G3BPs tether the TSC complex to lysosomes and suppress mTORC1 signaling.

Ras GTPase-activating protein-binding proteins 1 and 2 (G3BP1 and G3BP2, respectively) are widely recognized as core components of stress granules (SGs). We report that G3BPs reside at the cytoplasmic surface of lysosomes. They act in a non-redundant manner to anchor the tuberous sclerosis complex (TSC) protein complex to lysosomes and suppress activation of the metabolic master regulator mechanistic target of rapamycin complex 1 (mTORC1) by amino acids and insulin. Like the TSC complex, G3BP1 deficiency elicits phenotypes related to mTORC1 hyperactivity. In the context of tumors, low G3BP1 levels enhance mTORC1-driven breast cancer cell motility and correlate with adverse outcomes in patients. Furthermore, G3bp1 inhibition in zebrafish disturbs neuronal development and function, leading to white matter heterotopia and neuronal hyperactivity. Thus, G3BPs are not only core components of SGs but also a key element of lysosomal TSC-mTORC1 signaling.

RNA granules: functional compartments or incidental condensates?

RNA granules are mesoscale assemblies that form in the absence of limiting membranes. RNA granules contain factors for RNA biogenesis and turnover and are often assumed to represent specialized compartments for RNA biochemistry. Recent evidence suggests that RNA granules assemble by phase separation of subsoluble ribonucleoprotein (RNP) complexes that partially demix from the cytoplasm or nucleoplasm. We explore the possibility that some RNA granules are nonessential condensation by-products that arise when RNP complexes exceed their solubility limit as a consequence of cellular activity, stress, or aging. We describe the use of evolutionary and mutational analyses and single-molecule techniques to distinguish functional RNA granules from "incidental condensates."

Nucleoporin foci are stress-sensitive condensates dispensable for C. elegans nuclear pore assembly.

Nucleoporins (Nups) assemble nuclear pores that form the permeability barrier between nucleoplasm and cytoplasm. Nucleoporins also localize in cytoplasmic foci proposed to function as pore pre-assembly intermediates. Here, we characterize the composition and incidence of cytoplasmic Nup foci in an intact animal, C. elegans. We find that, in young non-stressed animals, Nup foci only appear in developing sperm, oocytes and embryos, tissues that express high levels of nucleoporins. The foci are condensates of highly cohesive FG repeat-containing nucleoporins (FG-Nups), which are maintained near their solubility limit in the cytoplasm by posttranslational modifications and chaperone activity. Only a minor fraction of FG-Nup molecules concentrate in Nup foci, which dissolve during M phase and are dispensable for nuclear pore assembly. Nucleoporin condensation is enhanced by stress and advancing age, and overexpression of a single FG-Nup in post-mitotic neurons is sufficient to induce ectopic condensation and organismal paralysis. We speculate that Nup foci are non-essential and potentially toxic condensates whose assembly is actively suppressed in healthy cells.

Germ granules in development.

A hallmark of all germ cells is the presence of germ granules: assemblies of proteins and RNA that lack a delineating membrane and are proposed to form via condensation. Germ granules across organisms share several conserved components, including factors required for germ cell fate determination and maintenance, and are thought to be linked to germ cell development. The molecular functions of germ granules, however, remain incompletely understood. In this Development at a Glance article, we survey germ granules across organisms and developmental stages, and highlight emerging themes regarding granule regulation, dynamics and proposed functions.

An Insulin-Responsive Sensor in the SIRT1 Disordered Region Binds DBC1 and PACS-2 to Control Enzyme Activity.

Current models of SIRT1 enzymatic regulation primarily consider the effects of fluctuating levels of its co-substrate NAD+, which binds to the stably folded catalytic domain. By contrast, the roles of the sizeable disordered N- and C-terminal regions of SIRT1 are largely unexplored. Here we identify an insulin-responsive sensor in the SIRT1 N-terminal region (NTR), comprising an acidic cluster (AC) and a 3-helix bundle (3HB), controlling deacetylase activity. The allosteric assistor DBC1 removes a distal N-terminal shield from the 3-helix bundle, permitting PACS-2 to engage the acidic cluster and the transiently exposed helix 3 of the 3-helix bundle, disrupting its structure and inhibiting catalysis. The SIRT1 activator (STAC) SRT1720 binds and stabilizes the 3-helix bundle, protecting SIRT1 from inhibition by PACS-2. Identification of the SIRT1 insulin-responsive sensor and its engagement by the DBC1 and PACS-2 regulatory hub provides important insight into the roles of disordered regions in enzyme regulation and the mode by which STACs promote metabolic fitness.

Germline MBD4 deficiency causes a multi-tumor predisposition syndrome.

We report an autosomal recessive, multi-organ tumor predisposition syndrome, caused by bi-allelic loss-of-function germline variants in the base excision repair (BER) gene MBD4. We identified five individuals with bi-allelic MBD4 variants within four families and these individuals had a personal and/or family history of adenomatous colorectal polyposis, acute myeloid leukemia, and uveal melanoma. MBD4 encodes a glycosylase involved in repair of G:T mismatches resulting from deamination of 5'-methylcytosine. The colorectal adenomas from MBD4-deficient individuals showed a mutator phenotype attributable to mutational signature SBS1, consistent with the function of MBD4. MBD4-deficient polyps harbored somatic mutations in similar driver genes to sporadic colorectal tumors, although AMER1 mutations were more common and KRAS mutations less frequent. Our findings expand the role of BER deficiencies in tumor predisposition. Inclusion of MBD4 in genetic testing for polyposis and multi-tumor phenotypes is warranted to improve disease management.

Validation of a Tool to Evaluate Nursing Students' Electronic Health Record Competency in Simulation.

AIM: The aim of the study was to establish reliability and validity of the Competency Assessment in Simulation of Electronic Health Records (CASE) tool. BACKGROUND: Effective teaching and learning practices, including valid and reliable assessment of students' electronic health record (EHR) competency, contribute to safe, high-quality, efficient nursing care. METHOD: The study used a mixed-methods design to test reliability and validity of the CASE tool. RESULTS: A nationally representative sample of faculty from universities representing 27 states provided scores for videos using the CASE tool. Forty-seven participants completed the first scoring survey; 22 of the 47 participants (47%) completed the second-round scoring. Intraclass correlation for the final score between the first and second responses shows the consistency of test-retest reliability (ICC = .78, p < .001). CONCLUSION: The CASE tool provided evidence of validity and reliability in evaluating EHR competency in simulation.

Local Sustained Delivery of Anti-IL-17A Antibodies Limits Inflammatory Bone Loss in Murine Experimental Periodontitis.

Periodontal disease (PD) is a chronic destructive inflammatory disease of the tooth-supporting structures that leads to tooth loss at its advanced stages. Although the disease is initiated by a complex organization of oral microorganisms in the form of a plaque biofilm, it is the uncontrolled immune response to periodontal pathogens that fuels periodontal tissue destruction. IL-17A has been identified as a key cytokine in the pathogenesis of PD. Despite its well documented role in host defense against invading pathogens at oral barrier sites, IL-17A-mediated signaling can also lead to a detrimental inflammatory response, causing periodontal bone destruction. In this study, we developed a local sustained delivery system that restrains IL-17A hyperactivity in periodontal tissues by incorporating neutralizing anti-IL-17A Abs in poly(lactic-coglycolic) acid microparticles (MP). This formulation allowed for controlled release of anti-IL-17A in the periodontium of mice with ligature-induced PD. Local delivery of anti-IL-17A MP after murine PD induction inhibited alveolar bone loss and osteoclastic activity. The anti-IL-17A MP formulation also decreased expression of IL-6, an IL-17A target gene known to induce bone resorption in periodontal tissues. This study demonstrates proof of concept that local and sustained release of IL-17A Abs constitutes a promising therapeutic strategy for PD and may be applicable to other osteolytic bone diseases mediated by IL-17A-driven inflammation.

Dominantly inherited micro-satellite instable cancer - the four Lynch syndromes - an EHTG, PLSD position statement.

The recognition of dominantly inherited micro-satellite instable (MSI) cancers caused by pathogenic variants in one of the four mismatch repair (MMR) genes MSH2, MLH1, MSH6 and PMS2 has modified our understanding of carcinogenesis. Inherited loss of function variants in each of these MMR genes cause four dominantly inherited cancer syndromes with different penetrance and expressivities: the four Lynch syndromes. No person has an "average sex "or a pathogenic variant in an "average Lynch syndrome gene" and results that are not stratified by gene and sex will be valid for no one. Carcinogenesis may be a linear process from increased cellular division to localized cancer to metastasis. In addition, in the Lynch syndromes (LS) we now recognize a dynamic balance between two stochastic processes: MSI producing abnormal cells, and the host's adaptive immune system's ability to remove them. The latter may explain why colonoscopy surveillance does not reduce the incidence of colorectal cancer in LS, while it may improve the prognosis. Most early onset colon, endometrial and ovarian cancers in LS are now cured and most cancer related deaths are after subsequent cancers in other organs. Aspirin reduces the incidence of colorectal and other cancers in LS. Immunotherapy increases the host immune system's capability to destroy MSI cancers. Colonoscopy surveillance, aspirin prevention and immunotherapy represent major steps forward in personalized precision medicine to prevent and cure inherited MSI cancer.

An Automatically Adaptive Digital Health Intervention to Decrease Opioid-Related Risk While Conserving Counselor Time: Quantitative Analysis of Treatment Decisions Based on Artificial Intelligence and Patient-Reported Risk Measures.

BACKGROUND: Some patients prescribed opioid analgesic (OA) medications for pain experience serious side effects, including dependence, sedation, and overdose. As most patients are at low risk for OA-related harms, risk reduction interventions requiring multiple counseling sessions are impractical on a large scale. OBJECTIVE: This study evaluates whether an intervention based on reinforcement learning (RL), a field of artificial intelligence, learned through experience to personalize interactions with patients with pain discharged from the emergency department (ED) and decreased self-reported OA misuse behaviors while conserving counselors' time. METHODS: We used data representing 2439 weekly interactions between a digital health intervention ("Prescription Opioid Wellness and Engagement Research in the ED" [PowerED]) and 228 patients with pain discharged from 2 EDs who reported recent opioid misuse. During each patient's 12 weeks of intervention, PowerED used RL to select from 3 treatment options: a brief motivational message delivered via an interactive voice response (IVR) call, a longer motivational IVR call, or a live call from a counselor. The algorithm selected session types for each patient each week, with the goal of minimizing OA risk, defined in terms of a dynamic score reflecting patient reports during IVR monitoring calls. When a live counseling call was predicted to have a similar impact on future risk as an IVR message, the algorithm favored IVR to conserve counselor time. We used logit models to estimate changes in the relative frequency of each session type as PowerED gained experience. Poisson regression was used to examine the changes in self-reported OA risk scores over calendar time, controlling for the ordinal session number (1st to 12th). RESULTS: Participants on average were 40 (SD 12.7) years of age; 66.7% (152/228) were women and 51.3% (117/228) were unemployed. Most participants (175/228, 76.8%) reported chronic pain, and 46.2% (104/225) had moderate to severe depressive symptoms. As PowerED gained experience through interactions over a period of 142 weeks, it delivered fewer live counseling sessions than brief IVR sessions (P=.006) and extended IVR sessions (P<.001). Live counseling sessions were selected 33.5% of the time in the first 5 weeks of interactions (95% CI 27.4%-39.7%) but only for 16.4% of sessions (95% CI 12.7%-20%) after 125 weeks. Controlling for each patient's changes during the course of treatment, this adaptation of treatment-type allocation led to progressively greater improvements in self-reported OA risk scores (P<.001) over calendar time, as measured by the number of weeks since enrollment began. Improvement in risk behaviors over time was especially pronounced among patients with the highest risk at baseline (P=.02). CONCLUSIONS: The RL-supported program learned which treatment modalities worked best to improve self-reported OA risk behaviors while conserving counselors' time. RL-supported interventions represent a scalable solution for patients with pain receiving OA prescriptions. TRIAL REGISTRATION: Clinicaltrials.gov NCT02990377; https://classic.clinicaltrials.gov/ct2/show/NCT02990377.

Characteristics and effectiveness of mentoring programmes for specialized and advanced practice nurses: A systematic review.

AIMS: (1) To identify, evaluate and summarize evidence about the objectives and characteristics of mentoring programmes for specialized nurses (SNs) or nurse navigators (NNs) and advanced practice nurses (APNs) and (2) to identify the effectiveness of these programmes. DESIGN: A systematic review based on PRISMA guidelines. DATA SOURCES: From November 2022 until 7 December 2022, four databases were searched: PubMed, EMBASE, CINAHL and The Cochrane Library. REVIEW METHODS: Study selection was performed independently by two researchers. Disagreements were discussed until consensus was reached. Data extraction was undertaken for included studies. Data synthesis was conducted using narrative analysis. Quality appraisal was performed using the Critical Appraisal Skill Programme (CASP) and Mixed Methods Appraisal Tool (MMAT). RESULTS: Twelve articles were included, all of which focused on mentoring programmes for APNs. Different forms of mentorship (e.g. (in)formal mentorship, work shadowing, workshops) were reported. Studies reported positive outcomes on job retention (n = 5), job satisfaction (n = 6), skills improvement (n = 7), satisfaction with the programme (n = 7) and confidence improvement (n = 4) among participants of mentoring programmes. CONCLUSION: There is a lack of uniformity and consistency in various elements of mentoring programmes. Further research is needed to develop mentoring programmes for both APNs and SNs/NNs in a systematic and theoretically underpinned manner. It is necessary to establish a thorough evaluation methodology, preferably using a mixed methods design that includes both a qualitative process evaluation and a comprehensive outcome evaluation using validated questionnaires, taking into account the NN/APN, the interprofessional team and organizational level. IMPACT: The synthesis of evidence may be useful to organizations developing and implementing mentoring programmes for both SN/NN and APN. The development of a mentoring programme for nursing experts should be considered a complex intervention that requires theoretical frameworks and contextual considerations. NO PATIENT OR PUBLIC CONTRIBUTION: Not applicable, as no patients or public were involved.

Electronic Health Record Maturity Matters! Texas Nurses Speak Out in Their Second Statewide Study.

With the passage of the Health Information Technology for Economic and Clinical Health Act in 2009, Texas nurses were faced with the rapid uptake of technology driven by this legislation. Texas Nurses Association and Texas Organization for Nursing Leadership formed a partnership to collectively track the impact on practicing nurses. The Health IT Committee was commissioned to evaluate the changing health information technology environment and associated solutions. As such, a study in 2015, entitled "Statewide Study Assessing the Experiences of Nurses with their Electronic Health Records," was conducted. The follow-up study in 2020 was conducted to compare 2015 and 2020 findings to identify improvements made on nurses' satisfaction with EHRs and identify improvement opportunities. The study design was an exploratory descriptive comparative analysis with a cross-sectional survey from a random sample of Texas nurses for the two study periods of 2015 (n = 1177) and 2020 (n = 1117). The Clinical Information Systems Implementation Evaluation Scale and a demographic survey including the Meaningful Use Maturity-Sensitive Index were the measurement instruments. Results and key covariates are discussed along with recommendations for achieving more mature EHRs and more mature organizational culture and leadership.

The first line of prevention: A public health nursing advocacy video.

Public health nurses (PHNs) serve as the first line of prevention in public health and safety threats such as the COVID-19 pandemic. Although PHNs provide vital services to protect communities and populations' health, a pervasive lack of knowledge exists regarding the PHN role among policymakers and the general public. Advocacy for investment in the public health nursing workforce remains a priority as staffing and financial constraints have created sizeable barriers for PHNs during the COVID-19 response. Creating an advocacy video with personal stories from PHNs emerges as a powerful and cost-effective strategy to increase the visibility of PHNs. For this project, interviews with PHNs from COVID-19 hot spots were used to create a 3-min advocacy video. PHNs featured in this video discussed the implications of rerouting resources to combat COVID-19 for the populations they serve. The authors disseminated the video through popular social media venues, public health and nursing organizations and nurse influencers to reach nursing students, faculty, and the public. Over an 8-week period, the video received 2732 views on social media with an average view duration of 2 min. This article includes strategies to maximize the impact of an advocacy video when shared with relevant stakeholders.

University students' profiles of burnout symptoms amid the COVID-19 pandemic in Germany and their relation to concurrent study behavior and experiences.

Burnout symptoms are prevalent among university students. This study examined students' understudied profiles of burnout symptoms and their relation to procrastination, dropout intentions, and study- and life satisfaction. We used cross-sectional data from two online-studies conducted in Germany in April 2020 amid the COVID-19 pandemic (N study1 = 597, N study2 = 857). Latent profile analyses indicated three profiles in both studies: (1) well-functioning, (2) moderately exhausted-inefficacious, and (3) burned-out. Most students belonged to Profiles 1 and 2 with low to moderate burnout symptoms. Students in Profile 3 reported the highest symptoms, most procrastination, strongest dropout intentions, and lowest study- and life satisfaction. The distinct profiles broaden knowledge about intra-individual differences in students' burnout experiences and underpin the need for tailored interventions.

Implementing supportive exercise interventions in the colorectal cancer care pathway: a process evaluation of the PREPARE-ABC randomised controlled trial.

BACKGROUND: A colorectal resection is standard treatment for patients with colorectal cancer (CRC). However, the procedure results in significant post-operative mortality and reduced quality of life. Maximising pre-operative cardiopulmonary fitness could improve post-surgical outcomes. PREPARE-ABC is a multi-centre, three-armed, randomised controlled trial investigating the effects of exercise interventions, with motivational support on short and longer-term recovery outcomes in CRC patients undergoing major lower-gastrointestinal surgery. The trial included an internal pilot phase with parallel process evaluation. The aim of the process evaluation was to optimise intervention implementation for the main trial. METHODS: Mixed methods process evaluation conducted in 14 UK hospitals between November 2016 and March 2018. Data included a site profile questionnaire and telephone scoping interview with hospital staff, 34 qualitative observations of standard care and 14 observations of intervention delivery, 13 semi-structured interviews with healthcare professionals (HCPs) and 28 semi-structured interviews with patients. Data analysis focused on describing intervention delivery within each arm, assessing fidelity, acceptability and how variation in delivery was linked to contextual characteristics. RESULTS: Standard care exercise advice was typically limited to maintaining current activity levels, and with lead-in time to surgery affecting whether any exercise advice was provided. Variation in HCP capacity affected the ability of colorectal units to deploy staff to deliver the intervention. Patients' exercise history and motivation prior to surgery influenced HCP perceptions and delivery of the motivational components. Observations indicated a high level of fidelity to delivery of the exercise interventions. All but one of the 28 interviewed patients reported increasing exercise levels as a result of receiving the intervention, with most finding them motivational and greatly valuing the enhanced level of social support (versus standard care) provided by staff. CONCLUSION: Hospital-supervised and home-based exercise interventions were highly acceptable for most patients undergoing surgery for CRC. Delivery of pre- and post-operative exercise within the CRC care pathway is feasible but systematic planning of capacity and resources is required to optimise implementation.

Interpersonal Violence: What Undergraduate Nursing Students Know.

A program evaluation of undergraduate nursing curricula content was completed and survey developed to assess undergraduate nursing students' knowledge about interpersonal violence. Students electively answered a 43-question survey regarding interpersonal violence as a public health problem. The sample included 104 traditional and accelerated undergraduate nursing students. Increasing scores during undergraduate program enrollment suggests that students receive some content on violence from the undergraduate curriculum. This study provides data about curricular deficits and proposes content revisions to prepare nursing students to address violence in patient populations.

Parents' concerns about Leavers celebrations: A cross-sectional study.

ISSUE ADDRESSED: "Schoolies' or "Leavers' is a mass celebration of the end of compulsory schooling where excessive drinking is considered integral to the experience. Leavers are at risk of alcohol-related harms. This paper reports the concerns of parents for their Year 12 students (age 17 years) when attending Leavers celebrations. METHODS: Parents of Year 12 students (n = 87) were asked to complete a survey in relation to their eldest school-aged child. Six items relating to parents' level of "concern' about Leavers celebrations were measured on a 5-point scale. RESULTS: Parents were concerned about their child experiencing peer pressure to consume alcohol (60%), 30% were neutral or unconcerned about peer pressure. Almost two thirds of parents were concerned about their child being injured as a result of their own alcohol use (66.7%). Parental concern relating to their child being injured because of others' alcohol use rated most highly (88.5%). CONCLUSIONS: Findings suggested that parents were more concerned with harm caused to their child by others than the use of alcohol by their own child. Parents were somewhat less concerned with peer pressure to drink, though given peer influence is a major factor in young people's decisions regarding alcohol, parents' apparent confidence in their children's capacity to resist peer pressure may be inflated. SO WHAT?: Future interventions reinforcing the important role that parents play in the decisions that young people make while at Leavers have the potential to reduce their alcohol intake and subsequent alcohol-related harm.

Good urodynamic practice adaptations during the COVID-19 pandemic.

Urodynamics testing forms the cornerstone of investigations when it comes to lower urinary tract dysfunction. It has to be done to the highest standards by following the International Continence Society Good Urodynamics Practice protocols. However, with the COVID-19 pandemic, certain adaptations to the urodynamics procedure need to be considered especially when it comes to quality control. This article aims to define these adaptations to help urodynamicists in their daily practice.

Weakness and cognitive impairment are independently and jointly associated with functional decline in aging Americans.

BACKGROUND: Discovering how certain health factors contribute to functional declines may help to promote successful aging. AIMS: To determine the independent and joint associations of handgrip strength (HGS) and cognitive function with instrumental activities of daily living (IADL) and activities of daily living (ADL) disability decline in aging Americans. METHODS: Data from 18,391 adults aged 50 years and over who participated in at least one wave of the 2006-2014 waves of the Health and Retirement Study were analyzed. A hand-held dynamometer assessed HGS and cognitive functioning was examined with a modified version of the Telephone Interview of Cognitive Status. IADL and ADL abilities were self-reported. Participants were stratified into four distinct groups based on their HGS and cognitive function status. Separate covariate-adjusted multilevel models were conducted for the analyses. RESULTS: Participants who were weak, had a cognitive impairment, and had both weakness and a cognitive impairment had 1.70 (95% confidence interval (CI) 1.57-1.84), 1.97 (CI 1.74-2.23), and 3.13 (CI 2.73-3.59) greater odds for IADL disability decline, respectively, and 2.26 (CI 2.03-2.51), 1.26 (CI 1.05-1.51), and 4.48 (CI 3.72-5.39) greater odds for ADL disability decline, respectively. DISCUSSION: HGS and cognitive functioning were independently and jointly associated with IADL and ADL disability declines. Individuals with both weakness and cognitive impairment demonstrated substantially higher odds for functional decline than those with either risk factor alone. CONCLUSIONS: Including measures of both HGS and cognitive functioning in routine geriatric assessments may help to identify those at greatest risk for declining functional capacity.

Redirection of miRNA-Argonaute Complexes to Specific Target Sites by Synthetic Adaptor Molecules.

Dysregulation of miRNAs is connected with a multitude of diseases for which antagomirs and miRNA replacement are discussed as therapeutic options. Here, we suggest an alternative concept based on the redirection of RISCs to non-native target sites. Metabolically stable DNA-LNA mixmers are used to mediate the binding of RISCs to mRNAs without any direct base complementarity to the presented guide RNA strand. Physical redirection of a dye-labeled miRNA model and of specific miRNA-programmed RISC fractions present in HeLa extracts is demonstrated by pull-down experiments with biotinylated capture oligonucleotides.