Highlights
Factors affecting microneedle insertion into skin are reviewed.
The use of artificial and computational skin models for the simulation of needle insertion is summarized.
Skin structures ...and models, as well as mechanical analyses, used to determine transdermal microneedle ability to insert into skin are highlighted in the review.
Transdermal microneedle (MN) patches are a promising tool used to transport a wide variety of active compounds into the skin. To serve as a substitute for common hypodermic needles, MNs must pierce the human
stratum corneum
(~ 10 to 20 µm), without rupturing or bending during penetration. This ensures that the cargo is released at the predetermined place and time. Therefore, the ability of MN patches to sufficiently pierce the skin is a crucial requirement. In the current review, the pain signal and its management during application of MNs and typical hypodermic needles are presented and compared. This is followed by a discussion on mechanical analysis and skin models used for insertion tests before application to clinical practice. Factors that affect insertion (e.g., geometry, material composition and cross-linking of MNs), along with recent advancements in developed strategies (e.g., insertion responsive patches and 3D printed biomimetic MNs using two-photon lithography) to improve the skin penetration are highlighted to provide a backdrop for future research.
Summary Background Severe ankle sprains are a common presentation in emergency departments in the UK. We aimed to assess the effectiveness of three different mechanical supports (Aircast brace, ...Bledsoe boot, or 10-day below-knee cast) compared with that of a double-layer tubular compression bandage in promoting recovery after severe ankle sprains. Methods We did a pragmatic, multicentre randomised trial with blinded assessment of outcome. 584 participants with severe ankle sprain were recruited between April, 2003, and July, 2005, from eight emergency departments across the UK. Participants were provided with a mechanical support within the first 3 days of attendance by a trained health-care professional, and given advice on reducing swelling and pain. Functional outcomes were measured over 9 months. The primary outcome was quality of ankle function at 3 months, measured using the Foot and Ankle Score; analysis was by intention to treat. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN37807450. Results Patients who received the below-knee cast had a more rapid recovery than those given the tubular compression bandage. We noted clinically important benefits at 3 months in quality of ankle function with the cast compared with tubular compression bandage (mean difference 9%; 95% CI 2·4–15·0), as well as in pain, symptoms, and activity. The mean difference in quality of ankle function between Aircast brace and tubular compression bandage was 8%; 95% CI 1·8–14·2, but there were little differences for pain, symptoms, and activity. Bledsoe boots offered no benefit over tubular compression bandage, which was the least effective treatment throughout the recovery period. There were no significant differences between tubular compression bandage and the other treatments at 9 months. Side-effects were rare with no discernible differences between treatments. Reported events (all treatments combined) were cellulitis (two cases), pulmonary embolus (two cases), and deep-vein thrombosis (three cases). Interpretation A short period of immobilisation in a below-knee cast or Aircast results in faster recovery than if the patient is only given tubular compression bandage. We recommend below-knee casts because they show the widest range of benefit. Funding National Co-ordinating Centre for Health Technology Assessment.
A new, automated method of detecting coronal mass ejections (CMEs) in three dimensions for the LASCO C2 and STEREO COR2 coronagraphs is presented. By triangulating isolated CME signal from the three ...coronagraphs over a sliding window of five hours, the most likely region through which CMEs pass at 5 R⊙ is identified. The centre and size of the region gives the most likely direction of propagation and approximate angular extent. The Automated CME Triangulation (ACT) method is tested extensively using a series of synthetic CME images created using a wireframe flux rope density model, and on a sample of real coronagraph data; including halo CMEs. The accuracy of the angular difference (σ) between the detection and true input of the synthetic CMEs is σ = 7.14°, and remains acceptable for a broad range of CME positions relative to the observer, the relative separation of the three observers and even through the loss of one coronagraph. For real data, the method gives results that compare well with the distribution of low coronal sources and results from another instrument and technique made further from the Sun. The true three dimension (3D)-corrected kinematics and mass/density are discussed. The results of the new method will be incorporated into the CORIMP database in the near future, enabling improved space weather diagnostics and forecasting.
Filling in biodiversity threat gaps Joppa, L. N.; O'Connor, B.; Visconti, P. ...
Science (American Association for the Advancement of Science),
04/2016, Letnik:
352, Številka:
6284
Journal Article
Recenzirano
Odprti dostop
Only 5% of global threat data sets meet a “gold standard”
The diversity of life on Earth—which provides vital services to humanity (
1
)—stems from the difference between rates of evolutionary ...diversification and extinction. Human activities have shifted the balance (
2
): Species extinction rates are an estimated 1000 times the “background” rate (
3
) and could increase to 10,000 times the background rate should species threatened with extinction succumb to pressures they face (
4
). Reversing these trends is a focus of the Convention on Biological Diversity's 2020 Strategic Plan for Biodiversity and its 20 Aichi Targets and is explicitly incorporated into the United Nations' 2030 Agenda for Sustainable Development and its 17 Sustainable Development Goals (SDGs). We identify major gaps in data available for assessing global biodiversity threats and suggest mechanisms for closing them.
STUDY QUESTION
Can the ranked expression levels of a cohort of cumulus cell (CC) genes be used to select MII oocytes with a potential for blastocyst development and live birth?
SUMMARY ANSWER
A ...ranking method containing four (HAS2, FSHR, VCAN, PR) of the eight genes evaluated in this study for identifying good quality MII oocytes provides a significantly better outcome compared with random selection and is equally as good as using all oocytes for ICSI.
WHAT IS KNOWN ALREADY
Recent evidence has identified a number of candidate genes in CC that have the potential to serve as markers of oocyte quality; however, a reliable method for selecting MII oocytes with blastocyst and live birth potential remains a challenge.
STUDY DESIGN, SIZE, DURATION
A group of 25 patients (<38 years old) underwent rFSH-stimulated ICSI treatment with single embryo replacement (SET). A total of 270 cumulus cell–oocyte complexes (COCs) were recovered and assessed.
MATERIALS, SETTING, METHODS
Expression levels of eight candidate genes (HAS2, FSHR, SLC2A4, ALCAM, SFRP2, VCAN, NRP1 and PR), corrected for RPL19, were measured in individual CC masses using multiplex QPCR. Expression levels of individual CC masses were assessed and ranked in relation to oocyte developmental indicators (blastocyst formation and live birth).
MAIN RESULTS AND THE ROLE OF CHANCE
From the 25 women, 19 (76%) had achieved a successful live birth delivery following SET. In this population, the selection of MII oocytes according to relative ranking levels of a subset of CC-expressed genes provided a significantly higher chance of identifying a good quality oocyte compared with selecting MII oocytes randomly (blastocyst: 1× MII oocyte: 52 versus 23%, P = 0.008; 3× MII oocytes: 80 versus 52%, P = 0.002; live birth: 1× MII oocyte: 31 versus 15%, P<0.05, 3× MII oocytes: 60 versus 38%, P < 0.05) and a similar chance to that of using all oocytes available after recovery (blastocyst: 80% versus 96%, P = 0.085, live birth: 60% versus 76%, P = 0.206).
LIMITATIONS, REASONS FOR CAUTION
The present method was validated only for young (<38 years) women, with male infertility, who had no signs of androgenicity, PCOS or endometriosis and were free of any chronic disease. This is a retrospective study that requires further validation in an unselected population.
WIDER IMPLICATIONS OF THE FINDINGS
Results presented in this study could be used to assist the selection of oocytes with high blastocyst developmental potential in frozen oocyte cycles and for the selection of embryos with high developmental potential as early as 18 h after ICSI (2PN stage) in fresh human IVF cycles.
STUDY FUNDING/COMPETING INTEREST(S)
Funding was provided by Fertility Associates Ltd and the New Zealand Government. The authors declare there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.
This paper presents results from a Direct Mapping Solution (DMS) comprised of an Applanix APX-15 UAV GNSS-Inertial system integrated with a Sony a7R camera to produce highly accurate ortho-rectified ...imagery without Ground Control Points on a Microdrones md4-1000 platform. A 55 millimeter Nikkor f/1.8 lens was mounted on the Sony a7R and the camera was then focused and calibrated terrestrially using the Applanix camera calibration facility, and then integrated with the APX-15 UAV GNSS-Inertial system using a custom mount specifically designed for UAV applications. In July 2015, Applanix and Avyon carried out a test flight of this system. The goal of the test flight was to assess the performance of DMS APX-15 UAV direct georeferencing system on the md4-1000. The area mapped during the test was a 250 x 300 meter block in a rural setting in Ontario, Canada. Several ground control points are distributed within the test area. The test included 8 North-South lines and 1 cross strip flown at 80 meters AGL, resulting in a ~1 centimeter Ground Sample Distance (GSD). Map products were generated from the test flight using Direct Georeferencing, and then compared for accuracy against the known positions of ground control points in the test area. The GNSS-Inertial data collected by the APX-15 UAV was post-processed in Single Base mode, using a base station located in the project area via POSPac UAV. The base-station’s position was precisely determined by processing a 12-hour session using the CSRS-PPP Post Processing service. The ground control points were surveyed in using differential GNSS post-processing techniques with respect to the base-station.
Background
The role of inflammation and cytokines in the pathophysiology of primary headache disorders is uncertain. We performed a systematic review and meta-analysis to synthesise the results of ...studies comparing peripheral blood cytokine levels between patients with migraine, tension-type headache, cluster headache, or new daily persistent headache (NDPH), and healthy controls; and in migraine between the ictal and interictal stages.
Methods
We searched PubMed/Medline and Embase from inception until July 2022. We included original research studies which measured unstimulated levels of any cytokines in peripheral blood using enzyme-linked immunosorbent assay or similar assay. We assessed risk of bias using the Newcastle–Ottawa Quality Assessment Scale. We used random effects meta-analysis with inverse variance weighted average to calculate standardised mean difference (SMD), 95% confidence intervals, and heterogeneity for each comparison. This study is registered with PROSPERO (registration number CRD42023393363). No funding was received for this study.
Results
Thirty-eight studies, including 1335 patients with migraine (32 studies), 302 with tension-type headache (nine studies), 42 with cluster headache (two studies), and 1225 healthy controls met inclusion criteria.
Meta-analysis showed significantly higher interleukin (IL)-6 (SMD 1.07, 95% CI 0.40–1.73,
p
= 0.002), tumour necrosis factor (TNF)-α (SMD 0.61, 95% CI 0.14–1.09,
p
= 0.01), and IL-8 (SMD 1.56, 95% CI 0.03–3.09,
p
= 0.04), in patients with migraine compared to healthy controls, and significantly higher interleukin-1β (IL-1β) (SMD 0.34, 95% CI 0.06–0.62,
p
= 0.02) during the ictal phase of migraine compared to the interictal phase. Transforming growth factor (TGF)-β (SMD 0.52, 95% CI 0.18–0.86,
p
= 0.003) and TNF-α (SMD 0.64, 95% CI 0.33–0.96,
p
= 0.0001) were both higher in patients with tension-type headache than controls.
Conclusions
The higher levels of the proinflammatory cytokines IL-6, IL-8 and TNF-α in migraine compared to controls, and IL-1β during the ictal stage, suggest a role for inflammation in the pathophysiology of migraine, however prospective studies are required to confirm causality and investigate the mechanisms for the increase in cytokine levels identified. Cytokines may also have a role in tension-type headache. Due a lack of data, no conclusions can be made regarding cluster headache or NDPH.
The success of protein, peptide and antibody based therapies is evident - the biopharmaceuticals market is predicted to reach $388 billion by 2024 1, and more than half of the current top 20 ...blockbuster drugs are biopharmaceuticals. However, the intrinsic properties of biopharmaceuticals has restricted the routes available for successful drug delivery. While providing 100% bioavailability, the intravenous route is often associated with pain and needle phobia from a patient perspective, which may translate as a reluctance to receive necessary treatment. Several non-invasive strategies have since emerged to overcome these limitations. One such strategy involves the use of microneedles (MNs), which are able to painlessly penetrate the
stratum corneum
barrier to dramatically increase transdermal drug delivery of numerous drugs. This review reports the wealth of studies that aim to enhance transdermal delivery of biopharmaceutics using MNs. The true potential of MNs as a drug delivery device for biopharmaceuticals will not only rely on acceptance from prescribers, patients and the regulatory authorities, but the ability to upscale MN manufacture in a cost-effective manner and the long term safety of MN application. Thus, the current barriers to clinical translation of MNs, and how these barriers may be overcome are also discussed.
► PRD offers an advantage over conventional deficit irrigation strategies because it helps reduce water use by separating the biochemical responses to water deficit from the physical effects of ...reduced water availability, allowing developmental processes associated with plant growth to remain unperturbed. Irrigating a reduced root zone volume in this way reduces crop water requirement. However, it is also important to understand that this technique pushes the crop to its limits and should only be applied to well established healthy trees. ► When applying PRD irrigation, it is important that water is supplied with sufficient frequency and depth of wetting to meet the water needs of the whole plant.
In Australian irrigated citriculture, fruit yield and quality outcomes are not tightly related to levels of plant available water, which raises the possibility of using mild water stress applied to part of the root zone, i.e. partial root zone drying, to stimulate physiological mechanisms that reduce tree water use by changing the relationship between stomatal conductance and ambient evaporative conditions.
The PRD technique alternates irrigation such that one side of the tree root zone is allowed to dry whilst the other side is irrigated. This significantly reduces the wetted soil volume at any point in time, whilst always maintaining a readily available water supply to part of the root zone. By adopting this irrigation strategy water use of mature Navel orange trees
C. sinensis (L.) Osbeck was reduced and water use efficiency was increased. The technique did not induce excessive fruitlet drop and crop yield was unaffected. Both fruit size and juice percentage slightly decreased whereas total soluble solids percentage (TSS) and juice acid percentage increased. As water use was reduced and juice quality attributes were increased, this technique has obvious benefits for juice fruit production.
PRD offers an advantage over conventional deficit irrigation strategies because it helps reduce water use by separating the biochemical signaling responses to water deficit in the dry part of the root zone from the physical effects of reduced stomatal conductance due to lower water availability, allowing developmental processes associated with plant growth to remain unperturbed. Irrigating a reduced root zone volume in this way reduces crop water requirement. However, it is also important to understand that this technique pushes the crop to its limits and should only be applied to well established healthy trees.
When applying PRD irrigation, it is important that water is supplied with sufficient frequency and depth of wetting to meet the water needs of the whole plant.
Multiple sclerosis (MS) is an inflammatory and neurodegenerative autoimmune disease of the central nervous system (CNS). Disease-modifying therapies (DMT) targeting inflammation have been shown to ...reduce disease activity in patients with relapsing⁻remitting MS (RRMS). The current therapeutic challenge is to find an effective treatment to halt disease progression and reverse established neural damage. Stem cell-based therapies have emerged to address this dilemma. Several types of stem cells have been considered for clinical use, such as autologous hematopoietic (aHSC), mesenchymal (MSC), neuronal (NSC), human embryonic (hESC), and induced pluripotent (iPSC) stem cells. There is convincing evidence that immunoablation followed by hematopoietic therapy (aHSCT) has a high efficacy for suppressing inflammatory MS activity and improving neurological disability in patients with RRMS. In addition, MSC therapy may be a safe and tolerable treatment, but its clinical value is still under evaluation. Various studies have shown early promising results with other cellular therapies for CNS repair and decreasing inflammation. In this review, we discuss the current knowledge and limitations of different stem cell-based therapies for the treatment of patients with MS.
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