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Background Ragweed pollen sensitivity is a common cause of allergic rhinitis (AR) worldwide. AR symptoms include itchy and runny eyes, sneezing, blocked nose, impaired sleep and social and emotional problems, which can have a significant impact on quality of life. Objective The objective of this analysis was to estimate utilities for two pooled standardised quality (SQ) ragweed sublingual immunotherapy (SLIT) tablet trials by applying a previously developed mapping algorithm. This study validated the algorithm and extended its application to ragweed seasonal allergy trials. The mapping algorithm relates disease-specific quality-of-life scores to preference-based utilities that may be used to calculate quality-adjusted life-years (QALYs) in cost-effectiveness studies. Methods A mapping algorithm based on a grass pollen allergy immunotherapy trial, GT-08 (EudraCT no. 2004-000083-27) was applied to pooled data from two ragweed pollen immunotherapy trials, P05233 (EudraCT 2008-003863-38) and P05234 (EudraCT 2008-003864-20) to generate EuroQoL 5-Dimensions, 3-Levels (EQ-5D-3L) utilities from Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ) data. Results The mean utility difference between the SQ ragweed SLIT tablet and placebo was 0.025 [95% confidence interval (CI) 0.011–0.038]. The SQ ragweed SLIT tablet showed an incremental quality-adjusted life-days (QALDs) benefit of 1.900 (95% CI 0.835–2.916) over 75 days. Conclusions Application of a previously developed mapping function allowed for the calculation of QALDs associated with the SQ ragweed SLIT tablet. The results showed a QALD benefit of the SQ ragweed SLIT tablet in P05233 and P05234 trials in the treatment of ragweed pollen-induced AR.

Background and aims Allergic rhinitis (AR) is an inflammatory disorder triggered by an allergic immune response to inhaled allergens. Birch pollen is the major allergenic tree pollen in parts of Europe. ITULAZAX® is a sublingual immunotherapy tablet for the treatment of adults with moderate‐to‐severe AR and/or conjunctivitis induced by pollen from the birch homologous group. The aim was to compare the costs of treating AR with ITULAZAX® versus subcutaneous ALUTARD SQ® Betula verrucosa (ALUTARD SQ®) from a Danish societal perspective. Methods A cost‐minimization model was developed to capture costs of allergy immunotherapy (AIT), interactions with healthcare professionals (HCPs) in three different care settings (general practice, allergy specialist, and hospital), and indirect costs arising from absenteeism and presenteeism. The cost‐minimization analysis was conducted over a 3‐year time horizon with costs reported in 2021 Danish Kroner (DKK) and Euros (EUR) based on the European Central Bank 365‐day average exchange rate. One‐way sensitivity analyses were performed. Results The base case analysis showed that the total cost of treatment over 3 years was estimated to be DKK 49,117 (EUR 6598) per patient with ALUTARD SQ®, compared with DKK 30,996 (EUR 4164) with ITULAZAX®, reflecting a cost saving of DKK 18,121 (EUR 2434) per patient with ITULAZAX® over 3 years. Over the 3‐year time horizon, costs of AIT were predicted to increase by DKK 17,928 (EUR 2408) with ITULAZAX®, while costs of interactions with HCPs were predicted to decrease by DKK 22,528 (EUR 3027) versus ALUTARD SQ®, more than offsetting the increased cost of ITULAZAX®. Conclusions Given the equivalent effectiveness of the two AIT products, and the cost savings with ITULAZAX® versus ALUTARD SQ® from a Danish societal perspective, ITULAZAX® should be considered as a cost‐saving alternative to ALUTARD SQ® for the treatment of birch pollen‐induced moderate‐to‐severe AR in adults.

Background This study investigated patients' preference for allergy immunotherapy (AIT) administered as either sublingual immunotherapy‐tablets versus monthly or weekly subcutaneous immunotherapy (SCIT) from a Spanish patient perspective. Methods A discrete choice experiment (DCE) consisting of two blocks with eight choice sets in each was constructed to elicit the preferences for AIT. Three attributes were included in the DCE for the mode of administration, including the frequency of administration, the risk of systemic reactions and the co‐payment. Adults and caregivers of children with moderate to severe allergic rhinitis (AR) were included if they were not currently receiving or had not previously received AIT. Results In total, 587 adults and 613 caregivers started the survey. Of those, 579 adults and 611 caregivers completed the survey and were included in the study. Both adults and caregivers had a significant preference for tablets compared with both monthly and weekly injections (p ≤ 0.0001). Furthermore, the respondents showed a significant preference for reducing the risk of systemic reactions. Subgroup analyses showed that caregivers of polyallergic children and female caregivers were significantly less price sensitive when choosing their preferred treatment. Conclusion Our study demonstrated that both adults with AR and caregivers of children with AR prefer daily SLIT‐tablets to SCIT with either a weekly or monthly dose schedule.

Allergic rhinitis (AR) is an immunoglobulin E antibody-mediated inflammatory condition that arises in response to inhaled allergens such as pollen. Pollens from trees in the birch homologous group are the most common allergenic tree pollens in Northern and Central Europe and North America. SQ® Tree SLIT-Tablet (ITULAZAX®) is a sublingual immunotherapy tablet indicated for moderate-to-severe AR and/or conjunctivitis induced by pollen from the birch homologous group. The present analysis evaluated the cost-utility of treating adults with AR with SQ Tree SLIT-Tablet versus placebo, both in combination with symptom-relieving medications, from a Swedish societal perspective. A model was developed to evaluate changes in cost and quality of life associated with using SQ Tree SLIT-Tablet relative to placebo in an adult population of individuals with AR. The model captured costs associated with symptom-relieving medications, healthcare professional interactions, SQ Tree SLIT-Tablet, and indirect costs arising from absenteeism and reduced workplace productivity. The analysis was conducted over 10 years with costs captured in 2021 Swedish Krona (SEK) and future costs and effects discounted at 3% per annum. One-way and probabilistic sensitivity analyses were conducted. Treatment with SQ Tree SLIT-Tablet resulted in an improvement of 0.041 quality-adjusted life years (QALYs) over 10 years versus placebo. From a Swedish societal perspective, costs increased by SEK 9077 over the same period, resulting in an incremental cost-utility ratio of SEK 223,445 per QALY gained. One-way sensitivity analysis showed that the model was most sensitive to assumptions around the disease-modifying effect of SQ Tree SLIT-Tablet. SQ Tree SLIT-Tablet improved quality of life in moderate-to-severe AR and/or conjunctivitis induced by pollen from the birch homologous group in Sweden, with only a modest increase in societal costs over a medium-term time horizon, representing good value for money at a willingness-to-pay threshold of SEK 700,000 per QALY.

People with allergic rhinitis (AR) who are not controlled on conventional therapy can be treated using allergy immunotherapy (AIT) administered as tablets, injections or drops. In the US, the use of sublingual immunotherapy as tablets (SLIT-tablets) is limited in comparison to subcutaneous immunotherapy (SCIT). This study investigated patients' preference for SLIT-tablets vs monthly or weekly SCIT from a US patient perspective. We carried out a discrete choice experiment (DCE) consisting of two blocks with eight choice sets. Adults and caregivers of children with moderate-to-severe AR were included if they had not previously or were not currently receiving AIT. Three attributes were included in the design: the mode and frequency of administration, the risk of systemic reactions and the co-payment. A total of 724 adults with AR and 665 caregivers of children with AR were included in the study. Both adults and caregivers had a significant preference for SLIT-tablets compared with both weekly and monthly injections and for less risk of anaphylactic shock. Caregivers were more risk-averse than adults when choosing their treatment, and the younger the child, the more risk-averse the caregiver. The preference for SLIT-tablets was found for both monoallergic and polyallergic adults and caregivers of monoallergic and polyallergic children. Respondents not wanting AIT for free were more risk-averse than those indicating that they wanted AIT for free. Our findings suggest that SLIT-tablets is the preferred route of administration for AIT among adults and caregivers of children with AR.

Defensins are antimicrobial peptides that are part of the innate immune system, contributing to the first line of defense against invading pathogens. Defensins and defensin-like peptides are functionally diverse, disrupting microbial membranes and acting as ligands for cellular recognition and signaling. Here we show that the tomato defensin DEF2 is expressed during early flower development. Defensin mRNA abundance, peptide expression and processing are differentially regulated in developing flowers. Antisense suppression or constitutive overexpression of DEF2 reduces pollen viability and seed production. Furthermore, overexpression of DEF2 pleiotropically alters the growth of various organs and enhances foliar resistance to the fungal pathogen Botrytis cinerea. Partially purified extracts from leaves of a DEF2-overexpressing line inhibited tip growth of B. cinerea. Besides providing insights into regulation of defensin expression, these data demonstrate that plant defensins, like their animal counterparts, can assume multiple functions related to defense and development.

At the local level, energy communities are at the forefront of the European Green Deal strategy offering new opportunities for citizens to get actively involved in energy markets. The scope of this study is to propose a multi-objective optimization framework to minimize both carbon dioxide emissions and total annual costs in an energy community, considering, within different constraints, a wide availability of decision variables including local renewable energy sources, sector coupling, storage and hydrogen. The methodology involves the coupling of the software EnergyPLAN with a multi-objective evolutionary algorithm, considering 2030 and 2050 as target years and modelling a set of eight types of scenarios, each consisting of 100 optimal systems out of 10,000. The case study is an energy community in the European Alps. The results show, on the one hand, the key role of sector coupling technologies such as cogeneration, heat pumps and electric vehicles in exploiting local renewable energy sources and, on the other hand, the higher costs in introducing both electricity storage to achieve a complete decarbonisation and hydrogen as an alternative strategy in the electricity, thermal and transport sectors.

IntroductionUndisplaced femoral neck fractures (FNFs) are usually treated by internal fixation (IF) but two randomised controlled trials (RCTs) have demonstrated advantages of treatment with arthroplasty. The complication rate was lowered but there were no clinically improved patient-reported outcome measures (PROM), which could be due to underpowering or choice of selected PROM as the studies do appear to report a better functional outcome. We will conduct an RCT comparing IF with arthroplasties in patients aged over 65 years with an undisplaced FNF.Methods and analysisAll hospitals in Denmark treating patients with hip fracture can provide patients for this study; therefore, the study can be considered a national RCT. Patients over 65 years old with an undisplaced FNF will be screened for eligibility and patients will only be excluded if they are unable to understand the study information (due to dementia or language), if they have a posterior tilt >20°, a pathological fracture or they cannot walk. Participants will be electronically randomised (in alternating blocks of 4 or 6) into either IF or arthroplasty. Postoperative care will follow the department standards.Primary and secondary outcomes and measuring points have been established in collaboration with patients with hip fracture by focus group interviews. The primary outcome measure is the New Mobility Score assessed after 1 year. Secondary outcomes are the Oxford Hip Score, EuroQol 5 domain (EQ-5D-5L), degree of posterior tilt, pain Verbal Rating Scale, reoperation and mortality.Ethics and disseminationThe study is approved by the Danish Data Protection Agency (19/7429) and the scientific ethics committee (S-20180036). All participants will sign an informed consent before entering the trial. Because this is a national trial, all relevant healthcare professionals in Denmark will automatically receive the trial results that will be published in international peer-reviewed journals.Trial registration numberClinicalTrials.gov Registry (NCT04075461).

Abstract Context The insulin-stimulating and glucagon-regulating effects of the 2 incretin hormones, glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), contribute to maintain normal glucose homeostasis. Impaired glucose tolerance occurs with high prevalence among patients with end-stage renal disease (ESRD). Objective To evaluate the effect of the incretin hormones on endocrine pancreatic function in patients with ESRD. Design and Setting Twelve ESRD patients on chronic hemodialysis and 12 matched healthy controls, all with normal oral glucose tolerance test, were included. On 3 separate days, a 2-hour euglycemic clamp followed by a 2-hour hyperglycemic clamp (3 mM above fasting level) was performed with concomitant infusion of GLP-1 (1 pmol/kg/min), GIP (2 pmol/kg/min), or saline administered in a randomized, double-blinded fashion. A 30% lower infusion rate was used in the ESRD group to obtain comparable incretin hormone plasma levels. Results During clamps, comparable plasma glucose and intact incretin hormone concentrations were achieved. The effect of GLP-1 to increase insulin concentrations relative to placebo levels tended to be lower during euglycemia in ESRD and was significantly reduced during hyperglycemia (50 [8–72]%, P = 0.03). Similarly, the effect of GIP relative to placebo levels tended to be lower during euglycemia in ESRD and was significantly reduced during hyperglycemia (34 [13–50]%, P = 0.005). Glucagon was suppressed in both groups, with controls reaching lower concentrations than ESRD patients. Conclusions The effect of incretin hormones to increase insulin release is reduced in ESRD, which, together with elevated glucagon levels, could contribute to the high prevalence of impaired glucose tolerance among ESRD patients.

•Nationwide factorial trial of all Danish patients with CKD and their GPs.•Evaluating if a single electronic letter can increase GDMT use in patients with CKD.•Uses national digital infrastructure for intervention delivery and data collection.•Primary endpoint is filled prescriptions of RASi or SGLT2i within 6 months. Treatment guidelines for chronic kidney disease (CKD) recommend sodium-glucose cotransporter 2 inhibitors (SGLT2i) as first-line treatment for a broad range of individuals with CKD, alongside renin-angiotensin system inhibitors (RASi). However, adoption of guidelines in clinical practice is often delayed, potentially leading to avoidable associated morbidity and mortality. Effective strategies are needed to improve implementation of guideline-directed medical therapy (GDMT) in patients with CKD. This trial will evaluate the effectiveness of electronic letter-based nudges, delivered via the Danish governmental electronic letter system to individuals with CKD, their general practices, or both, in increasing GDMT in individuals with CKD. NUDGE-CKD is a 2 × 2 factorial, nationwide implementation trial, with randomization at both the general practice and patient level. All Danish citizens with CKD and access to the official Danish electronic letter system were randomized in a 1:1 ratio to usual care (no letter) or to receive an electronic letter-based nudge on GDMT in CKD. All Danish general practices with a patient with CKD on their patient panel were also randomized 1:1 to usual care (no letter) or to receive an electronic informational nudge letter on GDMT in CKD. Data are collected through the Danish administrative health registries. The primary endpoint is a prescription of RASi or SGLT2i within 6 months of intervention delivery based on fill records. Secondary endpoints include components of the primary endpoint, as well as proportion of new CKD GDMT users. Prespecified exploratory endpoints include filled prescriptions of other cardio-renal-protective medications, general practice contacts, assessment of renal biomarkers and downstream clinical outcomes. A total 22,617 individuals with CKD were randomized to the patient-level intervention, and 28,069 individuals with CKD across 1,540 general practices were randomized to the general practice-level intervention. Intervention letters were delivered on August 19, 2024, and follow-up is currently ongoing (end of follow-up for primary endpoint: February 19, 2025). NUDGE-CKD is the first nationwide randomized trial of electronic letter-based nudges delivered to individuals with CKD and their general practices to increase uptake of GDMT in individuals with CKD. The trial will provide evidence into the usefulness of direct communication with patients and healthcare providers for real-world implementation of GDMT. Clinicaltrials.gov: NCT06300086, registered March 7, 2024 (https://clinicaltrials.gov/study/NCT06300086)