Search

Abstract A lack of advanced preclinical mouse tumor models impedes the progress in urothelial carcinoma research. We present here a novel fast, robust, reliable, and highly reproducible model for the genetic induction of bladder cancer in immunocompetent mice. Different sets of oncogenic transposons (Cmyc, Kras) and Cre drivers were transfected into the murine bladder wall of two different genetic backgrounds (Trp53 fl/fl and Braf V600E , Pten fl/fl , Ctnnb1 exon3-fl/fl). Transfection was carried out using in vivo electroporation of the bladder after surgical exploration and transmural or transurethral intravesical plasmid injection. Up to 100% of animals developed urothelial carcinomas of the bladder. Time to tumor onset ranged from 16 to 97 days with a median of approximately 23 days in the fastest groups. Histological examination identified orthotopic urothelial carcinomas in most cases, in some experimental groups up to 100%. The resulting tumors were highly invasive and often metastatic. Metastases were found in up to 100% of tumor bearing mice per group. Taken together, this study establishes the proof-of-principle that in vivo electroporation can be versatilely employed as a reliable, fast, and robust method for the highly reproducible induction of urothelial carcinomas in the murine bladder wall. This novel murine tumor model could pave the way towards more easily modelling subtype specific urothelial carcinomas in mice.

Abstract Background Body contouring surgery after massive weight loss is associated with different risk factors. Wound healing disorders and seromas commonly occur postoperatively. Bariatric interventions lead to massive weight loss with excess skin and soft tissue. In this study, perioperatively collected laboratory markers of this special patient population were analyzed. Methods Fifty-nine patients were analyzed retrospectively regarding bariatric surgery, weight loss, body contouring surgery, laboratory markers, and complication rates. Results Body contouring surgery (n = 117) was performed in 59 patients. Weight loss was achieved after gastric bypass (40.1%), gastric banding (33.9%), or sleeve gastrectomy (26.0%), with an average of 69.2 kg. The most common body contouring procedure included abdominoplasty (n = 50), followed by thigh lift (n = 29), mammaplasty (n = 19), brachioplasty (n = 14), and upper body lift (n = 5). Analysis of laboratory markers revealed no exceptional and clinically relevant variations. Correlation analysis revealed associations between resection weight, amount of drain fluid, and particular laboratory markers. Conclusion Analysis of perioperative laboratory markers in this special patient population after massive weight loss did not indicate clinically relevant risk factors regardless of the type of bariatric or body contouring surgery. Body contouring surgeries after bariatric interventions prove to be safe and low risk concerning perioperative laboratory markers and postoperative hospitalization.

Summary: Nutrient digestion, absorption, and export must be coordinated in the gut to meet the nutritional needs of the organism. We used the Drosophila intestine to characterize the mechanisms that coordinate the fate of dietary lipids. We identified enterocytes specialized in absorbing and exporting lipids to peripheral organs. Distinct hepatocyte-like cells, called oenocytes, communicate with these enterocytes to adjust intestinal lipid storage and export. A single transcription factor, Drosophila hepatocyte nuclear factor 4 (dHNF4), supports this gut-liver axis. In enterocytes, dHNF4 maximizes dietary lipid export by preventing their sequestration in cytoplasmic lipid droplets. In oenocytes, dHNF4 promotes the expression of the insulin antagonist ImpL2 to activate Foxo and suppress lipid retention in enterocytes. Disruption of this switch between lipid storage and export is associated with intestinal inflammation, suggesting a lipidic origin for inflammatory bowel diseases. These studies establish dHNF4 as a central regulator of intestinal metabolism and inter-organ lipid trafficking.

Advancements in the generative AI field have enabled the development of powerful educational avatars. These avatars embody a human and can, for instance, listen to users’ spoken input, generate an answer utilizing a large-language model, and reply by speaking with a synthetic voice. A theoretical introduction summarizes essential steps in developing AI-based educational avatars and explains how they differ from previously available educational technologies. Moreover, we introduce GPTAvatar, an open-source, state-of-the-art AI-based avatar. We then discuss the benefits of using AI-based educational avatars, which include, among other things, individualized and contextualized instruction. Afterward, we highlight the challenges of using AI-based educational avatars. Major problems concern incorrect and inaccurate information provided, as well as insufficient data protection. In the discussion, we provide an outlook by addressing advances in educational content and educational technology and identifying three crucial open questions for research and practice.

City Walking Tour Videos (CWTVs) are a novel source of Volunteered Geographic Information providing street-level imagery through video sharing platforms such as YouTube. We demonstrate that these videos contain rich information for urban analytical applications, by conducting a mobility study. We detect transport modes with a focus on active (pedestrians and cyclists) and motorised mobility (cars, motorcyclists and trucks). We chose the City of Paris as our area of interest given the rapid expansion of the bicycle network as a response to the Covid-19 pandemic and compiled a video corpus encompassing more than 66 hours of video footage. Through the detection of street names in the video and placename containing timestamps we extracted and georeferenced 1169 locations at which we summarise the detected transport modes. Our results show high potential of CWTVs for studying urban mobility applications. We detected significant shifts in the mobility mix before and during the pandemic as well as weather effects on the volumes of pedestrians and cyclists. Combined with the observed increase in data availability over the years we suggest that CWTVs have considerable potential for other applications in the field of urban analytics.

Summary: Background: Open partial pancreatoduodenectomy (OPD) represents the current gold standard of surgical treatment of a wide range of diseases of the pancreatic head but is associated with morbidity in around 40% of cases. Robotic partial pancreatoduodenectomy (RPD) is being used increasingly, yet, no randomised controlled trials (RCTs) of RPD versus OPD have been published, leaving a low level of evidence to support this practice. Methods: This investigator-initiated, exploratory RCT with two parallel study arms was conducted at a high-volume pancreatic centre in line with IDEAL recommendations (stage 2b). Patients scheduled for elective partial pancreatoduodenectomy (PD) for any indication were randomised (1:1) to RPD or OPD with a centralised web-based tool. The primary endpoint was postoperative cumulative morbidity within 90 days, assessed via the Comprehensive Complication Index (CCI). Biometricians were blinded to the intervention, but patients and surgeons were not. The trial was registered prospectively (DRKS00020407). Findings: Between June 3, 2020 and February 14, 2022, 81 patients were randomly assigned to RPD (n = 41) or OPD (n = 40), of whom 62 patients (RPD: n = 29, OPD: n = 33) were analysed in the modified intention to treat analysis. Four patients in the OPD group were randomised, but did not undergo surgery in our department and one patient was excluded in the RPD group due to other reason. Nine patients in the RPD group and 3 patients in the OPD were excluded from the primary analysis because they did not undergo PD, but rather underwent other types of surgery. The CCI after 90 days was comparable between groups (RPD: 34.02 ± 23.48 versus OPD: 36.45 ± 27.65, difference in means [95% CI]: −2.42 [−15.55; 10.71], p = 0.713). The RPD group had a higher incidence of grade B/C pancreas-specific complications compared to the OPD group (17 (58.6%) versus 11 (33.3%); difference in rates [95% CI]: 25.3% [1.2%; 49.4%], p = 0.046). The only complication that occurred significantly more often in the RPD than in the OPD group was clinically relevant delayed gastric emptying. Procedure-related and overall hospital costs were significantly higher and duration of surgery was longer in the RPD group. Blood loss did not differ significantly between groups. The intraoperative conversion rate of RPD was 23%. Overall 90-day mortality was 4.8% without significant differences between RPD and OPD. Interpretation: In the setting of a very high-volume centre, both RPD and OPD can be considered safe techniques. Further confirmatory multicentre RCTs are warranted to uncover potential advantages of RPD in terms of perioperative and long-term outcomes. Funding: Federal Ministry of Education and Research (BMBF: 01KG2010).

Abstract The range of applications of digital surface models of the bones in science and industry is wide. Three-dimensional reconstructions of bones are used in biomechanics, biomedical engineering, medical image processing, orthopedics, traumatology, radiology, patient education, anatomy, anthropometry, forensic anthropology, ergonomics, usability and human factors engineering, or accident and injury analysis and prevention. No open access database or repository of skeletal surface models of the full lower extremities exists. Therefore, the objective of this publication was to provide access to consistent complete bone models of the pelvis and lower limbs of multiple subjects, including biometric data. Segmentations and surface models of the bones of the lower extremities of more than twenty subjects were created from open access postmortem whole-body computed tomography scans. The database provides a broad range of applications by giving access to the data of the complete process chain, from the raw medical imaging data through the segmentations to the surface models.

Abstract To determine whether Xpert bladder cancer monitor, a noninvasive PCR-based biomarker test, can predict the need for 2nd transurethral resection of the bladder (TURB) better than clinical assessment. Patients scheduled for TURB were prospectively screened. After initial TURB, patients were assigned to 2nd TURB or follow-up cystoscopy at 3 months (FU) by clinicians’ discretion. Central urine cytology and Xpert monitor tests were performed prior to the 1st TURB and 2nd TURB or FU, respectively. Statistical analysis to compare clinical assessment and Xpert monitor comprised sensitivity (SENS), specificity (SPEC), NPV and PPV. Of 756 screened patients, 171 were included (114 with 2nd TURB, 57 with FU). Residual tumors were detected in 34 patients who underwent 2nd TURB, and recurrent tumors were detected in 2 patients with FU. SENS and SPEC of Xpert monitor were 83.3% and 53.0%, respectively, PPV was 32.6% and NPV was 92.1%. Clinical risk assessment outperformed Xpert monitor. In patients with pTa disease at initial TURB, Xpert monitor revealed a NPV of 96%. Xpert monitor was not superior than clinical assessment in predicting the need for 2nd TURB. It might be an option to omit 2nd TURB for selected patients with pTa disease.

Hand disorders can reduce wrist range of motion (ROM). The SARS-CoV-2 pandemic highlighted challenges in routine follow-up exams, making telemedicine a viable solution. This study evaluates the feasibility and accuracy of patient self-measured wrist ROM using a self-designed goniometer template. The template was designed to measure flexion/extension and radial/ulnar abduction movements. A cohort of 50 adults (25 males/25 females) participated in this prospective study. The exclusion criteria included wrist immobilization and ages outside of 18–65 years. Participants self-assessed their wrist ROM with the goniometer template. Measurements were independently performed by a student and a specialist using standard goniometry, as well as a resident using the self-designed goniometer. The results were blinded for unbiased analysis. Mean differences in ROM varied across movement directions, with minimal differences for ulnar abduction and more substantial deviations for radial abduction, extension and flexion. The patient–specialist comparison showed deviations below 5 degrees for flexion and ulnar abduction in 50% of cases. Telemedicine, expanded by the COVID-19 pandemic, offers significant potential for hand rehabilitation. Current methods of ROM assessment lack cost-effectiveness and simplicity. Our method, demonstrating comparable accuracy for most movements, provides a cost-effective, reliable alternative for remote ROM assessment, enhancing telemedicine practices in hand rehabilitation.

Abstract Background Shared decision-making is the gold standard for good clinical practice, and thus, psychometric instruments have been established to assess patients’ generic preference for participation (e.g., the Autonomy Preference Index, API). However, patients’ preferences may vary depending on the specific disease and with respect to the specific decision context. With a modified preference index (API-Uro), we assessed patients’ specific participation preference in preference-sensitive decisions pertaining to urological cancer treatments and compared this with their generic participation preference. Methods In Study 1, we recruited (N = 469) urological outpatients (43.1% urooncological) at a large university hospital. Participation preference was assessed with generic measures (API and API case vignettes) and with the disease-specific API-Uro (urooncological case vignettes describing medical decisions of variable difficulty). A polychoric exploratory factor analysis was used to establish factorial validity and reduce items. In Study 2, we collected data from N = 204 bladder cancer patients in a multicenter study to validate the factorial structure with confirmatory factor analysis. Differences between the participation preference for different decision contexts were analyzed. Results Study 1: Scores on the specific urooncological case vignettes (API-Uro) correlated with the generic measure (r = .44) but also provided incremental information. Among the disease-specific vignettes of the API-Uro, there were two factors with good internal consistency (α ≥ .8): treatment versus diagnostic decisions. Patients desired more participation for treatment decisions (77.8%) than for diagnostic decisions (22%), χ2(1) = 245.1, p ≤ .001. Study 2: Replicated the correlation of the API-Uro with the API (r = .39) and its factorial structure (SRMR = .08; CFI = .974). Bladder cancer patients also desired more participation for treatment decisions (57.4%) than for diagnostic decisions (13.3%), χ²(1) =84, p ≤ .001. Conclusions The desire to participate varies between treatment versus diagnostic decisions among urological patients. This underscores the importance of assessing participation preference for specific contexts. Overall, the new API-Uro has good psychometric properties and is well suited to assess patients’ preferences. In routine care, measures of participation preference for specific decision contexts may provide incremental, allowing clinicians to better address their patients’ individual needs.

Exploring the usability of educational virtual reality (VR) is essential. Research in this area can explain the adoption of VR as a new technology, contribute to examining paths toward effective learning, and provide recommendations for effective educational design. This study investigated usability in a sample of N = 64 university students learning about simplified construction engineering topics from an interactive VR field trip. Two research objectives were pursued. First, the level of achieved usability was examined using a mixed-methods approach, including data from semi-structured interviews and a survey on system usability and satisfaction. Second, the relationships between several connected variables (ease of use, usefulness, presence, and cognitive load) and system usability and satisfaction were investigated quantitatively. With respect to the first research objective, system usability and satisfaction were evaluated positively in the interviews and rated highly in the surveys. These results indicate that VR field trips, which are increasingly replacing excursions, are regarded as an appropriate instructional method. Concerning the second research objective, ease of use, usefulness, presence, and extraneous load were found to predict system usability. Further, the factors of usefulness, presence, and intrinsic cognitive load helped explain the variance in satisfaction. These findings highlight that the variables connected to system usability and satisfaction in VR learning vary. In addition to these and other theoretical implications, practical implications and recommendations for educational design are discussed.

Abstract Introduction Certain sociodemographic characteristics (e.g., older age) have previously been identified as barriers to patients' participation preference in shared decision‐making (SDM). We aim to demonstrate that this relationship is mediated by the perceived power imbalance that manifests itself in patients' negative attitudes and beliefs about their role in decision‐making. Methods We recruited a large sample (N = 434) of outpatients with a range of urological diagnoses (42.2% urooncological). Before the medical consultation at a university hospital, patients completed the Patients' Attitudes and Beliefs Scale and the Autonomy Preference Index. We evaluated attitudes as a mediator between sociodemographic factors and participation preference in a path model. Results We replicated associations between relevant sociodemographic factors and participation preference. Importantly, attitudes and beliefs about one's own role as a patient mediated this relationship. The mediation path model explained a substantial proportion of the variance in participation preference (27.8%). Participation preferences and attitudes did not differ for oncological and nononcological patients. Conclusion Patients' attitudes and beliefs about their role determine whether they are willing to participate in medical decision‐making. Thus, inviting patients to participate in SDM should encompass an assessment of their attitudes and beliefs. Importantly, negative attitudes may be accessible to change. Unlike stable sociodemographic characteristics, such values are promising targets for interventions to foster more active participation in SDM. Patient or Public Contribution This study was part of a larger project on implementing SDM in urological practice. Several stakeholders were involved in the design, planning and conduction of this study, for example, three authors are practising urologists, and three are psychologists with experience in patient care. In addition, the survey was piloted with patients, and their feedback was integrated into the questionnaire. The data presented in this study is based on patients' responses. Results may help to empower our patients.

Abstract Objectives To assess the predictive and prognostic value of changes in longitudinal neutrophile-to-lymphocyte (NLR) ratios in men receiving taxane-based chemotherapy for metastatic prostate cancer (PC). Methods Retrospective, unicentric cohort study of patients treated with either docetaxel for metastatic hormone-sensitive PC (mHSPC) or docetaxel or cabazitaxel for metastatic castration-refractory PC (mCRPC) at a tertiary referral hospital between 2010 and 2019. NLR ratios were calculated for each cycle. Next, slopes over the first three (NLR3) and over six cycles (NLR6) were calculated and analysed for biochemical/radiologic response and survival. Results A total of 36 mHSPC (docetaxel), 118 mCRPC (docetaxel) and 38 mCRPC (cabazitaxel) patients were included. NLR3 was significantly associated with 1-year-survival, radiographic and biochemical response in mCRPC (docetaxel) in uni- and multivariable analyses. In mCRPC (docetaxel), positive NLR3s were associated with favourable 1-year-survival. Conclusion This study demonstrated NLR3 as a prognostic marker in men receiving docetaxel for mCRPC. NLR3 might be a clinical tool to reflect the individual’s response to taxane-based chemotherapy. Thereby, NLR3 could complement existing biomarkers and help to early identify treatment failure before complications arise. Further prospective and multicentric studies are needed to extend and confirm the presented results.

Summary: METTL3 is the major writer of N6-Methyladenosine (m6A) and has been associated with controversial roles in cancer. This is best illustrated in urothelial carcinoma of the bladder (UCB), where METTL3 was described to have both oncogenic and tumor-suppressive functions. Here, we reinvestigated the role of METTL3 in UCB. METTL3 knockout reduced the oncogenic phenotype and m6A levels of UCB cell lines. However, complete depletion of METTL3/m6A was not achieved due to selection of cells expressing alternative METTL3 isoforms. Systematic vulnerability and inhibitor response analyses suggested that uroepithelial cells depend on METTL3 for viability. Furthermore, expression and survival analyses of clinical data revealed a complex role for METTL3 in UCB, with decreased m6A mRNA levels in UCB tumors. Our results suggest that METTL3 expression may be a suitable diagnostic UCB biomarker, as the enzyme promotes UCB formation. However, the suitability of the enzyme as a therapeutic target should be evaluated carefully.

Abstract Objective Patient‐centered care and shared decision making (SDM) are generally recognized as the gold standard for medical consultations, especially for preference‐sensitive decisions. However, little is known about psychological patient characteristics that influence patient‐reported preferences. We set out to explore the role of personality and anxiety for a preference‐sensitive decision in bladder cancer patients (choice of urinary diversion, UD) and to determine if anxiety predicts patients' participation preferences. Methods We recruited a sample of bladder cancer patients (N = 180, primarily male, retired) who awaited a medical consultation on radical cystectomy and their choice of UD. We asked patients to fill in a set of self‐report questionnaires before this consultation, including measures of treatment preference, personality (BFI‐10), anxiety (STAI), and participation preference (API and API‐Uro), as well as sociodemographic characteristics. Results Most patients (79%) indicated a clear preference for one of the treatment options (44% continent UD, 34% incontinent UD). Patients who reported more conscientiousness were more likely to prefer more complex methods (continent UD). The majority (62%) preferred to delegate decision making to healthcare professionals. A substantial number of patients reported elevated anxiety (32%), and more anxiety was predictive of higher participation preference, specifically for uro‐oncological decisions (β = 0.207, p

Abstract Small extracellular vesicles (sEV) purified from blood have great potential clinically as biomarkers for systemic disease; however interpretation is complicated by release of sEV ex vivo after blood taking. To quantify the problem and devise ways to minimise it, we characterised sEV in paired serum, plasma and platelet poor plasma (PPP) samples from healthy donors. Immunoblotting showed twofold greater abundance of CD9 in sEV fractions from fresh serum than from fresh plasma or PPP. MACSPlex confirmed this, and showed that proteins expressed on platelet sEV, either exclusively (CD41b, CD42a and CD62P) or more widely (HLA‐ABC, CD24, CD29 and CD31) were also twofold more abundant; by contrast non‐platelet proteins (including CD81) were no different. Storage of plasma (but not serum) increased abundance of platelet and selected leukocyte sEV proteins to at least that of serum, and this could be recapitulated by activating cells in fresh plasma by Ca2+, an effect abrogated in PPP. This suggests that a substantial proportion of sEV in serum and stored plasma were generated ex vivo, which is not the case for fresh plasma or PPP. Thus we provide strategies to minimise ex vivo sEV generation and criteria for identifying those that were present in vivo.

Abstract The most common host entry point of human adapted coronaviruses (CoV) including SARS-CoV-2 is through the initial colonization in the nostril and mouth region which is responsible for spread of the infection. Most recent studies suggest that the commercially available oral and nasal rinse products are effective in inhibiting the viral replication. However, the anti-viral mechanism of the active ingredients present in the oral rinses have not been studied. In the present study, we have assessed in vitro enzymatic inhibitory activity of active ingredients in the oral mouth rinse products: aloin A and B, chlorhexidine, eucalyptol, hexetidine, menthol, triclosan, methyl salicylate, sodium fluoride and povidone, against two important proteases of SARS-CoV-2 PLpro and 3CLpro. Our results indicate only aloin A and B effectively inhibited proteolytic activity of PLpro with an IC50 of 13.16 and 16.08 μM. Interestingly, neither of the aloin isoforms inhibited 3CLpro enzymatic activity. Computational structural modelling of aloin A and B interaction with PLpro revealed that, both aloin isoforms form hydrogen bond with Tyr268 of PLpro, which is critical for their proteolytic activity. Furthermore, 100 ns molecular dynamics (MD) simulation studies predicted that both aloin isoforms have strong interaction with Glu167, which is required for PLpro deubiquitination activity. Our results from the in vitro deubiquitinase inhibition assay show that aloin A and B isomers exhibit deubiquitination inhibitory activity with an IC50 value of 15.68 and 17.51 µM, respectively. In conclusion, the isoforms of aloin inhibit both proteolytic and the deubiquitinating activity of SARS-CoV-2 PLpro, suggesting potential in inhibiting the replication of SARS-CoV-2 virus.

Events profoundly influence human-environment interactions. Through repetition, some events manifest and amplify collective behavioral traits, which significantly affects landscapes and their use, meaning, and value. However, the majority of research on reaction to events focuses on case studies, based on spatial subsets of data. This makes it difficult to put observations into context and to isolate sources of noise or bias found in data. As a result, inclusion of perceived aesthetic values, for example, in cultural ecosystem services, as a means to protect and develop landscapes, remains problematic. In this work, we focus on human behavior worldwide by exploring global reactions to sunset and sunrise using two datasets collected from Instagram and Flickr. By focusing on the consistency and reproducibility of results across these datasets, our goal is to contribute to the development of more robust methods for identifying landscape preference using geo-social media data, while also exploring motivations for photographing these particular events. Based on a four facet context model, reactions to sunset and sunrise are explored for Where, Who, What, and When. We further compare reactions across different groups, with the aim of quantifying differences in behavior and information spread. Our results suggest that a balanced assessment of landscape preference across different regions and datasets is possible, which strengthens representativity and exploring the How and Why in particular event contexts. The process of analysis is fully documented, allowing transparent replication and adoption to other events or datasets.

Virtual Reality (VR) and photogrammetry are emerging technologies that facilitate and shape the ongoing digital transformation of education. VR offers new opportunities for creating immersive and interactive educational experiences. Photogrammetry enables new ways to create lifelike educational virtual environments and is becoming an alternative to manual 3D modeling with graphics software. The manner in which VR affects the authenticity of educational experiences has been addressed in previous educational and psychological research. Empirical papers have so far focused on the authenticity of educational VR environments created by 3D modeling. However, little is known about the authenticity of educational VR environments developed with photogrammetry. Given that VR provides rich multi-sensory experiences and interests can be stimulated by engaging contexts, educational VR environments also possess great potential to support interest development. What is still unknown regarding this topic are the beneficial characteristics of VR environments and the individual variables required to trigger and explain interest development. Consequently, we conducted an experiment following up on the mentioned authenticity and interest research questions in the context of higher education. A two-group between-subjects design was used and N = 64 educational science and psychology university students gathered information about a railroad bridge wearing a head-mounted display (HMD). The control group encountered an educational virtual environment created with 3D modeling. The intervention group was presented with the same educational virtual environment but the main object of the railroad bridge was generated by photogrammetry. Situational interest was measured in the pretest and the posttest; authenticity-related variables (i.e., presence and representation fidelity) were assessed in the posttest. Concerning authenticity, there were no significant group differences. Photogrammetry might thus not affect authenticity in educational contexts in which participants focus on gathering information. Regarding interest development, there were two main findings. First, interest in VR for learning increased from pretest to posttest, supporting that interest can be induced in VR. Second, a large share of posttest interest was explained by presence and pretest interest, highlighting the importance of these variables.

Alopecia areata is a common skin disease which is associated with psychosocial and financial burden. No curative therapy exists and, hence, affected persons resort to self-financed cosmetic solutions. However, studies on the economic impact of alopecia areata on individuals are limited. To estimate annual individual out-of-pocket costs in persons with alopecia areata, a cross-sectional study using a standardized online questionnaire was performed in Germany, Austria and Switzerland. A total of 346 individuals (95.1% women, mean age: 38.5 ± 11.6 years) with alopecia areata participated between April and August 2020. Mean additional spending on everyday necessities was 1,248€ per person per year, which was significantly influenced by the duration of the illness, the treatment provider, and disease severity. Hair replacement products and cosmetics accounted for the highest monthly costs, followed by costs for physician visits, hospital treatments, and medication. Most participants (n = 255, 73.7%) were currently not undergoing treatment, due to lack of efficacy, side-effects, costs and acceptance of the disease. Sex differences in expenses were observed, with women having higher expenditures. Alopecia areata-related out-of-pocket costs place a considerable financial burden on affected individuals, are higher compared with those of other chronic diseases, and should be considered in economic assessments of the impact of this disease.

Abstract Background Simulation-based learning with virtual patients is a highly effective method that could potentially be further enhanced by including reflection phases. The effectiveness of reflection phases for learning to diagnose has mainly been demonstrated for problem-centered instruction with text-based cases, not for simulation-based learning. To close this research gap, we conducted a study on learning history-taking using virtual patients. In this study, we examined the added benefit of including reflection phases on learning to diagnose accurately, the associations between knowledge and learning, and the diagnostic process. Methods A sample of N = 121 medical students completed a three-group experiment with a control group and pre- and posttests. The pretest consisted of a conceptual and strategic knowledge test and virtual patients to be diagnosed. In the learning phase, two intervention groups worked with virtual patients and completed different types of reflection phases, while the control group learned with virtual patients but without reflection phases. The posttest again involved virtual patients. For all virtual patients, diagnostic accuracy was assessed as the primary outcome. Current hypotheses were tracked during reflection phases and in simulation-based learning to measure diagnostic process. Results Regarding the added benefit of reflection phases, an ANCOVA controlling for pretest performance found no difference in diagnostic accuracy at posttest between the three conditions, F(2, 114) = 0.93, p = .398. Concerning knowledge and learning, both pretest conceptual knowledge and strategic knowledge were not associated with learning to diagnose accurately through reflection phases. Learners’ diagnostic process improved during simulation-based learning and the reflection phases. Conclusions Reflection phases did not have an added benefit for learning to diagnose accurately in virtual patients. This finding indicates that reflection phases may not be as effective in simulation-based learning as in problem-centered instruction with text-based cases and can be explained with two contextual differences. First, information processing in simulation-based learning uses the verbal channel and the visual channel, while text-based learning only draws on the verbal channel. Second, in simulation-based learning, serial cue cases are used to gather information step-wise, whereas, in text-based learning, whole cases are used that present all data at once.

Abstract Bladder cancer is one of the top 10 frequently occurring cancers and leads to most cancer deaths worldwide. Recently, blue light (BL) cystoscopy-based photodynamic diagnosis was introduced as a unique technology to enhance the detection of bladder cancer, particularly for the detection of flat and small lesions. Here, we aim to demonstrate a BL image-based artificial intelligence (AI) diagnostic platform using 216 BL images, that were acquired in four different urological departments and pathologically identified with respect to cancer malignancy, invasiveness, and grading. Thereafter, four pre-trained convolution neural networks were utilized to predict image malignancy, invasiveness, and grading. The results indicated that the classification sensitivity and specificity of malignant lesions are 95.77% and 87.84%, while the mean sensitivity and mean specificity of tumor invasiveness are 88% and 96.56%, respectively. This small multicenter clinical study clearly shows the potential of AI based classification of BL images allowing for better treatment decisions and potentially higher detection rates.

Abstract Renal cell carcinoma (RCC) is the deadliest primary genitourinary malignancy typically associated with asymptomatic initial presentation and poorly predictable survival. Next to established risk factors, tumor microenvironment may alter metastatic capacity and immune landscape. Due to their high concentrations, sulfoglycolipids (sulfatides) were among the first well-described antigens in RCC that are associated with worse prognosis. As sulfatide detection in routine diagnostics is not possible, we aimed to test the prognostic value of its protein counterpart, sulfatide-producing enzyme Gal3ST1. We performed retrospective long-term follow up analysis of Gal3ST1 expression as prognostic risk factor in a representative RCC patient cohort. We observed differentially regulated Gal3ST1 expression in all RCC types, being significantly more associated with clear cell RCC than to chromophobe RCC (p = 0.001). Surprisingly, in contrast to published observations from in vitro models, we could not confirm an association between Gal3ST1 expression and a malignant clinical behaviour of the RCC. In our cohort, Gal3ST1 did not significantly influence progression-free survival (Hazard Ratio (HR): 1.7 95% CI (0.6–4.9), p = 0.327). Particularly after adjusting for histology, T-stage, N-status and M-status at baseline, we observed no independent prognostic effect (HR = 1.0 95% CI (0.3–3.3), p = 0.96). The analysis of Gal3ST1 mRNA expression in a TCGA dataset supported the results of our cohort. Thus, Gal3ST1 might help to differentiate between chromophobe RCC and other frequent RCC entities but—despite previously published data from cell culture models—does not qualify as a prognostic marker for RCC. Further investigation of regulatory mechanisms of sulfatide metabolism in human RCC microenvironment is necessary to understand the role of this quantitatively prominent glycosphingolipid in RCC progression.

Here, the authors identify potential drugs that target 3-chymotrypsin like protease (3CLpro), which is a pivotal protease for the replication of SARS-CoV-2. They found that off-target inhibitors such as ivermectin and micafungin inhibit 3CLpro enzyme activity, suggesting that these molecules could constitute useful therapies to inhibit SARS-CoV-2 replication.

Abstract Comprehensive transcriptome expression analyses of bladder cancer revealed distinct lncRNA clusters with differential molecular and clinical characteristics. In this study, pivotal lncRNAs were assessed for their impact on survival and their differential expression between the molecular bladder cancer subtypes. FFPE samples from chemotherapy-naïve patients with muscle invasive bladder cancer (MIBC) were analyzed on the Nanostring nCounter platform for absolute quantification. An established 36-gene panel was used for molecular subtype classification into basal, luminal and infiltrated MIBC. In a second step, 14 pivotal lncRNAs were assessed for their molecular subtype attribution, and their predictive value in disease-specific survival. In silico validation was performed on a total of 487 MIBC patients (MDA, TGCA and Chungbuk cohort). Several pivotal lncRNAs showed a distinct molecular subtype attribution: e.g. MALAT1 showed a downregulation in the basal subtype (p = 0.009), TUG1 and CBR3AS1 showed an upregulation in the luminal subtype (p ≤ 0.001). High transcript levels of SNHG16, CBR3AS1 and H19 appeared to be predictive for a shorter disease-specific survival. Patients overexpressing putative oncogenes MALAT1 and TUG1 in MIBC tissue presented prolonged survival, suggesting tumor suppressive effects of both lncRNAs. The Nanostring nCounter proved to be a valid platform for the quantification of low-abundance transcripts including lncRNAs.

People with visible skin diseases often experience stigmatisation. The aim of this study was to develop and evaluate a new intervention for medical students to counter the stigmatisation of people with skin diseases. The intervention was evaluated using a randomised controlled design. Effectiveness was assessed at 3 time points. Data from 127 participants were analysed. Regarding the outcome “social distance”, a significant difference between the measurement points was observed for the intervention group (χ2(2) = 54.32, p

For clear cell renal cell carcinoma (ccRCC) risk-dependent diagnostic and therapeutic algorithms are routinely implemented in clinical practice. Artificial intelligence-based image analysis has the potential to improve outcome prediction and thereby risk stratification. Thus, we investigated whether a convolutional neural network (CNN) can extract relevant image features from a representative hematoxylin and eosin-stained slide to predict 5-year overall survival (5y-OS) in ccRCC. The CNN was trained to predict 5y-OS in a binary manner using slides from TCGA and validated using an independent in-house cohort. Multivariable logistic regression was used to combine of the CNNs prediction and clinicopathological parameters. A mean balanced accuracy of 72.0% (standard deviation [SD] = 7.9%), sensitivity of 72.4% (SD = 10.6%), specificity of 71.7% (SD = 11.9%) and area under receiver operating characteristics curve (AUROC) of 0.75 (SD = 0.07) was achieved on the TCGA training set (n = 254 patients / WSIs) using 10-fold cross-validation. On the external validation cohort (n = 99 patients / WSIs), mean accuracy, sensitivity, specificity and AUROC were 65.5% (95%-confidence interval [CI]: 62.9-68.1%), 86.2% (95%-CI: 81.8-90.5%), 44.9% (95%-CI: 40.2-49.6%), and 0.70 (95%-CI: 0.69-0.71). A multivariable model including age, tumor stage and metastasis yielded an AUROC of 0.75 on the TCGA cohort. The inclusion of the CNN-based classification (Odds ratio = 4.86, 95%-CI: 2.70-8.75, p < 0.01) raised the AUROC to 0.81. On the validation cohort, both models showed an AUROC of 0.88. In univariable Cox regression, the CNN showed a hazard ratio of 3.69 (95%-CI: 2.60-5.23, p < 0.01) on TCGA and 2.13 (95%-CI: 0.92-4.94, p = 0.08) on external validation. The results demonstrate that the CNN's image-based prediction of survival is promising and thus this widely applicable technique should be further investigated with the aim of improving existing risk stratification in ccRCC.

To date, only a single transcriptome-wide m6A sequencing study of clear cell renal cell carcinoma (ccRCC) has been reported, with no validation so far. Herein, by TCGA analysis of the KIRC cohort (n = 530 ccRCC; n = 72 normal), an external expression validation of 35 preidentified m6A targets was performed. Further in-depth expression stratification enabled assessment of m6A-driven key targets. Overall survival (OS) analysis and gene set enrichment analyses (GSEA) were conducted to assess their clinical and functional impact on ccRCC. In the hyper-up cluster significant upregulation was confirmed for NDUFA4L2, NXPH4, SAA1, and PLOD2 (40%) and in the hypo-up cluster for FCHSD1 (10%). Significant downregulation was observed for UMOD, ANK3, and CNTFR (27.3%) in the hypo-down cluster and for CHDH (25%) in the hyper-down cluster. In-depth expression stratification showed consistent dysregulation in ccRCC only for 11.67%: NDUFA4L2, NXPH4, and UMOD (NNU-panel). Patients with strong NNU panel dysregulation had significantly poorer OS (p = 0.0075). GSEA identified 13 associated and significantly upregulated gene sets (all p-values < 0.5; FDR < 0.25). External validation of the only available m6A sequencing in ccRCC consistently reduced dysregulated m6A-driven targets on the NNU panel with highly significant effects on OS. Epitranscriptomics are a promising target for developing novel therapies and for identifying prognostic markers for daily clinical practice.

Abstract is missing (Short communication)

The globally increasing prevalence of chronic inflammatory skin diseases has substantial costs. Biologicals have become available as therapeutic options, but are encumbered with barriers to prescription. The aim of this study was to evaluate the barriers to prescription of biologicals in the treatment of chronic dermatological diseases. Dermatologists working in private practices in the German federal states of Bavaria and Lower Saxony participated in a cross-sectional study. Economic and legal aspects, including “high therapy costs”, “low reimbursements”, and “fear of regress claims”, were identified as the most prevalent barriers. Significant differences between dermatologists from Bavaria and Lower Saxony were found only regarding the treatment of atopic dermatitis. This study demonstrates the prevalence of barriers to the prescription of biologicals in the treatment of chronic dermatological diseases. Overcoming these barriers could improve the usage of modern therapies and thereby expand patient-centred care for chronic skin diseases.

BackgroundTo compare severe infectious complication rates after transrectal prostate biopsies between cephalosporins and fluoroquinolones for antibiotic monoprophylaxis.Material and MethodsIn the multi-institutional cohort, between November 2014 and July 2020 patients received either cefotaxime (single dose intravenously), cefpodoxime (multiple doses orally) or fluoroquinolones (multiple-doses orally or single dose intravenously) for transrectal prostate biopsy prophylaxis. Data were prospectively acquired and retrospectively analyzed. Severe infectious complications were evaluated within 30 days after biopsy. Logistic regression models predicted biopsy-related infectious complications according to antibiotic prophylaxis, application type and patient- and procedure-related risk factors.ResultsOf 793 patients, 132 (16.6%) received a single dose of intravenous cefotaxime and were compared to 119 (15%) who received multiple doses of oral cefpodoxime and 542 (68.3%) who received fluoroquinolones as monoprophylaxis. The overall incidence of severe infectious complications was 1.0% (n=8). No significant differences were observed between the three compared groups (0.8% vs. 0.8% vs. 1.1%, p=0.9). The overall rate of urosepsis was 0.3% and did not significantly differ between the three compared groups as well.ConclusionMonoprophylaxis with third generation cephalosporins was efficient in preventing severe infectious complications after prostate biopsy. Single intravenous dose of cefotaxime and multiday regimen of oral cefpodoxime showed a low incidence of infectious complications

Various autoantibodies are detected more frequently in HIV-infected individuals than in HIV-negative controls; however, limited data exist regarding autoimmune blistering skin diseases. Using enzyme-linked immunoassay (ELISA) and indirect immunofluore­scence, no difference in the frequency and magnitude of autoantibodies against BP180, BP230, desmoglein 1 and 3 was found between 594 HIV-infected patients and 248 uninfected controls in this cross-sectional study (16.0% vs. 11.7%, respectively, for at least one positive ELISA, p = 0.11). Interestingly, reactive syphilis serology in both HIV-infected individuals and uninfected controls was associated with positive anti-BP180 ELISA results (adjusted odds ratio (OR) 2.14, 95% confidence interval (CI) 1.07–4.29, p = 0.03 and OR 4.70, CI 1.3–16.86; p = 0.0180). Our study shows a comparably low prevalence of cutaneous autoantibodies in both HIV-infected patients and uninfected controls lacking signs of autoimmune blistering skin disease. Positive BP180 ELISA in the absence of clinical signs of bullous pemphigoid should prompt further evaluation for syphilis antibodies.

Skin cancer is a major public health issue, which could be reduced through prevention programmes. How­ever, prevention utilization is not very prevalent. It is therefore important to understand individuals’ interest in skin cancer. Google AdWords Keyword Planner was used to identify the search volume of terms relating to skin cancer in 9 German cities between July 2014 and June 2018. From a total of 1,203 identified keywords, 1,047 search terms were related to skin cancer, which had a search volume of 3,460,980 queries for the study period. Most terms referred to “identifying skin cancer”. For melanoma, the number of Google searches per 100,000 inhabitants correlated with the cancer registry data for melanoma incidence rates (men: r = 0.810, women: r = 0.569). Assessment of this data for the different cities further enabled identification of regional variations, which could help to identify areas with a high need for targeted prevention campaigns.

Introduction: From the workplace engineering sciences, it is evident that work efficiency, measured by the criteria efficiency and effectiveness of therapy, economy and patient safety, is determined mainly by staff acceptance of new technology and reengineered workflows. Accordingly, the aim of this study was to ascertain and assess differences in terms of the acceptance of alternative types of prosthesis instrument configurations, oriented around the research question: “Which product features and process effects determine a high level of employee acceptance of use?”Materials and Methods: This study is designed as a before-and-after comparison, based on the usability engineering approach. In the first study phase, 46 employees participating in the process of providing instruments for a total knee arthroplasty (TKA) procedure were asked to examine the current working situation, using a standard instrumentation set, in terms of instrument handling, work burden, proneness to errors, patient risks, process efficiency, and effectiveness. In the second study phase, 20 weeks after having implemented a size-specific instrumentation set, the same 46 individuals were surveyed on the identical questions. Additionally, in both study phases the time needed to perform the sub-processes related to instrumentation logistics inside the operating room (OR) was measured, in order to identify process efficiency and cost-saving effects.Results: By using standard sets only 30% perceived a need for improvement. After 20 weeks, only 8% of the employees were satisfied with the previous equipment and 69% regarded the standard set as being relatively error-prone, endangering patient safety. In addition, 85% regarded the effectiveness of the standard process as limited. Finally, 75% considered the effectiveness of the reengineered process to be significantly higher, and 69% drew attention to the reduction of handling disadvantages. Furthermore, the time needed for instrumentation logistics inside the OR estimated at about 13 min less when using size-specific sets. This effect on process efficiency cost savings or the generation of additional revenue by performing additional procedures. Based on these findings, an ergonomic decision-making model has been developed.Conclusion: Innovative medical products such as size-specific instrumentation sets contribute to lower procedure costs and improved process efficiency in the operating room (OR). However, employee motivation to use a new technology as part of an optimized workflow organization, is crucial to achieving an enhanced level of effectiveness, efficiency and patient safety. Hence, it is advisable to enhance change-management efforts in order to reduce resistance to change and ensure the new technology is successful.

Recent advances in mass spectrometry (MS)‐based technologies are now set to transform translational cancer proteomics from an idea to a practice. Here, we present a robust proteomic workflow for the analysis of clinically relevant human cancer tissues that allows quantitation of thousands of tumor proteins in several hours of measuring time and a total turnaround of a few days. We applied it to a chemorefractory metastatic case of the extremely rare urachal carcinoma. Quantitative comparison of lung metastases and surrounding tissue revealed several significantly upregulated proteins, among them lysine‐specific histone demethylase 1 (LSD1/KDM1A). LSD1 is an epigenetic regulator and the target of active development efforts in oncology. Thus, clinical cancer proteomics can rapidly and efficiently identify actionable therapeutic options. While currently described for a single case study, we envision that it can be applied broadly to other patients in a similar condition.

In recent years, there has been a rapid rise in the development of engineered bamboo materials, which have the potential to play an important role as alternatives to conventional building materials. Despite the growing diversity of bamboo products available on the market, the international standardization of both bamboo products and their constituent elements is limited, and a lack of universal nomenclature is recognized as one of the main constraints on developing standards. Similar or identical terminology is used interchangeably to describe different bamboo elements, processes, or products across sectors and continents. In some cases, translated colloquial names are misleading and scientifically inaccurate, which forms a barrier to global collaboration and research, creates ambiguity, and potentially limits trade. The present work aims to address this gap by proposing a set of appropriate terms in English that accurately describe and differentiate between currently produced engineered bamboo products and their constituent elements, accompanied by parallel terms in Chinese and Spanish. From these, new categories of engineered bamboo building materials are proposed for the Harmonized System of product codes. This paper highlights current ambiguities and provides terminology together with clear definitions of the main primary elements, processing steps, and products.

Validation of musculoskeletal models for application in preoperative planning is still a challenging task. Ideally, the simulation results of a patient-specific musculoskeletal model are compared to corresponding in vivo measurements. Currently, the only possibility to measure in vivo joint forces is to implant an instrumented prosthesis in patients undergoing a total joint replacement. In this study, a musculoskeletal model of the AnyBody Modeling System was adapted patient-specifically and validated against the in vivo hip joint force measurements of ten subjects performing one-leg stance and level walking. The impact of four model parameters was evaluated; hip joint width, muscle strength, muscle recruitment, and type of muscle model. The smallest difference between simulated and in vivo hip joint force was achieved by using the hip joint width measured in computed tomography images, a muscle strength of 90 N/cm2, a third order polynomial muscle recruitment, and a simple muscle model. This parameter combination reached mean deviations between simulation and in vivo measurement during the peak force phase of 12% ± 14% in magnitude and 11° ± 5° in orientation for one-leg stance and 8% ± 6% in magnitude and 10° ± 5° in orientation for level walking.