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Clathrin-associated trafficking is a major mechanism for intracellular communication, as well as for cells to communicate with the extracellular environment. A decreased oxygen availability termed hypoxia has been described to influence this mechanism in the past. Mostly biochemical studies were applied in these analyses, which miss spatiotemporal information. We have applied live cell microscopy and a newly developed analysis script in combination with a GFP-tagged clathrin-expressing cell line to obtain insight into the dynamics of the effect of hypoxia. Number, mobility and directionality of clathrin-coated vesicles were analysed in non-stimulated cells as well as after stimulation with epidermal growth factor (EGF) or transferrin in normoxic and hypoxic conditions. These data reveal cargo-specific effects, which would not be observable with biochemical methods or with fixed cells and add to the understanding of cell physiology in hypoxia. The stimulus-dependent consequences were also reflected in the final cellular output, i.e. decreased EGF signaling and in contrast increased iron uptake in hypoxia. [ABSTRACT FROM AUTHOR]

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Copyright of Ethik in der Medizin is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Key message: Analyzing fine branch length characteristics in beech trees using single-tree QSMs derived from laser scanning reveals insights into drought-induced changes in vitality, which include branch shedding and reduced shoot growth. Climate change causes increasing temperatures and precipitation anomalies, which result in deteriorations of tree health and declines in ecosystem services of forests. It is therefore crucial to monitor tree vitality to preserve forests and their functions. However, methods describing tree vitality in situ are lacking reproducibility or are too laborious. Thus, we tested a laser-scanning based approach, assuming that an objective measurement of a tree's outer shape should reveal changes according to tree vitality. QSMs of similarly sized beech trees from stands with varying degrees of drought damage were used. Absolute and relative fine branch lengths, their ratio to lower order branches' lengths and their progressions over relative height were targeted to identify fine branch dieback and reduced growth. The absolute fine branch length was significantly lower for less vital beech trees, especially within the upper crown, leading to a less top-heavy vertical distribution of fine branches and a reduced fine-to-base order branch length ratio. Hence, height-dependent characteristics of fine branch lengths differed between vitalities. We conclude that using fine branch length characteristics derived from QSMs can be helpful in vitality assessments of beech trees. Still, uncertainties with regard to the plotwise assessment and problems with QSM quality are present. [ABSTRACT FROM AUTHOR]

Approximately 30% of seminoma (SEM) patients present with moderately elevated human chorionic gonadotropin (hCG) levels at first diagnosis. In case of high hCG serum levels, the presence of a non-SEM component, i.e. choriocarcinoma (CC), may be assumed. To characterize cases described as pure seminoma with high serum hCG levels, tissue samples and DNA were analyzed. Patient files from an international registry were screened for patients with SEM and extraordinarily high hCG serum levels. IHC and qRT-PCR analysis was performed for markers of SEM, embryonal carcinoma (EC) and CC/trophoblast cells. The cell lines TCam-2 (SEM), 2102EP, NCCIT, NT2/D1 (EC) and JAR, JEG3 and BeWo (CC) were included for comparison. Of 1031 SEM patients screened, 39 patients (3.7%) showed hCG serum levels > 1000 U/l. Of these, tumor material for IHC and RNA for qRT-PCR was available from n = 7 patients and n = 3 patients, respectively. Median pre-orchiectomy serum hCG level was 5356 U/l (range: 1224–40909 U/L). Histopathologically, all investigated samples were classified as SEM with syncytiotrophoblast sub-populations. SEM cells were SALL4+ / OCT3/4+ / D2-40+, while syncytiotrophoblast cells were hCG+ / GATA3+ / p63+ and SOX2−/CDX2−. qRT-PCR analysis detected trophoblast stem cell markers CDX2, EOMES and TFAP2C as well as the trophectoderm-specifier TEAD4, but not GATA3. Additionally, SOX17 and PRAME, but not SOX2, were detected, confirming the pure SEM-like gene expression signature of the analyzed samples. In conclusion, excessively increased hCG serum levels can appear in patients with pure SEM. To explain detectable hCG serum levels, it is important to diagnose the subtype of a SEM with syncytiotrophoblasts. [ABSTRACT FROM AUTHOR]

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The NLRP3-inflammasome is a cytosolic multiprotein complex that triggers an inflammatory response to certain danger signals. Recently adenosine diphosphate (ADP) was found to activate the NLRP3-inflammasome in murine macrophages via the P2Y1 receptor. Blockade of this signaling pathway reduced disease severity in a murine colitis-model. However, the role of the ADP/P2Y1-axis has not yet been studied in humans. This present study confirmed ADP-dependent NLRP3-inflammasome activation in murine macrophages, but found no evidence for a role of ADP in inflammasome activation in humans. We investigated the THP1 cell line as well as primary monocytes and further looked at macrophages. Although all cells express the three human ADP-receptors P2Y1, P2Y12 and P2Y13, independent of priming, neither increased ASC-speck formation could be detected with flow cytometry nor additional IL-1β release be found in the culture supernatant of ADP stimulated cells. We now show for the first time that the responsiveness of monocytes and macrophages to ADP as well as the regulation of its purinergic receptors is very much dependent on the species. Therefore the signaling pathway found to contribute to colitis in mice is likely not applicable to humans. [ABSTRACT FROM AUTHOR]

In light of an increasing frequency of climate change–related hazards such as landslides, climate adaptation is increasingly on the agenda of Norwegian municipalities. Nevertheless, municipalities face constraints in addressing these challenges, with smaller, remote municipalities being particularly susceptible. They often cover expansive geographical areas with high landslide risk, yet have limited financial resources, expertise, and personnel for climate adaptation. Consequently, the active involvement of citizens in adaptation plays an important role in these remote places. This paper investigates how citizens of three small remote communities deal with landslides, emphasizing the role of people–place relations in shaping adaptive practices. Grounded in assemblage theory, our analysis reveals that most citizens maintained a pragmatic relation to landslides, while only a few expressed concern. Regardless of the degree of concern, all citizens constructed landslides as integral element within their socio-material place assemblages, as part of their lives in the respective places. Furthermore, citizens developed various adaptive practices, including nature observation, reporting to authorities, and implementing practical preventive measures to control water that could trigger landslides. These practices are manifestations of socio-material assemblages that have evolved through citizens’ relations to their specific places. Importantly, irrespective of the level of concern regarding landslides, these practices were carried out as part of everyday life. Through these practices, enabled by experience-based, embodied, and often tacit local knowledge, citizens acted as community guardians. Thus, comprehensive people–place relations emerge as a pivotal factor for a community’s adaptative capacity in the face of climate change-induced hazards. [ABSTRACT FROM AUTHOR]

Acute Myeloid Leukemia (AML) is caused by multiple mutations which dysregulate growth and differentiation of myeloid cells. Cells adopt different gene regulatory networks specific to individual mutations, maintaining a rapidly proliferating blast cell population with fatal consequences for the patient if not treated. The most common treatment option is still chemotherapy which targets such cells. However, patients harbour a population of quiescent leukemic stem cells (LSCs) which can emerge from quiescence to trigger relapse after therapy. The processes that allow such cells to re-grow remain unknown. Here, we examine the well characterised t(8;21) AML sub-type as a model to address this question. Using four primary AML samples and a novel t(8;21) patient-derived xenograft model, we show that t(8;21) LSCs aberrantly activate the VEGF and IL-5 signalling pathways. Both pathways operate within a regulatory circuit consisting of the driver oncoprotein RUNX1::ETO and an AP-1/GATA2 axis allowing LSCs to re-enter the cell cycle while preserving self-renewal capacity. In Acute Myeloid Leukemia a population of quiescent leukemic stem cells (LSCs) evade chemotherapy and initiate relapse, but what makes them grow again is unknown. Here, the authors show (i) that LSCs hijack ectopic signaling pathways to kick-start their growth and (ii) that growth can be blocked with repurposed drugs in t(8;21) AML sub-type. [ABSTRACT FROM AUTHOR]

Summary: Extragonadal germ cell tumors (EGCT) are rare and comprise only 2–3% of all testicular germ cell tumors. The majority of EGCT are located in the mediastinum, followed by the retroperitoneum. Although histologically similar to germ cell tumors (GCT), EGCT have distinct histological patterns which result in a biologically aggressive variant of GCT with the need for interdisciplinary care in highly specialized centers. The majority of mediastinal EGCT harbor teratoma or yolk sac tumor elements. Treatment usually consists of a combination of systemic cytotoxic therapy and aggressive postchemotherapeutic surgery. First-line treatment for extragonadal seminomas and nonseminomas consists of three and four cycles of PEB or PEI, respectively. In patients with significantly elevated markers, a personalized approach based on adequate marker decline can be used, and in poor-risk patients, first-line high-dose chemotherapy might be discussed. Postchemotherapeutic surgery remains an integral part of the multidisciplinary treatment for nonseminomatous EGCT and it is of utmost importance that all residual masses, independent of size and location, are resected completely. Residual masses in seminomatous EGCTs rarely harbor vital cancer and might be followed by serial imaging studies or FDG-PET/CT. The prognosis of nonseminomatous EGCT is poor, with 5‑year overall survival rates of 17%, 60–70%, and 90% for poor, intermediate, and excellent prognosis, respectively. Prognosis for seminomatous EGCT is excellent, with 5‑year overall survival rates of 95% and 88% for good and intermediate prognosis, respectively. Salvage chemotherapy consists of high-dose chemotherapy or targeted therapy in very selected patients. [ABSTRACT FROM AUTHOR]

Background: Research has consistently shown that the motor system and emotional processes are interrelated in non-clinical as well as in clinical populations. Therefore, the body might be a promising target for the treatment of depression. Based on these notions, we developed Body, Breath and Mind (BBM) a minimally monitored online intervention combining body orientated Qi Gong practice with elements of behavioral activation (BA). This study aims to assess the feasibility of BBM. Methods: One hundred and ten adults showing at least moderate levels of depression were recruited and a single group pre-/post-test design was used. BBM consists of eight modules including Qi Gong as well as BA homework practice. Instructions for Qi Gong practice were given via video. Feasibility outcome measures included treatment adherence, preliminary effectiveness, satisfaction and practice time. Primary outcome measure was the Patient Health Questionnaire-9 (PHQ-9) assessing depressive symptoms. Results: We found significant reduction of depressive symptoms with a large effect size (dAV = – 1.82) and participants were satisfied with Qi Gong and BA elements as well as with the entire program. Thirty-four participants (31%) completed all eight modules. Conclusions: The findings suggest that it would be feasible to proceed to a randomized controlled trial to evaluate the potential of BBM, a program combining body-oriented and BA elements. [ABSTRACT FROM AUTHOR]

Copyright of Die Urologie is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Photon-counting detector (PCD)-CT allows for reconstruction of virtual non-iodine (VNI) images from contrast-enhanced datasets. This study assesses the diagnostic performance of aortic valve calcification scoring (AVCS) derived from VNI datasets generated with a 1st generation clinical dual-source PCD-CT. AVCS was evaluated in 123 patients (statistical analysis only comprising patients with aortic valve calcifications [n = 56; 63.2 ± 11.6 years]), who underwent contrast enhanced electrocardiogram-gated (either prospective or retrospective or both) cardiac CT on a clinical PCD system. Patient data was reconstructed at 70 keV employing a VNI reconstruction algorithm. True non-contrast (TNC) scans at 70 keV without quantum iterative reconstruction served as reference in all individuals. Subgroup analysis was performed in 17 patients who received both, prospectively and retrospectively gated contrast enhanced scans (n = 8 with aortic valve calcifications). VNI images with prospective/retrospective gating had an overall sensitivity of 69.2%/56.0%, specificity of 100%/100%, accuracy of 85.4%/81.0%, positive predictive value of 100%/100%, and a negative predictive value of 78.2%/75.0%. VNI images with retrospective gating achieved similar results. For both gating approaches, AVCSVNI showed high correlation (r = 0.983, P < 0.001 for prospective; r = 0.986, P < 0.001 for retrospective) with AVCSTNC. Subgroup analyses demonstrated excellent intra-individual correlation between different acquisition modes (r = 0.986, P < 0.001). Thus, VNI images derived from cardiac PCD-CT allow for excellent diagnostic performance in the assessment of AVCS, suggesting potential for the omission of true non-contrast scans in the clinical workup of patients with aortic calcifications. [ABSTRACT FROM AUTHOR]

Background: Multiple hereditary exostosis (MHE) is a rare autosomal dominant disorder characterized by multiple osteochondromas. There is a paucity of literature concerning total hip arthroplasty (THA) in patients with MHE. The aim of this study is to report long-term outcomes of THA in patients with MHE. Methods: Fourteen patients undergoing 15 THA's for the treatment of osteoarthritis in the presence of osteochondromas and proximal femoral deformity secondary to MHE were reviewed. Mean age at the time of surgery and follow-up was 56 and 12 years. Seven (47%) had uncemented femoral components. Eleven hips had coxa valga on preoperative imaging. Clinical outcomes were assessed with both Harris hip scores (HHS) and Musculoskeletal Tumor Society Scores (MSTS). Results: Following surgery, there was an improvement in the HHS (48–82, p < 0.01) and MSTS scores (41–70%, p < 0.01). Complications occurred in 5 patients leading to reoperation in 3 patients, of which 2 patients underwent a revision procedure at 19 and 20-years postoperative. The 10-year revision free survival was 100%. Conclusions: THA in the setting of MHE reliably improves patient function. One in three patients will have a postoperative complication; however, the long-term incidence of revision is low. [ABSTRACT FROM AUTHOR]

Standard axion electrodynamics has two closely related features. First, the coupling of a massless axion field to photons is quantized, in units proportional to the electric gauge coupling squared. Second, the equations of motion tell us that a time-dependent axion field in a background magnetic field sources an effective electric current, but a time-dependent axion field in a background electric field has no effect. These properties, which manifestly violate electric-magnetic duality, play a crucial role in experimental searches for axions. Recently, electric-magnetic duality has been used to motivate the possible existence of non-standard axion couplings, which can both violate the usual quantization rule and exchange the roles of electric and magnetic fields in axion electrodynamics. We show that these non-standard couplings can be derived from SL(2,ℤ) duality, but that they come at a substantial cost: in non-standard axion electrodynamics, all electrically charged particles become dyons when the axion traverses its field range, in a dual form of the standard Witten effect monodromy. This implies that there are dyons near the weak scale, leads to a large axion mass induced by Standard Model fermion loops, and dramatically alters Higgs physics. We conclude that non-standard axion electrodynamics, although interesting to consider in abstract quantum field theory, is not phenomenologically viable. [ABSTRACT FROM AUTHOR]

Purpose: Isolated recurrence in remnants of the seminal vesicles (SV) after treatment of primary prostate cancer (PCa) has become a more frequent entity with the widespread use of more sensitive next-generation imaging modalities. Salvage vesiculectomy is hypothesized to be a worthwhile management option in these patients. The primary goal of this study is to describe the surgical technique of this new treatment option. Secondary outcomes are peri- and post-operative complications and early oncological outcomes. Methods: Retrospective multicenter study, including 108 patients with solitary recurrence in the SV treated between January 2009 and June 2022, was performed. Patients with local recurrences outside the SVs or with metastatic disease were excluded. Both SVs were resected using a robot-assisted or an open approach. In selected cases, a concomitant lymphadenectomy was performed. Results: Overall, 31 patients (29%) reported complications, all but one grade 1 to 3 on the Clavien–Dindo Scale. A median PSA decrease of 2.07 ng/ml (IQR: 0.80–4.33, p < 0.001), translating into a median PSA reduction of 92% (IQR: 59–98%) was observed. At a median follow-up of 14 months, freedom from secondary treatment was 54%. Lymphadenectomy had a significant influence on PSA reduction (p = 0.018). Conclusion: Salvage vesiculectomy for PCa recurrence limited to the SV is a safe procedure with excellent PSA response and is a potential curative treatment in a subset of patients. A concomitant lymphadenectomy can best be performed in all patients that did not underwent one at primary treatment. [ABSTRACT FROM AUTHOR]

Purpose: Support groups might help survivors of allogeneic hematopoietic cell transplantations (HCT) to cope with medical, psychological, and social challenges. The aim of this project was (1) to establish a facilitated post-HCT support group and (2) to assess the participation behaviour. Methods: From 11/2013 until 7/2017, all adult patients who had received a HCT at our centre were invited to participate in a professionally facilitated support group. The format of the group was unstructured without any rules regarding regular attendance. The attendance was prospectively minuted by the facilitator. Reasons for non-attendance were assessed by a survey. Results: During the observation period, 53 group meetings were scheduled. Nine meetings were cancelled because of low attendance. Altogether 23 different patients (F: n=10; M: n=13) and 10 spouses (F: n=9; M: n=1) participated. Median participation was 5 [range 2–11]. With respect to all HCT patients who had the theoretical opportunity to attend, the mean participation rate was 7%. Thirteen patients and four spouses attended more than one meeting. The median count of participations among those participants was 8 [2-32]. The median interval from the first until the last participation was 16 months. The main reason reported for non-participation was the effort to get to the venue of the support group. Conclusions: To our knowledge, this is the first analysis on the attendance behaviour of the participants of a support group for HCT survivors. The results provide guidance for the organization of future support groups and indicate what participation rates can be expected and how they might be increased. [ABSTRACT FROM AUTHOR]

Purpose: Elderly cancer patients are less likely to be treated in accordance with evidence-based guideline recommendations. This study examines patient-related factors associated with deviations from guideline recommendations. Methods: Using medical documentation and cancer registry data, we investigated the treatment courses of female breast cancer patients aged 50 and older in Germany regarding compliance with German guidelines. Participants completed a questionnaire querying factors hypothesized to be associated with guideline adherence. We conducted univariate analyses to explore the data and select variables for multivariate logistic regression to estimate adjusted odds ratios. Results: Of 1150 participants, 206 (17.9%) were treated in deviation from guideline recommendations. Patients 70 years and older were more likely to be treated deviating from guideline recommendations than patients 50–69 years old (OR: 2.07; 95% CI: 1.52–2.80). Patients aged 50–69 years who reported that quality of life guided their treatment decision were more likely to be treated in deviation from guideline recommendations (AOR: 2.08; 95% CI: 1.11–3.92) than the elderly. In older patients, higher age was associated with an increased chance of receiving guideline-discordant care (AOR: 1.06; 95% CI: 1.01–1.11), as was depression diagnosed prior to cancer (AOR: 1.84; 95% CI: 1.00–3.40). Conclusion: Reasons for deviations from guideline recommendations in breast cancer patients differ by age. In decision-making concerning elderly patients, particular attention should be paid to those with pre-existing depressive disorders. Adequately addressing their needs and concerns could prevent inappropriate deviations from guideline recommendations. [ABSTRACT FROM AUTHOR]

We study towers of light particles that appear in infinite-distance limits of moduli spaces of 9-dimensional N = 1 string theories, some of which notably feature decompactification limits with running string coupling. The lightest tower in such decompactification limits consists of the non-BPS Kaluza-Klein modes of Type I′ string theory, whose masses depend nontrivially on the moduli of the theory. We work out the moduli-dependence by explicit computation, finding that despite the running decompactification the Distance Conjecture remains satisfied with an exponential decay rate α ≥ 1 / d − 2 in accordance with the sharpened Distance Conjecture. The related sharpened Convex Hull Scalar Weak Gravity Conjecture also passes stringent tests. Our results non-trivially test the Emergent String Conjecture, while highlighting the important subtlety that decompactifcation can lead to a running solution rather than to a higher-dimensional vacuum. [ABSTRACT FROM AUTHOR]

We derive formulas for the leading mass, entropy, and long-range self-force corrections to extremal black holes due to higher-derivative operators. These formulas hold for black holes with arbitrary couplings to gauge fields and moduli, provided that the leading-order solutions are static, spherically-symmetric, extremal, and have nonzero horizon area. To use these formulas, both the leading-order black hole solution and the higher-derivative effective action must be known, but there is no need to solve the derivative-corrected equations of motion. We demonstrate that the mass, entropy and self-force corrections involve linearly-independent combinations of the higher-derivative couplings at any given point in the moduli space, and comment on their relations to various swampland conjectures. [ABSTRACT FROM AUTHOR]

We present a method to construct the extended Kähler cone of any Calabi-Yau threefold by using Gopakumar-Vafa invariants to identify all geometric phases that are related by flops or Weyl reflections. In this way we obtain the Kähler moduli spaces of all favorable Calabi-Yau threefold hypersurfaces with h1,1 ≤ 4, including toric and non-toric phases. In this setting we perform an explicit test of the Weak Gravity Conjecture by using the Gopakumar-Vafa invariants to count BPS states. All of our examples satisfy the tower/sublattice WGC, and in fact they even satisfy the stronger lattice WGC. [ABSTRACT FROM AUTHOR]

A 58-year-old patient presented with a severe neurological deficit due to a stroke caused by an occlusion of the left internal carotid artery siphon. Standard treatment failed and neurosurgical consult was delayed. Because of a favorable perfusion imaging finding, microsurgical revascularization via an extra-intracranial bypass (left superficial temporal artery — left middle cerebral artery) was performed 36 hours after the onset of the symptoms. The outcome of the patient was favorable. The authors want to emphasize the need to actively seek patients with a severe neurological deficit and still viable brain tissue. The time window and treatment alternatives are discussed. [ABSTRACT FROM AUTHOR]

Abstract The delivery of genetic information has emerged as a valid therapeutic approach. Various reports have demonstrated that mRNA, besides its remarkable potential as vaccine, can also promote expression without inducing an adverse immune response against the encoded protein. In the current study, we set out to explore whether our technology based on chemically unmodified mRNA is suitable for passive immunization. To this end, various antibodies using different designs were expressed and characterized in vitro and in vivo in the fields of viral infections, toxin exposure, and cancer immunotherapies. Single injections of mRNA–lipid nanoparticle (LNP) were sufficient to establish rapid, strong, and long‐lasting serum antibody titers in vivo, thereby enabling both prophylactic and therapeutic protection against lethal rabies infection or botulinum intoxication. Moreover, therapeutic mRNA‐mediated antibody expression allowed mice to survive an otherwise lethal tumor challenge. In conclusion, the present study demonstrates the utility of formulated mRNA as a potent novel technology for passive immunization.

Background: Active surveillance after orchiectomy is the preferred management in clinical stage I (CSI) germ-cell tumours (GCT) associated with a 15 to 30% relapse rate. Patients and methods: In the IGCCCG Update database, we compared the outcomes of gonadal disseminated GCT relapsing from initial CSI to outcomes of patients with de novo metastatic GCT. Results: A total of 1014 seminoma (Sem) [298 (29.4%) relapsed from CSI, 716 (70.6%) de novo] and 3103 non-seminoma (NSem) [626 (20.2%) relapsed from CSI, 2477 (79.8%) de novo] were identified. Among Sem, no statistically significant differences in PFS and OS were found between patients relapsing from CSI and de novo metastatic disease [5-year progression-free survival (5y-PFS) 87.6% versus 88.5%; 5-year overall survival (5y-OS) 93.2% versus 96.1%). Among NSem, PFS and OS were higher overall in relapsing CSI patients (5y-PFS 84.6% versus 80.0%; 5y-OS 93.3% versus 88.7%), but there were no differences within the same IGCCCG prognostic groups (HR = 0.89; 95% CI: 0.70–1.12). Relapses in the intermediate or poor prognostic groups occurred in 11/298 (4%) Sem and 112/626 (18%) NSem. Conclusion: Relapsing CSI GCT patients expect similar survival compared to de novo metastatic patients of the same ICCCCG prognostic group. Intermediate and poor prognosis relapses from initial CSI expose patients to unnecessary toxicity from more intensive treatments. [ABSTRACT FROM AUTHOR]

Pathologic examination of prostate biopsies is time consuming due to the large number of slides per case. In this retrospective study, we validate a deep learning-based classifier for prostate cancer (PCA) detection and Gleason grading (AI tool) in biopsy samples. Five external cohorts of patients with multifocal prostate biopsy were analyzed from high-volume pathology institutes. A total of 5922 H&E sections representing 7473 biopsy cores from 423 patient cases (digitized using three scanners) were assessed concerning tumor detection. Two tumor-bearing datasets (core n = 227 and 159) were graded by an international group of pathologists including expert urologic pathologists (n = 11) to validate the Gleason grading classifier. The sensitivity, specificity, and NPV for the detection of tumor-bearing biopsies was in a range of 0.971–1.000, 0.875–0.976, and 0.988–1.000, respectively, across the different test cohorts. In several biopsy slides tumor tissue was correctly detected by the AI tool that was initially missed by pathologists. Most false positive misclassifications represented lesions suspicious for carcinoma or cancer mimickers. The quadratically weighted kappa levels for Gleason grading agreement for single pathologists was 0.62–0.80 (0.77 for AI tool) and 0.64–0.76 (0.72 for AI tool) for the two grading datasets, respectively. In cases where consensus for grading was reached among pathologists, kappa levels for AI tool were 0.903 and 0.855. The PCA detection classifier showed high accuracy for PCA detection in biopsy cases during external validation, independent of the institute and scanner used. High levels of agreement for Gleason grading were indistinguishable between experienced genitourinary pathologists and the AI tool. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the image quality of an ultra-low contrast medium and radiation dose CT pulmonary angiography (CTPA) protocol for the diagnosis of acute pulmonary embolism using a clinical photon-counting detector (PCD) CT system and compare its performance to a dual-energy-(DE)-CTPA protocol on a conventional energy-integrating detector (EID) CT system. Methods: Sixty-four patients either underwent CTPA with the novel scan protocol on the PCD-CT scanner (32 patients, 25 mL, CTDIvol 2.5 mGy·cm) or conventional DE-CTPA on a third-generation dual-source EID-CT (32 patients, 50 mL, CTDIvol 5.1 mGy·cm). Pulmonary artery CT attenuation, signal-to-noise ratio, and contrast-to-noise-ratio were assessed as objective criteria of image quality, while subjective ratings of four radiologists were compared at 60 keV using virtual monoenergetic imaging and polychromatic standard reconstructions. Interrater reliability was determined by means of the intraclass correlation coefficient (ICC). Effective dose was compared between patient cohorts. Results: Subjective image quality was deemed superior by all four reviewers for 60-keV PCD scans (excellent or good ratings in 93.8% of PCD vs. 84.4% of 60 keV EID scans, ICC = 0.72). No examinations on either system were considered "non-diagnostic." Objective image quality parameters were significantly higher in the EID group (mostly p < 0.001), both in the polychromatic reconstructions and at 60 keV. The ED (1.4 vs. 3.3 mSv) was significantly lower in the PCD cohort (p < 0.001). Conclusions: PCD-CTPA allows for considerable reduction of contrast medium and radiation dose in the diagnosis of acute pulmonary embolism, while maintaining good to excellent image quality compared to conventional EID-CTPA. Clinical relevance statement: Clinical PCD-CT allows for spectral assessment of pulmonary vasculature with high scan speed, which is beneficial in patients with suspected pulmonary embolism, frequently presenting with dyspnea. Simultaneously PCD-CT enables substantial reduction of contrast medium and radiation dose. Key Points: • The clinical photon-counting detector CT scanner used in this study allows for high-pitch multi-energy acquisitions. • Photon-counting computed tomography allows for considerable reduction of contrast medium and radiation dose in the diagnosis of acute pulmonary embolism. • Subjective image quality was rated best for 60-keV photon-counting scans. [ABSTRACT FROM AUTHOR]

We describe the higher-form and non-invertible symmetries of 4d N = 3 S-folds using the brane dynamics of their holographic duals. In cases with enhancement to N = 4 supersymmetry, our analysis reproduces the known field theory results of Aharony, Seiberg and Tachikawa, and is compatible with the effective action recently given by Bergman and Hirano. Likewise, for two specific N = 3 theories for which Zafrir has conjectured N = 1 Lagrangians our results agree with those implied by the Lagrangian description. In all other cases, our results imply novel predictions about the symmetries of the corresponding N = 3 field theories. [ABSTRACT FROM AUTHOR]

Chromosomal abnormalities in acute myeloid leukemia (AML) have significantly contributed to scientific understanding of its molecular pathogenesis, which has aided in the development of therapeutic strategies and enhanced management of AML patients. The diagnosis, prognosis and treatment of AML have also rapidly transformed in recent years, improving initial response to treatment, remission rates, risk stratification and overall survival. Hundreds of rare chromosomal abnormalities in AML have been discovered thus far using chromosomal analysis and next-generation sequencing. As a result, the World Health Organization (WHO) has categorized AML into subgroups based on genetic, genomic and molecular characteristics, to complement the existing French-American classification which is solely based on morphology. In this review, we aim to highlight the most clinically relevant chromosomal aberrations in AML together with the technologies employed to detect these aberrations in laboratory settings. [ABSTRACT FROM AUTHOR]

Purpose: Battle-related trauma is common in modern warfare and can lead to genitourinary injuries. In Western countries, urogenital injuries are rare in the civilian environment. The main objective of this study was to assess urological workload for surgeons on deployment. Material and methods: Data were acquired over a period of five years of deployment in a U.S. facility in Afghanistan. Results: German urological surgeons treated on average one urologic outpatient per day and performed 314 surgical interventions overall. Surgical interventions were categorized as battle-related interventions (BRIs, n = 169, 53.8%) and nonbattle-related interventions (non-BRIs, n = 145, 46.2%). In the BRI group, interventions were mainly performed on the external genitalia (n = 67, 39.6%), while in the non-BRI group, endourological procedures predominated (n = 109). This is consistent with a higher rate of abdominal or pelvic procedures performed in the BRI group (n = 51, 30.2%). Furthermore, the types of interventions performed on the external genitalia differed significantly. In the BRI group, 58.2% (n = 39) of interventions were scrotal explorations, but none of those procedures were performed in the non-BRI group (p < 0.001). However, 50.0% (n = 13) of scrotal explorations in the non-BRI group were due to suspected torsions of the testes followed by orchidopexy (BRI: n = 1, 1.5%, p < 0.001). Concerning outpatients, the consultation was mainly due to complaints concerning the external genitalia (32.7%, n = 252) or kidney/ureteral stones (23.5%, n = 181). Conclusion: While the treatment of urological outpatients in a deployment setting resembles the treatment of soldiers in Germany, BRIs requires abdominal/retroperitoneal urosurgical skills and basic skills in reconstructive surgery. [ABSTRACT FROM AUTHOR]

Purpose: Clinical communication and facilitating informed and sound medical decisions become challenging as patients age and suffer from age-associated impairments. Family caregivers are perceived as essential actors in addressing these challenges. Here, we explore physicians’ perspectives on family caregivers’ roles and their involvement in consultations and therapy decision-making situations of elderly cancer patients. Methods: We examined 38 semi-structured interviews with physicians from different specialities (oncologists, non-oncology specialists, and general practitioners) in Germany who treated elderly cancer patients. Data were analyzed using reflexive thematic analysis. Results: We identified five general and distinct perspectives on the involvement of family caregivers in the therapy process. Family caregivers are seen as (1) translators of medical information; (2) providers of support for the patient; (3) providers of information about the patient; (4) stakeholders with relevant points of view regarding the treatment decision; or (5) individuals who have a disruptive influence on the consultation. The interviewed physicians rarely involved family caregivers closely in consultations. Conclusions: Although physicians frequently attribute supportive roles to family caregivers, they rarely include them in consultations. Previous studies have found that a triadic setting is often better suited to agreeing upon a patient-centered and needs-based treatment decision for older cancer patients. We infer that physicians too rarely recognize the potential importance of family caregivers. Educators should further integrate family caregiver involvement and its implications in general medical education and professional training. [ABSTRACT FROM AUTHOR]

Purpose: The outcome of radiotherapy (RT) for prostate cancer (PCA) depends on the delivered dose. While the evidence for dose-escalated RT up to 80 gray (Gy) is well established, there have been only few studies examining dose escalation above 80 Gy. We initiated the present study to assess the safety of dose escalation up to 84 Gy. Methods: In our retrospective analysis, we included patients who received dose-escalated RT for PCA at our institution between 2016 and 2021. We evaluated acute genitourinary (GU) and gastrointestinal (GI) toxicity as well as late GU and GI toxicity. Results: A total of 86 patients could be evaluated, of whom 24 patients had received 80 Gy and 62 patients 84 Gy (35 without pelvic and 27 with pelvic radiotherapy). Regarding acute toxicities, no > grade 2 adverse events occurred. Acute GU/GI toxicity of grade 2 occurred in 12.5%/12.5% of patients treated with 80 Gy, in 25.7%/14.3% of patients treated with 84 Gy to the prostate only, and in 51.9%/12.9% of patients treated with 84 Gy and the pelvis included. Late GU/GI toxicity of grade ≥ 2 occurred in 4.2%/8.3% of patients treated with 80 Gy, in 7.1%/3.6% of patients treated with 84 Gy prostate only, and in 18.2%/0% of patients treated with 84 Gy pelvis included (log-rank test p = 0.358). Conclusion: We demonstrated that dose-escalated RT for PCA up to 84 Gy is feasible and safe without a significant increase in acute toxicity. Further follow-up is needed to assess late toxicity and survival. [ABSTRACT FROM AUTHOR]

Immunotherapy has revolutionized cancer treatment in recent years. Although currently approved checkpoint inhibitors (CPIs) yield remarkable anti-tumoral responses in several cancer types, a substantial proportion of patients do not benefit from such therapies. Local activation of innate immune signaling pathways is a promising approach to overcome the immunosuppressive tumor microenvironment, induce anti-tumor immunity, and improve the efficacy of CPI therapies. Here, we assessed the mode of action and efficacy of the RNA-based innate immune stimulator CV8102 for local immunotherapy in preclinical models. Intratumoral (i.t.) administration of CV8102 activated innate immune responses in the tumor microenvironment and draining lymph nodes, resulting in a dose-dependent anti-tumoral response. Combining i.t. CV8102 with systemic anti-programmed death protein 1 (PD-1) treatment further enhanced anti-tumoral responses, inducing tumor infiltration and activation of CD8+ T cells. The resulting memory response prevented tumor growth in rechallenged animals and impaired the growth of non-injected distal tumors. Therefore, i.t. CV8102 delivery is a promising approach for local cancer immunotherapy, especially in combination with CPIs. Clinical testing of CV8102 is ongoing (NCT03291002). [ABSTRACT FROM AUTHOR]

Self-compassion, which refers to being kind and understanding toward oneself when suffering or experiencing personal inadequacies, is widely seen as a protective factor against mental health problems in adolescents and adults. To date, most research is conducted on adults using the Self-Compassion Scale (SCS), although adolescence is seen as a challenging period in life. Self-compassion research has only recently started to focus on childhood and adolescence. We aimed to translate the English version of the SCS for adolescents into German, test its psychometric properties, and examine potential gender differences more closely. We used confirmatory factor analysis (CFA) to find the best-fitting model out of a two, three, and six-factorial solution. The sample consisted of 255 adolescents, 10 to 19 years old, from a community sample. The study was designed as an online survey. We found the six-factorial solution to best fit our data. Males were significantly more self-compassionate than females. The Self-Compassion Scale – Children and Adolescents (SCS-CA) and its subscales showed good internal consistency as well as good content, criterion, and construct validity with measures of mindfulness, quality of life, and psychopathology. We discuss implications of these findings for a better understanding of adolescent well-being and mental health, as well as potential benefits of a future application of this measure. Overall, our findings suggest that the developed questionnaire is an economical, valid, and reliable measure to assess self-compassion in German adolescents. Trial registration: From ClinicalTrials.gov, Identifier: NCT04034576 (registered 07/17/19). Highlights: Translation and validation of the SCS for adolescents from English to German with 10- to 19-year-olds from a community sample. CFA indicates that a six-factorial solution for SCS-CA in adolescents best fits the data. Good psychometric properties and replication of the link of self-compassion, mindfulness, and psychopathology. Male adolescents were significantly more self-compassionate than females. One step in better understanding adolescent well-being, mental health, and potential resilience factors. [ABSTRACT FROM AUTHOR]

Background: Testicular germ cell tumors (GCTs) are aggressive but highly curable tumors. To avoid over/undertreatment, reliable clinical staging of retroperitoneal lymph-node metastasis is necessary. Current clinical guidelines, in their different versions, lack specific recommendations on how to measure lymph-node metastasis. Objective: We aimed to assess the practice patterns of German institutions frequently treating testicular cancer for measuring retroperitoneal lymph-node size. Methods: An 8‐item survey was distributed among German university hospitals and members of the German Testicular Cancer Study Group. Results: In the group of urologists, 54.7% assessed retroperitoneal lymph nodes depending on their short-axis diameter (SAD) (33.3% in any plane, 21.4% in the axial plane), while 45.3% used long-axis diameter (LAD) for the assessment (42.9% in any plane, 2.4% in the axial plane). Moreover, the oncologists mainly assessed lymph-node size based on the SAD (71.4%). Specifically, 42.9% of oncologists assessed the SAD in any plane, while 28.5% measured this dimension in the axial plane. Only 28.6% of oncologists considered the LAD (14.3% in any plane, 14.3% in the axial plane). None of the oncologists and 11.9% of the urologists (n = 5) always performed an MRI for the initial assessment, while for follow-up imaging, the use increased to 36.5% of oncologists and 31% of urologists. Furthermore, only 17% of the urologists, and no oncologists, calculated lymph-node volume in their assessment (p = 0.224). Conclusion: Clear and consistent measurement instructions are urgently needed to be present in all guidelines across different specialistic fields involved in testicular cancer management. [ABSTRACT FROM AUTHOR]

Objectives: Despite various methodological concerns, previous studies mainly use questionnaires to assess mindfulness. Following a multi-measurement approach, the present study aimed to evaluate the added value of an experience-sampling measure in the context of posttraumatic stress disorder (PTSD) and depression. Method: Data were collected in a PTSD group, depression group, and control group (each n = 33). The Mindful-Breathing Exercise (MBE) was used as an experience-sampling method and the Five Facet Mindfulness Questionnaire (FFMQ) as a mindfulness questionnaire. Clinical variables included PTSD and depressive symptoms. Results: Scores from the MBE and the FFMQ were positively correlated in the control group (r = 0.48) and the depression group (r = 0.28), while a non-significant correlation emerged for the PTSD group. On the level of FFMQ facets, results were heterogeneous among the three groups. The MBE predicted hyperarousal (β = − 0.41) and intrusions (β = − 0.32) in the PTSD group, whereas the FFMQ predicted depressive symptoms in the depression group (β = − 0.41) and the control group (β = − 0.65). Compared to the control group, the PTSD group (d = 1.88) and the depression group (d = 1.67) demonstrated lower FFMQ scores. In terms of the MBE, there was a trend towards higher scores in the control group than either clinical group. Conclusions: Findings hint at conceptual overlaps and distinctive features of both measurement approaches. With respect to the clinical context, results suggest an added value of the MBE to questionnaire-based assessments of mindfulness with respect to its predictive value for hyperarousal and intrusions. Preregistration: This study is not pre-registered. [ABSTRACT FROM AUTHOR]

Background: The COVID-19 pandemic led to extensive restrictions in Germany in 2020, including the postponement of elective interventions. We examined the impact on ST-elevation myocardial infarction (STEMI) as an acute and non-postponable disease. Methods: Using German national records, all STEMI between 2017 and 2020 were identified. Using the number of STEMI cases between 2017 and 2019, we created a forecast for 2020 and compared it with the observed number of STEMI in 2020. Results: From 2017 to 2020, 248,062 patients were treated for STEMI in Germany. Mean age was 65.21 years and 28.36% were female. When comparing forecasted and observed STEMI in 2020, a correlation can be seen: noticeable fewer STEMI were treated in those weeks respectively months with an increasing COVID-19 hospitalization rate (monthly percentage decrease in STEMI: March − 14.85%, April − 13.39%, November − 11.92%, December − 22.95%). At the same time, the crude in-hospital mortality after STEMI increased significantly at the peaks of the first and second waves (relative risk/RR of monthly in-hospital mortality: April RR = 1.11 [95% CI 1.02; 1.21], November RR = 1.13 [1.04; 1.24], December RR = 1.16 [1.06; 1.27]). Conclusion: The COVID-19 pandemic led to a noticeable decrease in the number of STEMI interventions in Germany at the peaks of the first and second waves in 2020, corresponding to an increase in COVID-19 hospitalizations. At the same time, in-hospital mortality after STEMI increased significantly in these phases. Impact of the COVID-19 pandemic on STEMI numbers and in-hospital mortality in Germany. Relative difference between forecasted and observed STEMI numbers (above figure), the relative risk of in-hospital mortality (middle figure) as well as number of new hospital admissions for COVID-19 per million inhabitants according to Roser et al.27 (bottom figure). [ABSTRACT FROM AUTHOR]

Objectives: To systematically investigate the usability of virtual non-contrast reconstructions (VNC) derived from dual-layer CT (DLCT) for detection and size measurements of kidney stones with regards to different degrees of surrounding iodine-induced attenuation and radiation dose. Methods: Ninety-two kidney stones of varying size (3–14 mm) and composition were placed in a phantom filled with different contrast media/water mixtures exhibiting specific iodine-induced attenuation (0–1500 HU). DLCT-scans were acquired using CTDIvol of 2 mGy and 10 mGy. Conventional images (CI) and VNC0H-1500HU were reconstructed. Reference stone size was determined using a digital caliper (Man-M). Visibility and stone size were assessed. Statistical analysis was performed using the McNemar test, Wilcoxon test, and the coefficient of determination. Results: All stones were visible on CI0HU and VNC200HU. Starting at VNC400 HU, the detection rate decreased with increasing HU and was significantly lower as compared to CI0HU on VNC≥ 600HU (100.0 vs. 94.0%, p < 0.05). The overall detection rate was higher using 10 mGy as compared to 2 mGy protocol (87.9 vs. 81.8%; p < 0.001). Stone size was significantly overestimated on all VNC compared to Man-M (7.0 ± 3.5 vs. 6.6 ± 2.8 mm, p < 0.001). Again, the 10 mGy protocol tended to show a better correlation with Man-M as compared to 2 mGy protocol (R2 = 0.39–0.68 vs. R2 = 0.31–0.57). Conclusions: Detection and size measurements of kidney stones surrounded by contrast media on VNC are feasible. The detection rate of kidney stones decreases with increasing iodine-induced attenuation and with decreasing radiation dose as well as stone size, while remaining comparable to CI0HU on VNC ≤ 400 HU. Key Points: • The detection rate of kidney stones on VNC depends on the surrounding iodine-induced attenuation, the used radiation dose, and the stone size. • The detection rate of kidney stones on VNC decreases with greater iodine-induced attenuation and with lower radiation dose, particularly in small stones. • The visibility of kidney stones on VNC≤ 400 HUremains comparable to true-non-contrast scans even when using a low-dose technique. [ABSTRACT FROM AUTHOR]

The fusion oncoprotein RUNX1/ETO which results from the chromosomal translocation t (8;21) in acute myeloid leukemia (AML) is an essential driver of leukemic maintenance. We have previously shown that RUNX1/ETO knockdown impairs expression of the protein component of telomerase, TERT. However, the underlying molecular mechanism of how RUNX1/ETO controls TERT expression has not been fully elucidated. Here we show that RUNX1/ETO binds to an intergenic region 18 kb upstream of the TERT transcriptional start site and to a site located in intron 6 of TERT. Loss of RUNX1/ETO binding precedes inhibition of TERT expression. Repression of TERT expression is also dependent on the destabilization of the E3 ubiquitin ligase SKP2 and the resultant accumulation of the cell cycle inhibitor CDKN1B, that are both associated with RUNX1/ETO knockdown. Increased CDKN1B protein levels ultimately diminished TERT transcription with E2F1/Rb involvement. Collectively, our results show that RUNX1/ETO controls TERT expression directly by binding to its locus and indirectly via a SKP2—CDKN1B—E2F1/Rb axis. [ABSTRACT FROM AUTHOR]

Abstract Leukaemia‐propagating cells are more frequent in high‐risk acute B lymphoblastic leukaemia than in many malignancies that follow a hierarchical cancer stem cell model. It is unclear whether this characteristic can be more universally applied to patients from non‐‘high‐risk’ sub‐groups and across a broad range of cellular immunophenotypes. Here, we demonstrate in a wide range of primary patient samples and patient samples previously passaged through mice that leukaemia‐propagating cells are found in all populations defined by high or low expression of the lymphoid differentiation markers CD10, CD20 or CD34. The frequency of leukaemia‐propagating cells and their engraftment kinetics do not differ between these populations. Transcriptomic analysis of CD34high and CD34low blasts establishes their difference and their similarity to comparable normal progenitors at different stages of B‐cell development. However, consistent with the functional similarity of these populations, expression signatures characteristic of leukaemia propagating cells in acute myeloid leukaemia fail to distinguish between the different populations. Together, these findings suggest that there is no stem cell hierarchy in acute B lymphoblastic leukaemia. →See accompanying article http://dx.doi.org/10.1002/emmm.201202207

The Distance Conjecture holds that any infinite-distance limit in the scalar field moduli space of a consistent theory of quantum gravity must be accompanied by a tower of light particles whose masses scale exponentially with proper field distance ‖ϕ‖ as m ~ exp(−λ‖ϕ‖), where λ is order-one in Planck units. While the evidence for this conjecture is formidable, there is at present no consensus on which values of λ are allowed. In this paper, we propose a sharp lower bound for the lightest tower in a given infinite-distance limit in d dimensions: λ ≥ 1 / d − 2 . In support of this proposal, we show that (1) it is exactly preserved under dimensional reduction, (2) it is saturated in many examples of string/M-theory compactifications, including maximal supergravity in d = 4 – 10 dimensions, and (3) it is saturated in many examples of minimal supergravity in d = 4 – 10 dimensions, assuming appropriate versions of the Weak Gravity Conjecture. We argue that towers with λ < 1 / d − 2 discussed previously in the literature are always accompanied by even lighter towers with λ ≥ 1 / d − 2 , thereby satisfying our proposed bound. We discuss connections with and implications for the Emergent String Conjecture, the Scalar Weak Gravity Conjecture, the Repulsive Force Conjecture, large-field inflation, and scalar field potentials in quantum gravity. In particular, we argue that if our proposed bound applies beyond massless moduli spaces to scalar fields with potentials, then accelerated cosmological expansion cannot occur in asymptotic regimes of scalar field space in quantum gravity. [ABSTRACT FROM AUTHOR]

Purpose: In this review, we summarize and discuss contemporary treatment standards and possible selection criteria for decision making after failure of adjuvant or first-line cisplatin-based chemotherapy for primarily localized or metastatic germ cell tumors. Methods: This work is based on a systematic literature search conducted for the elaboration of the first German clinical practice guideline to identify prospective clinical trials and retrospective comparative studies published between Jan 2010 and Feb 2021. Study end points of interest were progression-free (PFS) and overall survival (OS), relapse rate (RR), and/or safety. Results: Relapses of clinical stage I (CS I) patients irrespective of prior adjuvant treatment after orchiectomy are treated stage adapted in accordance for primary metastatic patients. Surgical approaches for sole retroperitoneal relapses are investigated in ongoing clinical trials. The appropriate salvage chemotherapy for metastatic patients progressing or relapsing after first-line cisplatin-based chemotherapy is still a matter of controversy. Conventional cisplatin-based chemotherapy is the international guideline-endorsed standard of care, but based on retrospective data high-dose chemotherapy and subsequent autologous stem cell transplantation may offer a 10–15% survival benefit for all patients. Secondary complete surgical resection of all visible residual masses irrespective of size is paramount for treatment success. Conclusions: Patients relapsing after definite treatment of locoregional disease are to be treated by stage-adapted first-line standard therapy for metastatic disease. Patients with primary advanced/metastatic disease failing one line of cisplatin-based combination chemotherapy should be referred to GCT expert centers. Dose intensity is a matter of ongoing debate, but sequential high-dose chemotherapy seems to improve patients' survival. [ABSTRACT FROM AUTHOR]

The literature has shown an inverse volume-outcome relationship for transcatheter aortic valve implantation (TAVI). However, little is known about emergency admissions in Germany. Using German national electronic health records, we identified all isolated balloon-expandable and self-expanding transfemoral TAVI in 2018. The focus was on those patients with emergency admission. 17,295 patients were treated with TAVI, including 1682 emergency cases. 49.2% of the emergency admissions were female, the mean age was 81.2 years and the logistic EuroSCORE was 23.3%. The percentage of emergency cases was higher in lower volume than in higher volume centers (p < 0.001): In detail, centers performing < 50 TAVI showed an emergency admission rate of ~ 15%, those with > 200 TAVI a rate of ~ 11%. After propensity score adjustment, analyzing the outcomes for an increase in volume per 10 emergency admissions, higher volume centers showed significantly better outcomes regarding in-hospital mortality (OR = 0.872, p = 0.043), major bleeding (OR = 0.772, p = 0.001), stroke (OR = 0.816, p = 0.044), mechanical ventilation > 48 h (OR = 0.749, p = 0.001), length of hospital stay (risk adjusted difference in days of hospitalization per 10 emergency admissions: − 1.01 days, p < 0.001), and reimbursement (risk adjusted difference in reimbursement per 10 emergency admissions: -€314.89, p < 0.001). Results were not significant for acute kidney injury (OR = 0.951, p = 0.104), postoperative delirium (OR = 0.975, p = 0.480), and permanent pacemaker implantation (OR = 1.010, p = 0.732). In conclusion, regarding transfemoral TAVI, the percentage of emergency cases was higher in lower volume centers in Germany. However, higher volume centers show significantly better outcomes for in-hospital mortality and complication rates as well as resource utilization parameters. [ABSTRACT FROM AUTHOR]

Novel developments in genomic medicine may reduce the length of the diagnostic odyssey for patients with rare diseases. Health providers must thus decide whether to offer genome sequencing for the diagnosis of rare conditions in a routine clinical setting. We estimated the costs of singleton standard genetic testing and trio-based whole genome sequencing (WGS), in the context of the Scottish Genomes Partnership (SGP) study. We also explored what users value about genomic sequencing. Insights from the costing and value assessments will inform a subsequent economic evaluation of genomic medicine in Scotland. An average cost of £1,841 per singleton was estimated for the standard genetic testing pathway, with significant variability between phenotypes. WGS cost £6625 per family trio, but this estimate reflects the use of WGS during the SGP project and large cost savings may be realised if sequencing was scaled up. Patients and families valued (i) the chance of receiving a diagnosis (and the peace of mind and closure that brings); (ii) the information provided by WGS (including implications for family planning and secondary findings); and (iii) contributions to future research. Our costings will be updated to address limitations of the current study for incorporation in budget impact modelling and cost-effectiveness analysis (cost per diagnostic yield). Our insights into the benefits of WGS will guide the development of a discrete choice experiment valuation study. This will inform a user-perspective cost–benefit analysis of genome-wide sequencing, accounting for the broader non-health outcomes. Taken together, our research will inform the long-term strategic development of NHS Scotland clinical genetics testing services, and will be of benefit to others seeking to undertake similar evaluations in different contexts. [ABSTRACT FROM AUTHOR]