. This is the first review to analyze active and passive targeting strategies systematically for different target sites while also delineating between tissue homing and whole joint retention. By bringing together the lessons learned across numerous nano-scale platforms, researchers may be able to hone future nanomaterial designs, allowing emerging therapeutics to perform with clinically relevant efficacy and disease modifying potential.
Abstract
Background
Limited retrospective data suggest prophylactic oral vancomycin may prevent Clostridioides difficile infection (CDI). We sought to evaluate the effectiveness of oral vancomycin ...for the prevention of healthcare facility–onset CDI (HCFO-CDI) in targeted patients.
Methods
We conducted a randomized, prospective, open-label study at Novant Health Forsyth Medical Center in Winston-Salem, North Carolina, between October 2018 and April 2019. Included patients were randomized 1:1 to either oral vancomycin (dosed at 125 mg once daily while receiving systemic antibiotics and continued for 5 days postcompletion of systemic antibiotics OVP) or no prophylaxis. The primary endpoint was incidence of HCFO-CDI. Secondary endpoints included incidence of community-onset healthcare facility–associated CDI (CO-HCFA-CDI), incidence of vancomycin-resistant Enterococci (VRE) colonization after receiving OVP, adverse effects, and cost of OVP.
Results
A total of 100 patients were evaluated, 50 patients in each arm. Baseline and hospitalization characteristics were similar, except antibiotic exposure. No events of HCFO-CDI were noted in the OVP group compared with 6 (12%) in the no-prophylaxis group (P = .03). CO-HCFA-CDI was identified in 2 patients who were previously diagnosed with HCFO-CDI. No patients developed new VRE colonization, with only 1 patient reporting mild gastrointestinal side effects to OVP. A total of 600 doses of OVP were given during the study, with each patient receiving an average of 12 doses. Total acquisition cost of OVP was $1302, $26.04 per patient.
Conclusion
OVP appears to protect against HCFO-CDI during in-patient stay in targeted patients during systemic antibiotic exposure. Further prospective investigation is warranted.
The effectiveness of oral vancomycin prophylaxis (OVP) was evaluated. Those who received OVP did not develop healthcare facility–onset Clostridioides difficile infection compared with 12% of patients who received no prophylaxis. OVP was well tolerated with no apparent short-term risks.
Understanding intra-articular biodistribution is imperative as candidate osteoarthritis (OA) drugs become increasingly site-specific. Cartilage has been identified as opportunistic for therapeutic ...intervention, but poses numerous barriers to drug delivery. To facilitate drug delivery to cartilage, nanoscale vehicles have been designed with different features that target the tissue's matrix. However, it is unclear if these targeting strategies are influenced by OA and the associated structural changes that occur in cartilage. The goal of this work was to study the effectiveness of different cartilage-targeting nanomaterials with respect to cartilage localization and retention, and to determine how these outcomes change in OA. To address these questions, a nanoparticle (NP) system was developed, and the formulation was tuned to possess three distinct cartilage-targeting strategies: (1) passive targeting cationic NPs for electrostatic attraction to cartilage, (2) active targeting NPs with binding peptides for collagen type II, and (3) untargeted neutrally-charged NPs. Ex vivo analyses with bovine cartilage explants demonstrated that targeting strategies significantly improved NP associations with both healthy and OA-like cartilage. In vivo studies with collagenase-induced OA in rats revealed that disease state influenced joint biodistribution for all three NP formulations. Importantly, the extent of cartilage accumulation for each NP system was affected by disease differently; with active NPs, but not passive NPs, cartilage accumulation was increased in OA relative to healthy knees. Together, this work suggests that NPs can be strategically designed for site-specific OA drug delivery, but the biodistribution of the NPs are influenced by the disease conditions into which they are delivered.
As emerging drugs for osteoarthritis are becoming increasingly site-specific, the need for targeted intra-articular drug delivery has evolved. To improve drug delivery to cartilage, targeting strategies for nanomaterials have been developed, but the manner in which these targeted systems accumulate at different sites within the joint remains poorly understood. Moreover, it is unclear how nanomaterial-tissue interactions change in osteoarthritic conditions, as tissue structure and composition change after disease onset. By understanding how nanomaterials distribute within healthy and disease joints, we can advance targeted drug delivery strategies and improve therapeutic outcomes for emerging drugs.
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Bone metastases are common complications of solid tumors, particularly those of the prostate, breast, and lungs. Bone metastases can lead to painful and devastating skeletal-related events (SREs), ...such as pathological fractures and nerve compressions. Despite advances in treatment for cancers in general, options for bone metastases remain inadequate and generally palliative. Anticancer drugs (chemotherapy and radiopharmaceuticals) do not achieve therapeutic concentrations in the bone and are associated with dose-limiting side effects to healthy tissues. Nanomedicines, with their tunable characteristics, have the potential to improve drug targeting to bone metastases while decreasing side effects for their effective treatment. In this review, we present the current state of the art for nanomedicines to treat bone metastases. We also discuss new treatment modalities enhanced by nanomedicine and their effects on SREs and disease progression.
The Ocean Molecular Ecology (OME) program at the NOAA Pacific Marine Environmental Laboratory (PMEL) is a recently established research group that partners with several established PMEL and Alaska ...Fisheries Science Center (AFSC) programs including Ecosystems & Fisheries-Oceanography Coordinated Investigations (EcoFOCI), Ocean Carbon, and Earth-Ocean Interactions (EOI). The OME program utilizes a suite of molecular tools to support long-term research initiatives through genomics applications, and their development and application as novel environmental (e)DNA approaches has been key for facilitating collaborations within PMEL and NOAA Oceanic and Atmospheric Research, and across NOAA line offices.
This study aimed to provide long-term clinical data about an innovative epidermal radioisotope therapy called Rhenium-SCT
®
(Skin Cancer Therapy) for non-melanoma skin cancer (NMSC), based on the use ...of the non-sealed beta emitter rhenium-188.
52 NMSC patients with a mean age of 71.7 years were treated with rhenium-188 skin cancer therapy between the years 2005 and 2014. An acryl matrix containing rhenium-188 was applied on a plastic foil covering the tumor. The treatment time for reaching a radiation dose of 50 Gy was calculated by a software program. Patients' characteristics and clinical follow-up data were collected and retrospectively analyzed.
Overall 55 lesions (32 BCC, 19 SCC, 2 M. Bowen and 2 extramammary Paget's disease (EMPD)) mainly in the head and neck region (72.3%) were treated. The average size of the irradiation area was 9.79 cm
2
and the mean treatment time 46.35 min. All lesions showed a complete remission after a follow-up period between 3 and more than 12 months. No complications or other post-interventional problems were reported.
Rhenium-SCT
®
is considered as an effective, rapid, safe, painless treatment mostly performed in a single therapeutic session, regardless of the shape complexity, anatomical site and number of lesions.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Nitrous oxide (N2O) emissions are highly variable in space and time due to the complex interplay between soil, management practices and weather conditions. Micrometeorological techniques integrate ...emissions over large areas at high temporal resolution. This allows identification of causes of intra- and inter-annual variability of N2O emissions and development of robust emission factors (EF). Here, we investigated factors responsible for variability in N2O emissions during growing and non-growing seasons of corn and soybeans grown in an imperfectly drained silt loam soil, in Ontario, Canada. We used quasi-continuously (at half-hourly to hourly intervals) N2O fluxes measured via the flux-gradient technique over 11 years for corn and 5 years for soybeans and evaluated the uncertainty of default IPCC and Canada-specific EFs. In the growing season, emissions were controlled by soil nitrate content, soil moisture and temperature in the fertilized corn, while moisture and temperature regulated N2O emissions in the unfertilized soybeans. In the non-growing season, nitrogen (N) input from the crop residue did not affect the emissions, pointing to freeze-thaw cycles as mechanisms for enhanced N2O emissions. The non-growing season contribution to annual emissions was 38% in corn and 43% in soybeans. On average, annual emissions were 2.6-fold higher in corn than soybeans. Observed mean N2O EFs were 0.84% (0.12–2.02%) for growing season and 1.69% (0.29–7.32%) for yearly emissions. The growing season EF derived from long-term N2O emissions was 0.9 ± 0.14%. The interannual variability in N2O emissions and EFs can be attributed to management practices and annual weather variability. The default IPCC approach based on overall N input had poorer performance in predicting annual N2O emissions compared to the current Canadian methodology, which includes management and environmental factor in addition to N inputs. The observed emissions were further evaluated with a newly developed growing season N2O emission prediction approach for Canada. However, performance of the approach was poorer than IPCC or the current national Canadian approach. Additional tests of the new national methodology are recommended as well as consideration of non-growing season emissions.
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•Long-term N2O emission time series for corn and soybeans at one site were assessed.•Corn emitted 2.6-fold more N2O than soybeans, driven by NO3−, water content and temperature.•Freeze-thaw events contributed ~40% of annual emission.•Observed mean N2O EFs were 0.84% for growing season and 1.69% for year.•New proposed method for Canada's GHG inventory underestimated N2O emissions.
A major hurdle limiting the ability to treat and cure osteoarthritis, a common and debilitating disease, is rapid joint clearance and limited cartilage targeting of intra-articular therapies. ...Nanoscale drug carriers have the potential to improve therapeutic targeting and retention in the joint after direct injection; however, there still lacks a fundamental understanding of how the physicochemical properties of nanoparticles (NPs) influence localization to the degenerating cartilage and how joint conditions such as disease state and synovial fluid impact NP biodistribution. The goal of this study was to assess how physicochemical properties of NPs influence their interactions with joint tissues and, ultimately, cartilage localization. Ex vivo models of joint tissues were used to study how poly(lactide-co-glycolide) (PLGA) and polystyrene (PS) NP size, charge, and surface chemistry influence cartilage retention under normal and disease-mimicking conditions. Of the particles investigated, PLGA NPs surface-modified with a quaternary ammonium cation had the greatest retention within cartilage explants; however, retention was diminished 2- to 2.9-fold in arthritic tissue and in the presence of synovial fluid. Interactions with synovial fluid induced changes to NP surface properties and colloidal stability in vitro. The impact of NP charge on “off-target” synoviocyte uptake was also dependent on synovial fluid interactions. The results suggest that the design of nanocarriers for targeted drug delivery within the joint cannot be based on a single parameter such as zeta potential or size, and that the fate of injected delivery systems will likely be influenced by the disease state of the joint and the presence of synovial fluid.
Lightning flashes have been observed by a number of missions that visited or flew by Jupiter over the past several decades. Imagery led to a flash rate estimate of about 4 × 10
flashes per square ...kilometre per year (refs.
). The spatial extent of Voyager flashes was estimated to be about 30 kilometres (half-width at half-maximum intensity, HWHM), but the camera was unlikely to have detected the dim outer edges of the flashes, given its weak response to the brightest spectral line of Jovian lightning emission, the 656.3-nanometre Hα line of atomic hydrogen
. The spatial resolution of some cameras allowed investigators to confirm 22 flashes with HWHM greater than 42 kilometres, and to estimate one with an HWHM of 37 to 45 kilometres (refs.
). These flashes, with optical energies comparable to terrestrial 'superbolts'-of (0.02-1.6) × 10
joules-have been interpreted as tracers of moist convection originating near the 5-bar level of Jupiter's atmosphere (assuming photon scattering from points beneath the clouds)
. Previous observations of lightning have been limited by camera sensitivity, distance from Jupiter and long exposures (about 680 milliseconds to 85 seconds), meaning that some measurements were probably superimposed flashes reported as one
. Here we report optical observations of lightning flashes by the Juno spacecraft with energies of approximately 10
-10
joules, flash durations as short as 5.4 milliseconds and inter-flash separations of tens of milliseconds, with typical terrestrial energies. The flash rate is about 6.1 × 10
flashes per square kilometre per year, more than an order of magnitude greater than hitherto seen. Several flashes are of such small spatial extent that they must originate above the 2-bar level, where there is no liquid water
. This implies that multiple mechanisms for generating lightning on Jupiter need to be considered for a full understanding of the planet's atmospheric convection and composition.
Though the relationship between social capital and health has been widely studied, the evidence of this relationship in cardiovascular disease is limited, with varied and inconsistent measures. This ...scoping review seeks to address this gap by answering the following questions: (1) How has social capital been characterized and measured in the literature related to cardiovascular disease? and (2) What gaps exist in the evaluation of the relationship between social capital and cardiovascular disease?
A scoping review will be used to answer the research questions. The scoping review will apply established methods described by Arksey and O'Malley, Levac and colleagues, and the Joanne Briggs Institute: (1) identifying the research question(s); (2) identifying relevant studies; (3) selecting the studies; (4) charting the data; and (5) collating, summarizing, and reporting the results.
Our findings will be reported in accordance with the guidance provided in the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols (PRISMA-P) statement.
The synthesis of this evidence base is intended to provide a framework for how social capital has been defined and measured in the cardiovascular literature, with additional guidance for future research and evaluation. The findings will be disseminated through peer-reviewed publication and presentations at relevant seminars.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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