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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.

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.

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

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.

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.

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.

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.

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.

Karin Stober: Denkmalpflege zwischen künstlerischem Anspruch und Baupraxis. Über den Umgang mit Klosteranlagen nach der Säkularisation in Baden und Württemberg. (Veröffentlichungen der Kommission für geschichtliche Landeskunde in Baden-Württemberg, Reihe B, Band 152). W. Kohlhammer Verlag Stuttgart 2003. 367 Seiten mit zahlreichen Abbildungen. Kartoniert € 32.- ISBN 3-17-017844-X

Objectives Our objective was to evaluate the effects of benzathine cloxacillin (BC) and ceftiofur hydrochloride (CH) treatment at dry-off on prevalence of intramammary infections at calving, incidence of clinical mastitis and SCC and milk yield up to 100 DIM, and removal from the herd and reproductive responses within 100 DIM. Materials and Methods At dry-off, cows from 2 herds were assigned randomly to the BC (n = 1,160; Orbenin-DC, Merck Animal Health) and the CH (n = 1,183; Spectramast DC, Zoetis) treatments. Composite milk samples collected at dry-off and at calving were submitted for bacterial culture. Monthly milk samples were used to determine SCC. Days in milk at first insemination and pregnancy outcomes to first and second inseminations were compared between the 2 treatments. Results and Discussion Treatments did not differ regarding prevalence of intramammary infections at dry-off (BC = 45.2 ± 1.8% vs. CH = 42.6 ± 1.7%). Treatment did not affect the prevalence of intramammary infections at calving (BC = 39.1 ± 2.3% vs. CH = 40.4 ± 2.3%), incidence of clinical mastitis within 100 DIM (BC = 6.6 ± 1.0% vs. CH = 7.7 ± 1.1%), and milk yield up to 100 DIM (BC = 3.6 ± 0.03 kg × 103 vs. CH = 3.6 ± 0.03 kg × 103). Treatment did not affect reproductive outcomes. Implications and Applications Producers may choose between BC and CH at dry-off without being concerned about differences in prevalence of IMI at calving and lactational performance.

A systematic review of the literature was carried out using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) method to investigate the frequency of military thoracic gunshot wounds (GSWs) and deaths in combat theatres since World War Two (WW2). An electronic database search of World of Science, Scopus, Science Direct, PubMed and Microsoft Academic was conducted using the keywords ‘combat, casualties, thorax, gunshot, and military’ to identify peer-reviewed journals and conference papers on the topic. Twenty-three sources relevant to this review were identified and covered multiple theatres of operation. While there is a downward trend in the frequency of thoracic GSWs and fatalities likely due to the improvement of body armour, the improvement in medical treatment and increased frequency of improvised explosive devices (IEDs), the review shows that the advancement has not removed the likelihood of thoracic GSWs, which still accounted for approximately 15% of all thoracic injuries in the most recent combat theatres. The systematic review identifies that GSWs of the thorax continue to be a risk in military theatres and therefore, medical personnel should be aware of the frequency and severity of thoracic GSWs and should be prepared to treat these life-threatening injuries, as timely intervention is essential.

Forensic reconstructions and ballistic testing requires the use of consistent and repeatable simulants. Synthetic bone has been developed to be mechanically similar to human bone; however, it does not have the same viscoelastic properties. Bone acts as brittle and stiff material and fails instantly under high-energy events such as ballistic impacts. Consequently, bone simulants for use in ballistic testing should show comparable energy deposition to mammalian bones. This study aims to determine if Synbone® flat plates could be a viable proxy for Sus scrofa (domesticus) ribs in ballistic testing with 7.62 × 51 mm Full Metal Jacket ammunition. 5 mm, 6 mm and 12 mm quartered Synbone® plates were embedded into 10% ballistic gelatin and shot using 7.62 mm ammunition. The models were then analysed to compare the Synbone® to a previous Sus Scrofa (domesticus) rib study and focused on energy deposition, the number of fragments within the block, angle of deviation, onset of yaw, the temporary cavity, and the permanent wound channel. No significant difference was seen between the Sus Scrofa (domesticus) and the 5 mm Sybone®. There were significant differences observed between Sus Scrofa (domesticus) ribs and 6 mm Synbone® for the number of fragments, energy deposition and projectile tract diameter, and significant differences seen between Sus scrofa (domesticus) ribs and 12 mm Synbone® for the depth of onset of yaw, energy deposition and projectile tract diameter. This study indicates that the 5 mm Synbone® plate is a suitable proxy for Sus scrofa (domesticus) ribs for use with 7.62 × 51 mm FMJ ammunition in ballistic testing.