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Despite being under development for decades, RNA therapeutics have only recently emerged as viable drug platforms. The COVID-19 mRNA vaccines have demonstrated the promise and power of the platform technology. In response, novel RNA drugs are entering clinical trials at an accelerating rate. As the skin is the largest and most accessible organ, it has always been a preferred target for drug discovery. This holds true for RNA therapies as well, and multiple candidate RNA-based drugs are currently in development for an array of skin conditions. In this mini review, we catalog the RNA therapies currently in clinical trials for different dermatological diseases. We summarize the main types of RNA-related drugs and use examples of drugs currently in development to illustrate their key mechanism of action.

After a successful Marketing Authorization Application for clinical trials with time-to-event endpoints, the degree of the added benefit from new treatments remains unknown and needs to be assessed. Unfortunately, until now no clear definition for added benefit determination of a treatment exists. Nevertheless, European authorities / societies have developed 2 "additional benefit assessment" methods, which have up to now not been compared: the European Society for Medical Oncology (ESMO) developed a dual rule considering relative and absolute benefit. The German Institute for Quality and Efficiency in Health Care (IQWiG) developed a method using upper 95% hazard ratio confidence interval.We evaluate and compare both methods in an extensive simulation study including different censoring rates, failure time distributions, and treatment effects for sample size calculation. The methods' performance is assessed via Receiver Operating Characteristic curves, Spearman correlation, and percentage of achieved maximal scores.The results show that IQWiG's method has in many situations a lower maximal scoring proportion than ESMO's rule, that is, up to 28.5% versus 94.7%. Various failure time distributions lead to strongly changed maximal scoring percentages for ESMO. High positive correlation between the methods is present for moderate treatment effects.IQWiG's method is usually more conservative than ESMO's. ESMO's rule tends to be more susceptible for various failure time distributions. Using the lower confidence interval limit seems to be a better solution resulting in a higher true-positive rate without increasing the false-positive rate. Thus, IQWiG's method might need to be adapted accordingly to achieve a better overall classification.

ZUSAMMENFASSUNGIm Zeitraum vom 10. November 2020 bis zum 26. Dezember 2021 wurden im Katholischen Kinderkrankenhaus Wilhelmstift in Hamburg sechs Kinder mit MIS-C behandelt. Mögliche Differenzialdiagnosen wie das Kawasaki-Syndrom (KS), Toxisches Schocksyndrom sowie die Hämophagozytische Lymphohistiozytose konnten unter anderem durch den Nachweis einer positiven SARS-CoV-2-Serologie ausgeschlossen werden. Anders als beim KS sind Kinder mit MIS-C älter und fallen durch eine führende kardiale und abdominelle Symptomatik auf. Eine mit ventrikulärer Dysfunktion einhergehende Kreislaufinstabilität macht in der Regel eine intensivmedizinische Behandlung notwendig. Trotz des schweren Krankheitsverlaufs ist die MIS-C-Erkrankung unter adäquater Therapie (intravenöse Immunglobuline, Methylprednisolon, Azetylsalizylsäure sowie hämodynamischer Support) mit einer guten Prognose verbunden.

Mountain regions are fragile ecosystems and often host remarkably rich biodiversity, and thus they are especially under threat from ongoing global changes. Located in the Eastern Alps, Trentino–South Tyrol is bioculturally diverse but an understudied region from an ethnobotanical perspective. We explored the ethnomedicinal knowledge of the area from a cross-cultural and diachronic perspective by conducting semi-structured interviews with 22 local inhabitants from Val di Sole (Trentino) and 30 from Überetsch–Unterland (South Tyrol). Additionally, we compared the results with ethnobotanical studies conducted in Trentino and South Tyrol over 25 years ago. The historical comparison revealed that about 75% of the plants currently in use were also used in the past in each study region. We argue that the adoption of “new” medicinal species could have occurred through printed and social media and other bibliographical sources but may also be due to limitations in conducting the comparison (i.e., different taxonomic levels and different methodologies). The inhabitants of Val di Sole and Überetsch–Unterland have shared most medicinal plants over the past few decades, yet the most used species diverge (perhaps due to differences in local landscapes), and in South Tyrol, people appear to use a higher number of medicinal plants, possibly because of the borderland nature of the area.

BackgroundAtherosclerosis is the underlying cause of many cardiovascular diseases, such as myocardial infarction or stroke. B cells, and their production of pro- and anti-atherogenic antibodies, play an important role in atherosclerosis. In B cells, TRAF2 and NCK-interacting Kinase (TNIK), a germinal center kinase, was shown to bind to TNF-receptor associated factor 6 (TRAF6), and to be involved in JNK and NF-κB signaling in human B cells, a pathway associated with antibody production.ObjectiveWe here investigate the role of TNIK-deficient B cells in atherosclerosis.ResultsApoE−/−TNIKfl/fl (TNIKBWT) and ApoE−/−TNIKfl/flCD19-cre (TNIKBKO) mice received a high cholesterol diet for 10 weeks. Atherosclerotic plaque area did not differ between TNIKBKO and TNIKBWT mice, nor was there any difference in plaque necrotic core, macrophage, T cell, α-SMA and collagen content. B1 and B2 cell numbers did not change in TNIKBKO mice, and marginal zone, follicular or germinal center B cells were unaffected. Total IgM and IgG levels, as well as oxidation specific epitope (OSE) IgM and IgG levels, did not change in absence of B cell TNIK. In contrast, plasma IgA levels were decreased in TNIKBKO mice, whereas the number of IgA+ B cells in intestinal Peyer's patches increased. No effects could be detected on T cell or myeloid cell numbers or subsets.ConclusionWe here conclude that in hyperlipidemic ApoE−/− mice, B cell specific TNIK deficiency does not affect atherosclerosis.

Background: The subscapularis muscle, which is part of the rotator cuff, is located anterior to the shoulder. In anterior approaches to the shoulder, its supplying nerves are at risk of iatrogenic injury, which may cause postoperative complications. It is unclear whether there is any nerve-free zone in which a subscapularis split can be performed without risking nerve damage. Questions/purposes: In an anatomical study, we asked: (1) With the arm abducted 60° and externally rotated, what are the median and shortest distances between the entrance point of the subscapular nerves into subscapularis muscle and the myotendinous junction of this muscle? (2) What are those distances in other positions of the shoulder? (3) Did those measurements differ between specimen sexes or sides? Methods: In 84 shoulders of 66 embalmed anatomic specimens, the distance from the myotendinous junction of the subscapularis muscle to the entrance points of the subscapular nerves into the subscapularis muscle was measured using an inelastic thread and a millimeter gauge with the arm abducted 60° and rotated externally. In 16 of 84 shoulders, which were selected randomly, after taking the measurements with the arm abducted 60° and rotated externally, arm positions were changed and further measurements were taken with the arm abducted 60° and rotated neutrally, abducted 60° and rotated internally, and abducted 90° and rotated externally. The positions of the entrance points were described with statistical parameters and compared between different sides, sexes, and joint positions. Measurements were verified using eight fresh-frozen shoulders, showing no difference in distances compared with embalmed specimens and confirming reproducibility of measurements. Absolute distances were used to minimize possible distortion when using correlations and for straightforwardness and clinical applicability. Results: The median (range) distance was 43 mm (24 to 64) for the upper subscapular nerve and 38 mm (23 to 59) for the lower subscapular nerve with the arm rotated externally and abducted 60°. In the 16 subsamples, internal rotation decreased the distance to 34 mm (24 to 49) and 31 mm (15 to 43), respectively, and maximal external rotation and 90° of abduction increased it up to 49 mm (30 to 64) and 41 mm (27 to 56). Comparison of left and right sides yielded no difference. Comparison of sexes showed distances for the lower subscapular nerve of 36 mm (23 to 54) in females versus 39 mm (24 to 60) in males. Conclusion: In no specimen did the nerve come closer than 23 mm medial to the myotendinous junction with the arm rotated externally and abducted. Therefore, not exceeding a distance of 20 mm medial to the myotendinous junction with the arm rotated externally seems to provide sufficient protection from nerve injury during surgery. Clinical Relevance: Based on the described zone of 20 mm medial to the myotendinous junction, the risk of nerve injury in a subscapularis split approach can be minimized.

Forest plantations play an important role ecologically, contribute to carbon sequestration and support billions of dollars of economic activity each year through sustainable forest management and forest sector value chains. As the global demand for forest products and services increases, the marketplace is seeking more reliable data on forest plantations. Remote sensing technologies allied with machine learning, and most recently deep learning techniques, provide valuable data for inventorying forest plantations and related valuation products. In this work, deep semantic segmentation with U-net architecture was used to detect forest plantation areas using Sentinel-2 and CBERS-4A images of different areas of Brazil. First, the U-net models were built from an area of the Centre-East of Paraná State, and then the best models were tested in 3 new areas that present different characteristics. The U-net models built with Sentinel-2 images achieved promising results for areas similar to the ones used in the training set, with F1-score ranging from 0.9171 to 0.9499 and with Kappa values between 0.8712 to 0.9272, demonstrating the feasibility of deep semantic segmentation to detect forest plantations.

Adaptive planning of clinical trials allows modifying the entire trial design at any time point mid-course. In this paper, we consider the case when a trial-external update of the planning assumptions during the ongoing trial makes an unforeseen design adaptation necessary. We take up the idea to construct adaptive designs with defined features by solving an optimization problem and apply it to the situation of unplanned design reassessment. By using the conditional error principle, we present an approach on how to optimally modify the trial design at an unplanned interim analysis while at the same time strictly protecting the type I error rate. This linking of optimal design planning and the conditional error principle allows sound reactions to unforeseen events that make a design reassessment necessary.

Background and Purpose Prediction of futile recanalization (FR), i.e. failure of long-term functional independence despite full reperfusion in mechanical thrombectomy (MT), is instrumental in patients undergoing endovascular therapy. Methods Retrospective single-center analysis of patients treated for anterior circulation LVO ensuing successful MT (mTICI 2c–3) between January 2014 and April 2019. FR was defined as modified Rankin Scale (mRS) 90 days after stroke onset > 2 or mRS > pre-stroke mRS. Multivariable analysis was performed with variables available before treatment initiation regarding their association with FR. Performance of the regression model was then compared with a model including parameters available after MT. Results Successful MT was experienced by 549/1146 patients in total. FR occurred in 262/549 (47.7%) patients. Independent predictors of FR were male sex, odds ratio (OR) with 95% confidence interval (CI) 1.98 (1.31–3.05, p 0.001), age (OR 1.05, CI 1.03–1.07, p p p 0.025), neutrophile-lymphocyte ratio (OR 1.03, CI 1.00–1.06, p 0.022), baseline ASPECTS (OR 0.77, CI 0.68–0.88, p p 0.016). The prediction model’s Area Under the Curve was 0.78 (CI 0.74–0.82) and increased with parameters available after MT to 0.86 (CI 0.83–0.89) with failure of early neurological improvement being the most important predictor of FR (OR 15.0, CI 7.2–33.8). Conclusion A variety of preinterventional factors may predict FR with substantial certainty, but the prediction model can still be improved by considering parameters only available after MT, in particular early neurological improvement.

Deformitat; Escoliosi; Columna vertebral Deformidad; Escoliosis; Espina dorsal Deformity; Scoliosis; Spine Objective To evaluate Obeid-coronal malalignment (O-CM) modifiers according to age, sagittal alignment, and patient-reported outcome measures (PROMs), in the mobile spine. Methods Retrospective review of a prospective multicenter adult spinal deformity (ASD) database with 1,243 (402 nonoperative, 841 operative) patients with no prior fusion surgery. Patients were included if they were aged over 18 years and were affected by spinal deformity defined by one of: Cobb angle ≥ 20°, pelvic tilt ≥ 25°, sagittal vertical axis ≥ 5 cm, thoracic kyphosis ≥ 60°. Patients were classified according to the O-CM classification and compared to coronally aligned patients. Multivariate analysis was performed on the relationship between PROMs and age, global tilt (GT) and coronal malalignment (CM). Results Four hundred forty-three patients had CM of more than 2 cm compared to 800 who did not. The distribution of these modifiers was correlated to age. After multivariate analysis, using age and GT as confounding factors, we found that before the age of 50 years, 2A1 patients had worse sex life and greater satisfaction than patients without CM. After 50 years of age, patients with CM (1A1, 1A2) had worse self-image and those with 2A2, 2B had worse self-image, satisfaction, and 36-item Short Form Health Survey physical function. Self-image was the consistent determinant of patients opting for surgery for all ages. Conclusion CM distribution according to O-CM modifiers is age dependent. A clear correlation between the coronal malalignment and PROMs exists when using the O-CM classification and in the mobile spine, this typically affects self-image and satisfaction. Thus, CM classified according to O-CM modifiers is correlated to PROMs and should be considered in ASD

The Treaty of Lausanne, signed in Switzerland in July 1923, officially settled the conflict between the Ottoman Empire and the Allied forces. Not only did the Treaty establish the borders of the modern Turkish republic, but it also defined boundaries, political systems, and understandings of citizenship in the newly formed post-Ottoman nation-states. Here, Hans-Lukas Kieser recounts how the eight dramatic months of the Lausanne Conference concluded more than ten years of war and genocide in the late Ottoman Empire. Crucially, the Treaty was in favour of a homogeneous Turkish state in Asia Minor and became the basis for the compulsory 'unmixing of people' that facilitated the persecution of minority groups, including Armenians, Kurds, and Arabs. Not only did this significant yet oft-overlooked treaty mark the end of the League of Nations' project of self-determination and security for small peoples, but it was crucial in shaping the modern Middle East, and dictatorships in Turkey and Europe.

Overall Survival & Progression Free Survival

Supplementary Table 4

Supplementary Table 2

Serum CA19-9 levels

Supplementary Table 1

Purpose:To investigate the safety, clinical efficacy, virus pharmacokinetics, shedding, and immune response after administration of an oncolytic parvovirus (H-1PV, ParvOryx) to patients with metastatic pancreatic ductal adenocarcinoma (PDAC) refractory to first-line therapy.Patients and Methods:This is a noncontrolled, single-arm, open-label, dose-escalating, single-center clinical trial. Seven patients with PDAC and at least one liver metastasis were included. ParvOryx was administered intravenously on 4 consecutive days and as an intralesional injection, 6 to 13 days thereafter. Altogether, three escalating dose levels were investigated. In addition, gemcitabine treatment was initiated on day 28.Results:ParvOryx showed excellent tolerability with no dose-limiting toxicities. One patient had a confirmed partial response and one patient revealed an unconfirmed partial response according to RECIST criteria. Both patients showed remarkably long surivial of 326 and 555 days, respectively. Investigation of pharmacokinetics and virus shedding revealed dose dependency with no excretion of active virus particles in saliva or urine and very limited excretion in feces. H-1PV nucleic acids were detected in tumor samples of four patients. All patients showed T-cell responses to viral proteins. An interesting immunologic pattern developed in tumor tissues and in blood of both patients with partial response suggesting immune activation after administration of ParvOryx.Conclusions:The trial met all primary objectives, revealed no environmental risks, and indicated favorable immune modulation after administration of ParvOryx. It can be considered a good basis for further systematic clinical development alone or in combination with immunomodulatory compounds.

Supplementary Table 3

Virus shedding in urine and saliva

Virus shedding in feces

Despite being under development for decades, RNA therapeutics have only recently emerged as viable platform technologies. The COVID-19 mRNA vaccines have demonstrated the promise and power of the platform technology. In response, novel RNA drugs are entering clinical trials at an accelerating rate. As the skin is the largest and most accessible organ, it has always been a preferred target for drug discovery. This holds true for RNA therapies as well, and multiple candidate RNA-based drugs are currently in development for an array of skin conditions. In this mini review, we catalog the RNA therapies currently in clinical trials for different dermatological diseases. We summarize the main types of RNA-related drugs and use examples of drugs currently in development to illustrate their key mechanism of action.

Background: Shotgun metagenomic sequencing has the potential to provide bacterial strain-level resolution which is of key importance to tackle a host of clinical questions. While bioinformatics tools that achieve strain-level resolution are available, thorough benchmarking is needed to validate their use for less investigated and low biomass microbiomes like those from the upper respiratory tract. Methods: We analyzed a previously published dataset of longitudinally collected nasopharyngeal samples from Bangladeshi infants (Microbiota & Health study) and a novel dataset of oropharyngeal samples from Swiss children with cystic fibrosis. Data from bacterial cultures were used for benchmarking the parameters of StrainPhlAn 3, a bioinformatic tool designed for strain-level resolution. In addition, StrainPhlAn 3 results were compared to metagenomic assemblies and whole-genome sequencing data of S. aureus strains. Finally, strain retention analyses were performed. Results: After optimizing the analytical parameters, we compared our results to culture gold standard methods and achieved sensitivity values of 87% (S. pneumoniae), 80% (M. catarrhalis), 75% (H. influenzae) and 57% (S. aureus) for 420 nasopharyngeal and 75% (H. influenzae) and 46% (S. aureus) for 260 oropharyngeal samples. Comparing the phylogenetic tree of the core genome of 50 S. aureus isolates with a corresponding marker gene tree generated by StrainPhlAn 3 revealed a striking similarity in tree topology for all but three samples indicating adequate strain resolution. Quantitative analyses of longitudinally collected samples revealed clear signatures of strain retention for the four analyzed species. Conclusions: Comparison of StrainPhlAn 3 results to data from bacterial cultures revealed that strain-level tracking of the respiratory microbiome is feasible despite high content of host DNA when parameters are carefully optimized to fit low biomass microbiomes. This allowed to perform strain retention analyses applied to relevant pathobionts which will help to better understand the longitudinal dynamics of the upper respiratory microbiome during health and disease.

Single-cell nanopore sequencing of full-length mRNAs (scNanoRNAseq) is transforming singlecell multi-omics studies. However, challenges include computational complexity and dependence on short-read curation. To address this, we developed a comprehensive toolkit, scNanoGPS to calculate same-cell genotypes-phenotypes without short-read guidance. We applied scNanoGPS onto 23,587 long-read transcriptomes from 4 tumors and 2 cell lines. Standalone, scNanoGPS accurately deconvoluted error-prone long-reads into single-cells and single-molecules. Further, scNanoGPS simultaneously accessed both phenotypes (expressions/isoforms) and genotypes (mutations) of individual cells. Our analyses revealed that tumor and stroma/immune cells often expressed significantly distinct combinations of isoforms (DCIs). In a kidney tumor, we identified 924 genes with DCIs involved in cell-type-specific functions such asPDE10Ain tumor cells andCCL3in lymphocytes. Moreover, transcriptome-wide mutation analyses identified many cell-type-specific mutations includingVEGFAmutations in tumor cells andHLA-Amutations in immune cells, highlighting critical roles of different populations in tumors. Together, scNanoGPS facilitates applications of single-cell long-read sequencing.

Introduction: The Robert Mathys (RM) monoblock uncemented cup is a design less commonly used in primary total hip replacement. It’s purported advantages over modular cemented cups are: (1) its modulus of elasticity approximating bone, thus mimicking load transmission and the biomechanical behaviour of the cup to better match stresses on the acetabulum, leading to bone-preservation; and (2) as a 1-piece cup there is absence of a mobile interface between a liner and shell, preventing backside wear. Since its inception in 1983 there have been 3 major design changes: the RM Classic, the RM Pressfit, and the RM Vitamys with the most modern polyethylene (vitamin E). Methods: In a retrospective cohort study of the New Zealand Joint Registry, all designs of RM acetabular cup were reviewed. Data were included from1998 to 2018. All-cause revision rates, reasons for revision and the Oxford Hip Score (OHS) were assessed. Results: In total 13,272 acetabular cups were included. The all-cause revision rates did not differ between the designs. Revision rates for aseptic loosening in the RM Vitamys were lower, but the follow-up was shorter and more larger heads were used. There was no difference in the OHS. Conclusion: All implant designs were safe. The use of larger heads led to a decrease in revisions due to dislocation. It has to be waited out whether the RM Vitamys performs superior in the long-term due to the highly cross-linked polyethylene.

Adaptive designs are an increasingly popular method for the adaptation of design aspects in clinical trials, such as the sample size. Scoring different adaptive designs helps to make an appropriate choice among the numerous existing adaptive design methods. Several scores have been proposed to evaluate adaptive designs. Moreover, it is possible to determine optimal two-stage adaptive designs with respect to a customized objective score by solving a constrained optimization problem. In this paper, we use the conditional performance score by Herrmann et al. (2020) as the optimization criterion to derive optimal adaptive two-stage designs. We investigate variations of the original performance score, for example, by assigning different weights to the score components and by incorporating prior assumptions on the effect size. We further investigate a setting where the optimization framework is extended by a global power constraint, and additional optimization of the critical value function next to the stage-two sample size is performed. Those evaluations with respect to the sample size curves and the resulting design's performance can contribute to facilitate the score's usage in practice.

This study covers the preliminary assessment of a novel accelerator mass spectrometry technique for rapid quantitation of polonium-210 in water samples.

Rifles are often involved in violent deaths such as homicide and suicide. Consequently, expert knowledge and experimental forensic investigations are important to clarify the nature of ballistic trauma when applied to the human head and neurocranium. This study investigated differences in entrance wound morphology with Synbone® spheres which are described as being comparable to human flat bones. A series of ballistic experiments were conducted using two different rifle calibers (5.56 × 45 mm and 7.62 × 39 mm Full Metal Jacket (FMJ)). Synbone® spheres were used for close-range 0.3 m simulated executions as well as at 25 m and 35 m to simulate urban and military engagements. Results were compared with previously published experimental studies using similar military ammunition. In our study, entry wound morphology closely resembles real forensic cases compared to exit wound and overall shape morphology independently of the distance and the caliber. Circumferential delamination was clearly visible with full metal jacket (FMJ) rounds, yielding similar damage pattern morphology to the human crania. This study documented the presence of hydraulic burst or shock in all ten rounds from all three distances. Krönlein shots were also observed in some cases. Synbone® spheres constitute an acceptable synthetic surrogate for ballistic experiments. The present study offers new initial data on the behavior of Synbone® proxies in ballistic testing of military ammunitions; FMJ gunshot injuries to the human head, for distances that have not previously been published, suggesting that efficient tests can take place under these conditions. Further research on experimental ballistics with a larger number of controlled factors and multiple repetitions is recommended to verify the results of this pilot study before applied in forensic simulations.

Background The objective of this article is to describe for the first time a case of 90° spin out of a mobile bearing unicompartmental knee arthroplasty (UKA) polyethylene insert. In this report, we present a 57-year-old gentleman with a medial compartment UKA for osteoarthritis in 2017 who developed dislodgement and 90° rotation subsequent to traumatic injury when he was involved in a bus crash and impacted the anterolateral knee sustaining a valgus type injury 1 week postoperatively. Following the injury, he reported medial knee pain and a sensation of something moving within the joint. He was initially managed conservatively and progressed to full weight bearing; however, he experienced intermittent symptoms of catching and blocking of the joint, as well as medial knee swelling, that inhibited his ability to perform activities involving walking, kneeling, or pivoting. Imaging taken in 2018 show a 90° rotation of the polyethylene insert. These images showed the longitudinal metallic marker on the insert facing in an anteroposterior direction as opposed to the normal medial-lateral orientation. Failing conservative management, he presented to our clinic in 2019 and proceeded for revision of his UKA. Intraoperatively, his insert was reviewed and seen to easily spin on axis. The liner was therefore removed and upsized from a size 5 medium to a size 7 medium insert which provided excellent stability and stopped any further spinning. He has done tremendously well since the operation and reports full range of motion and no concerns. In patients with a history of pain, swelling, or locking following a UKA, it would be prudent to consider insert spinning, as well as the more common dislocation, through confirming the orientation of the metallic insert marker. Revision surgery to correct the spinning defect has proven effective with good resolution of symptoms and return to full range of motion.

The context of my contribution to the roundtable discussion was intended to be from a personal perspective. I have Indigenous roots and am a second-generation survivor of the Indian Day School and Residential School system. For myself, the issue of reconciliation in the church is visceral because my mother and her siblings experienced the detrimental effects of these assimilation policies that we now know as cultural genocide. The effects of these policies continue to be felt in subsequent generations; they are intergenerational and they are traumatic.

At the Canadian Theological Society conference in May 2022, a roundtable convened to discuss Pope Francis’ apology to Indigenous Peoples in Canada, offered in April 2022 in Rome. Each of the respondents, Archbishop Don Bolen (Regina, Saskatchewan), Dr. Christian Jamieson (Concordia University, Montreal, Quebec), Dr. Jeremy Bergen (Conrad Grebel University College, Waterloo, Ontario), and Rev. Daryold Winkler (Ottawa, Ontario), contributed insights and reflections from their own experiential and scholarly perspectives. Their contributions comprise the discussions that follow. Some of the respondents include reflections on the subsequent Papal visit to Canada in July 2022.

For much of European Christian history, asceticism has been associated with the capacity to transform individuals as well as societies. As an organised collaborative exercise in monasteries, asceticism enabled monks not only to live a life preparing for eternal life but also to generate ground-breaking technical and social innovations. Drawing on identity theories and recent developments in the social movement literature, we examine how asceticism has been the impetus for various individual and societal transformations and explore whether asceticism can still unfold such transformative power. In particular, we discuss whether and how ongoing movements for Voluntary Simplicity (VS) and further reflections on that, as found, for example, in the work of the sociologist Ulrich Beck, might assist humans in coping with climate change. Our article contributes to recent environmental ethics research by exploring the role of asceticism in potentially triggering collective climate action and its contribution to helping individuals to live meaningful lives in the face of climate change.

If design parameters are chosen appropriately, group sequential trial designs are known to be able to reduce the expected sample size under the alternative hypothesis compared to single-stage designs. The same holds true for the so-called 'gold-standard' design for non-inferiority trials, a design involving an experimental group, an active control group, and a placebo group. However, choosing design parameters that maximize the advantages of a two-stage approach for the three-arm gold-standard design for non-inferiority trials is not a straightforward task. In particular, optimal choices of futility boundaries for this design have not been thoroughly discussed in existing literature. We present a variation of the hierarchical testing procedure, which allows for the incorporation of binding futility boundaries at interim analyses. We show that this procedure maintains strong control of the family-wise type I error rate. Within this framework, we consider the futility and efficacy boundaries as well as the sample size allocation ratios as optimization parameters. This allows the investigation of the efficiency gain from including the option to stop for futility in addition to the ability to stop for efficacy. To analyze the extended designs, optimality criteria that include the design's performance under the alternative as well as the null hypothesis are introduced. On top of this, we discuss methods to limit the allocation of placebo patients in the trial while maintaining relatively good operating characteristics. The results of our numerical optimization procedure are discussed and a comparison of different approaches to designing a three-arm gold-standard non-inferiority trial is provided.

Traditional echo counting is an apparently simple fisheries acoustic tool that can provide quantitative estimates of fish density and abundance. The method has been widely used as it requires a minimum of equipment and the data analysis is decep­tively simple. Several echo-counting methods have been described in the literature. These gener­ally assume that the fish are all of the same acoustic size. This unrealistic assumption has led us to develop a new. stochastic echo-counting model that accounts for the wide distribution in acoustic fish sizes that is typical even for a group of fish of the same size. The new parametric model uses the Rayleigh or Rice probability density function to describe the wide distribution in acoustic fish size. Our major conclusions are that the traditional model may lead to a biased fish-density estimate and that better estimates of the mean acoustic fish size and other model parameters are very impor­tant.

European spine journal (2023). doi:10.1007/s00586-023-07831-0, Published by Springer, Berlin ; Heidelberg

In this study, data from thirteen laboratories from around the world are presented for a successful certification of uranium isotope ratios in uranium ore concentrate (UOC) certified reference materials from the National Research Council Canada. Different mass spectrometric measurement principles (including SF-ICP-MS, quadruple ICP-MS, TIMS, MC-ICP-MS, SIMS and AMS) and measurement procedures were employed. In general, data from all sources exhibit good consistency with TIMS and MC-ICP-MS showing superior performance. The three candidate UOC CRMs (UCLO-1, UCHI-1 and UPER-1) have natural uranium isotope ratios with certified values of 0.5304(7) × 10⁻⁴, 0.5475(2) × 10⁻⁴ and 0.5361(4) × 10⁻⁴ for n(²³⁴U)/n(²³⁸U) and 0.007 2563(13), 0.007 2563(10) and 0.007 2542(11) for n(²³⁵U)/n(²³⁸U), respectively, with expanded uncertainty (k = 2) applicable to the last digit of the value given in the parentheses. Information values for n(²³⁶U)/n(²³⁸U) in these three CRMs, measured by AMS, are also provided: 10 × 10⁻¹², 200 × 10⁻¹² and 22 × 10⁻¹². The uncertainties of the proposed certified values of uranium isotope ratios in UOC CRMs are superior to available reference materials, and the values of n(²³⁴U)/n(²³⁸U) and n(²³⁶U)/n(²³⁸U) show significant variation among the three CRMs.