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Background: The development of a medical device requires strict adherence to regulatory processes. Prehabilitation in this context is a new area in surgery that trains, coaches, and advises patients in mental well-being, nutrition, and physical activity. As staff is permanently drained from clinical care, remote and digital solutions with real-time assessments of data, including patient-related outcome reporting, may simplify preparation before major surgeries., Objective: This study aimed to evaluate the usability engineering process for the Prehab App, a newly developed medical device, in order to identify and adapt any design and usability flaws found., Methods: We hypothesized that formative and summative usability testing would achieve 80% interrater and intrarater reliability and consistency and that the safety-relevant scenarios would uncover undetected risks of the medical device (stand-alone software class IIa). In total, 8 experts and 8 laypersons (patients and potential patients) were asked to evaluate paper-based mockups, followed by an evaluation of the minimal viable product (MVP) of the Prehab App at least more than 8 weeks later after instruction and training. The experts had to face 5 and the laypersons 6 usability scenarios. Their evaluations were measured with the Mobile App Rating Scale (MARS) and trustworthiness checklists (range 0-64, with higher scores indicating trustworthiness), and the usability scenarios were evaluated with the After Scenario Questionnaire (ASQ) and a judgment by an observer. The time taken for the scenarios was also recorded., Results: MARS achieved constant scores of more than 4 out of 5 points for both experts and laypersons. The mean trustworthiness score was 51.3 (SD 2.7) for the experts and 50.8 (SD 2.1) for the laypersons (P=.68) in task I. The interrater correlation, shown by the Fleiss-Kappa value, was 0.87 (range 0.85-0.89) for all raters (N=16), 0.86 (range 0.82-0.91) for the experts (n=8, 50%), and 0.88 (range 0.84-0.93) for the laypersons (n=8, 50%), reflecting almost perfect agreement between the raters. This indicated the high quality of the usability. The usability scenarios were performed with ease, except for the onboarding part, when the wearable was required to be connected; this took a considerable amount of time and was recognized as a challenge to good usability., Conclusions: The formative and summative evaluation of the Prehab App design resulted in good-to-acceptable results of the design and usability of the critical and safety-relevant areas of the medical device and stand-alone software. Usability testing improves medical devices early in the design and development process, reduces errors, and mitigates risks, and in this study, it delivered a profound ethical and medical justification for a randomized controlled trial (RCT) of the Prehab App in a remote setting as a next step in the development process., Trial Registration: German Registry for Clinical Trials (DRKS00026985); https://drks.de/search/en/trial/DRKS00026985., (©Andreas A Schnitzbauer, Charlotte Detemble, Sara Fatima Faqar-Uz-Zaman, Julia Dreilich, Lisa Mohr, Svenja Sliwinski, Dora Zmuc, Mark Siller, Johannes Fleckenstein. Originally published in JMIR Formative Research (https://formative.jmir.org), 11.12.2024.)

Background: Research indicates a high prevalence of depressive disorders in individuals with autism spectrums disorders (ASD), highlighting a need for depression screening in this population. Both depression screening tools used in the general population and tools developed specifically for individuals with ASD are used in the ASD population. Because depressive symptoms may manifest differently in individuals with ASD, it is important to establish the psychometric properties of depression instruments in individuals with ASD to determine whether and how these instruments can be applied in assessing these individuals., Objective: Our objective was to synthesize knowledge regarding the psychometric properties of (a) depression instruments developed for the general populations and (b) depression instruments developed specifically for individuals with ASD., Methods: A scoping review was conducted using Covidence to identify, screen, and review available literature on the use and psychometric properties of generalized and ASD-specific depression instruments in individuals with ASD., Results: Results for both generalized and ASD-specific instruments indicated moderate psychometric strength, enough for these instruments to be potentially helpful in psychiatric assessments but not enough to be conclusive on their own. The data are limited by the small number of studies examining this population, that is, only 1 to 3 articles for each instrument, and the often-limited number of psychometric measurements taken in each study., Conclusions: As the prevalence of depression in individuals with ASD is high, reliable and valid measures are needed. Current research shows some support for existing instruments, although additional, more robust research is needed., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Online home exercises represent opportunities to increase physical activity levels. However, high dropout rates are commonly reported in such programmes. This study aimed to investigate the predictors of dropping out from an online home exercise programme., Methods: A total of 760 individuals from nine countries participated in this 8-week prospective cohort study derived from a randomised controlled trial. The participants were randomised into "4-week live-streamed exercise ->4-week recorded exercise" or "4-week no intervention ->4-week recorded exercise" group. Repeated measurements using weekly questionnaires were performed. Pain intensity, disability, mental well-being score, exercise motivation, sleep quality, impulsiveness/anxiety, and physical activity level were analysed., Results: A total of 53.8% (95% confidence interval [CI] 50.3%-57.3%) participants dropped out from the programme. The identified predictors of dropping out from the programme were: well-being (odds ratio [OR] 0.94, 95% CI 0.91-0.97) and disability (OR 1.02, 95% CI 1.002-1.04) at baseline considering the first 4 weeks; age (0.98; 95% CI 0.96-1.00) and baseline well-being (0.93; 95% CI 0.89-0.97) considering the entire follow-up (8 weeks); exercise motivation (0.92; 95% CI 0.87 to 0.97) and general impulsiveness/anxiety (1.04; 95% CI 1.01-1.07) repeated measured over time., Conclusion: About half of the participants dropped out from the online home exercise programme. Higher baseline scores in mental well-being and age predicted a reduction in dropping out. Higher baseline disability predicted an increase in dropping out. During the follow-up, higher exercise motivation was associated with a reduction in dropping out, and higher impulsiveness and anxiety were associated with an increase in dropping out., Competing Interests: The authors declare that they have no conflict of interest of any nature regarding this study., (©2024 The Author(s).)

Chromosomal instability is a hallmark of human cancer that is associated with aggressive disease characteristics. Chromosome mis-segregations help fuel natural selection, but they risk provoking a cGAS-STING immune response through the accumulation of cytosolic DNA. The mechanisms of how tumors benefit from chromosomal instability while mitigating associated risks, such as enhanced immune surveillance, are poorly understood. Here, we identify cGAS-STING-dependent upregulation of the nuclease TREX1 as an adaptive, negative feedback mechanism that promotes immune evasion through digestion of cytosolic DNA. TREX1 loss diminishes tumor growth, prolongs survival of host animals, increases tumor immune infiltration, and potentiates response to immune checkpoint blockade selectively in tumors capable of mounting a type I IFN response downstream of STING. Together, these data demonstrate that TREX1 induction shields chromosomally unstable tumors from immune surveillance by dampening type I IFN production and suggest that TREX1 inhibitors might be used to selectively target tumors that have retained the inherent ability to mount an IFN response downstream of STING. See related article by Lim et al., p. 663., (©2024 The Authors; Published by the American Association for Cancer Research.)

Background: A structured risk assessment of patients with validated and evidence-based tools can help to identify modifiable factors before major surgeries. The Protego Maxima trial investigated the value of a new digitized risk assessment tool that combines tools which can be easily used and implemented in the clinical workflow by doctors and qualified medical staff. The hypothesis was that the structured assessment and risk-grouping is predictive of short-term surgical quality reflected by complications and overall survival., Methods: The Protego Maxima Trial was a prospective cohort analysis of patients undergoing major surgery (visceral, thoracic, urology, vascular and gynecologic surgeries) as key inclusion criterion and the absence of an acute or acute on chronically decompensated pulmo-cardiovascular decompensation. Patients were risk-scored with the software (The Prehab App) that includes a battery of evidence-based risk assessment tools that allow a structured risk assessment. The data were grouped to predefined high and low risk groups and aggregate and individual scores. The primary outcome was to validate the predictive value of the RAI score and the TUG for overall survival in the high and low risk groups. Secondary outcomes were surgical outcomes at 90-days after surgery (overall survival, Clavien-Dindo (CD) 1-5 (all complications), and CD 3-5 (major complications)). The study was carried out in accordance with the DIN ISO 14,155, and the medical device regulation (MDR) at Frankfurt University Hospital between March 2022 and January 2023., Results: In total 267 patients were included in the intention to treat analysis. The mean age was 62.1 ± 12.4 years. Patients with a RAI score > 25 and/or a timed up and go (TUG) > 8 s had a higher risk for mortality at 90 days after surgery. The low-risk group predicted beneficial outcome and the high-risk group predicted adverse outcome in the ROC analysis (Area Under the Curve Receiver Operator Characteristics: AUROC > 0.800; p = 0.01). Risk groups (high vs. low) showed significant differences for 90-day survival (99.4% vs. 95.5%; p = 0.04) and major complications (16.4% vs. 32.4%; p < 0.001)., Conclusion: The proof-of-concept trial showed that a risk assessment with 'The Prehab App' may be viable to estimate the preoperative risk for mortality and major complications before major surgeries. The overall performance in this initial set of data indicated a certain reliability of the scoring and risk grouping, especially of the RAI score and the TUG. A larger data set will be required to proof the generalizability of the risk scoring to every subgroup and may be fostered by artificial intelligence approaches., Trial Registration: Ethics number: 2021-483-MDR/MPDG-zuständig monocentric; The Federal Institute for Pharmaceuticals and Medical Devices/BfArM, reference number: 94.1.04-5660-13655; Eudamed: CIV-21-07-0307311; German Clinical Trial Registry: DRKS 00026985., (© 2024. The Author(s).)

Background: Depressive disorders are frequently mis- and underdiagnosed in individuals with autism spectrum disorders (ASD)., Objective: Our objective was to identify and synthesize current knowledge regarding (1) the presentation of depressive symptoms and (2) the use of self-reports in assessing depressive symptoms in individuals with ASD and comparisons between self-reported and observer-reported symptoms. A scoping review was conducted to capture the full range of literature on the topic and to identify research gaps., Methods: Articles were identified through a search of academic literature and screened for relevance to the aims of the review., Results: In addition to typical depression symptoms, individuals with ASD may demonstrate atypical symptoms such as changes in autistic symptoms, self-injurious behavior, and psychomotor changes. Moreover, the review revealed a bias toward observer-reports of symptoms. Self-reports frequently were not included or were ascribed less weight than observer-reports. Self-reports typically differed from reports given by parents or other caregivers, but a consistent pattern in these differences has not been established., Conclusions: Further research on the use of self-reports in assessing depressive symptoms in individuals with ASD is needed. Self-reports may provide information not obtainable through observer-reports, and integrating both self- and observer-reports in psychiatric evaluations may produce more comprehensive and accurate assessments.

Background and Objectives: Extracorporeal photopheresis (ECP) is a widespread cellular therapy for graft-versus-host disease, autoimmune diseases and Sézary disease. One of the main effects of ECP is the apoptosis of leukocytes, but the therapeutic mechanisms are not completely known. The aim of this study was to investigate the effects on red blood cells, platelets and the induction of reactive oxygen species., Materials and Methods: We used human cells from healthy blood donors to simulate in vitro the composition in an apheresis bag. Cells were treated with 8-methoxypsoralen (8-MOP) and UVA. Red blood cell stability, platelet activity and induction of reactive oxygen species were analysed., Results: After 8-MOP and UVA treatment, the red blood cells showed high cell integrity with low levels of eryptosis and no increase of free haemoglobin or red blood cell distribution width (RDW). Red blood cell immune-associated antigens CD59 and CD147 were hardly affected by the treatment. Platelet glycoproteins CD41, CD62P and CD63 indicated strong platelet activation after 8-MOP and UVA treatment. Reactive oxygen species were slightly but not significantly induced by the treatment., Conclusion: The effect of the ECP therapy is probably not exclusively mediated by leukocytes. Platelet activation is another striking effect caused by the treatment of the apheresis product with 8-MOP/UVA. However, since we could hardly identify any evidence for eryptosis or haemolysis, it is unlikely that red blood cell eryptosis is part of the therapeutic mechanism. Further research on this topic seems to be promising., (© 2023 The Authors. Vox Sanguinis published by John Wiley & Sons Ltd on behalf of International Society of Blood Transfusion.)

Prehabilitation is a multimodal concept to improve functional capability prior to surgery, so that the patients' resilience is strengthened to withstand any peri- and postoperative comorbidity. It covers physical activities, nutrition, and psychosocial wellbeing. The literature is heterogeneous in outcomes and definitions. In this scoping review, class 1 and 2 evidence was included to identify seven main aspects of prehabilitation for the treatment pathway: (i) risk assessment, (ii) FITT (frequency, interventions, time, type of exercise) principles of prehabilitation exercise, (iii) outcome measures, (iv) nutrition, (v) patient blood management, (vi) mental wellbeing, and (vii) economic potential. Recommendations include the risk of tumor progression due to delay of surgery. Patients undergoing prehabilitation should perceive risk assessment by structured, quantifiable, and validated tools like Risk Analysis Index, Charlson Comorbidity Index (CCI), American Society of Anesthesiology Score, or Eastern Co-operative Oncology Group scoring. Assessments should be repeated to quantify its effects. The most common types of exercise include breathing exercises and moderate- to high-intensity interval protocols. The program should have a duration of 3-6 weeks with 3-4 exercises per week that take 30-60 min. The 6-Minute Walking Testing is a valid and resource-saving tool to assess changes in aerobic capacity. Long-term assessment should include standardized outcome measurements (overall survival, 90-day survival, Dindo-Clavien/CCI®) to monitor the potential of up to 50% less morbidity. Finally, individual cost-revenue assessment can help assess health economics, confirming the hypothetic saving of $8 for treatment for $1 spent for prehabilitation. These recommendations should serve as a toolbox to generate hypotheses, discussion, and systematic approaches to develop clinical prehabilitation standards., Competing Interests: AAS, CD and DZ have founded a company for the development of an app-based prehabilitation program. They did not receive any specific funding for this review. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer RROS declared a shared affiliation with the author KB to the handling editor at the time of review., (© 2023 Sliwinski, Werneburg, Faqar-Uz-Zaman, Detemble, Dreilich, Mohr, Zmuc, Beyer, Bechstein, Herrle, Malkomes, Reissfelder, Ritz, Vilz, Fleckenstein and Schnitzbauer.)

The urinary albumin- and protein-to-creatinine ratios (UACR and UPCR, respectively) are key endpoints in most clinical trials assessing risk of progression of chronic kidney disease (CKD). For the first time, the current study compares the UACR versus the UPCR head-to-head at early stages of CKD, taking use of the hereditary podocytopathy Alport syndrome (AS) as a model disease for any CKD. Urine samples originated from the prospective randomized, controlled EARLY PRO-TECT Alport trial (NCT01485978). Urine samples from 47 children with confirmed diagnoses of AS at very early stages of CKD were divided according to the current stage of AS: stage 0 (UACR < 30 mg/g), stage 1 (30-300 mg/g) or stage 2 (>300 mg/g). The range of estimated glomerular filtration rate was 75-187.6 mL/min. The mean age was 10.4 ± 4.5 years. In children at stage 0, proteinuria in spot urine, confirmed in 24 h urine, was almost ten times higher than albuminuria (106.4 ± 42.2 vs. 12.5 ± 9.7; p < 0.05); it was "only" about three times higher in stage 1 (328.5 ± 210.1 vs. 132.3 ± 80.5; p < 0.05) and almost equal in stage 2 (1481.9 ± 983.4 vs. 1109.7 ± 873.6; p = 0.36). In 17 children, UACRs and UPCRs were measured simultaneously in 24 h urine and spot urine in the same study visit. Interestingly, the UACR (and UPCR) in 24 h urine vs. in spot urine varied by less than 10% (266.8 ± 426.4 vs. 291.2 ± 530.2). In conclusion, our study provides the first evidence that in patients with normal glomerular filtration rate (GFR) and low amounts of albuminuria, especially in children with podocytopathies such as AS, measuring the UACR and UPCR in spot urine is a reliable and convenient alternative to 24 h urine collection. Our study advocates both the UACR and the UPCR as relevant diagnostic biomarkers in future clinical trials in children with glomerular diseases because the UPCR seems to be a very significant parameter at very early stages of podocytopathies. The German Federal Ministry of Education and Research funded this trial (01KG1104).

Introduction: Major surgery is associated with a high risk for postoperative complications, leading to an increase in mortality and morbidity, particularly in frail patients with a reduced cardiopulmonary reserve. Prehabilitation, including aerobic exercise training, aims to improve patients' physical fitness before major surgery and reduce postoperative complications, length of hospital stay and costs. The purpose of the study is to assess the usability, validity and safety of an app-based endurance exercise software in accordance with the Medical Device Regulation using wrist-worn wearables to measure heart rate (HR) and distance., Methods and Analysis: The PROTEGO MAXIMA trial is a prospective, interventional study with patients undergoing major elective surgery, comprising three tasks. Tasks I and II aim to assess the usability of the app, using evaluation questionnaires and usability scenarios. In Task IIIa, patients will undergo a structured risk assessment by the Patronus App, which will be correlated with the occurrence of postoperative complications after 90 days (non-interventional). In Task IIIb, healthy students and patients will perform a supervised 6 min walking test and a 37 min interval training on a treadmill based on HR reserve, wearing standard ECG limb leads and two smartwatches, which will be driven by the test software. The aim of this task is to assess the accuracy of HR measurement by the wearables and the safety, using specific alarm settings of the devices and lab testing of the participants (interventional)., Ethics and Dissemination: Ethical approval was granted by the Institutional Review Board of the University Hospital of Frankfurt and by the Federal Institute for Pharmaceuticals and Medical Products (BfArM, reference number 94.1.04-5660-13655) on 7 February 2022. The results from this study will be submitted to peer-reviewed journals and reported at suitable national and international meetings., Trial Registration Numbers: European Database on Medical Devices (CIV-21-07-037311) and German Clinical Trial Registry (DRKS00026985)., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

A recent in-vivo experiment has shown that force can be transmitted between the gastrocnemius and the hamstring muscles due to a direct tissue continuity. However, it remains unclear if this mechanical interaction is affected by the stiffness of the structural connection. This study therefore aimed to investigate the impact of the knee angle on myofascial force transmission across the dorsal knee. A randomized, cross-over study was performed, including n = 56 healthy participants (25.36 ± 3.9 years, 25 females). On two separate days, they adopted a prone position on an isokinetic dynamometer (knee extended or 60° flexed). In each condition, the device moved the ankle three times from maximal plantarflexion to maximal dorsal extension. Muscle inactivity was ensured using EMG. High-resolution ultrasound videos of the semimembranosus (SM) and the gastrocnemius medialis (GM) soft tissue were recorded. Maximal horizontal tissue displacement, obtained using cross-correlation, was examined as a surrogate of force transmission. SM tissue displacement was higher at extended (4.83 ± 2.04 mm) than at flexed knees (3.81 ± 2.36 mm). Linear regression demonstrated significant associations between (1) SM and GM soft tissue displacement (extended: R 2  = 0.18, p = 0.001; flexed: R 2  = 0.17, p = 0.002) as well as (2) SM soft tissue displacement and ankle range of motion (extended: R 2  = 0.103, p = 0.017; flexed: R 2  = 0.095, p = 0.022). Our results further strengthen the evidence that local stretching induces a force transmission to neighboring muscles. Resulting remote exercise effects such as increased range of motion, seem to depend on the stiffness of the continuity.Trial registration: DRKS (Deutsches Register Klinischer Studien), registration number DRKS00024420, first registered 08/02/2021, https://drks.de/search/de/trial/DRKS00024420 ., (© 2023. The Author(s).)

Background: Connective tissue links the skeletal muscles, creating a body-wide network of continuity. A recent in-vivo experiment demonstrated that passive elongation of the calf caused a caudal displacement of the semimembranosus muscle, indicating force transmission across the dorsal knee joint. However, it remains unclear as to whether this observation is dependent on the joint angle. If force would not be transmitted at flexed knees, this would reduce the number of postures and movements where force transmission is of relevance. Our trial, therefore, aims to investigate the influence of passive calf stretching with the knee in extended and flexed position on dorsal thigh soft tissue displacement., Methods: Participants are positioned prone on an isokinetic dynamometer. The device performs three repetitions of moving the ankle passively (5°/s) between plantar flexion and maximum dorsiflexion. With a washout-period of 24 hours, this procedure is performed twice in randomised order, once with the knee extended (0°) and once with the knee flexed (60°). Two high-resolution ultrasound devices will be used to visualize the soft tissue of the calf and dorsal thigh during the manoeuvre. Maximal horizontal displacement of the soft tissue [mm] during ankle movement will be quantified as a surrogate of force transmission, using a frame-by-frame cross-correlation analysis of the obtained US videos., Discussion: Understanding myofascial force transmission under in-vivo conditions is a pre-requisite for the development of exercise interventions specifically targeting the fascial connective tissue. Our study may thus provide health and fitness professional with the anatomical and functional basis for program design., Trial Registration: The study is registered at the German Clinical Trials Register (TRN: DRKS00024420), registered 8 Februar 2021, https://www.drks.de/drks&#95;web/navigate.do?navigationId=trial.HTML&TRIAL&#95;ID=DRKS00024420., Competing Interests: The authors have declared that no competing interests exist.

Objective: To explore the association of physical activity (PA) with musculoskeletal pain (MSK pain)., Design: Cross-sectional study SETTING: 14 countries (Argentina, Australia, Austria, Brazil, Chile, France, Germany, Italy, the Netherlands, Singapore, South Africa, Spain, Switzerland and the USA)., Participants: Individuals aged 18 or older., Primary and Secondary Outcome Measures: PA volumes were assessed with an adapted version of the Nordic Physical Activity Questionnaire-short. Prevalence of MSK pain was captured by means of a 20-item checklist of body locations. Based on the WHO recommendation on PA, participants were classified as non-compliers (0-150 min/week), compliers (150-300 min/week), double compliers (300-450 min/week), triple compliers (450-600 min/week), quadruple compliers (600-750 min/week), quintuple compliers (750-900 min/week) and top compliers (more than 900 min/week). Multivariate logistic regression was used to obtain adjusted ORs of the association between PA and MSK pain for each body location, correcting for age, sex, employment status and depression risk., Results: A total of 13 741 participants completed the survey. Compared with non-compliers, compliers had smaller odds of MSK pain in one location (thoracic pain, OR 0.77, 95% CI 0.64 to 0.93). Double compliance was associated with reduced pain occurrence in six locations (elbow, OR 0.70, 95% CI 0.50 to 0.98; forearm, OR 0.63, 95% CI 0.40 to 0.99; wrist, OR 0.74, 95% CI 0.57 to 0.98; hand, OR 0.57, 95% CI 0.40 to 0.79; fingers, OR 0.72, 95% CI 0.52 to 0.99; abdomen, OR 0.61, 95% CI 0.41 to 0.91). Triple to top compliance was also linked with lower odds of MSK pain (five locations in triple compliance, three in quadruple compliance, two in quintuple compliance, three in top compliance), but, at the same time, presented increased odds of MSK pain in some of the other locations., Conclusion: A dose of 300-450 min WHO-equivalent PA/week was associated with lower odds of MSK pain in six body locations. On the other hand, excessive doses of PA were associated with higher odds of pain in certain body locations., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Prediabetes impacts 88 million U.S. adults, yet uptake of evidence-based treatment with intensive lifestyle interventions and metformin remains exceedingly low. After incorporating feedback from 15 primary care providers collected during semi-structured interviews, we developed a novel Prediabetes Clinical Decision Support (PreDM CDS) from August 2019 to February 2020. This tool included order options enabling prediabetes management in a single location within the electronic health record. We conducted a retrospective observational study examining the feasibility of implementing this tool at Erie Family Health Centers, a large community health center, examining its use and related outcomes among patients for whom it was used vs not. Overall, 7,424 eligible patients were seen during the implementation period (February 2020 to August 2021), and the PreDM CDS was used for 108 (1.5 %). Using the PreDM CDS was associated with higher rates of hemoglobin A1c orders (70.4 % vs 22.2 %; p < 0.001), lifestyle counseling (38.0 % vs 7.8 %; p < 0.001), and metformin prescription orders (5.6 % vs 2.6 %; p = 0.06). Exploratory analyses revealed small, nonsignificant weight loss among patients for whom the PreDM CDS was used. This study demonstrates the feasibility of developing and implementing the PreDM CDS in primary care. Its low use was likely related to not imposing an interruptive 'pop-up' alert, as well as major changes in workflows and clinical priorities during the Covid-19 pandemic. Use of the tool was associated with improved process outcomes. Future efforts with the PreDM CDS should follow standard CDS implementation processes that were not possible due to the Covid-19 pandemic., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 The Author(s).)

Recent investigations suggested pigeon associated Rotavirus Typ A genotype G18P[17] (RVA) as a causative agent of the classical 'young pigeon disease' (YPD). YPD was first described in the late 1980 s as an acute, mainly seasonally recurring disorder of mostly juvenile domestic pigeons (Columba livia) with clinical signs such as anorexia, dairrhea, vomiting, congested crops, weight loss and occasionally mortality. Various studies in the past indicated a multifactorial nature of YPD. Several pathogens, such as pigeon circovirus 1, avian adenoviruses and Escherichia coli were also suggested, but none of these could reproduce the disease experimentally. However, the impact of other pathogens on the clinical development of YPD cannot be excluded and requires further investigation. This present review summarizes available information on RVA-induced disease in pigeons, its association with YPD, the transmission, and diagnosis of the infection, and on prophylactic strategies to prevent RVA outbreaks., Competing Interests: We declare no conflict of interest., (Thieme. All rights reserved.)

Objective: Public life restrictions associated with the COVID-19 pandemic caused reductions in physical activity (PA) and decreases in mental and somatic health. Considering the interplay between these factors, we investigated the effects of digital home exercise (DHE) during government-enforced lockdowns., Methods: A multicentre randomised controlled trial was performed allocating healthy individuals from nine countries (N=763; 523 female) to a DHE or an inactive control group. During the 4-week main intervention, DHE members engaged in live-streamed multicomponent home exercise. Subsequently, both groups had access to prerecorded workouts for an additional 4 weeks. Outcomes, assessed weekly, included PA level (Nordic Physical Activity Questionnaire-Short), anxiety (Generalized Anxiety Disorder Scale-7), mental well-being (WHO-5 Questionnaire), sleep quality (Medical Outcome Study Sleep Scale), pain/disability (Chronic Pain Grade Scale) and exercise motivation (Self-Concordance Scale). Mixed models were used for analysis., Results: Live-streamed DHE consistently increased moderate PA (eg, week 1: 1.65 times more minutes per week, 95% CI 1.40 to 1.94) and vigorous PA (eg, week 1: 1.31 times more minutes per week, 95% CI 1.08 to 1.61), although the effects decreased over time. In addition, exercise motivation, sleep quality and anxiety were slightly improved for DHE in the 4-week live streaming period. The same applied to mental well-being (mean difference at week 4: +0.99, 95% CI 0.13 to 1.86), but an inverted trend was observed after live streaming was substituted by prerecorded exercise., Conclusions: Live-streamed DHE represents an efficacious method to enhance PA and selected markers of health during pandemic-related public life restrictions. However, research on implementation is warranted to reduce dropout rates., Trial Registration Number: DRKS00021273., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: Following an assessment of safe sleep practices (SSP) and nurses' safe sleep knowledge in a Neonatal Intensive Care Unit (NICU), an evidence-based 2-part safe sleep program including nurse education and the use of safe sleep cards was developed in an attempt to increase SSP., Design: A quality improvement project with time-series methodology, including observational and survey data collection., Sample: To assess SSP, sleep environment audits were completed pre- ( N = 48) and post- safe sleep program ( N = 44). To assess nurses' safe sleep knowledge, a safe sleep questionnaire was distributed pre-education ( N = 48) and post-education ( N = 23)., Main Outcome Variable: The change in SSP (ΔSSP) following safe sleep program implementation and change in nurses' safe sleep knowledge (ΔKnowledge) following education., Results: SSP increased from 25 percent to 61 percent compliance, and nurses' knowledge scores increased from 83 percent to 97 percent., (© Copyright 2022 Springer Publishing Company, LLC.)

The B-type natriuretic peptide (BNP), a member of the natriuretic peptide family and a cardiac hormone, is produced mainly in the ventricular myocytes and released into the circulation due to mechanical stimuli during an increasing cardiac wall stretch. BNP has a significant role in the regulation of the cardiovascular system and body fluid. The concentration of this hormone and of the biologically inactive amino-terminal-prohormone in the blood plasma is a helpful diagnostic tool for detecting cardiovascular diseases in human medicine and can be used as a prognostic marker for the risk of mortality, whilst such a tool does not exist for avian medicine. To date, the amino acid sequence of BNP is not known for many of the species commonly presented in avian consultation. In this study, the amino acid sequence of BNP and the prepropeptide was described for 12 parrot species as well as 3 raptor and 3 owl species by polymerase chain reaction (PCR) after RNA isolation from the heart. The results showed a high similarity between the amino acid sequences in the mature peptide region of the BNP. The prepropeptide showed several differences between the examined species, some of them shared by closely related species.

Antibodies against FGFR3 define a subgroup of sensory neuropathy (SN). The aim of this study was to identify the epitope(s) of anti-FGFR3 autoantibodies and potential epitope-dependent clinical subtypes. Using SPOT methodology, five specific candidate epitopes, three in the juxtamembrane domain (JMD) and two in the tyrosine kinase domain (TKD), were screened with 68 anti-FGFR3-positive patients and 35 healthy controls. The identified epitopes cover 6/15 functionally relevant sites of the protein. Four patients reacted with the JMD and 11 with the TKD, partly even in a phosphorylation-state dependent manner. The epitope could not be identified in the others. Patients with antibodies recognizing TKD exhibited a more severe clinical and electrophysiological impairment than others., (Copyright © 2021 Elsevier B.V. All rights reserved.)

In captivity, cardiovascular diseases are common in grey parrots. The diagnosis of these diseases in living birds is difficult, and new diagnostic possibilities would be desirable. The heart is an important endocrine organ in which cardiomyocytes synthetise B-type natriuretic peptide (BNP) and release it into the bloodstream. This hormone has a significant role in cardiovascular and body fluid regulation. The blood concentration of BNP is used in human medicine and small animal medicine as a diagnostic tool in the identification of heart diseases and as a prognostic marker for the risk of mortality. The nucleotide and amino acid sequence of BNP was described in Congo (n = 4) and Timneh (n = 3) grey parrots by PCR after RNA isolation from the atria and ventricles. The results showed a high similarity between the nucleotide sequences of the grey parrots' BNP and the already known sequence of this hormone in chickens. The amino acid sequence of the mature peptide region is consistent in these three species. BNP plasma concentration could be a possible blood parameter for identifying clinically manifest cardiovascular diseases in grey parrots as it is in other species., (© 2021. The Author(s).)

Objective: The available literature indicates a high prevalence of the zoonotic pathogen Salmonella (S.) enterica serovar Infantis in the common swift ( Apus apus ). This long-distance migrant, which only consumes aerial plankton, can reach high population densities in places with suitable breeding sites. Dedicated competent private persons take part in the hand rearing of juvenile common swifts in wildlife rescue centres, which unavoidably results in close contact with these avian patients. For this reason, we examined common swifts for shedding of Salmonella spp., Material and Methods: In the years 2014 and 2019, intestinal swabs or fresh faeces of common swifts (2014: n = 54; 2019: n = 62) were examined microbiologically (DIN EN ISO 6579; Annex D) in the area of Hannover, Lower Saxony, Germany., Results: Salmonella spp. could not be detected in any of the examined common swifts within the investigation period and the studied area in 2014 and 2019., Conclusion and Clinical Relevance: The results illustrate that the common swift is unlikely to be a natural reservoir of Salmonella spp. For the transmission of salmonella by swifts the local conditions with the corresponding environmental impact seem to play a significant role, and the risk of transmission should be assessed according to the region to be examined., Competing Interests: The authors confirm that there is no conflict of interest., (Thieme. All rights reserved.)

Purpose: The purpose of this study was to examine the development and preliminary effectiveness of a novel Prediabetes Decision Aid on adoption of intensive lifestyle interventions (ILIs) and metformin. Little research has focused on increasing uptake of these evidence-based treatments, especially among non-English speakers and those with low educational attainment., Methods: Investigators developed an English and Spanish decision aid displaying information about type 2 diabetes (T2DM) risk and treatments to prevent T2DM and prompting patients to identify next steps for management. This pilot study was a single-arm, pretest-posttest trial of 40 adult patients with prediabetes, obesity, and ≥1 office visit within the prior 12 months. Participants reviewed this tool briefly with a study team member, and data were collected on 3 coprimary outcomes: knowledge about T2DM risk, decisional conflict, and intention to adopt treatment. Exploratory outcomes included subsequent documentation of prediabetes in chart notes and adoption of ILIs or metformin., Results: Almost all participants were women, with nearly half expressing Spanish language preference and low educational attainment. A nonsignificant increase in knowledge was observed across all subgroups. Decisional conflict was significantly reduced from pretest to posttest and was similar between subgroups defined by language preference and educational attainment. While intention to adopt ILIs increased across all subgroups, this change was only significant among Spanish speakers and participants with low educational attainment. At 6 months, 17 participants had subsequent provider documentation of prediabetes, and 12 adopted ILIs or metformin., Conclusions: The decision aid improved patient-reported outcomes and promoted treatment adoption in a diverse patient sample.

Most countries affected by the COVID-19 pandemic have repeatedly restricted public life to control the contagion. However, the health impact of confinement measures is hitherto unclear. We performed a multinational survey investigating changes in mental and physical well-being (MWB/PWB) during the first wave of the pandemic. A total of 14,975 individuals from 14 countries provided valid responses. Compared to pre-restrictions, MWB, as measured by the WHO-5 questionnaire, decreased considerably during restrictions (68.1 ± 16.9 to 51.9 ± 21.0 points). Whereas 14.2% of the participants met the cutoff for depression screening pre-restrictions, this share tripled to 45.2% during restrictions. Factors associated with clinically relevant decreases in MWB were female sex (odds ratio/OR = 1.20, 95% CI: 1.11-1.29), high physical activity levels pre-restrictions (OR = 1.29, 95% CI 1.16-1.42), decreased vigorous physical activity during restrictions (OR = 1.14, 95% CI: 1.05-1.23), and working (partially) outside the home vs. working remotely (OR = 1.29, 95% CI: 1.16-1.44/OR = 1.35, 95% CI: 1.23-1.47). Reductions, although smaller, were also seen for PWB. Scores in the SF-36 bodily pain subscale decreased from 85.8 ± 18.7% pre-restrictions to 81.3 ± 21.9% during restrictions. Clinically relevant decrements of PWB were associated with female sex (OR = 1.62, 95% CI: 1.50-1.75), high levels of public life restrictions (OR = 1.26, 95% CI: 1.18-1.36), and young age (OR = 1.10, 95% CI: 1.03-1.19). Study findings suggest lockdowns instituted during the COVID-19 pandemic may have had substantial adverse public health effects. The development of interventions mitigating losses in MWB and PWB is, thus, paramount when preparing for forthcoming waves of COVID-19 or future public life restrictions., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Wilke, Hollander, Mohr, Edouard, Fossati, González-Gross, Sánchez Ramírez, Laiño, Tan, Pillay, Pigozzi, Jimenez-Pavon, Sattler, Jaunig, Zhang, van Poppel, Heidt, Willwacher, Vogt, Verhagen, Hespanhol and Tenforde.)

Antibody display technologies enable the successful isolation of antigen-specific antibodies with therapeutic potential. The key feature that facilitates the selection of an antibody with prescribed properties is the coupling of the protein variant to its genetic information and is referred to as genotype phenotype coupling. There are several different platform technologies based on prokaryotic organisms as well as strategies employing higher eukaryotes. Among those, phage display is the most established system with more than a dozen of therapeutic antibodies approved for therapy that have been discovered or engineered using this approach. In recent years several other technologies gained a certain level of maturity, most strikingly mammalian display. In this review, we delineate the most important selection systems with respect to antibody generation with an emphasis on recent developments., (© 2021 Bernhard Valldorf et al., published by De Gruyter, Berlin/Boston.)

Governments have restricted public life during the COVID-19 pandemic, inter alia closing sports facilities and gyms. As regular exercise is essential for health, this study examined the effect of pandemic-related confinements on physical activity (PA) levels. A multinational survey was performed in 14 countries. Times spent in moderate-to-vigorous physical activity (MVPA) as well as in vigorous physical activity only (VPA) were assessed using the Nordic Physical Activity Questionnaire (short form). Data were obtained for leisure and occupational PA pre- and during restrictions. Compliance with PA guidelines was calculated based on the recommendations of the World Health Organization (WHO). In total, n = 13,503 respondents (39 ± 15 years, 59% females) were surveyed. Compared to pre-restrictions, overall self-reported PA declined by 41% (MVPA) and 42.2% (VPA). Reductions were higher for occupational vs. leisure time, young and old vs. middle-aged persons, previously more active vs. less active individuals, but similar between men and women. Compared to pre-pandemic, compliance with WHO guidelines decreased from 80.9% (95% CI: 80.3-81.7) to 62.5% (95% CI: 61.6-63.3). Results suggest PA levels have substantially decreased globally during the COVID-19 pandemic. Key stakeholders should consider strategies to mitigate loss in PA in order to preserve health during the pandemic.

Cyclic GMP-AMP synthase (cGAS) recognition of cytosolic DNA is critical for the immune response to cancer and pathogen infection. Here, we discover that cGAS-DNA phase separation is required to resist negative regulation and allow efficient sensing of immunostimulatory DNA. We map the molecular determinants of cGAS condensate formation and demonstrate that phase separation functions to limit activity of the cytosolic exonuclease TREX1. Mechanistically, phase separation forms a selective environment that suppresses TREX1 catalytic function and restricts DNA degradation to an outer shell at the droplet periphery. We identify a TREX1 mutation associated with the severe autoimmune disease Aicardi-Goutières syndrome that increases penetration of TREX1 into the repressive droplet interior and specifically impairs degradation of phase-separated DNA. Our results define a critical function of cGAS-DNA phase separation and reveal a molecular mechanism that balances cytosolic DNA degradation and innate immune activation., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Micronuclei are aberrant nuclear compartments that can form as a result of chromosome mis-segregation. Frequent loss of micronuclear envelope integrity exposes DNA to the cytoplasm, leading to chromosome fragmentation and immune activation. Here, we use micronuclei purification to show that the endoplasmic reticulum (ER)-associated nuclease TREX1 inhibits cGAS activation at micronuclei by degrading micronuclear DNA upon micronuclear envelope rupture. We demonstrate that the ER accesses ruptured micronuclei and plays a critical role in enabling TREX1 nucleolytic attack. TREX1 mutations, previously implicated in immune disease, untether TREX1 from the ER, disrupt TREX1 localization to micronuclei, diminish micronuclear DNA damage, and enhance cGAS activation. These results establish ER-directed resection of micronuclear DNA by TREX1 as a critical regulator of cytosolic DNA sensing in chromosomally unstable cells and provide a mechanistic basis for the importance of TREX1 ER tethering in preventing autoimmunity., Competing Interests: Declaration of interests J.M. has received consulting fees from Ono Pharmaceutical Co. His spouse is an employee of and has equity in Bristol Myers Squibb., (Copyright © 2020 Elsevier Inc. All rights reserved.)

During dynamic ultrasound assessments, unintended transducer movement over the skin needs to be prevented as it may bias the results. The present study investigated the validity of two methods quantifying transducer motion. An ultrasound transducer was moved on a pre-specified 3 cm distance over the semitendinosus muscle of eleven adults (35.8 ± 9.8 years), stopping briefly at intervals of 0.5 cm. Transducer motion was quantified (1) measuring the 2-D displacement of the shadow produced by reflective tape (RT) attached to the skin and (2) using a marker-based, three-dimensional movement analysis system (MAS). Differences between methods were detected with Wilcoxon tests; associations were checked by means of intraclass correlation coefficients (ICC 3.1) and Bland-Altman plots. Values for RT (r = 0.57, p < 0.001) and MAS (r = 0.19, p = 0.002) were significantly higher than true distances (TD). Strong correlations were found between RT and TD (ICC: 0.98, p < 0.001), MAS and TD (ICC: 0.95, p < 0.001), and MAS and RT (ICC: 0.97, p < 0.001). Bland-Altman plots showed narrow limits of agreement for both RT (-0.49 to 0.13 cm) and MAS (-0.49 to 0.34 cm) versus TD. RT and MAS are valid methods to quantify US transducer movement. In view of its low costs and complexity, RT can particularly be recommended for application in research and clinical practice.

High-intensity functional training (HIFT) has become a popular method in the sports and fitness sector. In contrast to unimodal approaches such as strength or endurance training, it has been hypothesized to induce concurrent adaptations in multiple markers of motor function. However, to date, the effectiveness of HIFT in this regard has not been studied. The present systematic review quantified the chronic effects of HIFT on motor function in healthy individuals. A multilevel meta-analysis with a robust random effects meta-regession model was used to pool the standardized mean differences (SMD) between (a) HIFT and (b) no-exercise (NEX) as well as conventional endurance, resistance and balance training for outcomes of muscle strength, endurance capacity and balance. The influence of possible effect modifiers such as program duration, session duration, age or sex was examined in a moderator analysis. Seventeen papers with moderate to high methodological quality (PEDro scale) were identified. Compared to NEX, HIFT had small to moderate positive effects on endurance capacity (SMD: 0.42, 95% CI 0.07-0.78, p = 0.03) and strength (0.60, 95% CI 0.02-1.18, p = 0.04) but no effect on balance (SMD: - 0.10, 95% CI - 1.13 to 0.92, p = 0.42). Regarding endurance, HIFT showed similar effectiveness as moderate-intensity endurance training (SMD: - 0.11, 95% CI - 1.17 to 0.95, p = 0.75) and high-intensity interval endurance training (SMD: - 0.15, 95% CI - 1.4 to 1.1, p = 0.66). No comparisons of HIFT vs. classical resistance or balance training were found. Moderator analyses revealed no influence of most effect modifiers. However, regarding endurance, females seemed to respond more strongly to HIFT in the comparison to NEX (p < .05). HIFT appears to represent an appropriate method to induce chronic improvements in motor function. While being superior to NEX and non-inferior to endurance training, current evidence does not allow a comparison against resistance and balance training. The impact of possible effect moderators should be further elucidated in future research.

Confinement measures during the COVID-19 pandemic have caused substantial reductions in global physical activity (PA) levels. In view of the manifold health benefits of PA, the development of interventions counteracting this trend is paramount. Our survey with 15,261 participants (38 ± 15 years, 58.5% females) examined preferences towards digital home exercise programs in 14 countries affected by COVID-19. More than two-thirds of the sample (68.4%, n = 10,433) indicated being interested in home exercise, and most participants were willing to work out at least three times per week (89.3%, n = 9328). Binary logistic regression revealed that female sex, working part-time, younger age, and being registered in a gym were associated with willingness to exercise. Flexibility (71.1%, n = 7377), resistance (68.6%, n = 7116), and endurance training (62.4%, n = 6478) were the most preferred types of exercise. Our results may guide health providers in developing individually tailored PA interventions during the current and future pandemics.

Young pigeon disease syndrome (YPDS) is characterized as a seasonally occurring, acute and primarily enteric medical condition of mainly juvenile domestic pigeons (Columba livia) with highly variable mortality reaching more than 50%. Although the syndrome has been known in Europe for almost three decades, its aetiology remains largely obscure. Recently, a previously unknown pigeon-associated clade of Rotavirus A (RVA) genotype G18P[17] was detected in Europe and Australia in association with fatal diseases resembling YPDS. Here we show for the first time, that peroral inoculation of healthy juvenile homing pigeons with two genetically different cell culture isolates of RVA G18P[17] (10 6.3 foci-forming units per bird) induces an acute and self-limiting YPDS-like disease in all infected birds. Clinical signs included regurgitation, diarrhoea, congested crops, anorexia and weight loss, as described for naturally RVA-infected pigeons. In agreement with the original outbreaks, RVA isolate DR-7 induced more pronounced clinical signs as compared to isolate DR-5, indicating strain-dependent virulence factors to contribute to variable disease outcomes observed in the field. All inoculated birds developed rotavirus-reactive antibodies starting at seven days after inoculation. High levels of viral RNA and infectious virus were detectable in cloacal swabs and faecal samples already three days after inoculation. While shedding of infectious virus subsided within few days, moderate viral RNA levels were still detectable in cloacal swabs, faeces, and tissue samples at the end of the experiment three weeks after inoculation. Histopathological analysis at this time point revealed inflammatory lesions in spleens and livers of pigeons from both infected groups. In summary, we fulfilled Henle-Koch's postulates and confirmed RVA G18P[17] as a primary cause of YPDS-like diseases in domestic pigeons. By establishing an infection model, we provide a crucial tool for future research, such as identification of transmission routes and establishing vaccination regimes., (© 2020 The Authors. Transboundary and Emerging Diseases Published by Blackwell Verlag GmbH.)

Introduction: The worldwide spread of the novel coronavirus (SARS-CoV2) has prompted numerous countries to restrict public life. Related measures, such as limits on social gatherings, business closures, or lockdowns, are expected to considerably reduce the individual opportunities to move outside the home. As physical activity (PA) and sport participation significantly contribute to health, this study has two objectives. The objectives of this study are to assess changes in PA and well-being since the coronavirus outbreak in affected countries. Additionally, we will evaluate the impact of digital home-based exercise programs on PA as well as physical and mental health outcomes. Method: A multinational network trial will be conducted with three planned phases (A, B, and C). Part A consists of administering a structured survey. It investigates changes in PA levels and health during the coronavirus outbreak and measures the preferences of the participants regarding online training programs. Part B is a two-armed randomized-controlled trial. Participants assigned to the intervention group (IG) will complete a digital 4-week home exercise training (live streaming via internet) guided by the survey results on content and time of program. The control group (CG) will not receive the program. Part C is 4-week access of both CG and IG to a digital archive of pre-recorded workouts from Part B. Similar to Part A, questionnaires will be used in both Part B and C to estimate the effects of exercise on measures of mental and physical health. Results and Discussion: The ASAP project will provide valuable insights into the importance of PA during a global pandemic. Our initial survey is the first to determine how governmental confinement measures impact bodily and mental well-being. Based on the results, the intervention studies will be unique to address health problems potentially arising from losses in PA. If proven effective, the newly developed telehealth programs could become a significant and easy-to-distribute factor in combating PA decreases. Results of the study may hence guide policy makers on methods to maintain PA and health when being forced to restrict public life. Study Register: DRKS00021273., (Copyright © 2020 Wilke, Mohr, Tenforde, Vogel, Hespanhol, Vogt, Verhagen and Hollander.)

The purpose of this quality improvement project was to develop an evidence-based protocol designed for pressure injury prevention for neonates and children in a pediatric cardiac care unit located in the Midwestern United States. The ultimate goal of the project was dissemination across all pediatric critical care and acute care inpatient arenas, but the focus of this initial iteration was neonates and children requiring cardiac surgery, extracorporeal support in the form of extracorporeal membranous oxygenation and ventricular assist devices in the cardiac care unit, or cardiac transplantation. A protocol based upon the National Pressure Ulcer Advisory Panel guidelines was developed and implemented in the pediatric cardiac care unit. Pediatric patients were monitored for pressure injury development for 6 months following protocol implementation. During the 40-month preintervention period, 60 hospital-acquired pressure injuries (HAPIs) were observed, 13 of which higher than stage 3. In the 6-month postintervention period, we observed zero HAPI greater than stage 2. We found that development and use of a standardized pressure injury prevention protocol reduced the incidence, prevalence, and severity of HAPIs among patients in our pediatric cardiac care unit.

The architecture of the neurovascular unit (NVU) is controlled by the communication of neurons, glia, and vascular cells. We found that the neuronal guidance cue reelin possesses proangiogenic activities that ensure the communication of endothelial cells (ECs) with the glia to control neuronal migration and the establishment of the blood-brain barrier in the mouse brain. Apolipoprotein E receptor 2 (ApoER2) and Disabled1 (Dab1) expressed in ECs are required for vascularization of the retina and the cerebral cortex. Deletion of Dab1 in ECs leads to a reduced secretion of laminin-α4 and decreased activation of integrin-β1 in glial cells, which in turn control neuronal migration and barrier properties of the NVU. Thus, reelin signaling in the endothelium is an instructive and integrative cue essential for neuro-glia-vascular communication., (Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Competing Interests: Disclosure The authors report no conflicts of interest in this work.

Microtubule targeting agents (MTAs) are a mainstay in the treatment of a wide range of tumors. However, acquired resistance to chemotherapeutic drugs is a common mechanism of disease progression and a prognostic-determinant feature of malignant tumors. In prostate cancer (PC), resistance to MTAs such as the taxane Docetaxel dictates treatment failure as well as progression towards lethal stages of disease that are defined by a poor prognosis and high mortality rates. Though studied for decades, the array of mechanisms contributing to acquired resistance are not completely understood, and thus pose a significant limitation to the development of new therapeutic strategies that could benefit patients in these advanced stages of disease. In this protocol, we describe the generation of Docetaxel-resistant prostate cancer cell lines that mimic lethal features of late-stage prostate cancer, and therefore can be used to study the mechanisms by which acquired chemoresistance arises. Despite potential limitations intrinsic to a cell based model, such as the loss of resistance properties over time, the Docetaxel-resistant cell lines produced by this method have been successfully used in recent studies and offer the opportunity to advance our molecular understanding of acquired chemoresistance in lethal prostate cancer.

Patient- and family-centered care is endorsed by leading health care organizations. To incorporate the family in interdisciplinary rounds in the pediatric intensive care unit, it is necessary to prepare the family to be an integral member of the child's health care team. When the family is part of the health care team, interdisciplinary rounds ensure that the family understands the process of interdisciplinary rounds and that it is an integral part of the discussion. An evidence-based protocol to provide understanding and support to families related to interdisciplinary rounds has significant impact on satisfaction, trust, and patient outcomes., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Separation of human sister chromatids involves the removal of DNA embracing cohesin ring complexes. Ring opening occurs by prophase-pathway-dependent phosphorylation and separase-mediated cleavage, with the former being antagonized at centromeres by Sgo1-dependent PP2A recruitment. Intriguingly, prophase pathway signaling and separase's proteolytic activity also bring about centriole disengagement, whereas Sgo1 is again counteracting this licensing step of later centrosome duplication. Here, we demonstrate that alternative splice variants of human Sgo1 specifically and exclusively localize and function either at centromeres or centrosomes. A small C-terminal peptide encoded by exon 9 of SGO1 (CTS for centrosomal targeting signal of human Sgo1) is necessary and sufficient to drive centrosomal localization and simultaneously abrogate centromeric association of corresponding Sgo1 isoforms. Cohesin is shown to be a target of the prophase pathway at centrosomes and protected by Sgo1-PP2A. Accordingly, premature centriole disengagement in response to Sgo1 depletion is suppressed by blocking ring opening of an engineered cohesin., (Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.)

In this paper, we study a two-parameter family of convex billiard tables, by taking the intersection of two round disks (with different radii) in the plane. These tables give a generalization of the one-parameter family of lemon-shaped billiards. Initially, there is only one ergodic table among all lemon tables. In our generalized family, we observe numerically the prevalence of ergodicity among the some perturbations of that table. Moreover, numerical estimates of the mixing rate of the billiard dynamics on some ergodic tables are also provided.

LINC-NIRVANA is a near-infrared Fizeau interferometric imager that will operate at the Large Binocular Telescope. In preparation for the commissioning of this instrument, we conducted experiments for calibrating the high-layer wavefront sensor of the layer-oriented multi-conjugate adaptive optics system. For calibrating the multi-pyramid wavefront sensor, four light sources were used to simulate guide stars. Using this setup, we developed the push-pull method for calibrating the interaction matrix. The benefits of this method over the traditional push-only method are quantified, and also the effects of varying the number of push-pull frames over which aberrations are averaged is reported. Finally, we discuss a method for measuring mis-conjugation between the deformable mirror and the wavefront sensor, and the proper positioning of the wavefront sensor detector with respect to the four pupil positions.

In the field of adaptive optics, multi-conjugate adaptive optics (MCAO) can greatly increase the size of the corrected field of view (FoV) and also extend sky coverage. By applying layer oriented MCAO (LO-MCAO) [4], together with multiple guide stars (up to 20) and pyramid wavefront sensors [7], LINC-NIRVANA (L-N for short) [1] will provide two AO-corrected beams to a Fizeau interferometer to achieve 10 milliarcsecond angular resolution on the Large Binocular Telescope. This paper presents first laboratory results of the AO performance achieved with the high layer wavefront sensor (HWS). This sensor, together with its associated deformable mirror (a Xinetics-349), is being operated in one of the L-N laboratories. AO reference stars, spread across a 2 arc-minute FoV and with aberrations resulting from turbulence introduced at specific layers in the atmosphere, are simulated in this lab environment. This is achieved with the Multi-Atmosphere Phase screen and Stars (MAPS) [2] unit. From the wavefront data, the approximate residual wavefront error after correction has been calculated for different turbulent layer altitudes and wind speeds. Using a somewhat undersampled CCD, the FWHM of stars in the nearly 2 arc-minute FoV has also been measured. These test results demonstrate that the high layer wavefront sensor of LINC-NIRVANA will be able to achieve uniform AO correction across a large FoV., (© 2011 Optical Society of America)

Aim: The insulin receptor substrate-1 (IRS-1) is a multisite docking protein which plays a central role in the signal transduction of growth factors such as insulin and insulin-like growth factors (IGF-1 and IGF-2). It is found to be frequently overexpressed in human hepatocellular carcinoma (HCC)., Methods: To study IRS-1 overexpression in hepatocytes in vivo, transgenic mice overexpressing IRS-1 exclusively in hepatocytes were created, showing enhanced hepatocyte proliferation in young animals. In the present study, the phenotype of IRS-1 transgenic animals was characterized over a period of two years. The livers of transgenic and control mice were analyzed for IRS-1 expression and phosphorylation, activation of the downstream mitogen-activated protein kinase (MAPK) cascade and phosphatidylinositol 3' kinase (PI3'K) and macroscopical and histological abnormalities., Results: The enhanced hepatocyte proliferation observed in young IRS-1 transgenic animals was no longer detectable in adult mice. Despite constitutive overexpression and phosphorylation of IRS-1, MAPK- and IRS-1-associated PI3'K activity were significantly reduced in older transgenic mice. Furthermore, no premalignant lesions or HCC were detected in IRS-1 transgenic animals up to the age of 24 months., Conclusions: Therefore, additional mechanisms such as enhanced growth factor expression or impaired negative feedback control mechanisms may augment IRS-1 overexpression in human hepatocarcinogenesis.

Most hepatocellular carcinomas (HCCs) express oncofetal alpha-fetoprotein (AFP). We and others have demonstrated efficient tumor control mediated by cellular immune responses in mice bearing subcutaneous tumors derived from the AFP-expressing murine HCC cell line Hepa 1-6 by DNA vaccination against AFP. In the present study, we examined AFP DNA vaccination in the AFP-expressing primary murine HCC model BW7756. In this model AFP DNA vaccination resulted in only minimal lymphocytic infiltration and failed to control tumor growth. To augment the AFP-specific cellular immune response, intratumoral expression of chemokine IP-10 (interferon-inducible protein-10) and the proinflammatory cytokine interleukin (IL)-12 by adenoviral vectors (AdmIL-12 and AdmIP-10) was analyzed. Intratumoral injection of AdmIL-12 and AdmIP-10 resulted in transient tumor regressions, without prolongation of animal survival. By contrast, AFP DNA vaccination followed by intratumoral injection of AdmIL-12 and AdmIP-10 resulted in tumor regression in all animals and in prolongation of animal survival; in 25% of animals the tumors became undetectable. This study demonstrates for the first time that activation of effector cells against a tumor antigen induced by the combination of DNA vaccination and intratumoral chemokine and cytokine expression is superior to the respective treatment strategies alone. This effect may be mediated by attraction of activated effector cells to the tumor tissue.

Due to limited treatment options the prognosis of patients with advanced hepatocellular cancer (HCC) has remained poor. To investigate an alternative therapeutic approach, we examined the feasibility of radioiodine therapy of HCC following human sodium iodide symporter (NIS) gene transfer using a mouse alpha-fetoprotein (AFP) promoter construct to target NIS expression to HCC cells. For this purpose, the murine Hepa 1-6 and the human HepG2 hepatoma cell lines were stably transfected with NIS cDNA under the control of the tumor-specific AFP promoter. The stably transfected Hepa 1-6 cell line showed a 10-fold increase in iodide accumulation, while HepG2 cells accumulated (125)I approximately 60-fold. Tumor-specific NIS expression was confirmed on mRNA level by northern blot analysis, and on protein level by immunostaining, that revealed primarily membrane-associated NIS-specific immunoreactivity. In an in vitro clonogenic assay up to 78% of NIS-transfected Hepa 1-6 and 93% of HepG2 cells were killed by (131)I exposure, while up to 96% of control cells survived. In vivo NIS-transfected HepG2 xenografts accumulated 15% of the total (123)I administered per gram tumor with a biological half-life of 8.38 h, resulting in a tumor absorbed dose of 171 mGy MBq(-1) (131)I. After administration of a therapeutic (131)I dose (55.5 MBq) tumor growth of NIS expressing HepG2 xenografts was significantly inhibited. In conclusion, tumor-specific iodide accumulation was induced in HCC cells by AFP promoter-directed NIS expression in vitro and in vivo, which was sufficiently high to allow a therapeutic effect of (131)I. This study demonstrates the potential of tumor-specific NIS gene therapy as an innovative treatment strategy for HCC.

Motivation: Quantitative experimental data is the critical bottleneck in the modeling of dynamic cellular processes in systems biology. Here, we present statistical approaches improving reproducibility of protein quantification by immunoprecipitation and immunoblotting., Results: Based on a large data set with more than 3600 data points, we unravel that the main sources of biological variability and experimental noise are multiplicative and log-normally distributed. Therefore, we suggest a log-transformation of the data to obtain additive normally distributed noise. After this transformation, common statistical procedures can be applied to analyze the data. An error model is introduced to account for technical as well as biological variability. Elimination of these systematic errors decrease variability of measurements and allow for a more precise estimation of underlying dynamics of protein concentrations in cellular signaling. The proposed error model is relevant for simulation studies, parameter estimation and model selection, basic tools of systems biology., Availability: Matlab and R code is available from the authors on request. The data can be downloaded from our website www.fdm.uni-freiburg.de/~ckreutz/data.

Hepatocellular carcinoma (HCC) is one of the most common malignant tumors in some areas of the world. The prognosis of HCC patients is generally very poor with a 5-year survival rate of less than 5%. Therapeutic strategies include surgery (resection or liver transplantation) and non-surgical interventions, such as percutaneous ethanol injection or radiofrequency thermal ablation as well as transarterial embolization or chemoembolization. Therefore, the development and evaluation of novel HCC treatment strategies such as the use of antiangiogenic, antiproliferative or antiinflammatoric drugs, immune therapeuticals, gene therapy and internal or external radiation are of utmost importance. This review should give an overview of possible alternative therapies in HCC treatment.

Therapeutic options for patients with hepatocellular carcinoma (HCC) are still limited. Only patients with small HCC are considered for curative treatment options such as resection, liver transplantation or local ablation. Systemic treatment of advanced HCC is still impaired by the high level of resistance to chemotherapy and irradiation. In addition, most patients with HCC are highly susceptible to toxic side effects due to their impaired liver function. Novel treatment options are based on the increasing understanding of molecular mechanisms involved in tumorigenesis, tumor progression and metastasis. Such "targeted therapies" aim at growth factors and their receptors, intracellular signal transduction and cell cycle control. Anti-angiogenesis targets the tumor vasculature. Gene therapeutic strategies are based on the transfer of therapeutic genes in target tissues to express highly active proteins such as suicide genes or cytokines. Tumor cell death by cell lysis is the mechanism of oncolytic viruses, which are able to selectively replicate in tumor cells. This mechanism may be augmented by the addition of therapeutic genes expressed by recombinant oncolytic viruses. The induction of a potent immune response to tumor antigens by vaccination strategies or by adoptive transfer of activated immune cells aim at the specific destruction of tumor cells by effector T-cells targeted to tumor antigens.

Malignant liver tumors are either originating from the liver, such as the primary liver tumors hepatocellular carcinoma and the cholangiocellular carcinoma, or metastases from extrahepatic malignancies. Apart from surgical procedures (resection, liver transplantation) percutaneous local-ablative (ethanol injection, radiofrequency thermal ablation as well as radiation therapy) and transarterial interventions are non-surgical therapeutic options. While these regional therapies have been shown in randomised controlled studies to be effective for hepatocellular carcinoma, their therapeutic efficacy in cholangiocellular carcinoma and liver metastases has not been shown. In the following we will summarize the regional therapeutic options in primary and secondary liver tumors.