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Following a health technology assessment, the Health Service Executive (HSE) supported reimbursement of dupilumab subject to a managed access protocol (MAP) being implemented. Reimbursement is restricted to a subgroup of the fully licensed indication, that is, moderate-to-severe refractory atopic dermatitis (AD) in adults and adolescents 12 years and older. This study provides an overview of the first year of the MAP.
Methods
All reimbursement applications submitted to the HSE Medicines Management Programme between 1 April 2021 and 31 March 2022 were reviewed. Key demographic and clinical characteristics of the approved population were analyzed. Reimbursement claims data within the specified period were extracted from the HSE Primary Care Reimbursement Services national pharmacy claims database. All data were compiled and analyzed using SPSS Statistics 27. Expenditure estimates were based on wholesale prices and were exclusive of value-added tax, fees, and confidential rebates.
Results
During the study period, 382 applications were submitted, 96 percent (n=365) of which were approved. Among approved patients, the mean age was 35 years (range 12 to 79 years), the mean number of years between AD diagnosis and approval was 22.65 years (range 1 to 78 years), and 65 percent (n=238) were men. The mean Eczema Area and Severity Index score was 28.72 and the mean (Children’s) Dermatology Life Quality Index score was 19.72. Approved patients who had unsuccessfully tried other systemic immunosuppressants had trialed up to five different medicines (mean=1.6). Year one expenditure was EUR2.4million, with 70 percent of approved patients accessing treatment.
Conclusions
Most applications submitted through the MAP were approved. These patients met the predefined evidence-based eligibility criteria for treatment. Patient numbers were higher than estimated, suggesting that the MAP did not hinder access. Utilizing health technology management by way of a MAP has facilitated access to expensive medicines for patients with the greatest need, while controlling expenditure for the payer.
Increasingly in Ireland, there are specific criteria attached to reimbursement approval for new medicines. Health technology assessment (HTA) identifies where uncertainty is greatest in relation to clinical and cost-effectiveness evidence and budget impact estimates; our health technology management (HTM) approach uses these outputs from HTA to design protocols to manage these uncertainties in the post-reimbursement phase.
Methods
A bespoke managed access protocol (MAP) is developed for each medicine reimbursed under this approach, informed by uncertainties highlighted in the HTA, directions from the decision-maker, and relevant particulars arising from commercial negotiations. Individual patient reimbursement applications are submitted via an online application system linked directly to the national pharmacy claims system. Pharmacists review the applications and approve reimbursement support where the patient meets the reimbursement criteria. The process is adaptive, allowing expansion of the criteria to include previously excluded patient cohorts, and the addition of new indications. It can also work across differing reimbursement arrangements (hospital/primary care).
Results
The MAP for liraglutide for weight management confines reimbursement to patients with a body mass index greater than or equal to 35 kg/m², prediabetes, and high risk for cardiovascular disease. Phase I reimbursement support lasts for six months; patients not attaining greater than or equal to five percent weight loss are deemed non-responders as per the HTA, and reimbursement support is discontinued. The MAP for dupilumab confined reimbursement support to adults with refractory moderate-to-severe atopic dermatitis, where cost-effectiveness was plausible in the HTA. The MAP for calcitonin-gene-related-peptides monoclonal antibodies confines reimbursement support to patients with chronic migraine, refractory to at least three prophylactic treatments, where cost-effectiveness was plausible in the HTA.
Conclusions
Across these MAPs, over 3,000 patients accessed novel treatments for chronic illnesses in September 2023. HTM provides an effective mechanism to facilitate access to high-cost medicines for targeted patient groups, while providing increased oversight and budgetary certainty. Key to acceptance is utilization of HTA outputs to implement evidence-based HTM measures targeting specific uncertainties as highlighted in the HTA report.
This Element outlines the origins and evolution of an international award-winning development intervention, index-based livestock insurance (IBLI), which scaled from a small pilot project in Kenya to a design that underpins drought risk management products and policies across Africa. General insights are provided on i) the economics of poverty, risk management, and drylands development; ii) the evolving use of modern remote sensing and data science tools in development; iii) the science of scaling; and iv) the value and challenges of integrating research with operational implementation to tackle development and humanitarian challenges in some of the world's poorest regions. This title is also available as Open Access on Cambridge Core.
Aquatic ecosystems - lakes, ponds and streams - are hotspots of biodiversity in the cold and arid environment of Continental Antarctica. Environmental change is expected to increasingly alter Antarctic aquatic ecosystems and modify the physical characteristics and interactions within the habitats that they support. Here, we describe physical and biological features of the peripheral ‘moat’ of a closed-basin Antarctic lake. These moats mediate connectivity amongst streams, lake and soils. We highlight the cyclical moat transition from a frozen winter state to an active open-water summer system, through refreeze as winter returns. Summer melting begins at the lakebed, initially creating an ice-constrained lens of liquid water in November, which swiftly progresses upwards, creating open water in December. Conversely, freezing progresses slowly from the water surface downwards, with water at 1 m bottom depth remaining liquid until May. Moats support productive, diverse benthic communities that are taxonomically distinct from those under the adjacent permanent lake ice. We show how ion ratios suggest that summer exchange occurs amongst moats, streams, soils and sub-ice lake water, perhaps facilitated by within-moat density-driven convection. Moats occupy a small but dynamic area of lake habitat, are disproportionately affected by recent lake-level rises and may thus be particularly vulnerable to hydrological change.
The primary objective was to analyze the impact of the national cyberattack in May 2021 on patient flow and data quality in the Paediatric Emergency Department (ED), amid the SARS-CoV-2 (COVID-19) pandemic.
Methods:
A single site retrospective time series analysis was conducted of three 6-week periods: before, during, and after the cyberattack outage. Initial emergent workflows are described. Analysis includes diagnoses, demographic context, key performance indicators, and the gradual return of information technology capability on ED performance. Data quality was compared using 10 data quality dimensions.
Results:
Patient visits totaled 13 390. During the system outage, patient experience times decreased significantly, from a median of 188 minutes (pre-cyberattack) down to 166 minutes, most notable for the period from registration to triage, and from clinician review to discharge (excluding admitted patients). Following system restoration, most timings increased. Data quality was significantly impacted, with data imperfections noted in 19.7% of data recorded during the system outage compared to 4.7% before and 5.1% after.
Conclusions:
There was a reduction in patient experience time, but data quality suffered greatly. A hospital’s major emergency plan should include provisions for digital disasters that address essential data requirements and quality as well as maintaining patient flow.
This study compared the field performance of red clover germplasm UK2014, selected for 2,4-D tolerance, to Kenland, a standard variety grown in the transition zone of the United States. UK2014 and Kenland were seeded in the spring of 2017 and 2018. Single applications of 0, 1.12, or 2.24 kg ae ha−1 2,4-D-amine were made in June, August, or October. One week after the treatments, yields were determined. Visible herbicide injury ratings were made prior to harvest and regrowth was visibly assessed 1 wk after harvest. Red clover stands were visibly assessed the following spring. Kenland, across all application timings, was injured by 2,4-D more than UK2014, with mean injury ratings of 39% and 63% compared with 26% and 37% at 1.12 and 2.24 kg 2,4-D ae ha−1, respectively. At equivalent rates, Kenland regrowth was less than UK2014 at all application timings. UK2014 regrowth after 2,4-D treatment ranged from 65% to 91%, whereas Kenland regrowth ranged from 12% to 72%. Applications of 2,4-D in October were the most damaging to stands of both UK2014 and Kenland the following spring, but Kenland stands were reduced much more than those of UK2014. Kenland and UK2014 had similar season total yields when not treated with 2,4-D (means of 7,550 and 7,880 dry matter kg ha−1, respectively in 2017 and 5,280 dry matter kg ha−1 for both in 2018). Kenland season total yield in 2017 was reduced by both 2,4-D rates applied in June or August and at all timings in 2018. UK2014 season total yield in 2017 was reduced only when 2.24 kg 2,4-D ae ha−1 was applied in August. In 2018, 2.24 kg ae ha−1 2,4-D resulted in reduced UK2014 season total yield across application timings. UK2014 has greater 2,4-D tolerance than Kenland, but additional selection might be beneficial.
Methiozolin is a new herbicide with an unknown mechanism of action (MOA) for control of annual bluegrass (Poa annua L.) in several warm- and cool-season turfgrasses. In the literature, methiozolin was proposed to be a pigment inhibitor via inhibition of tyrosine aminotransferases (TATs) or a cellulose biosynthesis inhibitor (CBI). Here, exploratory research was conducted to characterize the herbicide symptomology and MOA of methiozolin. Arabidopsis (Arabidopsis thaliana L.) and P. annua exhibited a similar level of susceptibility to methiozolin, and arrest of meristematic growth was the most characteristic symptomology. For example, methiozolin inhibited A. thaliana root growth (GR50 8 nM) and shoot emergence (GR80 ˜50 nM), and apical meristem growth was completely arrested at rates greater than 500 nM. We concluded that methiozolin was neither a TAT nor a CBI inhibitor. Methiozolin had a minor effect on chlorophyll and alpha-tocopherol content in treated seedlings (<500 nM), and supplements in the proposed TAT pathway could not lessen phytotoxicity. Examination of microscopic images of roots revealed that methiozolin-treated (100 nM) and untreated seedlings had similar root cell lengths. Thus, methiozolin inhibits cell proliferation and not elongation from meristematic tissue. Subsequently, we suspected methiozolin was an inhibitor of the mevalonic acid (MVA) pathway, because its herbicidal symptomologies were nearly indistinguishable from those caused by lovastatin. However, methiozolin did not inhibit phytosterol production, and MVA pathway metabolites did not rescue treated seedlings. Further experiments showed that methiozolin produced a physiological profile very similar to cinmethylin across a number of assays, a known inhibitor of fatty-acid synthesis through inhibition of thioesterases (FATs). Experiments with lesser duckweed (Lemna aequinoctialis Welw.; syn. Lemna paucicostata Hegelm.) showed that methiozolin also reduced fatty-acid content in Lemna with a profile similar, but not identical, to cinmethylin. However, there was no difference in fatty-acid content between treated (1 µM) and untreated A. thaliana seedlings. Methiozolin also bound to both A, thaliana and L. aequinoctialis FATs in vitro. Modeling suggested that methiozolin and cinmethylin have comparable and overlapping FAT binding sites. While there was a discrepancy in the effect of methiozolin on fatty-acid content between L. aequinoctialis and A. thaliana, the overall evidence indicates that methiozolin is a FAT inhibitor and acts in a similar manner as cinmethylin.
Catatonia is a psychomotor dysregulation syndrome of diverse aetiology, increasingly recognised as a prominent feature of N-methyl-d-aspartate receptor antibody encephalitis (NMDARE) in adults. No study to date has systematically assessed the prevalence and symptomatology of catatonia in children with NMDARE. We analysed 57 paediatric patients with NMDARE from the literature using the Bush-Francis Catatonia Rating Scale. Catatonia was common (occurring in 86% of patients), manifesting as complex clusters of positive and negative features within individual patients. It was both underrecognised and undertreated. Immunotherapy was the only effective intervention, highlighting the importance of prompt recognition and treatment of the underlying cause of catatonia.
Herbicide resistance has for decades been an increasing problem of agronomic crops such as corn and soybean. Several weed species have evolved herbicide resistance in turfgrass systems such as golf courses, sports fields, and sod production—particularly biotypes of annual bluegrass and goosegrass. Consequences of herbicide resistance in agronomic cropping systems indicate what could happen in turfgrass if herbicide resistance becomes broader in terms of species, distribution, and mechanisms of action. The turfgrass industry must take action to develop effective resistance management programs while this problem is still relatively small in scope. We propose that lessons learned from a series of national listening sessions conducted by the Herbicide Resistance Education Committee of the Weed Science Society of America to better understand the human dimensions affecting herbicide resistance in crop production provide tremendous insight into what themes to address when developing effective resistance management programs for the turfgrass industry.
The rupture of atherosclerotic plaques is the prerequisite for adverse cardiovascular events. Calcification morphology plays a critical role in plaque stability, therefore accurate calcification classification is essential for favourable patient management. Blood biomarkers may be a worthwhile approach to stratify patients based on calcification phenotype. Vitamin K-dependent Matrix γ-carboxyglutamate (Gla) protein (MGP) is a potent inhibitor of vascular calcification. Recent studies have demonstrated the potential utility of circulating non-functional MGP (dp-ucMGP) measurements to determine arterial stiffness and calcification levels. The objective of this study was to examine the relationship between circulating dp-ucMGP and calcification phenotype within symptomatic atherosclerotic lesions. Consenting patients undergoing standard endarterectomy procedures were recruited (n = 29). Fasting venous blood was collected preoperatively. Circulating plasma levels of dp-ucMGP were quantified using the inaKtif MGP (dp-ucMGP) iSYS kit. A bicinchoninic acid assay was used to standardise the total protein content present in each sample. High-resolution micro-CT imaging was conducted on the excised atherosclerotic specimens postoperatively. ImageJ post-processing was used to accurately quantify the calcification volume (≥ 130 Hounsfield Units) and determine the total number of calcified particles (3D objects counter plugin). Thirteen carotid (average age 71 years, 9 male) and fourteen peripheral lower limb (average age 65 years, 12 male) patients were examined. One patient had a carotid and a peripheral lower limb plaque (age 79, male). Peripheral lower limb specimens have larger volumes of calcification and higher numbers of calcified particles than carotid samples (472 ± 310 vs 85 ± 113mm3, p < 0.0005; 13919 ± 16034 vs 3476 ± 6208, p = 0.061.) While a higher dp-ucMGP value was noted in carotid than peripheral lower limb patients (214 ± 52 vs 169 ± 36pmol/L, p = 0.014) there was no correlation between circulating dp-ucMGP and calcification volume or number of calcified particles (rs = -0.329 and rs = 0.046). Previous research also found that peripheral lower limb lesions contain higher volumes of calcification than carotid lesions. There is currently no published data on calcified particle comparisons. Patients with symptomatic carotid disease are assumed to have a degree of peripheral arterial disease, this could explain the higher levels of circulating dp-ucMGP in carotid patients. The current study did not examine the dietary patterns of individuals with regards to Vitamin K intake or analyse other areas of the vasculature for additional calcification. This may interfere with dp-ucMGP measurements. This study serves as a preliminary investigation into the potential of dp-ucMGP as a blood based biomarker to distinguish between symptomatic atherosclerotic calcification phenotypes.
While mastery of aspects of music theory is relevant to rapid learning and understanding of a new choral part, many choirs comprise members with no formal education in music theory. Also, the language of music theory is not intuitive, with many terms having meanings different from those in common use, which can present obstacles for mature learners. The authors hypothesised that students joining an internationally recognised university choir might master aspects of music theory as a by-product of rehearsals. This was tested by having new admissions to such a choir complete a music theory test at the commencement and at the end of a year. The test evaluated the ability to name and write intervals and name notes and the duration of notes. Overall results did not reject the hypothesis. Subjects with no formal music training also showed most, and statistically significant, improvement in the questions related to intervals, which are arguably the most useful skills for choristers who do not sight-read. This appears to be a new finding: the literature shows occasional references to music theory skills, but their acquisition in a learning-by-doing style is not reported. Some insights into ways of enhancing choral performance are a by-product of the principal focus of the study.
The regeneration niche defines the specific environmental requirements of the early phases of a plant's life cycle. It is critical for the long-term persistence of plant populations, particularly for obligate seeders that are highly vulnerable to stochastic events in fire-prone ecosystems. Here, we assessed germination characteristics and the relationship between population structure, soil seed bank density and fire response in Stachystemon vinosus (Euphorbiaceae), a rare endemic shrub from Western Australia, from burnt and long unburnt habitats. Many plants in long unburnt habitat were similar in size to those in recently burnt habitat. Soil seed bank density was related to plant abundance and fire history with density lower in burnt than unburnt sites. Thus, inter-fire recruitment may play a critical role in the requirements of the study species. To assess the dormancy status and germination requirements we used a ‘move-along’ experiment with temperatures from six seasonal phases of the year. Seeds were incubated under light and dark conditions, with and without smoked water, and with and without dry after-ripening. Germination was most effective when seeds were treated with smoked water and incubated in the dark at temperatures resembling autumn/winter conditions. After-ripening increased germination in light and dark incubated seeds in the absence of smoked water but was unnecessary for optimal germination in smoked water treated seeds. Irrespective of treatment, seeds showed a requirement for cooler temperatures for germination. These results suggest that rising temperatures and changes in fire regime associated with global warming may alter future germination responses of Stachystemon vinosus.
Several grass and broadleaf weed species around the world have evolved multiple-herbicide resistance at alarmingly increasing rates. Research on the biochemical and molecular resistance mechanisms of multiple-resistant weed populations indicate a prevalence of herbicide metabolism catalyzed by enzyme systems such as cytochrome P450 monooxygenases and glutathione S-transferases and, to a lesser extent, by glucosyl transferases. A symposium was conducted to gain an understanding of the current state of research on metabolic resistance mechanisms in weed species that pose major management problems around the world. These topics, as well as future directions of investigations that were identified in the symposium, are summarized herein. In addition, the latest information on selected topics such as the role of safeners in inducing crop tolerance to herbicides, selectivity to clomazone, glyphosate metabolism in crops and weeds, and bioactivation of natural molecules is reviewed.
Seven half-day regional listening sessions were held between December 2016 and April 2017 with groups of diverse stakeholders on the issues and potential solutions for herbicide-resistance management. The objective of the listening sessions was to connect with stakeholders and hear their challenges and recommendations for addressing herbicide resistance. The coordinating team hired Strategic Conservation Solutions, LLC, to facilitate all the sessions. They and the coordinating team used in-person meetings, teleconferences, and email to communicate and coordinate the activities leading up to each regional listening session. The agenda was the same across all sessions and included small-group discussions followed by reporting to the full group for discussion. The planning process was the same across all the sessions, although the selection of venue, time of day, and stakeholder participants differed to accommodate the differences among regions. The listening-session format required a great deal of work and flexibility on the part of the coordinating team and regional coordinators. Overall, the participant evaluations from the sessions were positive, with participants expressing appreciation that they were asked for their thoughts on the subject of herbicide resistance. This paper details the methods and processes used to conduct these regional listening sessions and provides an assessment of the strengths and limitations of those processes.
Herbicide resistance is ‘wicked’ in nature; therefore, results of the many educational efforts to encourage diversification of weed control practices in the United States have been mixed. It is clear that we do not sufficiently understand the totality of the grassroots obstacles, concerns, challenges, and specific solutions needed for varied crop production systems. Weed management issues and solutions vary with such variables as management styles, regions, cropping systems, and available or affordable technologies. Therefore, to help the weed science community better understand the needs and ideas of those directly dealing with herbicide resistance, seven half-day regional listening sessions were held across the United States between December 2016 and April 2017 with groups of diverse stakeholders on the issues and potential solutions for herbicide resistance management. The major goals of the sessions were to gain an understanding of stakeholders and their goals and concerns related to herbicide resistance management, to become familiar with regional differences, and to identify decision maker needs to address herbicide resistance. The messages shared by listening-session participants could be summarized by six themes: we need new herbicides; there is no need for more regulation; there is a need for more education, especially for others who were not present; diversity is hard; the agricultural economy makes it difficult to make changes; and we are aware of herbicide resistance but are managing it. The authors concluded that more work is needed to bring a community-wide, interdisciplinary approach to understanding the complexity of managing weeds within the context of the whole farm operation and for communicating the need to address herbicide resistance.
Microwave dielectric heating methods for the preparation of a number of arsenate, phosphate, vanadate, molybdate and carbonate minerals and their deuterated analogues are reported; rapid and efficient syntheses of these have been achieved. The application of this to the study of vibrational spectroscopy of minerals is discussed, with particular reference to scorodite.
OBJECTIVES/SPECIFIC AIMS: Accumulation of cholesterol-laden macrophages in arterial walls leads to atherosclerosis. LXRs induce expression of genes that are atheroprotective in macrophages including CCR7, a chemokine receptor that promotes their emigration from the plaque. CCR7 expression has been shown to be negatively regulated by phosphorylation of LXRα at S198 and is reduced in diabetic mice that show impaired plaque regression. I hypothesized that LXRα phosphorylation at S198 diminishes macrophage emigration from atherosclerotic plaque and contributes to impaired regression in diabetes. METHODS/STUDY POPULATION: Inducible LXRα S198A phosphorylation deficient knock in mouse were used as donors for bone marrow transplantation into mice prone to develop atherosclerosis. Plaques were developed by placing mice on western diet; and regression was induced by lowering their lipid levels. Aortic plaques were then analyzed by using morphometric, histological, and molecular analyses in control and diabetic mice expressing either LXRα WT or LXRα S198A during regression. RESULTS/ANTICIPATED RESULTS: Surprisingly, lack of phosphorylation increased plaque macrophage content and impaired regression under normoglycemic condition; however, it did not exacerbate diabetic regression. Plaques in diabetic mice were associated with increased LXRα S198 phosphorylation. Consistent with this, LXRα phosphorylation is enhanced in macrophages cultured under hyperglycemic conditions indicating glucose-dependent regulation of LXRα phosphorylation. Monocyte trafficking studies reveal that lack of phosphorylation and diabetes independently increase recruitment of monocytes in the plaque that might contribute to increased macrophage content. Importantly, I found that diabetes also increases macrophage retention in the plaque, which is reversed in the absence of phosphorylation. We predict that this increased retention results from inhibition of emigration of plaque macrophages through enhanced phosphorylation in diabetes. DISCUSSION/SIGNIFICANCE OF IMPACT: These findings suggest that inhibiting LXRα phosphorylation could be beneficial in diabetic atherosclerosis to reverse the accumulation of macrophages in the plaque. This study imparts insight on regulation of plaque macrophage trafficking through LXRα S198 phosphorylation.
A comprehensive analysis of early dinosaur relationships raised the possibility that the group may have originated in Laurasia (Northern Hemisphere), rather than Gondwana (Southern Hemisphere) as often thought. However, that study focused solely on morphology and phylogenetic relationships and did not quantitatively evaluate this issue. Here, we investigate dinosaur origins using a novel Bayesian framework uniting tip-dated phylogenetics with dynamic, time-sliced biogeographic methods, which explicitly account for the age and locality of fossils and the changing interconnections of areas through time due to tectonic and eustatic change. Our analysis finds strong support for a Gondwanan origin of Dinosauria, with 99 % probability for South America (83 % for southern South America). Parsimony analysis gives concordant results. Inclusion of time-sliced biogeographic information affects ancestral state reconstructions (e.g., high connectivity between two regions increases uncertainty over which is the ancestral area) and influences tree topology (disfavouring uniting fossil taxa from localities that were widely separated during the relevant time slice). Our approach directly integrates plate tectonics with phylogenetics and divergence dating, and in doing so reaffirms southern South America as the most likely area for the geographic origin of Dinosauria.
McMurdo Dry Valleys (MDV; Ross Sea region, Antarctica) precipitation exhibits extreme seasonality in ion concentration, 3–5 orders of magnitude between summer and winter precipitation. To identify aerosol sources and investigate causes for the observed amplitude in concentration variability, four snow pits were sampled along a coast–Polar Plateau transect across the MDV. The elevation of the sites ranges from 50 to 2400 m and the distance from the coast from 8 to 93 km. Average chemistry gradients along the transect indicate that most species have either a predominant marine or terrestrial source in the MDV. Empirical orthogonal function analysis on the snow-chemistry time series shows that at least 57% of aerosol deposition occurs concurrently. A conceptual climate model, based on meteorological observations, is used to explain the strong seasonality in the MDV. Our results suggest that radiative forcing of the ice-free valleys creates a surface low-pressure cell during summer which promotes air-mass flow from the Ross Sea. The associated precipitating air mass is relatively warm, humid and contains a high concentration of aerosols. During winter, the MDV are dominated by air masses draining off the East Antarctic ice sheet, that are characterized by cold, dry and low concentrations of aerosols. The strong differences between these two air-mass sources create in the MDV a polar version of the monsoonal flow, with humid, warm summers and dry, cold winters.