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Sustaining a well-designed healthcare intervention justifies the resources allocated during its conceptualization and implementation and maximizes its clinical benefits, but staff influences on sustainment have been studied insufficiently. This study evaluates the effects of pharmacy staff (i.e., pharmacists/technicians) perceptions about the sustainability of Senior Safe , a U.S. pharmacy-based intervention to reduce older adult over-the-counter (OTC) medication misuse. Three months after introducing Senior Safe into 67 pharmacies in a large Midwestern health-system, all pharmacy staff (N = 279) received a survey invitation. Fifty-nine pharmacists and 94 technicians completed the survey. Using logistic regression modeling for the 14 belief-based survey items, and staff roles (pharmacist or technician), the final factors significantly predicting staff views that Senior Safe was sustainable were as follows: perceiving Senior Safe as well-integrated into leadership operations (OR = 5.606, < 0.001) and believing the intervention reduced OTC misuse (OR = 8.217, < 0.001). Also, technicians were more confident than pharmacists about Senior Safe's sustainment and its OTC misuse reduction success. Overall, an intervention's sustainability relies on those using it. Since the principal predictor of maintaining Senior Safe was its perceived effectiveness, increasing staff buy-in and awareness of an intervention's benefits may be central to its long-term viability. With an aging U.S. population, sustainable solutions to older adult medication misuse remain critical.

Background Measuring intervention fidelity can help justify the transition of evidence-based practices into everyday community-based practices by helping identify components of the intervention supporting the intervention’s uptake. Current methods to measure fidelity include self-reported data, observational data using audio or video recordings, and in-vivo observations, but these are limited due to cost-ineffectiveness, time inefficiency, and external validity threats. Photo coding is proposed as a new, pragmatic method of observational data to measure intervention fidelity, as was used in a pharmacy system re-design intervention (Senior Safe™) to improve over-the-counter (OTC) medication safety for older adults. Methods Guided by human factors engineering principles, Senior Safe re-shelved OTC medications based on safety level, and signage was added to designate safer and high-risk products. Senior Safe was implemented by pharmacy leadership and maintained by pharmacy staff. Pharmacy leadership and researchers collaborated to take photos of Senior Safe two times (Time 1 and Time 2), at least three months apart, to examine intervention layout and medication categorization fidelity. A Layout Codebook was constructed to evaluate the conformity of signage to ergonomic principles. A Medication Categorization Codebook was designed to assess whether the signage was properly allocated to the designated products. Two research assistants and two PharmD students coded the photos. A fidelity standard of ≥ 80% concordance with intervention guidelines was used to signify high-fidelity. Results Fidelity was assessed within 67 pharmacy sites implementing Senior Safe. All sites achieved ≥ 80% fidelity concordance between Time 1 and Time 2 for the Layout Codebook. Alternatively, for the Medication Categorization Codebook, 97% of sites met high-fidelity standards during Time 1, compared to 85% of sites at Time 2, indicating statistically significant negative drift. Overall, over half of all Time 1 and Time 2 concordance rates involving the Layout and Medication Categorization Codebooks exceeded the ≥ 80% high-fidelity standard. Conclusion Measuring intervention fidelity is useful in determining whether interventions are sustained and successfully transitioned into community-based practice. Photo coding is an innovative approach to measure intervention fidelity and allows researchers to identify multiple layers of concordance and discordance to intervention guidelines. Organizations are encouraged to investigate intervention fidelity, including identifying discordance and adaptation needs.

The increase in people with complex chronic health conditions is stressing the US health care delivery system. Community pharmacies play a role in ensuring patients' safe medication use for chronic care management (CCM), but their efforts are undermined by volatile work demands and other system barriers. Medication safety in community pharmacies is a multidimensional issue shaped by the work system and interactions among pharmacists, primary care providers, and patients. The objective is to create and evaluate a system of CCM that supports safe medication use. The CCM system design will focus on creating and evaluating a Medication Safety Map (MedSafeMap) for patients with complex chronic health conditions. This study has three aims: (1) identify and define community pharmacy work system design requirements for safe medication practices, enabling resilient performance; (2) design and develop MedSafeMap, a feasible and sustainable solution, to facilitate safe medication practices through resilient performance; and (3) implement MedSafeMap in community pharmacies and pilot-test its impact on pharmacy staff attitudes, behaviors, and performance. This study will leverage participatory design and human factors engineering methods throughout the 3 aims. For aim 1, four rounds of qualitative observations within 6 pharmacy sites will be conducted to parse areas MedSafeMap could address. Two rounds of interviews with pharmacists and technicians from each of the sites will be used to expand upon areas of interest identified during the observations. Observational and interview data will be used to construct functional resonance analysis method models and resilience narratives to map both risks and best practices within the system based on daily workplace factors. For aim 2, focus groups with pharmacist and technician stakeholders will be guided by participatory stakeholder engagement to inform prototyping for MedSafeMap. Simulation-based research involving standardized patients in CCM scenarios will be used to test and refine MedSafeMap components. Finally, for aim 3, MedSafeMap will be implemented in pharmacies. Observations using the work observation method by activity timing (WOMBAT) for the time and motion study will aid in understanding how MedSafeMap impacts pharmacy staff workflow. We will assess adoption challenges and resilience-focused attitudes, behaviors, and performance to support CCM. As of August 2025, all 6 pharmacy sites have been recruited. Three of the 4 rounds of observations, 2 rounds of interviews with 12 pharmacists and 12 technicians from the study sites, and the 6 focus groups have been conducted. Preparations for the simulations are ongoing. MedSafeMap is an innovative approach that will guide pharmacists and technicians in safely providing care to patients with complex chronic health conditions. It will help them navigate the complex tasks and communications between the pharmacy, patient, and primary care provider arising with this type of complex care. DERR1-10.2196/69011.

Background/Objectives: Intravenous thrombolytic therapy remains the cornerstone of managing acute ischemic stroke (AIS) patients. Given the potential adverse effects of thrombolysis, patients are admitted to an intensive care unit (ICU) for close monitoring following administration. Alternative post-thrombolytic pathways may provide safe, cost-effective care in certain populations. We aimed to determine the proportion of patients treated with thrombolytics who required ICU care for reasons other than frequent neurologic monitoring and to define their characteristics. Methods: We retrospectively (May 2020–August 2022) reviewed patients ≥ 18 years of age who received Tenecteplase (TNK) or tissue plasminogen activator (tPA) for AIS at our stroke center. Patients were classified as requiring ICU care if they required intubation within 24 h of admission, required neurosurgical intervention, had symptomatic hemorrhagic conversion or brain compression, required a continuous infusion for hemodynamic management, or were in status epilepticus. Univariate and multivariable statistical analyses were performed. The study protocol was deemed exempt by our Institutional Review Board. Results: 262 patients met inclusion criteria. A total of 54 (20.6%) required ICU care. Multivariable analysis showed that patients on antithrombotic therapies prior to arrival (AOR: 3.344, p = 0.002) or who presented with higher initial NIH stroke scale (AOR: 1.116, p < 0.001) had a significantly higher likelihood of requiring an ICU level of care. Conclusions: In our cohort, approximately 21% of patients required critical care. Antithrombotic therapy before admission and greater NIH stroke scale on arrival were associated with an increased likelihood of requiring ICU care. Further prospective studies are indicated to assess the efficacy of alternative settings for post-thrombolytic care in selected AIS patients; however, our findings suggest that a specific subset of patients with AIS can be safely and effectively cared for in a non-ICU setting. This may have implications for the provision of safe, effective care while optimizing healthcare resource utilization.

Coronavirus infection induces the unfolded protein response (UPR), a cellular signalling pathway composed of three branches, triggered by unfolded proteins in the endoplasmic reticulum (ER) due to high ER load. We have used RNA sequencing and ribosome profiling to investigate holistically the transcriptional and translational response to cellular infection by murine hepatitis virus (MHV), often used as a model for the Betacoronavirus genus to which the recently emerged SARS-CoV-2 also belongs. We found the UPR to be amongst the most significantly up-regulated pathways in response to MHV infection. To confirm and extend these observations, we show experimentally the induction of all three branches of the UPR in both MHV- and SARS-CoV-2-infected cells. Over-expression of the SARS-CoV-2 ORF8 or S proteins alone is itself sufficient to induce the UPR. Remarkably, pharmacological inhibition of the UPR greatly reduced the replication of both MHV and SARS-CoV-2, revealing the importance of this pathway for successful coronavirus replication. This was particularly striking when both IRE1α and ATF6 branches of the UPR were inhibited, reducing SARS-CoV-2 virion release (~1,000-fold). Together, these data highlight the UPR as a promising antiviral target to combat coronavirus infection.

Examine non-respiratory comorbidities that may affect prognosis in acute hypoxic respiratory failure (AHRF) and respiratory trajectories, comparing those with COVID and non-COVID etiologies of AHRF. This is a retrospective cohort study of patients with AHRF from COVID and non-COVID etiologies treated with high flow oxygen, noninvasive ventilation, or endotracheal intubation in ICUs in two United States hospitals. We compared drivers of prognosis and respiratory trajectories between 241 patients with AHRF from COVID and 99 patients with non-COVID AHRF. Patients with COVID had a lower prevalence of major comorbidities or terminal illness (OR 0.14), neurologic disease (OR 0.19), goals of care limitations (OR 0.54), and shock (OR 0.11). A lower proportion of the COVID group were managed with invasive mechanical ventilation (IMV) early in their AHRF course (OR 0.15); however, fewer COVID patients had improvement in AHRF in the first 7 days (OR 0.49), and a greater proportion of COVID patients required IMV on day 14 (OR 2.57). Additionally, fewer COVID patients died or transitioned to comfort care within 14 days following AHRF onset (OR 0.24), and more COVID patients had severe hypoxemia at end-of-life (OR 2.42). Patients with AHRF from COVID had fewer non-respiratory comorbidities or goals of care limitations, more prolonged respiratory failure and higher risk of mortality related to hypoxemia. These differences could explain why patients with COVID AHRF may experience greater benefit from disease-specific therapies targeting AHRF compared to patients with non-COVID AHRF.

Pacific salmon (Oncorhynchus spp.) are at the center of social–ecological systems that have supported Indigenous peoples around the North Pacific Rim since time immemorial. Through generations of interdependence with salmon, Indigenous Peoples developed sophisticated systems of management involving cultural and spiritual beliefs, and stewardship practices. Colonization radically altered these social–ecological systems, disrupting Indigenous management, consolidating authority within colonial governments, and moving most harvest into mixed-stock fisheries. We review Indigenous management of salmon, including selective fishing technologies, harvest practices, and governance grounded in multigenerational place-based knowledge. These systems and practices showcase pathways for sustained productivity and resilience in contemporary salmon fisheries. Contrasting Indigenous systems with contemporary management, we document vulnerabilities of colonial governance and harvest management that have contributed to declining salmon fisheries in many locations. We suggest that revitalizing traditional systems of salmon management can improve prospects for sustainable fisheries and healthy fishing communities and identify opportunities for their resurgence.

Diffuse Intrinsic Pontine Gliomas (DIPGs) are deadly paediatric brain tumours where needle biopsies help guide diagnosis and targeted therapies. To address spatial heterogeneity, here we analyse 134 specimens from various neuroanatomical structures of whole autopsy brains from nine DIPG patients. Evolutionary reconstruction indicates histone 3 (H3) K27M—including H3.2K27M—mutations potentially arise first and are invariably associated with specific, high-fidelity obligate partners throughout the tumour and its spread, from diagnosis to end-stage disease, suggesting mutual need for tumorigenesis. These H3K27M ubiquitously-associated mutations involve alterations in TP53 cell-cycle ( TP53/PPM1D ) or specific growth factor pathways ( ACVR1/PIK3R1 ). Later oncogenic alterations arise in sub-clones and often affect the PI3K pathway. Our findings are consistent with early tumour spread outside the brainstem including the cerebrum. The spatial and temporal homogeneity of main driver mutations in DIPG implies they will be captured by limited biopsies and emphasizes the need to develop therapies specifically targeting obligate oncohistone partnerships. Diffuse Intrinsic Pontine Gliomas are diagnosed by sampling a small portion of the tumour. Here, using multiple samples from tumours, the authors analyse the spatial and temporal distribution of driver mutations revealing that H3K27M mutations arise first in tumorigenesis followed by a specific invariable sequence of driver mutations, which are homogeneously distributed across the tumour mass.

Phagocytic clearance of dying cells, termed efferocytosis, is essential for maintaining tissue homeostasis, yet our understanding of efferocytosis regulation remains incomplete. Here we perform a FACS-based, genome-wide CRISPR knockout screen in primary mouse macrophages to search for novel regulators of efferocytosis. The results show that Wdfy3 knockout in macrophages specifically impairs uptake, but not binding, of apoptotic cells due to defective actin disassembly. Additionally, WDFY3 interacts with GABARAP, thus facilitating LC3 lipidation and subsequent lysosomal acidification to permit the degradation of apoptotic cell components. Mechanistically, while the C-terminus of WDFY3 is sufficient to rescue the impaired degradation induced by Wdfy3 knockout, full-length WDFY3 is required to reconstitute the uptake of apoptotic cells. Finally, WDFY3 is also required for efficient efferocytosis in vivo in mice and in vitro in primary human macrophages. This work thus expands our knowledge of the mechanisms of macrophage efferocytosis, as well as supports genome-wide CRISPR screen as a platform for interrogating complex functional phenotypes in primary macrophages. Efferocytosis describes the engulfment and clearance of apoptotic cells by phagocytes. Here the authors identify in primary mouse macrophage WDFY3 as a regulator for efferocytosis, in which c-terminal WDFY3 is sufficient to modulate degradation while full-length WDFY3 is required to modulate the uptake of apoptotic cells.

Abstract Background In 2015, pneumonia remained the leading cause of mortality in children aged 1–59 months. Methods Data from 1802 human immunodeficiency virus (HIV)–negative children aged 1–59 months enrolled in the Pneumonia Etiology Research for Child Health (PERCH) study with severe or very severe pneumonia during 2011–2014 were used to build a parsimonious multivariable model predicting mortality using backwards stepwise logistic regression. The PERCH severity score, derived from model coefficients, was validated on a second, temporally discrete dataset of a further 1819 cases and compared to other available scores using the C statistic. Results Predictors of mortality, across 7 low- and middle-income countries, were age <1 year, female sex, ≥3 days of illness prior to presentation to hospital, low weight for height, unresponsiveness, deep breathing, hypoxemia, grunting, and the absence of cough. The model discriminated well between those who died and those who survived (C statistic = 0.84), but the predictive capacity of the PERCH 5-stratum score derived from the coefficients was moderate (C statistic = 0.76). The performance of the Respiratory Index of Severity in Children score was similar (C statistic = 0.76). The number of World Health Organization (WHO) danger signs demonstrated the highest discrimination (C statistic = 0.82; 1.5% died if no danger signs, 10% if 1 danger sign, and 33% if ≥2 danger signs). Conclusions The PERCH severity score could be used to interpret geographic variations in pneumonia mortality and etiology. The number of WHO danger signs on presentation to hospital could be the most useful of the currently available tools to aid clinical management of pneumonia. We developed a severity score for childhood pneumonia cases presenting to hospital and compared its ability to predict mortality with other tools. The findings reinforce the utility of World Health Organization danger signs and pulse oximetry for clinical management of pneumonia cases.