Disease-Agnostic Electronic Adherence Aid for Subcutaneous at-Home and Self-Administration Devices-The Lowest Common Denominator Based on a Cross-Indication Survey.

The value of connected devices and health apps with features such as adherence trackers, dosing reminders, and remote communication tools for users and healthcare providers has been assessed to support home-based subcutaneous administration. A comprehensive survey was conducted with 605 participants, including users and caregivers, from eight countries. Medical conditions encompassed ankylosing spondylitis, asthma, cerebral palsy, cluster headaches, Crohn's disease, hemophilia, lupus, migraine, multiple sclerosis, Parkinson's disease, plaque psoriasis, psoriatic arthritis, rheumatoid arthritis, spasticity, spondyloarthritis, and ulcerative colitis. Utilizing a maximum difference scaling methodology, the survey gauged participant preferences regarding specific attributes and features of connected drug delivery devices. Irrespective of demographic factors like age, gender, nationality, or the specific medical condition, the device's ability to verify a successful injection stood out as universally valued. The second and third most valued attributes pertained to temperature-related indicators or warnings. These features do not necessitate the use of a connected device and can be integrated into existing autoinjector platforms. The survey findings support the development of a universal adherence tool for at-home subcutaneous dosing, independent of a specific medical condition. This tool may be gradually improved with disease-specific features. Once established as a platform, manufacturers can launch any subcutaneous medication and later integrate real-world evidence for enhanced educational, treatment, and diagnostic capabilities. This approach is crucial for advancing connected adherence tools in decentralized healthcare, aligning with user and healthcare system needs while translating scientific innovation into practical solutions.

A guide to open science practices for animal research.

Translational biomedical research relies on animal experiments and provides the underlying proof of practice for clinical trials, which places an increased duty of care on translational researchers to derive the maximum possible output from every experiment performed. The implementation of open science practices has the potential to initiate a change in research culture that could improve the transparency and quality of translational research in general, as well as increasing the audience and scientific reach of published research. However, open science has become a buzzword in the scientific community that can often miss mark when it comes to practical implementation. In this Essay, we provide a guide to open science practices that can be applied throughout the research process, from study design, through data collection and analysis, to publication and dissemination, to help scientists improve the transparency and quality of their work. As open science practices continue to evolve, we also provide an online toolbox of resources that we will update continually.

Acceptance of universal varicella vaccination among Swiss pediatricians and general practitioners who treat pediatric patients.

BACKGROUND: Over the last two decades, several countries have initiated universal varicella vaccination (UVV) programs in infants. In 2019, the Swiss National Immunization Technical Advisory Group (NITAG) decided to start evaluating the introduction of universal varicella vaccination. There is a theoretical concern that suboptimal vaccination coverage could lead to a shift in the varicella incidence to older age groups, thereby potentially increasing complication rates. To achieve a high vaccination coverage rate, it is important that practicing physicians comply with a potential recommendation for UVV. We studied the perception of varicella and the current vaccination behavior among Swiss pediatricians and general practitioners (GPs) who treat children. We also assessed their intention to advise parents to vaccinate their children against varicella in the event the Swiss NITAG will recommend UVV. METHODS: Primary data was collected through a structured, 20-min online survey with Swiss pediatricians and GPs who treat children. RESULTS: 150 physicians participated in the study: 40 GPs in the German-speaking part, 20 GPs in the French-speaking part, 67 pediatricians in the German-speaking part, and 23 pediatricians in the French-speaking part. The majority (64%) of all participants reported that they currently recommend varicella vaccination for risk groups according to the national immunization plan. About one third of physicians (35%) - predominantly pediatricians - currently already recommend it for all infants. In these situations, a measles, mumps, rubella, varicella combination vaccine is currently used by 58% for the first dose and by 59% for the second dose. 86% of participants stated that they would advise parents to have their children vaccinated against varicella in case of a recommendation for UVV by the Swiss NITAG. 68% responded that they expect many questions from parents and 65% agreed that they have good arguments to convey the importance of varicella vaccination. CONCLUSIONS: The survey study results show that most participating pediatricians and GPs indicated a favorable attitude towards childhood vaccination against varicella in the setting of a Swiss NITAG recommendation for UVV. This data shows the importance of NITAG recommendations in influencing vaccine education and supporting achievement of high coverage of varicella vaccination.

Awake, sedated or anaesthetised for regional anaesthesia block placements?: A retrospective registry analysis of acute complications and patient satisfaction in adults.

BACKGROUND: Whether adults should be awake, sedated or anaesthetised during establishment of regional anaesthesia is still debated and there is little information on the relative safety of each. In paediatric practice, there is often little choice but to use sedation or anaesthesia as otherwise the procedures would be too distressing and patient movement would be hazardous. OBJECTIVE(S): The objective of this study was to evaluate complications related to central and peripheral regional block and patient satisfaction in awake, sedated and anaesthetised adult patients. DESIGN: A retrospective registry analysis. SETTING: The German Network of Regional Anaesthesia database was analysed between 2007 and 2012. PATIENTS: We included data of 42 654 patients and defined three groups: group I awake (n = 25 004), group II sedated (n = 15 121) and group III anaesthetised (n = 2529) for block placement. MAIN OUTCOME MEASURES: Odds ratios [OR; 95% confidence interval (CI)] were calculated with logistic regression analysis and adjusted for relevant confounders to determine the risk of block-related complications in sedated or anaesthetised patients compared with awake patients. RESULTS: Rates of local anaesthetic systemic toxicity were comparable between the groups [awake 0.02% (95% CI: 0.002 to 0.0375), sedated 0.02% (0.003 to 0.042) and anaesthetised 0% (0 to 0.12%)], as were the rates of pneumothorax [awake 0.035% (0 to 0.074), sedated 0% (0 to 0.002) and anaesthetised 0.2% (0 to 0.56)]. Considering peripheral nerve blocks, sedated patients had a decreased risk for multiple skin puncture [adjusted OR: 0.78 (95% CI: 0.71 to 0.85), premature termination [0.45 (0.22 to 0.91)], primary failure [0.58 (0.40 to 0.83)] and postoperative paraesthesia [0.35 (0.28 to 0.45)], but an increased risk for a bloody tap [1.82 (1.50 to 2.21)]. General anaesthesia increased the risk of a bloody tap [adjusted OR: 1.33 (95% CI: 1.01 to 1.78)] and multiple skin puncture [1.28 (1.12 to 1.46)], but decreased the risk for postoperative paraesthesia [0.16 (0.06 to 0.38)]. In neuraxial sites, sedation increased the risk for multiple skin puncture [adjusted OR: 1.18 (95% CI: 1.09 to 1.29)], whereas block placement under general anaesthesia decreased the risk for multiple skin puncture [0.53 (0.39 to 0.72)] and bloody tap but significantly increased the risk for postoperative paraesthesia related to a catheter [2.45 (1.19 to 5.02)]. Sedation was associated with a significant improvement in patient satisfaction. CONCLUSION: Sedation may improve safety and success of peripheral nerve block placement. Block placement under general anaesthesia in adults should be reserved for experienced anaesthesiologists and special situations.

Versatile Viral Vector Strategies for Postscreening Target Validation and RNAi ON-Target Control.

Our approach aims to optimize postscreening target validation strategies using viral vector-driven RNA interference (RNAi) cell models. The RNAiONE validation platform is an array of plasmid-based expression vectors that each drives tandem expression of the gene of interest (GOI) with one small hairpin RNA (shRNA) from a set of computed candidate sequences. The best-performing shRNA (>85% silencing efficiency) is then integrated in an inducible, all-in-one lentiviral vector to transduce pharmacologically relevant cell types that endogenously express the GOI. VariCHECK is used subsequently to combine the inducible knockdown with an equally inducible rescue of the GOI for ON-target phenotype verification. The complete RNAiONE-VariCHECK system relies on three key elements to ensure high predictability: (1) maximized silencing efficiencies by a focused shRNA validation process, (2) homogeneity of the RNAi cell pools by application of sophisticated viral vector technologies, and (3) exploiting the advantages of inducible expression systems. By using a reversible expression system, our strategy adds critical information to hot candidates from RNAi screens and avoids potential side effects that may be caused by other, irreversible genomic manipulation methods such as transcription activator-like effector nucleases (TALEN) or clustered regularly interspaced short palindromic repeats/Cas9 (CRISPR/Cas). This approach will add credibility to top-hit screening candidates and protect researchers from costly misinterpretations early in the preclinical drug development process.

Diabetes: a risk factor for catheter-associated infections.

BACKGROUND AND OBJECTIVES: The incidence of infectious complications associated with continuous regional anesthesia techniques is a matter of concern. Our objective was to determine whether patients suffering from diabetes are at an increased risk of catheter-related infectious complications. METHODS: The German Network for Regional Anaesthesia database was analyzed between 2007 and 2012. After proof of plausibility, data of 36,881 patients undergoing continuous regional anesthesia were grouped in I: no diabetes (n = 32,891) and II: any diabetes (n = 3990). The analysis focused on catheter-related infections after strict definition. Differences among the groups were tested with t and χ tests. Odds ratios were calculated with logistic regression and adjusted for potential confounders. RESULTS: Patients with a diagnosis of diabetes had an increased incidence of catheter-related infections (no diabetes 3.0% vs any diabetes 4.2%; P < 0.001). Among all patients, diabetes remained an independent risk factor for infections for all sites after the adjustment for potential confounders (odds ratio [OR] = 1.26; 95% confidence interval [95% CI], 1.02-1.55; P = 0.036). The risk of infection was significantly increased in peripheral catheters only in the lower limb (adjusted OR = 2.42; 95% CI, 1.05-5.57; P = 0.039). If neuraxial catheters were used, the risk was significantly increased only in lumbar epidural (adjusted OR = 2.09; 95% CI, 1.18-3.73; P = 0.012) for diabetic patients compared with nondiabetic patients. CONCLUSIONS: The presence of diabetes is associated with an increased risk for catheter-related infections in lower limb and lumbar epidural. Specific care should be taken to avoid and detect infections in this population.

To what extent are task-switching deficits in children with attention-deficit/hyperactivity disorder independent of impaired inhibition?

Executive functions, higher-order cognitive functions needed for goal-directed behavior, have been studied extensively in the search for endophenotypes for ADHD, yet results have been inconclusive. We examine the performance of children with ADHD in task switching as an as yet understudied potential endophenotype. A group of 20 children with ADHD and a group of 23 children without ADHD (ages 7-12) performed a task-switching paradigm and a Go/No-Go Task. Children with ADHD displayed significantly greater specific switch costs, that is, compared to control children they were especially impaired directly after task switches. There were no group differences with respect to the general switch costs, which are estimated by comparing performance on single task blocks to the block where both tasks are intermixed. Specific switch costs and Go/No-Go error rate were significantly correlated; yet, group differences in the task-switching paradigm remained significant even when inhibition was controlled for. This pattern of results suggests that children with ADHD are neither generally impaired in executive function nor only impaired with respect to inhibition. Instead, they display a highly specific deficit with regard to the flexible suppression and amplification of different task rules according to the context. Our conclusion that task switching has the potential to be added to the list of ADHD endophenotypes is strengthened by the independence of task-switching deficits and inhibition.

GAS2L3, a target gene of the DREAM complex, is required for proper cytokinesis and genomic stability.

The mammalian DREAM complex is a key regulator of cell-cycle-regulated gene transcription and drives the expression of many gene products required for mitosis and cytokinesis. In this study, we characterized GAS2L3, which belongs to the GAS2 family of proteins with putative actin- and microtubule-binding domains as a target gene of DREAM. We found that GAS2L3 localizes to the spindle midzone and the midbody during anaphase and cytokinesis, respectively. Biochemical studies show that GAS2L3 binds to and bundles microtubules as well as F-actin in vitro. Strikingly, the RNAi-mediated knockdown of GAS2L3 results in chromosome segregation defects in multinucleated cells and in cells with multi-lobed nuclei. Likewise, chronic downregulation of GAS2L3 causes chromosome loss and aneuploidy. Time-lapse videomicroscopy experiments in GAS2L3-knockdown cells reveal abnormal oscillation of chromatin and the spindle during cytokinesis. Taken together, our data reveal novel, important roles of GAS2L3 for faithful cell division. Our work thus contributes to the understanding of how DREAM regulates cytokinesis.

[Deficient adaptive regulation of emotion in children with ADHD]. / Defizitäre adaptive emotions- regulation bei kindern mit ADHS.

OBJECTIVES: The current study investigates whether children with and without ADHD differ in their implementation of emotion-regulation strategies. In addition, it explores whether the regulation patterns of ADHD children are related to co-occurring behavioral and emotional problems. METHODS: A group of 21 children with ADHD and a group of 20 children without ADHD (ages 10-13) completed the Questionnaire on Emotion Regulation in Children and Adolescents (FEEL-KJ, Grob & Smolenski, 2005). Furthermore, we employed the parent-rated Strengths and Difficulties Questionnaire (Woerner, Becker & Rothenberger, 2004) to assess the socioemotional problems of ADHD children. RESULTS: Self-reports revealed group differences in terms of adaptive emotion regulation, though no group differences were found in terms of maladaptive emotion regulation. Specifically, children with ADHD reported less frequently applying the strategies "Cognitive Problem Solving," "Problem-Oriented Acting," "Mood Enhancement," "Reevaluation," and "Distraction." Children with ADHD also reported seeking social support less frequently than the controls. Moreover, significant negative correlations were found between adaptive coping and co-occurring behavioral and emotional problems. CONCLUSIONS: Children with and without ADHD specifically differ in their application of problem-oriented emotion-regulation strategies, especially those ADHD children suffer from co-occurring problems who particularly infrequently apply adaptive emotion regulation strategies.

Lin9, a subunit of the mammalian DREAM complex, is essential for embryonic development, for survival of adult mice, and for tumor suppression.

The retinoblastoma tumor suppressor protein (pRB) and related p107 and p130 "pocket proteins" function together with the E2F transcription factors to repress gene expression during the cell cycle and development. Recent biochemical studies have identified the multisubunit DREAM pocket protein complexes in Drosophila melanogaster and Caenorhabditis elegans in regulating developmental gene repression. Although a conserved DREAM complex has also been identified in mammalian cells, its physiological function in vivo has not been determined. Here we addressed this question by targeting Lin9, a conserved core subunit of DREAM. We found that LIN9 is essential for early embryonic development and for viability of adult mice. Loss of Lin9 abolishes proliferation and leads to multiple defects in mitosis and cytokinesis because of its requirement for the expression of a large set of mitotic genes, such as Plk1, Aurora A, and Kif20a. While Lin9 heterozygous mice are healthy and normal, they are more susceptible to lung tumorigenesis induced by oncogenic c-Raf than wild-type mice. Together these experiments provide the first direct genetic evidence for the role of LIN9 in development and mitotic gene regulation and they suggest that it may function as a haploinsufficient tumor suppressor.

LINC, a human complex that is related to pRB-containing complexes in invertebrates regulates the expression of G2/M genes.

Here we report the identification of the LIN complex (LINC), a human multiprotein complex that is required for transcriptional activation of G2/M genes. LINC is related to the recently identified dREAM and DRM complexes of Drosophila and C. elegans that contain homologs of the mammalian retinoblastoma tumor suppressor protein. The LINC core complex consists of at least five subunits including the chromatin-associated LIN-9 and RbAp48 proteins. LINC dynamically associates with pocket proteins, E2F and B-MYB during the cell cycle. In quiescent cells, LINC binds to p130 and E2F4. During cell cycle entry, E2F4 and p130 dissociate and LINC switches to B-MYB and p107. Chromatin Immunoprecipitation experiments demonstrate that LINC associates with a large number of E2F-regulated promoters in quiescent cells. However, RNAi experiments reveal that LINC is not required for repression. In S-phase, LINC selectively binds to the promoters of G2/M genes whose products are required for mitosis and plays an important role in their cell cycle dependent activation.