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Ex vivo human skin models are valuable tools in skin research due to their physiological relevance. Traditionally, standard cultivation is performed in a cell culture incubator with a defined temperature of 37 °C and a specific atmosphere enriched with CO2 to ensure media stability. Maintaining the model under these specific conditions limits its flexibility in assessing exposures to which the skin is exposed to in daily life, for example changes in atmospheric compositions. In this study we demonstrated that the foreskin-derived skin model can be successfully cultured at room temperature outside a CO2 incubator using a CO2-independent, serum-free media. Over a cultivation period of three days, the integrity of the tissue and the preservation of immune cells is well maintained, indicating the models stability and resilience under the given conditions. Exposing our Medical University of Graz - human Organotypic Skin Explant Culture (MUG-hOSEC) model to cytotoxic and inflammatory stimuli results in responses analyzable within the supernatant. Besides the common analysis of released proteins upon treatment, such as cytokines and enzymes, we have included extracellular vesicle to obtain a more comprehensive picture of cell communication.

Large-scale sequencing efforts have been undertaken to understand the mutational landscape of the coding genome. However, the vast majority of variants occur within non-coding genomic regions. We designed an integrative computational and experimental framework to identify recurrently mutated non-coding regulatory regions that drive tumor progression. Applying this framework to sequencing data from a large prostate cancer patient cohort revealed a large set of candidate drivers. We used (1) in silico analyses, (2) massively parallel reporter assays, and (3) in vivo CRISPR interference screens to systematically validate metastatic castration-resistant prostate cancer (mCRPC) drivers. One identified enhancer region, GH22I030351, acts on a bidirectional promoter to simultaneously modulate expression of the U2-associated splicing factor SF3A1 and chromosomal protein CCDC157. SF3A1 and CCDC157 promote tumor growth in vivo. We nominated a number of transcription factors, notably SOX6, to regulate expression of SF3A1 and CCDC157. Our integrative approach enables the systematic detection of non-coding regulatory regions that drive human cancers.

Abstract Ex vivo human skin models are valuable tools in skin research due to their physiological relevance. Traditionally, standard cultivation is performed in a cell culture incubator with a defined temperature of 37 °C and a specific atmosphere enriched with CO2 to ensure media stability. Maintaining the model under these specific conditions limits its flexibility in assessing exposures to which the skin is exposed to in daily life, for example changes in atmospheric compositions. In this study we demonstrated that the foreskin-derived skin model can be successfully cultured at room temperature outside a CO2 incubator using a CO2-independent, serum-free media. Over a cultivation period of three days, the integrity of the tissue and the preservation of immune cells is well maintained, indicating the model’s stability and resilience under the given conditions. Exposing our Medical University of Graz – human Organotypic Skin Explant Culture (MUG-hOSEC) model to cytotoxic and inflammatory stimuli results in responses analyzable within the supernatant. Besides the common analysis of released proteins upon treatment, such as cytokines and enzymes, we have included extracellular vesicle to obtain a more comprehensive picture of cell communication.

Abstract We report direct measurements of the magnetic field screening at the limits of the Meissner phase for two superconducting niobium (Nb) samples. The samples are processed with two different surface treatments that have been developed for superconducting radio-frequency (SRF) cavity applications—a “baseline” treatment and an oxygen-doping (“O-doping”) treatment. The measurements show: (1) that the screening length is significantly longer in the “O-doping” sample compared to the “baseline” sample; (2) that the screening length near the limits of the Meissner phase increases with applied field; (3) the evolution of the screening profile as the material transitions from the Meissner phase to the mixed phase; and (4) a demonstration of the absence of any screening profile for the highest applied field, indicative of the full flux entering the sample. Measurements are performed utilizing the $$\beta$$ β -detected nuclear magnetic resonance ( $$\beta$$ β -NMR) technique that allows depth resolved studies of the local magnetic field within the first 100 nm of the surface. The study takes advantage of the $$\beta$$ β -SRF beamline, a new facility at TRIUMF, Canada, where field levels up to 200 mT are available parallel to the sample surface to replicate radio frequency fields near the Meissner breakdown limits of Nb.

Abstract Cytomegalovirus (CMV) infection poses risks to newborns, necessitating effective therapies. Given that the damage includes both viral infection of brain cells and immune system-related damage, here we investigate the involvement of cellular prion protein (PrP), which plays vital roles in neuroprotection and immune regulation. Using a murine model, we show the role of PrP in tempering neonatal T cell immunity during CMV infection. PrP-null mice exhibit enhanced viral control through elevated virus-specific CD8 T cell responses, leading to reduced viral titers and pathology. We further unravel the molecular mechanisms by showing CMV-induced upregulation followed by release of PrP via the metalloproteinase ADAM10, impairing CD8 T cell response specifically in neonates. Additionally, we confirm PrP downregulation in human CMV (HCMV)-infected fibroblasts, underscoring the broader relevance of our observations beyond the murine model. Furthermore, our study highlights how PrP, under the stress of viral pathogenesis, reveals its impact on neonatal immune modulation.

Abstract Aortic dissections (ADs) are serious conditions of the main artery of the human body, where a tear in the inner layer of the aortic wall leads to the formation of a new blood flow channel, named false lumen. ADs affecting the aorta distally to the left subclavian artery are classified as a Stanford type B aortic dissection (type B AD). This is linked to substantial morbidity and mortality, however, the course of the disease for the individual case is often unpredictable. Computed tomography angiography (CTA) is the gold standard for the diagnosis of type B AD. To advance the tools available for the analysis of CTA scans, we provide a CTA collection of 40 type B AD cases from clinical routine with corresponding expert segmentations of the true and false lumina. Segmented CTA scans might aid clinicians in decision making, especially if it is possible to fully automate the process. Therefore, the data collection is meant to be used to develop, train and test algorithms.

Summary:. Augmentation mastopexy has attracted the attention of numerous authors seeking to improve surgical outcomes and ensure breast implant stability. The utilization of the dual plane technique with a lateral sling, pioneered by Ono and Karner, has demonstrated effectiveness in providing long-term implant support. However, challenges arise in cases of anatomical variations, such as a short pectoralis major (PM) muscle or chest, necessitating alternative approaches like the composite sling. This study presents a technique designed to elongate and broaden the lateral sling to enhance implant support. The composite sling incorporates components from the abdominal part of the PM muscle, the aponeurotic/muscular part of the external oblique muscle, and the cranial part of the rectus abdominis. Procedures were performed on 29 patients using the composite sling technique from July 2022 to October 2023. The follow-up period ranged from 6 to 18 months (average of 11.89 months). The lateral sling approach was successfully extended to cases with a short PM muscle or chest, previously managed using the dual plane technique without inferolateral support. No increase in complications or implant displacements was observed compared with the original lateral sling approach. However, four reoperations addressed issues such as dog ears, scarring, and minor asymmetries. Consistent results were observed throughout the follow-up period, particularly in maintaining upper pole fullness and preventing lower pole ptosis. The composite sling approach provides a viable solution for cases where the original sling technique is impractical. Its implementation could broaden surgical options and optimize results, particularly in cases of unfavorable anatomy.

Sustainable agriculture demands alternatives to fossil fuels. The FCTRAC project adopts a circular economy approach, focusing on zero-emission solutions. A fuel-cell-powered electric tractor with 95 kW, derived from a diesel model (STEYR 4130 Expert CVT) was developed. It integrates key components such as a 700 bar compressed hydrogen storage system, fuel cell, electric drive, and high-voltage battery. Leveraging existing driveline technology minimizes costs and development risks of the project. The vehicle achieves comparable performance, optimal visibility, as well as single type approval for on-road usage. This paper details the vehicle architecture, design, and key integration challenges, advancing the development of zero-emission agricultural machinery.

Incidenca melanoma v svetu in Sloveniji še vedno narašča, se je pa preživetje v zadnjih 20 letih izboljšalo, predvsem zaradi zgodnejšega odkrivanja melanoma in enotnih pristopov v primarnem zdravljenju. Posodobljena Priporočila v letu 2024 prinašajo precej novosti, predvsem v diagnostičnih postopkih odkrivanja in zamejitve zgodnjih stadijev melanoma, kot tudi natančnih priporočil sledenja po primarnem zdravljenju, na področju kirurškega zdravljenja in pa predvsem sistemskega zdravljenja, tako metastatske bolezni, predvsem pa v adjuvan- tnem sistemskem zdravljenju v visoko rizičnem stadiju II, in neo- adjuvantnem sistemskem zdravljenju operabilnega melanoma. V tokratna Priporočila smo vključili tudi poglavji prehranskega in paliativnega tima.

Natural biomaterials are commonly used as tissue engineering scaffolds due to their biocompatibility and biodegradability. Plant‐derived materials have also gained significant interest due to their abundance and as a sustainable resource. This study evaluates the corn‐derived protein zein as a plant‐derived substitute for animal‐derived gelatin, which is widely used for its favorable cell adhesion properties. Limited studies exist evaluating pure zein for tissue engineering. Herein, fibrous zein scaffolds are evaluated in vitro for cell adhesion, growth, and infiltration into the scaffold in comparison to gelatin scaffolds and are further studied in a subcutaneous model in vivo. Human mesenchymal stem cells (MSCs) on zein scaffolds express focal adhesion kinase and integrins such as α v β 3, α 4, and β 1 similar to gelatin scaffolds. MSCs also infiltrate zein scaffolds with a greater penetration depth than cells on gelatin scaffolds. Cells loaded onto zein scaffolds in vivo show higher cell proliferation and CD31 expression, as an indicator of blood vessel formation. Findings also demonstrate the capability of zein scaffolds to maintain the multipotent capability of MSCs. Overall, findings demonstrate plant‐derived zein may be a suitable alternative to the animal‐derived gelatin and demonstrates zein's potential as a scaffold for tissue engineering.

We pursued the hypothesis that specific glycans can be used to distinguish breast cancer stem cells (CSCs) and influence their function. Comparison of CSCs and non-CSCs from multiple breast cancer models revealed that CSCs are distinguished by expression of α2,3 sialylated core2 O-linked glycans. We identified a lectin, SLBR-N, which binds to O-linked α2,3 sialic acids, that was able to enrich for CSCs in vitro and in vivo. This O-glycan is expressed on CD44 and promotes its interaction with hyaluronic acid, facilitating CD44 signaling and CSC properties. In contrast, FUT3, which contributes to sialyl Lewis X (sLeX) production, is preferentially expressed in the non-CSC population, and it antagonizes CSC function. Collectively, our data indicate that SLBR-N can be more efficient at enriching for CSCs than CD44 itself because its use avoids the issues of CD44 splicing and glycan status. These data also reveal how differential glycosylation influences CSC fate.

Amorphous indium gallium zinc oxide (a-IGZO) is becoming an increasingly important technological material. Transport in this material is conceptualized as the heavy disorder of the material causing a conduction or mobility band-edge that randomly varies and undulates in space across the entire system. Thus, transport is envisioned as being dominated by percolation physics as carriers traverse this varying band-edge landscape of “hills” and “valleys”. It is then something of a missed opportunity to model such a system using only a compact approach—despite this being the primary focus of the existing literature—as such a system can easily be faithfully reproduced as a true microscopic TCAD model with a real physically varying potential. Thus, in this work, we develop such a “microscopic” TCAD model of a-IGZO and detail a number of key aspects of its implementation. We then demonstrate that it can accurately reproduce experimental results and consider the issue of the addition of non-conducting band-tail states in a numerically efficient manner. Finally, two short studies of 3D effects are undertaken to illustrate the utility of the model: specifically, the cases of variation effects as a function of device size and as a function of surface roughness scattering.

Avoided level crossing muon spin resonance (ALC-μSR) is used to characterize muoniated free radicals. These radicals are used as probes of the local environment and reorientational motion of specific components in complex systems. The parameter that provides information about the anisotropic motion is the motionally-averaged muon dipolar-hyperfine coupling constant (Dμ‖). The ALC-μSR spectra of muoniated radicals in anisotropic environments frequently have Lorentzian-like Δ1 resonances, which makes it challenging to extract Dμ‖. In this paper, we derive a means to estimate|Dμ‖| from ALC-μSR spectra with Lorentzian-like resonances by measuring the amplitude, width, and position of the Δ1 resonance and the amplitude, width, and position of a Δ0 resonance. Numerical simulations were used to test this relationship for radicals with a wide range of muon and proton hyperfine parameters. We use this methodology to determine |Dμ‖| for the Mu adducts of the cosurfactant 2-phenylethanol in C12E4 bilayers. From this we determined the amplitude of the anisotropic reorientational motion of the cosurfactant.

Background Atopic dermatitis is a chronic relapsing inflammatory skin condition. One of the most common skin disorders in children, atopic dermatitis typically manifests before the age of 5 years, but it can develop at any age. Atopic dermatitis is characterised by dry, inflamed skin accompanied by intense itchiness (pruritus). Objectives To appraise the clinical and cost effectiveness of abrocitinib, tralokinumab and upadacitinib within their marketing authorisations as alternative therapies for treating moderate-to-severe atopic dermatitis compared to systemic immunosuppressants (first-line ciclosporin A or second-line dupilumab and baricitinib). Data sources Studies were identified from an existing systematic review (search date 2019) and update searches of electronic databases (MEDLINE, EMBASE, CENTRAL) to November 2021, from bibliographies of retrieved studies, clinical trial registers and evidence provided by the sponsoring companies of the treatments under review. Methods A systematic review of the clinical effectiveness literature was carried out and a network meta-analysis undertaken for adults and adolescents at different steps of the treatment pathway. The primary outcome of interest was a combined response of Eczema Area and Severity Index 50 + Dermatology Life Quality Index ≥ 4; where this was consistently unavailable for a step in the pathway, an analysis of Eczema Area and Severity Index 75 was conducted. A de novo economic model was developed to assess cost effectiveness from the perspective of the National Health Service in England. The model structure was informed through systematic review of the economic literature and by consulting clinical experts. Effectiveness data were obtained from the network meta-analysis. Costs and utilities were obtained from the evidence provided by sponsoring companies and standard UK sources. Results Network meta-analyses indicate that abrocitinib 200 mg and upadacitinib 30 mg may be more effective, and tralokinumab may be less effective than dupilumab and baricitinib as second-line systemic therapies. Abrocitinib 100 mg and upadacitinib 15 mg have a more similar effectiveness to dupilumab. Upadacitinib 30 and 15 mg are likely to be more effective than ciclosporin A as a first-line therapy. Upadacitinib 15 mg, abrocitinib 200 and 100 mg may be more effective than dupilumab in adolescents. The cost effectiveness of abrocitinib and upadacitinib for both doses is dependent on the subgroup of interest. Tralokinumab can be considered cost-effective as a second-line systemic therapy owing to greater cost savings per quality-adjusted life-year lost. Conclusions The primary strength of the analysis of the three new drugs compared with current practice for each of the subpopulations is the consistent approach to the assessment of clinical and cost effectiveness. However, the conclusions are limited by the high uncertainty around the clinical effectiveness and lack of data for the primary outcome for comparisons with baricitinib and for the adolescent and adult first-line populations. Future work and limitations The most significant limitation that Eczema Area and Severity Index 50 + Dermatology Life Quality Index ≥ 4 could not be obtained for the adolescent and adult first-line systemic treatment populations is due to a paucity of data for dupilumab and ciclosporin A. A comparison of the new drugs against one another in addition to current practice would be beneficial to provide a robust view on which treatments are the most cost-effective. Study registration This study is registered as PROSPERO CRD42021266219. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Evidence Synthesis programme (NIHR award ref: 135138) and is published in full in Health Technology Assessment; Vol. 28, No. 4. See the NIHR Funding and Awards website for further award information. Plain language summary Atopic dermatitis is one of the most common skin conditions in children but can also develop in adulthood. People with atopic dermatitis have dry, red (inflamed) skin that is also extremely itchy (pruritus). There is no cure for atopic dermatitis. Therapy starts with topical treatments that are applied to the skin, such as emollients. Severe forms of atopic dermatitis are often treated with systemic treatments, which are drugs that are provided as tablets or an injection. Ciclosporin A is often the first systemic therapy given. If atopic dermatitis does not get better with ciclosporin A, options available in the National Health Service are dupilumab and baricitinib. New therapies that have been evaluated in clinical trials for atopic dermatitis but have not been assessed for use in the National Health Service are abrocitinib, tralokinumab and upadacitinib. The aim of this project is to review the medical benefits, risks and value for money for the National Health Service of abrocitinib, tralokinumab and upadacitinib for the treatment of moderate-to-severe atopic dermatitis in a multiple technology appraisal. Our review found that: For children aged between 12 and 18 years, abrocitinib and a low dose of upadacitinib (15 mg) are good value for money for the National Health Service. For adults who need a first systemic treatment, upadacitinib is unlikely to be good value for money for the National Health Service. For adults who are still suffering from their atopic dermatitis after having a systemic treatment and need a different drug, upadacitinib 15 mg and tralokinumab could be good value for money for the National Health Service if they are used on their own. For adults who are still suffering from their atopic dermatitis after having a systemic treatment and need a different drug, but need to take it with steroid cream, abrocitinib 100 mg, upadacitinib 15 mg and tralokinumab could all be good value for money for the National Health Service. Scientific summary Background Atopic dermatitis (AD), often referred to as atopic eczema, is a chronic relapsing inflammatory skin condition. One of the most common skin disorders in children, AD typically manifests before the age of 5 years, but can develop at any age. AD is characterised by dry, inflamed skin accompanied by intense itchiness (pruritus). As many as 1 in 5 children and 1 in 10 adults in the UK are estimated to have AD, with about 18% of cases of childhood AD categorised as moderate and 2% as severe. Of adults with AD, it has been reported that 5% of cases are severe. Of the people who need treatment for AD, 7% are estimated to have moderate-to-severe disease. Atopic dermatitis is currently uncurable, and the goal of treatment is to improve symptoms and achieve long-term disease control. Those with moderate-to-severe AD that only partially responds to treatment, and those presenting with severe disease, are referred to secondary care for a more specialised therapy, where phototherapy [predominantly ultraviolet B (UVB)] is frequently the first treatment option. If phototherapy is unsuccessful, subsequent treatment typically constitutes systemic treatments. Systemic treatment options available within the NHS for the management of AD in line with their marketing authorisations are ciclosporin A (CsA) in the first-line setting, and baricitinib and dupilumab as subsequent therapies. The three interventions for which an evaluation of the clinical and cost effectiveness in the treatment of moderate-to-severe AD form the basis of this report are abrocitinib, tralokinumab and upadacitinib. The clinical and cost effectiveness of these treatments at their recommended dose or doses versus treatment options available in the NHS for moderate-to-severe AD was evaluated in the positions in the treatment pathway proposed by the sponsoring company. The proposed positions are: Abrocitinib: second-line systemic therapy for adolescents second-line systemic therapy for adults. Tralokinumab: second-line systemic therapy for adults. Upadacitinib: adolescents first-line systemic therapy for adults second-line systemic therapy for adults. Objectives The research objectives of the multiple technology appraisal (MTA) are to appraise the clinical and cost effectiveness of abrocitinib, tralokinumab and upadacitinib within their marketing authorisations as alternative therapies for treating moderate-to-severe AD in the UK clinical setting compared to systemic immunosuppressants (first-line CsA or second-line dupilumab and baricitinib). Methods Studies were identified from an existing systematic review (search date 2019) and update searches of electronic databases (MEDLINE, EMBASE, CENTRAL) up to November 2021, from bibliographies of retrieved studies, clinical trial registers and evidence submissions provided by companies. Clinical studies and economic evaluations were included based on pre-specified inclusion criteria. Screening of title and abstracts to identify potentially relevant studies and evaluation of full-text publications were done independently by two reviewers. Data from included studies were extracted into a standardised data extraction form by one reviewer and validated by a second. Quality of included studies was assessed independently by two reviewers using standard checklists. Extracted data and quality assessment for each study were presented in structured tables. Where sufficient comparable data were available for an outcome measure, network meta-analysis (NMA) was performed using a Bayesian Markov Chain Monte Carlo simulation. The primary outcome of the review of clinical effectiveness was Eczema Area and Severity Index (EASI) 50 + Dermatology Life Quality Index (DLQI) ≥ 4 and EASI 75 was explored as a scenario. Treatment effects were analysed as odds ratios (ORs). A de novo hybrid economic model was developed to assess the cost effectiveness of the three new drugs, comprising a short-term (1 year) decision tree component, to capture the treatment induction phase and treatment response assessments, followed by a long-term (lifetime), three-state Markov model. In consultation with clinical experts, the Evidence Assessment Group (EAG) selected baseline characteristics for the model from the upadacitinib trials, which were considered representative of the eligible patient population in England. Estimates of treatment response, based on the composite outcome of EASI 50 + DLQI ≥ 4 from the NMA of clinical effectiveness data, were used in the short-term model. Conditional discontinuation data (defined as people whose condition responded to treatment at week 16 but withdrew from treatment for any reason at week 52) were used to estimate week-52 outcomes as well as long-term treatment discontinuation. Conditional discontinuation data were provided by the companies. Where there was a paucity of data, the EAG adopted a drug class approach to fill the gaps, where upadacitinib was used to inform Janus kinase inhibitors and tralokinumab was used to inform monoclonal antibodies. Additionally, in the long-term model treatment, waning assumptions were applied to all treatments as patients may lose response to treatment over time and these were informed by assumptions accepted in the NICE technology assessment of dupilumab for treating moderate to severe atopic dermatitis (TA534). Rates of adverse events and flare (based on the use of rescue medication) associated with each treatment were obtained from the companies, and where data gaps existed, a similar drug class approach was adopted for the missing data. Utilities based on drug class were obtained from key trials of upadacitinib and tralokinumab. Costs were obtained from standard UK sources. Probabilistic, one-way and scenario analyses were carried out to assess parameter uncertainty. Results The EAG identified 23 studies of relevance to the MTA. Most of the studies included in the assessment of clinical effectiveness were considered to be well-conducted and well-designed Phase III randomised controlled trials (RCTs), and, as such, are at an overall low risk of bias. However, the identified studies predominantly included mixed populations of people with moderate-to-severe AD, with some studies comprising both adolescents and adults, as well as a combination of people receiving systemic therapy as a first-line or second-line regimen. Thus, data informing the NMAs for the populations and outcomes of interest to the MTA are predominantly derived from post hoc subgroups. There were considerable amounts of uncertainty, and the vast majority of results were not statistically significant. However, there were consistent trends across the outcomes (EASI 50 + ΔDLQI ≥ 4 and EASI 75), interventions (combination therapy or monotherapy) and populations (adults in the first- or second-line setting and adolescents). Treatment with abrocitinib 200 mg leads to a better response, assessed as either EASI 50 + ΔDLQI ≥ 4 or EASI 75, than dupilumab, whereas there was less of a difference in the effectiveness between dupilumab and abrocitinib 100 mg with some comparisons showing a benefit in favour of dupilumab and others favouring abrocitinib 100 mg. Both doses of abrocitinib were more effective than baricitinib 4 mg (EASI 75 for adults in the second-line setting) and in the adolescent population, both doses of abrocitinib were more effective than dupilumab (EASI 75). Although significantly better than placebo, tralokinumab treatment was numerically, but not statistically significantly, less effective than treatment with either dupilumab or baricitinib 4 mg (response assessed as either EASI 50 + ΔDLQI ≥ 4 or EASI 75). Similar to abrocitinib, treatment with upadacitinib 30 mg led to a better response (assessed as either EASI 50 + ΔDLQI ≥ 4 or EASI 75) than dupilumab, whereas there was less of a difference in the effectiveness between dupilumab and upadacitinib 15 mg with some comparisons showing a benefit in favour of dupilumab and others favouring upadacitinib 15 mg. Both doses of upadacitinib were more effective than baricitinib 4 mg (EASI 75 for adults in the second-line setting). In the adolescent population, upadacitinib 15 mg was more effective than dupilumab (EASI 75). The National Institute for Health and Care Excellence (NICE) typically considers interventions a cost-effective use of the NHS resources if the incremental cost-effectiveness ratio (ICER) sits within a £20,000–30,000 threshold. The decision rule is reversed if an intervention is less costly and less effective (south-west quadrant), such that if the ICER is >£20,000–30,000 threshold, it can be considered a cost-effective use of NHS resources. For the adolescent population analyses, both doses of abrocitinib and upadacitinib 15 mg were less costly and more effective than dupilumab, resulting in dominant probabilistic ICERs. For the adult second-line monotherapy population, upadacitinib 15 mg is less costly and more effective than dupilumab (dominant) and tralokinumab was less costly and less effective than dupilumab (south-west quadrant ICER of £409,271). For the adult second-line combination therapy population, compared with dupilumab, abrocitinib 100 mg, upadacitinib 15 mg and tralokinumab were associated with south-west quadrant probabilistic ICERs of £58,920, £204,598 and £285,653, respectively. Compared with dupilumab, the following were not considered a cost-effective use of NHS resources with ICERs above £30,000 threshold commonly used by NICE: upadacitinib 15/30 mg (adult first-line combination therapy), abrocitinib 100/200 mg and upadacitinib 30 mg (adult second-line monotherapy), and abrocitinib 200 mg and upadacitinib 30 mg (adult second-line combination therapy). The key drivers of cost effectiveness were week-16 response probabilities and conditional discontinuation probabilities (used to inform the week-52 response and annual discontinuation), which are as expected, as these are the key effectiveness estimates in the model. In particular, the NMA for week-16 response was associated with substantial uncertainty, especially for abrocitinib, due to small numbers informing the network. Key scenarios that had a substantial impact on the cost-effectiveness results were reducing the time horizon in the adult analyses to 5 years and 18 years of age for the adolescent analyses, as well as using data from TA534 and an alternative NMA where censoring for rescue therapy was included. The EAG cautions the interpretation of the cost-effectiveness results presented in the MTA report as they are based on list prices for abrocitinib, baricitinib, dupilumab, tralokinumab and upadacitinib, but all have confidential patient access scheme (PAS) in place. Conclusions The population which is most likely to be important for decision-making is the adult second-line systemic treatment subgroup, in particular, the combination treatment analyses, as all three new drugs have a proposed position in this part of the treatment pathway. Furthermore, clinical experts advising the EAG considered combination therapy is more widely using in clinical practice in England. For this population, composite outcome data were available for each new treatment under consideration, as well as for one of the relevant comparators, dupilumab (which is approved for use by NICE at this step in the treatment pathway). Baricitinib, in combination with topical corticosteroid (TCS), is also a relevant comparator in the adult second-line systemic treatment population. However, composite outcome data for baricitinib were not made available to the EAG for inclusion in the clinical effectiveness analysis. Instead, the EAG obtained EASI 75 data for baricitinib and included this in the adult second-line systemic combination treatment NMA. As such, a scenario looking at the cost effectiveness of each of the three new drugs compared with baricitinib was explored to support decision-making. As the adult first-line systemic treatment and adolescent populations are also relevant for decision-making, the EAG was able to produce base-case cost-effectiveness results for the new drugs using the EASI 75 outcome, as the composite outcome was unavailable. However, RCT data for CsA were not available for the comparison with upadacitinib in the first-line setting, but observational data were identified that could be used in the NMA. Though the EAG notes that even though observational data for CsA are the best available evidence, it is associated with the bias inherent in observational studies and the results should be interpreted with caution. Additionally, for the adult first-line systemic treatment population, outcome data were only available for combination therapy, but the EAG’s clinical experts considered it to be more relevant for clinical practice. Thus, the EAG considered missing monotherapy data are unlikely to be critical for decision-making for the adult first-line systemic treatment subgroup. Analyses of the adolescent population were limited to assessing monotherapy, as combination data for dupilumab were unavailable to inform the NMA. Thus, the adolescent monotherapy analyses may potentially underestimate the relative effectiveness of the treatments when used in combination with TCS in clinical practice, as combination treatment results typically demonstrate higher treatment effectiveness. The summary of product characteristics for both abrocitinib and upadacitinib takes into consideration circumstances, where moving to the lower or higher dose of each drug may be beneficial and this is likely to happen in clinical practice. However, analyses exploring increasing or decreasing dose for abrocitinib and upadacitinib were not possible as efficacy data based on titrating dose are unavailable. Nonetheless, the EAG considers that clinical and cost-effectiveness results for abrocitinib and upadacitinib by low and high dose are useful to facilitate consideration of the impact of dose titration for each drug. The robustness of the clinical and cost-effectiveness analyses is limited by the use of post hoc subgroups; while the use of subgroups increases the comparability and applicability of the analyses, it introduces bias and uncertainty to the results generated by the NMAs. In particular, the sample size of the second-line systemic therapy subgroup in the abrocitinib trials was very small as the majority of patients in the abrocitinib trials were eligible for first-line rather than second-line systemic therapy. This research assesses the clinical and cost effectiveness of abrocitinib, tralokinumab and upadacitinib as alternative therapies for treating moderate-to-severe AD compared to standard practice with systemic immunosuppressants. At the different steps in the treatment pathway assessed, new options were identified that represent a cost-effective use of scarce NHS resources. Study registration This study is registered as PROSPERO CRD42021266219. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Evidence Synthesis programme (NIHR award reference: 135138) and is published in full in Health Technology Assessment; Vol. 28, No. 4. See the NIHR Funding and Awards website for further award information.

One means of increasing voting participation among populations that have been deliberately disenfranchised in the past is to make it easier for them to reach polling locations. The potential abuse of power posed by determining voting locations is underscored by the well-established effect of distance to polling locations on voter turnout. In this work, we address two open questions related to the effect of access to polling locations on voting participation. First, we extend previous studies by evaluating five voting location accessibility metrics in terms of their relationship to voter turnout. Second, in light of concerns about disenfranchisement of non-white voters, we evaluate whether the effects of voting accessibility on participation varies by race. We evaluate voting in the City of Atlanta, Georgia, during the 2020 general election, which occurred during the COVID-19 pandemic. We find that the likelihood of voting differs by as much as 2% for people located one minute closer to a polling location by car, although this relationship is only evident using one of the five accessibility measures. This estimate may be muted due to the prevalence of absentee voting during the pandemic. We also find that the effects of accessibility vary depending on a voters’ race, raising questions about the mechanisms behind the relationship between accessibility and voter participation. Overall, our findings point to the importance of equitable provision of accessible in-person polling locations and transportation to the polls to avoid posing barriers to voting, even in regions that have unrestricted access to mail-in voting.

Background:. Augmentation mastopexy remains a challenging surgery and has been frequently associated with suboptimal outcomes and remarkable reoperation rates, and one of the greatest challenges in mastopexy surgery is areolar lift, especially when implants are simultaneously used. Through the authors’ experience, this study is aimed to show a modification of the vertical approach with greater safety of the areolar pedicle. Methods:. The study included all patients who underwent augmentation mastopexy surgery performed by the authors between 2019 and 2022, whether primary or nonprimary, and performed a retrospective chart review of all patients who underwent this procedure. Results:. The length of the areolar lift ranged from 0 cm to 14 cm. Among the 17.4% of nonprimary mastopexies, the longest areolar lift was 11 cm. No cases of nipple–areola complex ischemia/necrosis were observed. With this technique, there were 6.2% complications (n = 31), none of which were considered serious. Conclusions:. This surgical sequence is a safe option for areolar lift in augmentation mastopexy. The vertical approach also has the advantage of producing considerably shorter horizontal scars. It is also reproducible, keeping the implant stable, which results in consistent long-term results.

The Outcome Questionnaire is a self-report questionnaire developed mainly for treatment impact assessment and monitoring of status change because it can measure the cross-sectional condition very accurately by being sensitive to small changes. The present study aimed to psychometrically evaluate and validate the instrument on a sample of Hungarian university students. 7,695 higher education students (28.6% male, 68.8% female, 1% other, M = 23.7, SD = 6.78) participated in the study and completed a questionnaire package (OQ-45, Beck Depression Inventory, WHO Well-being Questionnaire-5, Connor-Davidson Resilience Scale, MOS-Social Support Survey, Maslach Burnout Inventory-SS) online, developed to measure general and more specific mental health conditions. The Hungarian version of the questionnaire has a high internal consistency (Cronbach’s alpha = 0.951). Based on the confirmatory factor analysis, the original three-factor version of the instrument (due to inadequate fit indicators) did not gain support in our sample. Five subscales were identified and subjected to content analysis in the exploratory factor analysis. Our final questionnaire consists of 39 items. The full scale and the subscales show a high correlation with other questionnaires measuring similar constructs. The psychometric indicators of the questionnaire are adequate and, therefore, considered reliable. The separation of the five factors was confirmed by construct and convergent validation. The questionnaire’s psychometric properties may be worth testing in the future on a clinical sample and a sample of adults from a wider age range. The use of the measurement tool has important implications in research areas beyond therapeutic impact assessment, as it may offer a bridging solution to the methodological problems encountered in the construction of complex questionnaire packages consisting of several instruments. International findings suggest that some items in the questionnaire are particularly sensitive to cultural context, so it is crucial to use a measure adapted to the region of the study sample. Other strengths of the questionnaire include its ability to address subclinical and clinical symptoms in one dimension and provide a comprehensive cross-sectional picture of the bio-psycho-social status of individuals, which allows systematic monitoring of a large and heterogeneous population (higher education students).

Problem, research strategy, and findings: Transportation equity research addresses questions of participation and planning process or the distribution of transportation’s benefits and burdens. This work largely elides issues related to youth and student travel. Existing work on school trip mode choice does not engage deeply with the equity implications of its findings. Education equity researchers identify the abstract notion of choice as equity enhancing but do not engage with the realities of disparate transportation resources and infrastructure. In this review essay, we articulate the contours of transportation equity, youth travel, and school choice research. We use emerging perspectives on “mobility justice” to frame the issues and provide vocabulary that can help bring education and transportation together in planners’ everyday work. Takeaway for practice: A mobility justice framework encourages critical thought and action to address the root causes of inequities. Our conclusions make three contributions to research and practice: 1) challenging school district leaders to think about choice systems designed for access to schools, not just access to information about available options; 2) clarifying the broader implications of school choice by refusing to look away from the racial implications of forecasts; and 3) elucidating the need for a regional perspective.

Problem, research strategy, and findings: Transportation equity research addresses questions of participation and planning process or the distribution of transportation’s benefits and burdens. This work largely elides issues related to youth and student travel. Existing work on school trip mode choice does not engage deeply with the equity implications of its findings. Education equity researchers identify the abstract notion of choice as equity enhancing but do not engage with the realities of disparate transportation resources and infrastructure. In this review essay, we articulate the contours of transportation equity, youth travel, and school choice research. We use emerging perspectives on “mobility justice” to frame the issues and provide vocabulary that can help bring education and transportation together in planners’ everyday work. Takeaway for practice: A mobility justice framework encourages critical thought and action to address the root causes of inequities. Our conclusions make three contributions to research and practice: 1) challenging school district leaders to think about choice systems designed for access to schools, not just access to information about available options; 2) clarifying the broader implications of school choice by refusing to look away from the racial implications of forecasts; and 3) elucidating the need for a regional perspective.

The present study aimed to examine some potential predictors of homophobia against lesbians and gay individuals. Our sample comprised 722 heterosexual participants aged 18–74, mostly women (self-reported gender; 224 men and 498 women) with various educational backgrounds (i.e., High School, Bachelor’s, and Master’s degrees). Participants filled in self-reported scales measuring sexual orientation beliefs (incremental vs. entity views), religiosity, social media use, and perceived gender-transcendent social roles. Correlation analyses and multiple regression models were computed separately for men and women. For all participants, homophobia against lesbians (HAL) was negatively associated with participants’ age, religiosity, and gender-transcendent social roles and positively with incremental views about sexuality. However, only in the case of women was HAL positively related to social media use. Next, for both men and women, homophobia against gay individuals (HAG) was negatively related to age, religiosity, and gender-transcendent social roles. However, only in the case of women, HAG was positively related to social media use online and incremental views about sexuality. In the case of men, the most significant predictor of HAL was the perceived gender-transcendent social roles and HAG – perceived gender-linked social roles. For women, perceived gender-linked social roles were the most significant predictor of both HAL and HAG. Results are discussed regarding their use for interventions aimed at reducing homophobia among heterosexual individuals.

Abstract Flexible sensors are currently the subject of intensive research, as they allow cost‐effective and environmentally friendly production of large‐area, flexible, and when fabricated on ultrathin substrates, highly conformable devices. Among many intriguing applications, tactile and biosignal monitoring, where lightweight sensors with high wearing comfort are particularly interesting, is focused on here. The required spatiotemporal resolution of the signals is achieved by integrating the sensors in an active matrix configuration. Organic ferroelectric transducers of high uniformity, characterized, for example, by a sensitivity spread of only 1.5%, are combined with similarly uniform ultralow noise level organic thin film transistors operating below 5 V, showing, for example, a threshold voltage variation of just 0.13 V, in a 12 × 12 sensor array. The transistors transition frequency of up to 160 kHz (saturation range) and 17 kHz (linear range) allows for a high spatiotemporal resolution of ≈3 mm at a frame rate of 1400 fps. The thickness of only 2.8 µm renders the organic active matrix sensor sheet ultraflexible and therefore virtually imperceptible on the human skin. Real‐time monitoring of tactile modes in a subset of 8 × 3 pixels and of the pulse wave including heart rate and blood pressure using four sensors of the matrix is demonstrated.

Abstract Background Clear cell sarcomas (CCSs) are translocated aggressive malignancies, most commonly affecting young adults with a high incidence of metastases and a poor prognosis. Research into the disease is more feasible when adequate models are available. By establishing CCS cell lines from a primary and metastatic lesion and isolating healthy fibroblasts from the same patient, the in vivo process is accurately reflected and aspects of clinical multistep carcinogenesis recapitulated. Methods Isolated tumor cells and normal healthy skin fibroblasts from the same patient were compared in terms of growth behavior and morphological characteristics using light and electron microscopy. Tumorigenicity potential was determined by soft agar colony formation assay and in vivo xenograft applications. While genetic differences between the two lineages were examined by copy number alternation profiles, nuclear magnetic resonance spectroscopy determined arginine methylation as epigenetic features. Potential anti-tumor effects of a protein arginine n-methyltransferase type I (PRMT1) inhibitor were elicited in 2D and 3D cell culture experiments using cell viability and apoptosis assays. Statistical significance was calculated by one-way ANOVA and unpaired t-test. Results The two established CCS cell lines named MUG Lucifer prim and MUG Lucifer met showed differences in morphology, genetic and epigenetic data, reflecting the respective original tissue. The detailed cell line characterization especially in regards to the epigenetic domain allows investigation of new innovative therapies. Based on the epigenetic data, a PRMT1 inhibitor was used to demonstrate the targeted antitumor effect; normal tissue cells isolated and immortalized from the same patient were not affected with the IC50 used. Conclusions MUG Lucifer prim, MUG Lucifer met and isolated and immortalized fibroblasts from the same patient represent an ideal in vitro model to explore the biology of CCS. Based on this cell culture model, novel therapies could be tested in the form of PRMT1 inhibitors, which drive tumor cells into apoptosis, but show no effect on fibroblasts, further supporting their potential as promising treatment options in the combat against CCS. The data substantiate the importance of tailored therapies in the advanced metastatic stage of CCS.

Measurement(s) land cover Technology Type(s) visual interpretation of satellite imagery Sample Characteristic - Location Indonesia