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Objectives: End-of-life (EOL) transitions to hospital can be burdensome for older adults and may contribute to poor outcomes. We investigated the association of disease trajectory and place of care with EOL burdensome transitions., Design: Retrospective cohort study using administrative data., Setting/participants: Ontarians aged ≥65 years who died between 2015 and 2018 and received long-term care (LTC) or home care 6 months before death., Methods: Disease trajectories were defined based on EOL functional decline: terminal illness, organ failure, frailty, sudden death, and other. Places of care included LTC, EOL home care, and non-EOL home care. Burdensome transitions were defined as early (≥3 hospitalizations for any reason or ≥2 hospitalizations due to pneumonia, urinary tract infection, sepsis, or dehydration in the last 90 days of life) or late (≥1 hospitalizations for any reason in the last 3 days of life). Multinomial logistic regression tested for effect modification between disease trajectory and places of care on burdensome transitions., Results: Of 110,776 decedents, 40.7% had organ failure, 37.5% had frailty, and 12.8% had a terminal illness, with the remainder in sudden death or other categories. Most were in LTC (62.5%), and 37.5% received home care, with 6.8% receiving designated EOL home care and 30.7% non-EOL home care. There was a significant interaction (P < .001) between disease trajectory and care settings. Compared with terminal illness, organ failure was associated with increased odds of early transitions across all care settings [odds ratios (ORs) ranging 1.14-1.21]. Frailty was associated with increased odds of early transitions solely for non-EOL home care recipients (OR 1.17, 95% CI 1.06-1.28). Organ failure and frailty were associated with increased odds of late transitions across all settings, with organ failure having greater odds in LTC (organ failure OR 2.29, 95% CI 2.02-2.60, vs frailty OR 1.79, 95% CI 1.58-2.04)., Conclusions and Implications: Disparities exist in burdensome transitions, notably for noncancer decedents with organ failure in LTC. Enhancing palliative care may help reduce burdensome transitions and improve patient outcomes., Competing Interests: Disclosures The authors declare no conflicts of interest., (Copyright © 2024 Post-Acute and Long-Term Care Medical Association. Published by Elsevier Inc. All rights reserved.)

Idiopathic inflammatory myopathies (IIMs) are a rare and heterogeneous group of chronic autoimmune disorders. Up to 40% of IIM patients have long-term sequelae and significant functional disability. Its management can be challenging and new therapies are badly needed. The small number of cases with diverse presentations and different diagnostic criteria significantly affect clinical trial results. Only IVIG has been internationally approved for IIM patients. Most clinical trials of new biologic therapies have failed to meet their primary endpoints in IIM, with only one biologic drug recommended for refractory IIM treatment (rituximab), although not approved. We review several new emerging biologic drugs, including B cell depletion therapies, abatacept, Janus kinase inhibitors, and aldesleukin. Encouragingly, some phase II randomized controlled trials have evaluated the efficacy and safety of new biologics in IIM, demonstrating an improvement in clinical and laboratory measures., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: The Social Vulnerability Index (SVI) has previously been demonstrated to correlate with worse postoperative outcomes after surgery, but the association of SVI with short- and long-term outcomes after colon cancer surgery has been underexplored., Methods: This is a retrospective cross-sectional study of Medicare patients aged 65 to 99 years who underwent colectomy for colon cancer between 2016 and 2020, merged with SVI at the census tract level. We tested the association between SVI with emergent colectomy and 30-day and 1-year mortality using a multivariable logistic regression model adjusted for patient demographics and hospital characteristics., Results: The cohort included 169,498 patients who underwent colectomy for colon cancer. Medicare patients living in areas in the highest quintile of social vulnerability were more likely to undergo unplanned colectomy for colon cancer than those in the lowest quintile (35.6% vs 28.9%; adjusted odds ratio [aOR], 1.36; 95% CI, 1.31-1.41; P < .001). Similarly, patients living in areas in the highest quintile of social vulnerability experienced higher risk-adjusted rates of 30-day mortality (3.4% vs 2.9%; aOR, 1.20; 95% CI, 1.12-1.29; P < .001) and 1-year mortality (10.8% vs 8.6%; aOR, 1.30; 95% CI, 1.22-1.37; P < .001) than patients living in the lowest quintile of social vulnerability. When evaluating the elective and unplanned cohorts separately, these differences persisted., Conclusion: Among Medicare patients undergoing colectomy for colon cancer, high social vulnerability was associated with an increased risk of unplanned operations and worse short- and long-term postoperative outcomes in both the emergent and elective settings. Providers should seek to mitigate disparate surgical outcomes by addressing structural inequities in social resources., (Copyright © 2024 Society for Surgery of the Alimentary Tract. Published by Elsevier Inc. All rights reserved.)

Age is a major risk factor for cancer, but how aging impacts tumor control remains unclear. In this study, we establish that aging of the immune system, regardless of the age of the stroma and tumor, drives lung cancer progression. Hematopoietic aging enhances emergency myelopoiesis, resulting in the local accumulation of myeloid progenitor-like cells in lung tumors. These cells are a major source of interleukin (IL)-1⍺, which drives the enhanced myeloid response. The age-associated decline of DNA methyltransferase 3A enhances IL-1⍺ production, and disrupting IL-1 receptor 1 signaling early during tumor development normalized myelopoiesis and slowed the growth of lung, colonic, and pancreatic tumors. In human tumors, we identified an enrichment for IL-1⍺-expressing monocyte-derived macrophages linked to age, poorer survival, and recurrence, unraveling how aging promotes cancer and offering actionable therapeutic strategies.

As bacterial symbionts transition from a motile free-living state to a sessile biofilm state, they must coordinate behavior changes suitable to each lifestyle. Cyclic diguanylate (c-di-GMP) is an intracellular signaling molecule that can regulate this transition, and it is synthesized by diguanylate cyclase (DGC) enzymes and degraded by phosphodiesterase (PDE) enzymes. Generally, c-di-GMP inhibits motility and promotes biofilm formation. While c-di-GMP and the enzymes that contribute to its metabolism have been well studied in pathogens, considerably less focus has been placed on c-di-GMP regulation in beneficial symbionts. Vibrio fischeri is the sole beneficial symbiont of the Hawaiian bobtail squid ( Euprymna scolopes ) light organ, and the bacterium requires both motility and biofilm formation to efficiently colonize. c-di-GMP regulates swimming motility and cellulose exopolysaccharide production in V. fischeri . The genome encodes 50 DGCs and PDEs, and while a few of these proteins have been characterized, the majority have not undergone comprehensive characterization. In this study, we use protein overexpression to systematically characterize the functional potential of all 50 V . fischeri proteins. All 28 predicted DGCs and 10 of the 14 predicted PDEs displayed at least one phenotype consistent with their predicted function, and a majority of each displayed multiple phenotypes. Finally, active site mutant analysis of proteins with the potential for both DGC and PDE activities revealed potential activities for these proteins. This work presents a systems-level functional analysis of a family of signaling proteins in a tractable animal symbiont and will inform future efforts to characterize the roles of individual proteins during lifestyle transitions.IMPORTANCECyclic diguanylate (c-di-GMP) is a critical second messenger that mediates bacterial behaviors, and Vibrio fischeri colonization of its Hawaiian bobtail squid host presents a tractable model in which to interrogate the role of c-di-GMP during animal colonization. This work provides systems-level characterization of the 50 proteins predicted to modulate c-di-GMP levels. By combining multiple assays, we generated a rich understanding of which proteins have the capacity to influence c-di-GMP levels and behaviors. Our functional approach yielded insights into how proteins with domains to both synthesize and degrade c-di-GMP may impact bacterial behaviors. Finally, we integrated published data to provide a broader picture of each of the 50 proteins analyzed. This study will inform future work to define specific pathways by which c-di-GMP regulates symbiotic behaviors and transitions.

Objectives: Childhood-onset systemic lupus erythematosus (cSLE), representing 15%-20% of individuals with SLE, has been difficult to study globally due to differences between registries. This initiative, supported by Childhood Arthritis Rheumatology Research Alliance (CARRA) and Paediatric Rheumatology European Society (PReS), aims to create Core and Expanded cSLE Datasets to standardise and enhance research worldwide., Methods: 21 international cSLE experts and 4 patients participated in a Delphi process (questionnaires, 2 topic-specific focus groups and 3 virtual consensus meetings) to create 2 standardised cSLE datasets. The Core cSLE Dataset was designed to include data essential to meaningful clinical research across many settings. The Expanded cSLE Dataset was designed for centres able to consistently collect data to address broader research questions. Final data items for the Core and Expanded datasets were determined by consensus defined as >80% agreement) using an adapted nominal group technique and voting., Results: The resulting Core cSLE Dataset contains 46 items, including demographics, clinical features, laboratory results, medications and significant adverse events. The Expanded cSLE Dataset adds 26 additional items and includes patient-reported outcomes. Consensus was also achieved regarding the frequency and time points for data collection: baseline, quarterly follow-up visits, annually and flare visits., Conclusion: Standardised Core and Expanded cSLE Datasets for registry-based international cSLE research were defined through the consensus of global experts and patient/caregiver representatives, endorsed by CARRA and PReS. These datasets incorporate disease-specific and patient-specific features, optimised for diverse settings to facilitate international collaborative research for children and adolescents with SLE worldwide., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ on behalf of EULAR.)

Schizophrenia and schizoaffective disorder present burdens to patients and health systems through elevated healthcare resource utilization (HCRU) and costs. However, there is a paucity of evidence describing these burdens across payor types. To identify unmet needs, this study characterized patients with schizophrenia or schizoaffective disorder by payor type. We identified patients aged 12-94 years with newly diagnosed schizophrenia or schizoaffective disorder (index date) between 01/01/2014 and 08/31/2020 with continuous enrollment for 12 months before and after index date from the Healthcare Integrated Research Database. After stratifying by post-index relapse frequency (0, 1, or ≥2) and payor type (commercial, Medicare Advantage/Supplemental (Medigap)/Part D, or managed Medicaid), we examined patient characteristics, treatment patterns, HCRU, costs, and relapse patterns and predictors. During follow-up, 25% of commercial patients, 29% of Medicare patients, and 37% of Medicaid patients experienced relapse. Atypical antipsychotic discontinuation was most common among Medicaid patients, with 65% of these patients discontinuing during follow-up. Compared to commercial patients, Medicare and Medicaid patients had approximately half as many psychotherapy visits during follow-up (12 vs. 5 vs. 7 visits, respectively). Relative to baseline, average unadjusted all-cause costs during follow-up increased by 105% for commercial patients, 66% for Medicare patients, and 77% for Medicaid patients. Patients with schizophrenia or schizoaffective disorder had high HCRU and costs but consistently low psychotherapy utilization, and they often discontinued pharmacologic therapy and experienced relapse. These findings illustrate the high burden and unmet need for managing these conditions and opportunities to improve care for underserved patients., (© 2024. The Author(s).)

Injunctive social norms are societal standards for how people are expected to behave. When individuals transgress these norms, they face social sanctions for their behavior. These sanctions can take many forms ranging from verbal or non-verbal reactions and from disapproval to ostracism. We review the stable characteristics and situational variables that affect a bystander's tendency to enact social sanctions against someone who violates an injunctive social norm. Stable characteristics include the bystander's extraversion, altruism, the belief that others can change their behavior, and their cultural background. Situational factors include the extent to which the violated norm implicates the bystander, the social hierarchies among the bystander and transgressor, the presence of additional bystanders, and (when applicable) the bystander's relationship to the victim of the norm violation. We also discuss the costs that a bystander can incur by attempting to enact social sanctions. We conclude with a discussion of the application of social sanctions to enforce pro-social social norms., Competing Interests: Declaration of competing interest 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., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Context: Codesign is a methodology that includes active collaboration between stakeholders in designing solutions and has been used in the development and implementation of palliative care (PC) interventions., Objectives: To synthesize the state of evidence for codesign in the development of PC interventions., Methods: We searched PubMed, EMBASE, and CINAHL for peer-reviewed studies published after 1995 that reported evidence of codesigned interventions and outcomes in patients receiving palliative, hospice, or end-of-life care. We screened studies through independent and blinded dual review within Covidence and assessed study quality with the 2018 Mixed Methods Appraisal Tool. We narratively synthesized codesign duration, engagement approach, stakeholders involved, intervention designs, follow-ups, and outcomes, comparing among codesigns reporting meaningful improvement in outcomes. We created a best practice checklist which we used to evaluate codesign use in each study., Results: About 1,036 abstracts and 54 full text articles were screened. Twenty-eight studies met inclusion criteria and were abstracted. Feedback collection modalities ranged from iterative drafting, pilot testing, advisory panels, workshops, focus groups, and interviews. Thirteen studies applied pretesting/prototyping through pretest post-test, focus groups, prototypes, alpha and beta testing, and mock-ups. Eleven studies reported improved outcomes, eight of which utilized iterative codesign. All the studies reporting improved outcomes mentioned meeting with stakeholders at least twice. Two studies met all criteria in our codesign best practice checklist., Conclusion: Codesigned PC interventions demonstrate high variance in the modality of acquiring feedback and application of codesign. Successful codesign leading to improvement in outcomes is achieved by involving patients, caregivers, and providers in iterating intervention design., (Published by Elsevier Inc.)

Digital medicine has increasing influence on the German healthcare system. In times of social distancing during the ongoing coronavirus disease 2019 (COVID-19) pandemic, digital tools enable health professionals to maintain medical care. Furthermore, digital elements have potential to provide effective guideline-oriented treatment to a broad range of patients independently from location and time. This survey was used to assess the attitudes of members of the German Pain Society (health professionals) and of associated self-help groups (patients) towards digital medicine. It was sent out as an online survey to health professionals in September 2020 and to patients in February 2021. The survey referred especially to present usage, attitude and potential concerns regarding particular digital elements. Furthermore, technical affinity was assessed. In total, 250 health professionals and 154 patients participated in the survey. The results show that-although digital elements are already known-a substantial proportion of health professionals still lack broad transfer to regular treatment. The potential of digital tools seems to be recognized by both groups; interestingly, patients consider digital medicine as more useful than health professionals. Nevertheless, concerns about for example data security or digital competence remain in both groups. Taken together, our results indicate that disruptive changes, as the implementation of digital medicine in the healthcare system, have to be guided by intense education and channeled by political policies in order to successfully integrate digital elements into medicine on a long-term basis. This would be in favor for all involved parties and is demanded especially by patients., (© 2023. The Author(s), under exclusive licence to Springer Medizin Verlag GmbH, ein Teil von Springer Nature.)

Objectives: This study aims to determine the independent impact of definitions of remission/low disease activity (LDA) on direct/indirect costs (DCs, ICs) in a multicentre inception cohort., Methods: Patients from 31 centres in 10 countries were enrolled within 15 months of diagnosis and assessed annually. Five mutually exclusive disease activity states (DAS) were defined as (1) remission off-treatment: clinical (c) SLEDAI-2K=0, without prednisone/immunosuppressants; (2) remission on-treatment: cSLEDAI-2K=0, prednisone ≤5 mg/day and/or maintenance immunosuppressants; (3) LDA-Toronto Cohort (TC): cSLEDAI-2K≤2, without prednisone/immunosuppressants; (4) modified lupus LDA state (mLLDAS): SLEDAI-2K≤4, no activity in major organs/systems, no new activity, prednisone ≤7.5 mg/day and/or maintenance immunosuppressants and (5) active: all remaining assessments.At each assessment, patients were stratified into the most stringent DAS fulfilled and the proportion of time in a DAS since cohort entry was determined. Annual DCs/ICs (2021 Canadian dollars) were based on healthcare use and lost workforce/non-workforce productivity over the preceding year.The association between the proportion of time in a DAS and annual DC/IC was examined through multivariable random-effects linear regressions., Results: 1692 patients were followed a mean of 9.7 years; 49.0% of assessments were active. Remission/LDA (per 25% increase in time in a remission/LDA state vs active) were associated with lower annual DC/IC: remission off-treatment (DC -$C1372; IC -$C2507), remission on-treatment (DC -$C973; IC -$C2604,) LDA-TC (DC -$C1158) and mLLDAS (DC -$C1040). There were no cost differences between remission/LDA states., Conclusions: Our data suggest that systemic lupus erythematosus patients who achieve remission, both off and on-therapy, and reductions in disease activity incur lower costs than those experiencing persistent disease activity., Competing Interests: Competing interests: MRWB has received consulting fees, speaking fees and/or honoraria from AbbVie, AstraZeneca, GlaxoSmithKline, Janssen and Sanofi Genzyme. MFU-G has received consulting and/or speaking fees from AstraZeneca, GlaxoSmithKline, Ferrer and a research grant from Janssen. CG has received consulting fees, speaking fees, and/or honoraria from AstraZeneca, Abbvie, Amgen, Sanofi, and UCB (less than $10 000 each). DJW has received consulting fees from Merck, EMD Serono, Pfizer, Lilly and Glenmark (less than $10 000 each). PRF has received consulting fees from AstraZeneca and GlaxoSmithKline (less than $10 000 each). DDG received consulting fees and/or honoraria from GlaxoSmithKline and AstraZeneca (less than $10 000). INB has received consulting fees, speaking fees, and/or honoraria from Eli Lilly, UCB, Roche, Merck Serono, MedImmune (less than $10 000 each) and grants from UCB, Genzyme Sanofi, and GlaxoSmithKline. EMG has paid consultation with investment analysts Guidepoint Global Gerson Lerman Group. RR-G has received consulting fees from Cabaletta, BristolMyersSquibb, Biogen, Merck, and Ampel Solutions (all less than $10 000 each). RFvV has received consulting fees, speaking fees and/or honoraria from AbbVie, AstraZeneca, Biotest, Bristol Myers Squibb, Celgene, GlaxoSmithKline, Janssen, Lilly, Novartis, Pfizer, and UCB (less than $10 000 each) and research support from AbbVie, Bristol Myers Squibb, GlaxoSmithKline, Pfizer and UCB. MI has received consulting fees from UCB and Amgen (less than $10 000 each). KK has received grants from UCB, Human Genome Sciences/GlaxoSmithKline, Takeda, Ablynx, Bristol-Myers Squibb, Pfizer, and Kyowa Hakko Kirin, and has received consulting fees from Exagen Diagnostics, Genentech, Eli Lilly, Bristol-Myers Squibb and Anthera (less than $10 000 each). AEC has received consulting fees, speaking fees, and/or honoraria from AstraZeneca, BristolMyersSquibb, GlaxoSmithKline, Roche and Otsuka (less than $10 000 each) and a research grant from GlaxoSmithKline. No other disclosures relevant to this article were reported., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ on behalf of EULAR.)

As bacterial symbionts transition from a motile free-living state to a sessile biofilm state, they must coordinate behavior changes suitable to each lifestyle. Cyclic diguanylate (c-di-GMP) is an intracellular signaling molecule that can regulate this transition, and it is synthesized by diguanylate cyclase (DGC) enzymes and degraded by phosphodiesterase (PDE) enzymes. Generally, c-di-GMP inhibits motility and promotes biofilm formation. While c-di-GMP and the enzymes that contribute to its metabolism have been well-studied in pathogens, considerably less focus has been placed on c-di-GMP regulation in beneficial symbionts. Vibrio fischeri is the sole beneficial symbiont of the Hawaiian bobtail squid ( Euprymna scolopes ) light organ, and the bacterium requires both motility and biofilm formation to efficiently colonize. C-di-GMP regulates swimming motility and cellulose exopolysaccharide production in V. fischeri . The genome encodes 50 DGCs and PDEs, and while a few of these proteins have been characterized, the majority have not undergone comprehensive characterization. In this study, we use protein overexpression to systematically characterize the functional potential of all 50 V. fischeri proteins. All 28 predicted DGCs and 14 predicted PDEs displayed at least one phenotype consistent with their predicted function, and a majority of each displayed multiple phenotypes. Finally, active site mutant analysis of proteins with the potential for both DGC and PDE activities revealed potential activities for these proteins. This work presents a systems-level functional analysis of a family of signaling proteins in a tractable animal symbiont and will inform future efforts to characterize the roles of individual proteins during lifestyle transitions.

Background: Nephrologists routinely provide end-of-life care for patients with kidney failure (KF) on maintenance dialysis. Involvement of primary care and palliative care physicians may enhance this experience., Objective: The objective was to describe outpatient care patterns in the last year of life and the end-of-life acute care utilization for patients with KF on maintenance dialysis., Design: Retrospective cohort study using population-level health administrative data., Setting & Participants: Outpatient and inpatient care during the last year of life among patients who died between 2017 and 2019, receiving maintenance dialysis in Ontario, Canada., Measurements: The primary exposure is patterns of physician specialties providing outpatient care in the last year of life. Outcomes include outpatient encounters in the last year of life, acute care visitation in the last month of life, and place of death., Methods: We reported the count and percentage of categorical outcomes and the median (interquartile range) for numeric outcomes. We produced time series plots of the mean monthly percentage of encounters to different specialties stratified by physician specialty patterns. We evaluated differences in outcomes by physician specialty patterns using analysis of variance (ANOVA) and Pearson's chi-square tests ( P < .05, two-tailed)., Results: Among 6866 patients, the median age at death was 73, 36.1% were female, and 87.8% resided in urban regions. Three patterns emerged: a primary care, nephrology, and palliative care triad (25.5%); a primary care and nephrology dyad (59.3%); and a non-primary care pattern (15.2%). Palliative care involvement is concentrated near death. Of all, 81.4% spent at least 1 day in hospital or emergency department in the last month, but those with primary care, palliative care, and nephrology involvement had the fewest acute care deaths (65.8%)., Limitations: Outpatient care patterns were defined using physician billing codes, potentially missing care from other providers., Conclusions: Nephrology and primary care predominantly manage outpatient care in the last year of life for patients with KF on maintenance dialysis, with consistent acute care use across care patterns except for the place of death. Future research should explore associations between patterns of care and end-of-life outcomes to identify the most optimal model of care for patients with KF on maintenance dialysis., Competing Interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: MMS has received consultancy fees from AstraZeneca, Bayer, Otsuka, and GlaxoSmithKline. The remaining authors declared no potential conflicts of interest concerning the research, authorship, and/or publication of this article., (© The Author(s) 2024.)

We apply an approach from cognitive linguistics by mapping Conceptual Metaphor Theory (CMT) to the visualization domain to address patterns of visual conceptual metaphors that are often used in science infographics. Metaphors play an essential part in visual communication and are frequently employed to explain complex concepts. However, their use is often based on intuition, rather than following a formal process. At present, we lack tools and language for understanding and describing metaphor use in visualization to the extent where taxonomy and grammar could guide the creation of visual components, e.g., infographics. Our classification of the visual conceptual mappings within scientific representations is based on the breakdown of visual components in existing scientific infographics. We demonstrate the development of this mapping through a detailed analysis of data collected from four domains (biomedicine, climate, space, and anthropology) that represent a diverse range of visual conceptual metaphors used in the visual communication of science. This work allows us to identify patterns of visual conceptual metaphor use within the domains, resolve ambiguities about why specific conceptual metaphors are used, and develop a better overall understanding of visual metaphor use in scientific infographics. Our analysis shows that ontological and orientational conceptual metaphors are the most widely applied to translate complex scientific concepts. To support our findings we developed a visual exploratory tool based on the collected database that places the individual infographics on a spatio-temporal scale and illustrates the breakdown of visual conceptual metaphors.

We developed and validated an instrument to measure the perceived readability in data visualization: PREVis. Researchers and practitioners can easily use this instrument as part of their evaluations to compare the perceived readability of different visual data representations. Our instrument can complement results from controlled experiments on user task performance or provide additional data during in-depth qualitative work such as design iterations when developing a new technique. Although readability is recognized as an essential quality of data visualizations, so far there has not been a unified definition of the construct in the context of visual representations. As a result, researchers often lack guidance for determining how to ask people to rate their perceived readability of a visualization. To address this issue, we engaged in a rigorous process to develop the first validated instrument targeted at the subjective readability of visual data representations. Our final instrument consists of 11 items across 4 dimensions: understandability, layout clarity, readability of data values, and readability of data patterns. We provide the questionnaire as a document with implementation guidelines on osf.io/9cg8j. Beyond this instrument, we contribute a discussion of how researchers have previously assessed visualization readability, and an analysis of the factors underlying perceived readability in visual data representations.

Cyclic diguanylate (c-di-GMP) is a near-ubiquitous signaling molecule that regulates the motility-to-sessility transition in many bacterial species. Among the phenotypes influenced by c-di-GMP are biofilm formation, motility, cell cycle, and virulence. The hallmark phenotypes regulated by c-di-GMP-biofilm formation and motility-are key determinants of host-bacterial interactions. A large body of research has identified the roles of c-di-GMP in regulating phenotypes in culture. While numerous studies have investigated roles for c-di-GMP during the establishment and maintenance of pathogenic host-bacterial associations, considerably less attention has been devoted to defining the roles of c-di-GMP during beneficial and commensal associations. This review describes the known roles of c-di-GMP in regulating phenotypes that contribute to host colonization, with a focus on knowledge gaps and future prospects for examining c-di-GMP during beneficial colonization.

We present a systematic review, an empirical study, and a first set of considerations for designing visualizations in motion, derived from a concrete scenario in which these visualizations were used to support a primary task. In practice, when viewers are confronted with embedded visualizations, they often have to focus on a primary task and can only quickly glance at a visualization showing rich, often dynamically updated, information. As such, the visualizations must be designed so as not to distract from the primary task, while at the same time being readable and useful for aiding the primary task. For example, in games, players who are engaged in a battle have to look at their enemies but also read the remaining health of their own game character from the health bar over their character's head. Many trade-offs are possible in the design of embedded visualizations in such dynamic scenarios, which we explore in-depth in this paper with a focus on user experience. We use video games as an example of an application context with a rich existing set of visualizations in motion. We begin our work with a systematic review of in-game visualizations in motion. Next, we conduct an empirical user study to investigate how different embedded visualizations in motion designs impact user experience. We conclude with a set of considerations and trade-offs for designing visualizations in motion more broadly as derived from what we learned about video games. All supplemental materials of this paper are available at osf.io/3v8wm/.

We introduce DiffFit, a differentiable algorithm for fitting protein atomistic structures into an experimental reconstructed Cryo-Electron Microscopy (cryo-EM) volume map. In structural biology, this process is necessary to semi-automatically composite large mesoscale models of complex protein assemblies and complete cellular structures that are based on measured cryo-EM data. The current approaches require manual fitting in three dimensions to start, resulting in approximately aligned structures followed by an automated fine-tuning of the alignment. The DiffFit approach enables domain scientists to fit new structures automatically and visualize the results for inspection and interactive revision. The fitting begins with differentiable three-dimensional (3D) rigid transformations of the protein atom coordinates followed by sampling the density values at the atom coordinates from the target cryo-EM volume. To ensure a meaningful correlation between the sampled densities and the protein structure, we proposed a novel loss function based on a multi-resolution volume-array approach and the exploitation of the negative space. This loss function serves as a critical metric for assessing the fitting quality, ensuring the fitting accuracy and an improved visualization of the results. We assessed the placement quality of DiffFit with several large, realistic datasets and found it to be superior to that of previous methods. We further evaluated our method in two use cases: automating the integration of known composite structures into larger protein complexes and facilitating the fitting of predicted protein domains into volume densities to aid researchers in identifying unknown proteins. We implemented our algorithm as an open-source plugin (github.com/nanovis/DiffFit) in ChimeraX, a leading visualization software in the field. All supplemental materials are available at osf.io/5tx4q.

We propose and study a novel cross-reality environment that seamlessly integrates a monoscopic 2D surface (an interactive screen with touch and pen input) with a stereoscopic 3D space (an augmented reality HMD) to jointly host spatial data visualizations. This innovative approach combines the best of two conventional methods of displaying and manipulating spatial 3D data, enabling users to fluidly explore diverse visual forms using tailored interaction techniques. Providing such effective 3D data exploration techniques is pivotal for conveying its intricate spatial structures-often at multiple spatial or semantic scales-across various application domains and requiring diverse visual representations for effective visualization. To understand user reactions to our new environment, we began with an elicitation user study, in which we captured their responses and interactions. We observed that users adapted their interaction approaches based on perceived visual representations, with natural transitions in spatial awareness and actions while navigating across the physical surface. Our findings then informed the development of a design space for spatial data exploration in cross-reality. We thus developed cross-reality environments tailored to three distinct domains: for 3D molecular structure data, for 3D point cloud data, and for 3D anatomical data. In particular, we designed interaction techniques that account for the inherent features of interactions in both spaces, facilitating various forms of interaction, including mid-air gestures, touch interactions, pen interactions, and combinations thereof, to enhance the users' sense of presence and engagement. We assessed the usability of our environment with biologists, focusing on its use for domain research. In addition, we evaluated our interaction transition designs with virtual and mixed-reality experts to gather further insights. As a result, we provide our design suggestions for the cross-reality environment, emphasizing the interaction with diverse visual representations and seamless interaction transitions between 2D and 3D spaces.

We present the results of an exploratory study on how pairs interact with speech commands and touch gestures on a wall-sized display during a collaborative sensemaking task. Previous work has shown that speech commands, alone or in combination with other input modalities, can support visual data exploration by individuals. However, it is still unknown whether and how speech commands can be used in collaboration, and for what tasks. To answer these questions, we developed a functioning prototype that we used as a technology probe. We conducted an in-depth exploratory study with 10 participant pairs to analyze their interaction choices, the interplay between the input modalities, and their collaboration. While touch was the most used modality, we found that participants preferred speech commands for global operations, used them for distant interaction, and that speech interaction contributed to the awareness of the partner's actions. Furthermore, the likelihood of using speech commands during collaboration was related to the personality trait of agreeableness. Regarding collaboration styles, participants interacted with speech equally often whether they were in loosely or closely coupled collaboration. While the partners stood closer to each other during close collaboration, they did not distance themselves to use speech commands. From our fndings, we derive and contribute a set of design considerations for collaborative and multimodal interactive data analysis systems. All supplemental materials are available at https://osf.io/8gpv2.

The rise in ESBL-producing and carbapenem-resistant Gram-negative bacterial infections is alarming. Aminoglycosides remain attractive for treating urinary tract infections (UTIs). However, aminoglycosides-associated acute kidney injury (AKI) raises concerns, especially in patients with underlying renal impairment. We conducted a retrospective cohort study to evaluate the risk of AKI in patients with UTI empirically treated with amikacin. Among 395 patients (median age 41.9 years [IQR 28.3-67.1], 342 [86.6%] female), 162 (41.0%) received amikacin and 233 (59.0%) were empirically treated with other antibiotics. AKI incidence was low (5.6%) and not associated with amikacin exposure (OR 0.56, 95% CI 0.22-1.43, p  = 0.23), even in those with pre-existing renal impairment or AKI on admission. The clinical outcomes (including cure by the third day, AKI, maximal creatinine, length of stay, mortality, and readmission) did not differ between the groups. Once-daily amikacin may offer a safe UTI treatment option amid increasing multi-drug resistance.

Objective: Dermatomyositis (DM) symptoms negatively affect the quality of life of individuals living with the disease. Disease-specific, patient-reported outcome (PRO) instruments are needed to assess symptoms important to individuals with DM. This study aimed to conceptualize patient DM experience and disease activity definition to refine the development of the Dermatomyositis Disease Symptom Questionnaire (DM-DSQ), a novel PRO instrument capturing patient-reported symptoms., Methods: An observational, qualitative study was conducted with 30 individuals with DM (aged ≥ 18 yrs) in the US. A 1-hour semistructured interview, including concept elicitation and cognitive debriefing, was conducted with each participant. Inductive coding was used to identify concepts; a saturation analysis was conducted to confirm sample size. Concepts from transcripts were used to refine the preliminary conceptual model and DM-DSQ items., Results: Concept elicitation analysis findings included disease symptoms (eg, muscle weakness) and functional impacts (eg, walking). The analysis achieved conceptual saturation; the first 5 interviews uncovered most of the concepts. During cognitive debriefing of the DM-DSQ, participants found the items relevant, comprehensive, and easily understood (except for "skin sensitivity in sunlight"). The revised DM-DSQ content appears preliminarily valid in the patient population surveyed, pending further additions and debriefing based on refinement of the preliminary conceptual disease model and items., Conclusion: The DM-DSQ is being used in a phase II clinical trial and could become a valuable tool for studies evaluating PROs in patients with DM. Preliminary results indicate its content validity; extensive psychometric analysis using clinical trial data will determine its ability to capture symptoms for patients with DM.

Objective: To assess the impact of concomitant systemic lupus erythematosus (SLE) on the clinicopathological manifestations of thrombotic antiphospholipid syndrome (APS)., Methods: This single-centre, retrospective study compared clinical and antiphospholipid antibody (aPL) data from 118 patients, 58 with SLE-associated APS (SLE-APS), and 60 with primary APS., Results: Median follow-up was 13.9 (IQR 7.7-19.3) and 8.6 years (3.5-10.6) for the SLE-APS cohort and PAPS cohort, respectively. Age at diagnosis of APS was lower in the SLE-APS cohort (mean 35.9 vs PAPS: 46.7 years; p < 0.05). Distribution of aPL subtypes was similar across cohorts. 198 thrombotic events were identified overall (index plus recurrent), with venous thromboembolism (VTE) and arterial thrombosis each occurring in just over half of patients in both cohorts. Microvascular thrombosis (12.1% vs 0%), and a mixed (any combination of venous, arterial and microvascular) thrombotic phenotype (19.0% vs 6.7%, p = 0.05) were more prevalent in SLE-APS patients. Recurrent thrombosis incidence rates (∼0.5 events/10-patient years), and Kaplan-Meier recurrence-free survival after index thrombosis, were similar. In the PAPS cohort, only: (i) triple-aPL-positivity was associated with a significantly higher recurrent thrombosis event rate (incidence rate ratio 2.22, p = 0.03) and lower recurrence-free survival after first thrombosis (log-rank test p = 0.01); (ii) lupus anticoagulant (LA)-positivity was associated with higher prevalance of arterial thrombosis (RR 2.69, p = 0.01), and lower prevlance of VTE (RR 0.48, p < 0.001), versus LA-negativity., Conclusion: Concomitant SLE does not appear to modify long-term recurrent thrombosis risk, or aPL phenotypes, in patients with APS. Triple-aPL-positivity and LA-positive status may have less influence on thrombotic outcomes in patients with SLE-APS compared to PAPS., Competing Interests: Declaration of conflicting interestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: HC reports, outside the submitted work, institutional research support and support to attend scientific meetings from Bayer Healthcare; Roche Advisory Board; Consultancy fees from UCB Biopharma and Speaker fees from Technoclone paid to University College London Hospitals Charity. ME reports consultancy fees from Alexion Pharmaceutical. PM, MP, LT, JR, IT and DI have nothing to disclose.

Background: Parents have reported increased symptoms of depression and anxiety during the COVID-19 pandemic. This study evaluated changes in mental health and addiction (MHA)-related health service use among mothers and other birthing parents during the COVID-19 pandemic., Methods: We conducted a repeated cross-sectional study using health administrative data in Ontario, Canada. The population included all mothers and birthing parents (≥1 child aged 1-18, no children <1 to exclude postpartum parents) between January 2016 and December 2021. We compared rates of MHA-related outpatient physician visits, hospitalizations, and emergency department (ED) visits during COVID-19 (March 2020-December 2021) to pre-COVID-19 (pre-March 2020)., Results: MHA-related outpatient visit rates increased by 17 % (rate ratio (RR) 1.17, 95 % CI 1.16-1.18) during COVID-19. Monthly utilization rates remained higher than expected across the COVID-19 period. MHA-related ED visit rates remained lower than expected during COVID-19, while MHA-related hospitalization rates returned to expected levels by August 2020. The largest relative increases in MHA-related outpatient visits during COVID-19 were in mothers and other birthing parents living in higher income (RR 1.20, 95 % CI 1.19-1.22) or urban areas (RR 1.20, 95 % CI 1.18-1.21), with children aged 1-3 years (RR 1.23, 95 % CI 1.20-1.25) and with no history of MHA-related health service use (RR 1.20, 95 % CI 1.19-1.21)., Limitations: This study only captured physician-delivered MHA-related health service use., Conclusions: The COVID-19 pandemic was associated with an increase in MHA-related outpatient visits among mothers and other birthing parents. These findings point to the need for improvements in mental health service access., Competing Interests: Declaration of competing interest The authors have no conflicts to declare., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Objectives: Large vessel occlusion (LVO) strokes may be eligible for treatment with intravenous thrombolysis (IVT) and endovascular therapy (EVT). Patients selected for treatment have better neurologic outcomes with EVT, and delays in this therapy lead to worse outcomes. However, EVT is offered at a limited number of hospitals, referred to as endovascular stroke centers (ESC). This poses a difficult decision for EMS: to take potential stroke patients to the closest primary stroke center (PSC) or longer transport time to a more distant ESC. We hypothesized that patients with LVO stroke undergoing EVT transported directly to an ESC would have more favorable outcomes as measured by the modified Rankin scale (mRS) at 90 days, compared to transport to a PSC followed by transfer to an ESC., Methods: The OPUS-REACH consortium examined transportation patterns and outcomes in patients with LVO stroke who received endovascular treatment. This cohort includes 2400 patients with LVO stroke throughout eight endovascular centers in the Northeast U.S. from 2015 to 2020. All patients enrolled in the OPUS-REACH database were eligible for inclusion. Patients were excluded if they were missing the pickup address, had an in-hospital stroke, or arrived via mobile stroke unit. The remaining patients were separated into two groups: the bypass group, with transportation by EMS to an ESC by bypassing PSC, and the non-bypass group, with initial transport to PSC and interfacility transport to an ESC. The primary outcome was the modified Rankin scale (mRS) at 90 days, where 0-2 was defined as "good"., Results: The primary outcome did not reach significance with 40% of the bypass group as compared with the 33.1% of the non-bypass group having a "good" outcome. However, the bypass group underwent shorter times from last-known-well to both thrombolysis (120.9 vs 153.3 min, p  < 0.001) and thrombectomy (356.1 vs 454.8 min, p  = 0.001)., Conclusions: In patients with LVO stroke who undergo thrombectomy, EMS transport directly to an ESC results in shorter time thrombectomy, although we did not observe a difference in 90-day functional outcomes. Additionally, bypass to reach a more capable endovascular stroke center does not delay administration of IVT from time of LKW.

Purpose: With the expansion of neonatal care in sub-Saharan Africa (SSA), an increasing number of premature babies are at risk to develop retinopathy of prematurity (ROP). Previous studies have quantified the cost-effectiveness of addressing ROP in middle-income countries, but few have focused on SSA. This study estimates the cost of a national program for ROP screening and anti-VEGF injection treatment in Rwanda compared to the status quo., Methods: Medical cost data were collected from King Faisal Hospital in Rwanda (July 2022). Societal burden of vision loss included lost productivity and quality-adjusted life years (QALYs). Published data on epidemiology and natural history of ROP were used to estimate burden and sequelae of ROP in Rwanda. Cost of a national program for screening and treating a one-year birth cohort was compared to the status quo using a decision analysis model., Results: Cost of ROP screening and treatment was $738 per infant. The estimated equipment cost necessary for the startup of a national program was $58,667. We projected that a national program could avert 257 cases of blindness in the cohort and increase QALYs compared to the status quo. Screening and treatment for ROP would save an estimated $270,000 for the birth cohort from reductions in lost productivity., Conclusion: The cost of screening and anti-VEGF treatment for ROP is substantially less than the indirect cost of vision loss due to ROP. Allocating additional funding towards expansion of ROP screening and treatment is cost-saving from a societal perspective compared to current practice.

The synaptonemal complex (SC) is a zipper-like protein structure that aligns homologous chromosome pairs and regulates recombination during meiosis. Despite its conserved appearance and function, how synapsis occurs between chromosome axes remains elusive. Here, we demonstrate that Polo-like kinases (PLKs) phosphorylate a single conserved residue in the disordered C-terminal tails of two paralogous SC subunits, SYP-5 and SYP-6, to establish an electrostatic interface between the SC central region and chromosome axes in C. elegans . While SYP-5/6 phosphorylation is dispensable for the ability of SC proteins to self-assemble, local phosphorylation by PLKs at the pairing center is crucial for SC elongation between homologous chromosome axes. Additionally, SYP-5/6 phosphorylation is essential for asymmetric SC disassembly and proper PLK-2 localization after crossover designation, which drives chromosome remodeling required for homolog separation during meiosis I. This work identifies a key regulatory mechanism by which localized PLK activity mediates the SC-axis interaction through phosphorylation of SYP-5/6, coupling synapsis initiation to homolog pairing.

Objectives: Long-term care (LTC) homes provide personal and medical care 24/7 to individuals unable to live at home due to illness or disability and are often the final place of care and death for their residents. Therefore, LTC homes are tasked with providing quality end-of-life care, often requiring injectable symptom management medications to relieve distressing symptoms (eg, pain). In this study, we aimed to understand the enablers and barriers to prescribing and administering end-of-life symptom management medications in LTC homes., Design: Qualitative study., Setting and Participants: From February 2021 to December 2022, we conducted virtual semi-structured interviews with health care providers (physicians and nurses) who worked in Ontario LTC homes and family caregivers of residents who died in LTC., Methods: We analyzed interview transcripts using thematic analysis., Results: We identified 4 themes related to factors that may impact the prescribing and administering of medications for end-of-life symptom management: (1) identifying the end-of-life period and symptoms, (2) communication among health care providers and between health care providers and family caregivers, (3) health care provider competency with end-of-life medications, and (4) resources for LTC staff to support medication prescribing and administrating., Conclusions and Implications: In LTC, there are distinct challenges in the prescribing and administrating of end-of-life symptom management medications. Our findings can be used to inform interventions aimed at improving end-of-life care for LTC residents. However, these interventions require buy-in and investment from the provincial government and the LTC sector., Competing Interests: Disclosures The authors declare no conflicts of interest., (Copyright © 2024 AMDA – The Society for Post-Acute and Long-Term Care Medicine. Published by Elsevier Inc. All rights reserved.)

Subtalar dislocations of the talonavicular and talocalcaneal joints are rare, accounting for approximately one percent of all dislocations.1 These dislocations are typically the result of a high energy mechanism and present a challenge during reduction attempts. We present the case of a male in his early 20's who presented to the emergency department after a motorcycle accident with right foot and ankle pain and obvious deformity. Emergent X-ray and immediate attempt at reduction are of utmost importance with these dislocations. After multiple failed attempts at reduction in the ED, this patient was taken to the operating room for an open reduction with podiatry. This case report reviews the pathophysiology and management of this rare injury including nerve blocks and reduction techniques., Topics: Subtalar dislocation, trauma, podiatry, joint reduction, nerve blocks, local anesthesia., (© 2024 Maybury, et al.)

Background: To address the threat of retinopathy of prematurity (ROP) in Sub-Saharan Africa (SSA), the Stop Infant Blindness in Africa (SIBA) project introduced a comprehensive program, including subspecialty training and oxygen management equipment., Methods: A before-and-after retrospective cohort study compared preterm infants < 1750 g or < 34 weeks' gestation before (2022) and after (2023) program implementation. Outcomes included: the proportion with severe ROP, the proportion with Zone III vascularization on first examination, and factors associated with severe ROP., Results: Overall, 140 infants were screened before and 122 after program implementation. The proportion with Zone III vascularization increased from 16.1% (N = 11) pre-intervention to 44.9% (N = 32) post-intervention (p = 0.001). The proportion with severe ROP decreased from 27.8% (N = 19) to 12.8% (N = 9, p = 0.03). Factors predicting severe ROP on adjusted analyses were gestational age and blood transfusion., Conclusion: In SSA, introduction of a comprehensive program to prevent and treat ROP can decrease the risk of severe ROP., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Aspiration into the respiratory tract is a rare complication of capsule endoscopy. We describe a patient whose small bowel capsule endoscopy was complicated by aspiration into the proximal trachea without apparent respiratory symptoms. Spontaneous expulsion of the capsule device through coughing occurred approximately 10 hours later., (© 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The American College of Gastroenterology.)

Pharmacodynamic (PD) models are mathematical models of cellular reaction networks that include drug mechanisms of action. These models are useful for studying predictive therapeutic outcomes of novel drug therapies in silico. However, PD models are known to possess significant uncertainty with respect to constituent parameter data, leading to uncertainty in the model predictions. Furthermore, experimental data to calibrate these models is often limited or unavailable for novel pathways. In this study, we present a Bayesian optimal experimental design approach for improving PD model prediction accuracy. We then apply our method using simulated experimental data to account for uncertainty in hypothetical laboratory measurements. This leads to a probabilistic prediction of drug performance and a quantitative measure of which prospective laboratory experiment will optimally reduce prediction uncertainty in the PD model. The methods proposed here provide a way forward for uncertainty quantification and guided experimental design for models of novel biological pathways., (© 2024. The Author(s).)

Inadequate inpatient bowel preparation can lead to repeat procedures, prolonged hospital stays, and increased financial burden. In this quality improvement project, the authors developed an electronic medical record (EMR)-based order set with precise instructions and anticipatory guidance for inpatient bowel preparation before colonoscopy. The current study is a nonrandomized intervention study. The authors compared 2 groups: an intervention group using a newly developed, consensus-based, standardized EMR bowel preparation order set and a control group using previously existing EMR bowel preparation orders. Bowel preparation outcomes were followed over the course of 16 months. The aim was to improve inpatient colonoscopy bowel preparation, as evaluated by the Boston Bowel Preparation Scale, procedure delays, and length of hospital stay. We additionally evaluated the groups' demographics and patient-level factors. A total of 459 inpatient colonoscopies were evaluated over a 16-month period. The intervention group consisted of 227 inpatient colonoscopies, while the control group consisted of 232. The intervention group showed superior Boston Bowel Preparation Scale score and decreased length of hospital stay. The number of adequate bowel preparations increased in the intervention group when compared to the control group from 77% to 86%. The creation of an EMR-based order set is a low-cost and sustainable action that can be easily implemented throughout a hospital system., (Copyright © 2024 the American College of Medical Quality.)

Objectives: Age has a significant impact on systemic lupus erythematosus (SLE). However, data on very late-onset SLE (vlSLE) are scarce. We have compared the clinical and serological features of vlSLE patients with younger-onset patients., Methods: We assessed the clinical and laboratory data of all patients fulfilling SLE classification criteria evaluated at a university hospital from 1978 to 2023. Patients were divided into 4 groups according to age at diagnosis: juvenile SLE (jSLE <8 years); adult SLE (aSLE 18-49 years); late SLE (lSLE 50-59 years); vlSLE (≥60 years)., Results: 845 patients were enrolled. The jSLE, aSLE, lSLE, and vlSLE groups included 153, 630, 47, and 15 patients, respectively. The vlSLE group tended to have a lower female-to-male ratio (4:1; p=0.282), was mainly Caucasian (93.3%; p<0.001), and had the lowest survival time (20.3 years; p<0.001). vlSLE patients had the lowest prevalence of positive anti-dsDNA antibodies (26.7%; p=0.010) and low C3 levels (13.3%; p<0.001). Although arthritis was less common among vlSLE patients (73.3%; p=0.043), they more commonly developed Sjögren's syndrome (SS 33.3%; p<0.001) and rheumatoid arthritis (RA 13.3%; p<0.001). Infections and malignancy were the main causes of death., Conclusions: Compared with younger patients, in vlSLE, female predominance is less pronounced. Arthritis, anti-dsDNA antibodies and low C3 levels are less frequent. SS and RA are more common. Despite lower disease activity, vlSLE patients have the lowest survival rate. While uncommon, SLE should not be excluded as a possible diagnosis in the elderly.

Background: Optimal secondary prevention antithrombotic therapy for patients with antiphospholipid syndrome (APS)-associated ischemic stroke, transient ischemic attack, or other ischemic brain injury is undefined. The standard of care, warfarin or other vitamin K antagonists at standard or high intensity (international normalized ratio (INR) target range 2.0-3.0/3.0-4.0, respectively), has well-recognized limitations. Direct oral anticoagulants have several advantages over warfarin, and the potential role of high-dose direct oral anticoagulants vs high-intensity warfarin in this setting merits investigation., Objectives: The Rivaroxaban for Stroke patients with APS trial (RISAPS) seeks to determine whether high-dose rivaroxaban could represent a safe and effective alternative to high-intensity warfarin in adult patients with APS and previous ischemic stroke, transient ischemic attack, or other ischemic brain manifestations., Methods: This phase IIb prospective, randomized, controlled, noninferiority, open-label, proof-of-principle trial compares rivaroxaban 15 mg twice daily vs warfarin, target INR range 3.0-4.0. The sample size target is 40 participants. Triple antiphospholipid antibody-positive patients are excluded. The primary efficacy outcome is the rate of change in brain white matter hyperintensity volume on magnetic resonance imaging, a surrogate marker of presumed ischemic damage, between baseline and 24 months follow-up. Secondary outcomes include additional neuroradiological and clinical measures of efficacy and safety. Exploratory outcomes include high-dose rivaroxaban pharmacokinetic modeling., Conclusion: Should RISAPS demonstrate noninferior efficacy and safety of high-dose rivaroxaban in this APS subgroup, it could justify larger prospective randomized controlled trials., (© 2024 The Author(s).)

Systemic Lupus Erythematosus (SLE) is an autoimmune disease, the pathophysiology and genetic basis of which are incompletely understood. Using a forward genetic screen in multiplex families with systemic lupus erythematosus (SLE) we identified an association between SLE and compound heterozygous deleterious variants in the non-receptor tyrosine kinases (NRTKs) ACK1 and BRK. Experimental blockade of ACK1 or BRK increased circulating autoantibodies in vivo in mice and exacerbated glomerular IgG deposits in an SLE mouse model. Mechanistically, non-receptor tyrosine kinases (NRTKs) regulate activation, migration, and proliferation of immune cells. We found that the patients' ACK1 and BRK variants impair efferocytosis, the MERTK-mediated anti-inflammatory response to apoptotic cells, in human induced Pluripotent Stem Cell (hiPSC)-derived macrophages, which may contribute to SLE pathogenesis. Overall, our data suggest that ACK1 and BRK deficiencies are associated with human SLE and impair efferocytosis in macrophages.

Background and Aims: Small bowel gastrointestinal bleeding (GIB) is associated with multiple blood transfusions, prolonged and/or multiple hospital admissions, utilization of significant healthcare resources, and negative effects on patient quality of life. There is a well-recognized association between antithrombotic medications and small bowel GIB. We aimed to identify the diagnostic yield of small bowel capsule endoscopy (SBCE) in patients on antithrombotic medications and the impact of SBCE on treatment course., Methods: The electronic medical records of nineteen hundred eighty-six patients undergoing SBCE were retrospectively reviewed., Results: The diagnostic yield for detecting stigmata of recent bleeding and/or actively bleeding lesions in SBCE was higher in patients that were on antiplatelet agents (21.6%), patients on anticoagulation (22.5%), and in patients that had their SBCE performed while they were inpatient (21.8%), when compared to the patients not on antiplatelet agents (12.1%), patients not on anticoagulation (13.5%), and with patients that had their SBCE performed in the outpatient setting (12%). Of 318 patients who had stigmata of recent bleeding and/or actively bleeding lesion(s) identified on SBCE, SBCE findings prompted endoscopic evaluation (small bowel enteroscopy, esophagogastroduodenoscopy (EGD), and/or colonoscopy) in 25.2%, with endoscopic hemostasis attempted in 52.5%., Conclusions: Our study, the largest conducted to date, emphasizes the importance of performing SBCE as part of the evaluation for suspected small bowel bleeding, particularly in patients taking antithrombotic therapy, and especially during their inpatient hospital stay., (© 2024. The Author(s).)

Background: Females diagnosed with systemic lupus erythematosus (SLE) face an elevated risk of adverse pregnancy outcomes (APOs). However, the evidence regarding whether a similar association exists in patients with undifferentiated connective tissue disease (UCTD) is inconclusive., Methods: We conducted a retrospective review (2006-2019) of pregnancy outcomes among patients with SLE (n = 51) and UCTD (n = 20) within our institution. We examined the occurrence of various APOs, encompassing miscarriage, stillbirth, termination, preterm birth, pre-eclampsia, eclampsia, HELLP syndrome, intrauterine growth restriction, abruption placentae, congenital heart block, or other cardiac abnormalities., Results: The mean age at pregnancy was 35 ± 7.0 years for patients with SLE and 35 ± 6.8 years for those with UCTD (p = 0.349). The proportion of Caucasian women was 47% in SLE and 80% in UCTD. Pregnancies in both groups were planned (81% in SLE and 77% in UCTD), and patients presented with inactive disease at conception (96% in SLE and 89% in UCTD). Hydroxychloroquine at conception was utilized by 86% of women with SLE, in contrast to 36% in the UCTD group. Both, SLE and UCTD cohorts exhibited low rates of disease flares during pregnancy and/or puerperium (14% vs. 10%). The incidence of APOs was 15.6% in SLE patients compared to 5% in those with UCTD (Risk difference 19.5%; 95% confidence interval: -3.9 to 43.1; p = 0.4237)., Conclusion: Our study underscores the importance of strategic pregnancy planning and the maintenance of appropriate treatment throughout pregnancy to ensure optimal disease management and minimize adverse outcomes in both SLE and UCTD pregnancies., (Copyright © 2024. Published by Elsevier España, S.L.U.)

Objective: To examine changes in the prescribing of end-of-life symptom management medications in long-term care (LTC) homes during the COVID-19 pandemic., Design: Retrospective cohort study using routinely collected health administrative data in Ontario, Canada., Setting and Participants: We included all individuals who died in LTC homes between January 1, 2017, and March 31, 2021. We separated the study into 2 periods: before COVID-19 (January 1, 2017, to March 17, 2020) and during COVID-19 (March 18, 2020, to March 31, 2021)., Methods: For each LTC home, we measured the percentage of residents who died before and during COVID-19 who had a subcutaneous symptom management medication prescription in their last 14 days of life. We grouped LTC homes into quintiles based on their mean prescribing rates before COVID-19, and examined changes in prescribing during COVID-19 and COVID-19 outcomes across quintiles., Results: We captured 75,438 LTC residents who died in Ontario's 626 LTC homes during the entire study period, with 19,522 (25.9%) dying during COVID-19. The mean prescribing rate during COVID-19 ranged from 46.9% to 79.4% between the lowest and highest prescribing quintiles. During COVID-19, the mean prescribing rate in the lowest prescribing quintile increased by 9.6% compared to before COVID-19. Compared to LTC homes in the highest prescribing quintile, homes in the lowest prescribing quintile experienced the highest proportion of COVID-19 outbreaks (73.4% vs 50.0%), the largest mean outbreak intensity (0.27 vs 0.09 cases/bed), the highest mean total days with a COVID-19 outbreak (72.7 vs 24.2 days), and the greatest proportion of decedents who were transferred and died outside of LTC (22.1% vs 8.6%)., Conclusions and Implications: LTC homes in Ontario had wide variations in the prescribing rates of end-of-life symptom management medications before and during COVID-19. Homes in the lower prescribing quintiles had more COVID-19 cases per bed and days spent in an outbreak., Competing Interests: Disclosure The authors declare no conflicts of interest., (Copyright © 2024 AMDA – The Society for Post-Acute and Long-Term Care Medicine. Published by Elsevier Inc. All rights reserved.)

Microfluidic membrane oxygenators are designed to mimic branching vasculature of the native lung during extracorporeal lung support. To date, scaling of such devices to achieve clinically relevant blood flow and lung support has been a limitation. We evaluated a novel multilayer microfluidic blood oxygenator (BLOx) capable of supporting 750-800 ml/min blood flow versus a standard hollow fiber membrane oxygenator (HFMO) in vivo during veno-venous extracorporeal life support for 24 hours in anesthetized, mechanically ventilated uninjured swine (n = 3/group). The objective was to assess feasibility, safety, and biocompatibility. Circuits remained patent and operated with stable pressures throughout 24 hours. No group differences in vital signs or evidence of end-organ damage occurred. No change in plasma free hemoglobin and von Willebrand factor multimer size distribution were observed. Platelet count decreased in BLOx at 6 hours (37% dec, P = 0.03), but not in HFMO; however, thrombin generation potential was elevated in HFMO (596 ± 81 nM·min) versus BLOx (323 ± 39 nM·min) at 24 hours ( P = 0.04). Other coagulation and inflammatory mediator results were unremarkable. BLOx required higher mechanical ventilator settings and showed lower gas transfer efficiency versus HFMO, but the stable device performance indicates that this technology is ready for further performance scaling and testing in lung injury models and during longer use conditions., Competing Interests: Disclosure: The authors have no conflicts of interest to report. Opinions, interpretations, conclusions and recommendations are those of the author and are not necessarily endorsed by the Department of Defense or the US Army. Figure 1 was created with Biorender.com ., (Copyright © ASAIO 2024.)

We examine visual representations of data that make use of combinations of both 2D and 3D data mappings. Combining 2D and 3D representations is a common technique that allows viewers to understand multiple facets of the data with which they are interacting. While 3D representations focus on the spatial character of the data or the dedicated 3D data mapping, 2D representations often show abstract data properties and take advantage of the unique benefits of mapping to a plane. Many systems have used unique combinations of both types of data mappings effectively. Yet there are no systematic reviews of the methods in linking 2D and 3D representations. We systematically survey the relationships between 2D and 3D visual representations in major visualization publications-IEEE VIS, IEEE TVCG, and EuroVis-from 2012 to 2022. We closely examined 105 articles where 2D and 3D representations are connected visually, interactively, or through animation. These approaches are designed based on their visual environment, the relationships between their visual representations, and their possible layouts. Through our analysis, we introduce a design space as well as provide design guidelines for effectively linking 2D and 3D visual representations.

Background: Legalization of assisted dying is progressively expanding worldwide. In Canada, the Medical Assistance in Dying Act became law in 2016. As assisted dying regulations evolve worldwide, comprehending its subjective impact and broader consequences, especially on family members, becomes pivotal for shaping practice, policy, and training., Aim: The goal of this study is to understand the experience of family caregivers on the assisted dying procedure day., Design: Qualitative, thematic analysis, research using semi-structured interviews., Setting/participants: Family caregivers of patients who received assisted dying in two hospitals in Canada were recruited. Interviews were conducted at least 6 months after patient death. Conceptual saturation was achieved after analyzing 18 interviews., Results: While caregivers expressed gratitude for the availability of Medical Assistance in Dying, they also described the procedure day as potentially jarring and unsettling. We identified five aspects that shaped their experience: attuned support from the clinical team; preparation for clinical details; congruence between the setting and the importance of the event; active participation and ceremony; and pacing and timing of the procedure. Together, these aspects impacted the level of uneasiness felt by caregivers on the procedure day., Conclusions: This study emphasized the importance of a family-centered approach to delivering Medical Assistance in Dying. It underscored recognizing the needs of family caregivers during the procedure day and offering strategies to ease their experience. Healthcare providers in jurisdictions where assisted dying is legal or deliberated should consider the applicability of these findings to their unique context., Competing Interests: Declaration of conflicting interestsThe author(s) declare they have no potential conflicts of interest with respect to the research, authorship, and/or publication of this article other than authors’ roles in the medical assistance in dying programs at the University Health Network (SH, GR, ML) and Sunnybrook Health Sciences Centre (DS, SB, EIG).

Microbial biofilms represent an important lifestyle for bacteria and are dynamic three-dimensional structures. Cyclic dimeric guanosine monophosphate (c-di-GMP) is a ubiquitous signaling molecule that is known to be tightly regulated with biofilm processes. While measurements of global levels of c-di-GMP have proven valuable toward understanding the genetic control of c-di-GMP production, there is a need for tools to observe the local changes of c-di-GMP production in biofilm processes. We have developed a label-free method for the direct detection of c-di-GMP in microbial colony biofilms using matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI). We applied this method to the enteric pathogen Vibrio cholerae , the marine symbiont V. fischeri , and the opportunistic pathogen Pseudomonas aeruginosa PA14 and detected spatial and temporal changes in c-di-GMP signal that accompanied genetic alterations in factors that synthesize and degrade the compound. We further demonstrated how this method can be simultaneously applied to detect additional metabolites of interest from a single sample.

Despite a checkered racial history, people in the United States generally believe the nation has made steady, incremental progress toward achieving racial equality. In this article, we investigate whether this U.S. racial progress narrative will extend to how the workforce views the effectiveness of organizational efforts surrounding diversity, equity, and inclusion. Across three studies (N = 1,776), we test whether Black and White U.S. workers overestimate organizational racial progress in executive representation. We also examine whether these misperceptions, surrounding organizational progress, drive misunderstandings regarding the relative ineffectiveness of common organizational diversity policies. Overall, we find evidence that U.S. workers largely overestimate organizational racial progress, believe that organizational progress will naturally improve over time, and that these misperceptions of organizational racial progress may drive beliefs in the effectiveness of diversity, equity, and inclusion policies. (PsycInfo Database Record (c) 2024 APA, all rights reserved).