Despite mandated primary series, health care personnel still hesitant about COVID-19 vaccine and immunizing children.

IMPORTANCE: Healthcare personnel (HCP) are important messengers for promoting vaccines, for both adults and children. Our investigation describes perceptions of fully vaccinated HCP about COVID-19 vaccine for themselves and primary series for their children. OBJECTIVE: To determine associations between sociodemographic, employment characteristics and perceptions of COVID-19 vaccines among HCP overall and the subset of HCP with children, who were all mandated to receive a COVID-19 vaccine, in a large US metropolitan region. DESIGN: Cross-sectional survey of fully vaccinated HCP from a large integrated health system. SETTING: Participants were electronically enrolled within a multi-site NYS healthcare system from December 21, 2021, to January 21, 2022. PARTICIPANTS: Of 78,000 employees, approximately one-third accessed promotional emails; 6,537 employees started surveys and 4165 completed them. Immunocompromised HCP (self-reported) were excluded. EXPOSURE(S) (FOR OBSERVATIONAL STUDIES): We conducted a survey with measures including demographic variables, employment history, booster status, child vaccination status; vaccine recommendation, confidence, and knowledge. MAIN OUTCOME(S) AND MEASURES: The primary outcome was COVID-19 vaccine hesitancy for all dose types - primary series or booster doses - among HCP. RESULTS: Findings from 4,165 completed surveys indicated that almost 17.2 % of all HCP, including administrative and clinical staff, were hesitant or unsure about receiving a COVID-19 vaccine booster, despite the NYS recommendation to do so. Depending on age group, between 20 % and 40 % of HCP were hesitant about having their children vaccinated for COVID-19, regardless of clinical versus non-clinical duties. In multivariable regression analyses, lack of booster dose, unvaccinated children, females, income less than $50,000, and residence in Manhattan remained significantly associated with vaccine hesitancy. CONCLUSIONS AND RELEVANCE: Despite mandated COVID-19 vaccination, a substantial proportion of HCP remained vaccine hesitant towards adult booster doses and pediatric COVID-19 vaccination. While provider recommendation has been the mainstay of combatting COVID-19 vaccine hesitancy, a gap exists between HCP-despite clinical or administrative status-and the ability to communicate the need for vaccination in a healthcare setting. While previous studies describe the HCP vaccine mandate as a positive force to overcome vaccine hesitancy, we have found that despite a mandate, there is still substantial COVID-19 vaccine hesitancy, misinformation, and reluctance to vaccinate children.

Unraveling the mechanisms of PAMless DNA interrogation by SpRY-Cas9.

CRISPR-Cas9 is a powerful tool for genome editing, but the strict requirement for an NGG protospacer-adjacent motif (PAM) sequence immediately next to the DNA target limits the number of editable genes. Recently developed Cas9 variants have been engineered with relaxed PAM requirements, including SpG-Cas9 (SpG) and the nearly PAM-less SpRY-Cas9 (SpRY). However, the molecular mechanisms of how SpRY recognizes all potential PAM sequences remains unclear. Here, we combine structural and biochemical approaches to determine how SpRY interrogates DNA and recognizes target sites. Divergent PAM sequences can be accommodated through conformational flexibility within the PAM-interacting region, which facilitates tight binding to off-target DNA sequences. Nuclease activation occurs ~1000-fold slower than for Streptococcus pyogenes Cas9, enabling us to directly visualize multiple on-pathway intermediate states. Experiments with SpG position it as an intermediate enzyme between Cas9 and SpRY. Our findings shed light on the molecular mechanisms of PAMless genome editing.

Mechanical properties of clot made from human and bovine whole blood differ significantly.

Thromboembolism - that is, clot formation and the subsequent fragmentation of clot - is a leading cause of death worldwide. Clots' mechanical properties are critical determinants of both the embolization process and the pathophysiological consequences thereof. Thus, understanding and quantifying the mechanical properties of clots is important to our ability to treat and prevent thromboembolic disease. However, assessing these properties from in vivo clots is experimentally challenging. Therefore, we and others have turned to studying in vitro clot mimics instead. Unfortunately, there are significant discrepancies in the reported properties of these clot mimics, which have been hypothesized to arise from differences in experimental techniques and blood sources. The goal of our current work is therefore to compare the mechanical behavior of clots made from the two most common sources, human and bovine blood, using the same experimental techniques. To this end, we tested clots under pure shear with and without initial cracks, under cyclic loading, and under stress relaxation. Based on these data, we computed and compared stiffness, strength, work-to-rupture, fracture toughness, relaxation time constants, and prestrain. While clots from both sources behaved qualitatively similarly, they differed quantitatively in almost every metric. We also correlated each mechanical metric to measures of blood composition. Thereby, we traced this inter-species variability in clot mechanics back to significant differences in hematocrit, but not platelet count. Thus, our work suggests that the results of past studies that have used bovine blood to make in vitro mimics - without adjusting blood composition - should be interpreted carefully. Future studies about the mechanical properties of blood clots should focus on human blood alone.

Occurrences and implications of pathogenic and antibiotic-resistant bacteria in different stages of drinking water treatment plants and distribution systems.

Different stages of drinking water treatment plants (DWTPs) play specific roles in diverse contaminants' removal present in natural water sources. Although the stages are recorded to promote adequate treatment of water, the occurrence of pathogenic bacteria (PB) and antibiotic-resistant bacteria (ARB) in the treated water and the changes in their diversity and abundance as it passed down to the end users through the drinking water distribution systems (DWDSs), is a great concern, especially to human health. This could imply that the different stages and the distribution system provide a good microenvironment for their growth. Hence, it becomes pertinent to constantly monitor and document the diversity of PB and ARB present at each stage of the treatment and distribution system. This review aimed at documenting the occurrence of PB and ARB at different stages of treatment and distribution systems as well as the implication of their occurrence globally. An exhaustive literature search from Web of Science, Science-Direct database, Google Scholar, Academic Research Databases like the National Center for Biotechnology Information, Scopus, and SpringerLink was done. The obtained information showed that the different treatment stages and distribution systems influence the PB and ARB that proliferate. To minimize the human health risks associated with the occurrence of these PB, the present review, suggests the development of advanced technologies that can promote quick monitoring of PB/ARB at each treatment stage and distribution system as well as reduction of the cost of environomics analysis to promote better microbial analysis.

Effect of psychological intervention in cushioning work-induced stress among secondary school home economics teachers: Implications for policy and administration.

BACKGROUND/OBJECTIVE: Work demands in the contemporary Nigerian work environment are a critical concern to many including occupational stress researchers. This informed the current study to investigate the effect of psychological intervention in cushioning teachers' stress in public secondary schools in Nigeria. METHODS: A randomized control design was applied. The participants were 80 secondary school home economics teachers. They were randomized into 2 groups, that is, treatment and waitlisted arms. The former was designed as a 12-session cognitive behavior intervention while the latter was waitlisted and the members received theirs at the end of the study. Both group members were evaluated at the pretest, posttest, and follow-up test to understand the baseline of the problem, treatment outcome, and sustainability respectively. Perceived Stress Scale and Teacher irrational belief scale were used as test tools. Data from the 3-time tests were analyzed using multivariate statistic. RESULTS: The main effect results showed a significant reduction in teachers' stress and irrational beliefs due to cognitive behavior intervention. The follow-up test results also indicate that the impactful benefit of cognitive behavioral intervention on job stress reduction was significantly sustained over time. Regarding the influence of gender, the result shows no significant influence of gender on teachers' job stress in schools. CONCLUSION: This study suggests that cognitive behavior intervention can decrease work-induced stress among secondary school home economics teachers. Therefore, the management of schools is enjoined to deploy the services of cognitive behavior therapists to monitor the mood and mental health of teachers.

Liking Predicts Judgments of Authenticity in Real-Time Interactions More Robustly Than Personality States or Affect.

We conducted three studies involving small group interactions (N = 622) that examined whether Big Five personality states, affect, and/or liking predict judgments of others' authenticity. Study 1 (n = 119) revealed that neither self-rated personality states nor affect predicted other-rated authenticity. Instead, other-rated liking was the only predictor of other-rated authenticity. Study 2 (n = 281) revealed that other-rated personality states and affect were significant predictors of other-rated authenticity, but other-rated liking was a more important factor in predicting other-rated authenticity than specific behaviors or affect. Based on these results, Study 3 (n = 222) examined whether experimental manipulation of likability had a causal effect on other-ratings of authenticity. Likable actors were indeed judged as more authentic. Together, this suggests that we judge people we like as more authentic and that likability may be more important than the "objective" content of behavior.

Gastroesophageal reflux and PPI exposure alter gut microbiota in very young infants.

Importance: Infants with symptomatic Gastroesophageal reflux are treated with pharmacological therapy that includes proton pump inhibitors (PPI) with clinical improvement. The alterations to gut microbiome profiles in comparison to infants without reflux is not known. Objective: To determine the effect of PPI therapy on gut bacterial richness, diversity, and proportions of specific taxa in infants when compared to infants not exposed to acid suppressive therapy. Design setting and participants: This cohort study was conducted at the Stony Brook Hospital in Stony Brook, NY between February 2016, and June 2019. Infants meeting inclusion criteria were enrolled in a consecutive fashion. Results: A total of 76 Infants were recruited and 60 were enrolled in the study, Twenty nine infants met clinical criteria for reflux and were treated with PPI therapy: median [IQR] gestation: 38.0 weeks [34.7-39.6 weeks]; median [IQR] birthweight: 2.95 Kg [2.2-3.4]; 14 [46.7%] male) and 29 infant were healthy controls median [IQR] gestation: 39.1 weeks [38-40 weeks]; median [IQR] birthweight: 3.3 Kg [2.2-3.4]; 17 [58.6%] male); 58 stool samples from 58 infants were analyzed. There were differences in Shannon diversity between the reflux and control groups. The reflux group that was exposed to PPI therapy had increased relative abundance of a diverse set of genera belonging to the phylum Firmicutes. On the other hand, the control group microbiota was dominated by Bifidobacterium, and a comparatively lower level of enrichment and abundance of microbial taxa was observed in this group of infants. Conclusions and relevance: We observed significant differences in both α- and ß-diversity of the microbiome, when the two groups of infants were compared. The microbiome in the reflux group had more bacterial taxa and the duration of PPIs exposure was clearly associated with the diversity and abundance of gut microbes. These findings suggest that PPI exposure among infants results in early enrichment of the intestinal microbiome.

Sediment microbiome diversity and functional profiles of unprotected arid-tropical natural wetlands in South Africa revealed by shotgun metagenomics data.

The Limpopo province, located in the arid-tropical region in northeastern South Africa, is renowned for its diverse natural wetlands, some of which are currently unprotected. These wetlands play a crucial role in preserving biodiversity, purifying water, controlling floods, and supporting agricultural production for rural communities. Unfortunately, human activities such as agricultural effluents, run-offs, domestic wastewater, and plastics pollution, along with the impacts of climate change, are mounting pressures on these ecosystems. However, there is limited information on the microbial ecology of natural wetlands in this region, considering the changing anthropogenic activities. The data presented represents the first report on the microbial and functional diversity of sediment microbiomes associated with unprotected arid-tropical natural wetlands in South Africa. Metagenomic shotgun sequencing was performed on sediment samples from ten different wetlands using the Illumina NextSeq 2000 platform. Taxonomic profiling of 328,625,930 high-quality sequencing reads using the MetaPhlAn v3.0 pipeline revealed that Bacteria were the most abundant kingdom (54.5 %), followed by Viruses (0.40 %), Archaea (0.01 %), and Eukaryota (0.36 %). Among bacteria, the most prevalent taxa belonged to the phylum Proteobacteria, particularly the classes Gammaproteobacteria and Betaproteobacteria, which accounted for 83 % of bacterial sequences. The Terrabacteria group, consisting of the phyla Firmicutes and Actinobacteria, made up 3 % of the bacterial population. The abundance of these top bacterial taxa varied across different wetland samples, both at the genus and species levels. In addition, hierarchical clustering based on Bray-Curtis dissimilarity distances of fungal, protist, archaea, and virus species showed distinct clustering of sediment samples from different wetlands. Functional annotation of the metagenomes identified 1224-1702 enzyme classes, 84,833-198,397 gene families, and 280-400 pathways across the various wetland sediments. The data provide crucial baseline information on the microbial and functional diversity of sediment communities in arid tropical wetlands. This knowledge will contribute to a better understanding of these unique environments and can aid in their management and conservation efforts in rural South Africa.

Genetic and Functional Modifications Associated with Ovarian Cancer Cell Aggregation and Limited Culture Conditions.

The aggregation of cancer cells provides a survival signal for disseminating cancer cells; however, the underlying molecular mechanisms have yet to be elucidated. Using qPCR gene arrays, this study investigated the changes in cancer-specific genes as well as genes regulating mitochondrial quality control, metabolism, and oxidative stress in response to aggregation and hypoxia in our progressive ovarian cancer models representing slow- and fast-developing ovarian cancer. Aggregation increased the expression of anti-apoptotic, stemness, epithelial-mesenchymal transition (EMT), angiogenic, mitophagic, and reactive oxygen species (ROS) scavenging genes and functions, and decreased proliferation, apoptosis, metabolism, and mitochondrial content genes and functions. The incorporation of stromal vascular cells (SVF) from obese mice into the spheroids increased DNA repair and telomere regulatory genes that may represent a link between obesity and ovarian cancer risk. While glucose had no effect, glutamine was essential for aggregation and supported proliferation of the spheroid. In contrast, low glucose and hypoxic culture conditions delayed adhesion and outgrowth capacity of the spheroids independent of their phenotype, decreased mitochondrial mass and polarity, and induced a shift of mitochondrial dynamics towards mitophagy. However, these conditions did not reduce the appearance of polarized mitochondria at adhesion sites, suggesting that adhesion signals that either reversed mitochondrial fragmentation or induced mitobiogenesis can override the impact of low glucose and oxygen levels. Thus, the plasticity of the spheroids' phenotype supports viability during dissemination, allows for the adaptation to changing conditions such as oxygen and nutrient availability. This may be critical for the development of an aggressive cancer phenotype and, therefore, could represent druggable targets for clinical interventions.

Estimating the prevalence of COVID-19 cases through the analysis of SARS-CoV-2 RNA copies derived from wastewater samples from North Dakota.

The SARS-CoV-2 virus was first detected in December 2019, which prompted many researchers to investigate how the virus spreads. SARS-CoV-2 is mainly transmitted through respiratory droplets. Symptoms of the SARS-CoV-2 virus appear after an incubation period. Moreover, the asymptomatic infected individuals unknowingly spread the virus. Detecting infected people requires daily tests and contact tracing, which are expensive. The early detection of infectious diseases, including COVID-19, can be achieved with wastewater-based epidemiology, which is timely and cost-effective. In this study, we collected wastewater samples from wastewater treatment plants in several cities in North Dakota and then extracted viral RNA copies. We used log-RNA copies in the model to predict the number of infected cases using Quantile Regression (QR) and K-Nearest Neighbor (KNN) Regression. The model's performance was evaluated by comparing the Mean Absolute Percentage Error (MAPE). The QR model performs well in cities where the population is >10000. In addition, the model predictions were compared with the basic Susceptible-Infected-Recovered (SIR) model which is the golden standard model for infectious diseases.

Depression, Anxiety, Energy, and Fatigue Among Nurses Who Cared for Patients During the COVID-19 Pandemic: A Cross-Sectional Study.

Purpose of Study: Nurses around the world have faced challenges during the coronavirus disease 2019 (COVID-19) pandemic. This study examined the association between depression and anxiety and trait energy and trait fatigue, and baseline health status and work characteristics. Design of Study: A cross-sectional study. Methods: A survey was conducted to collect self-reported data from nurses involved in patient care in Northern Virginia. Depression and anxiety were assessed using the Patient-Reported Outcomes Measurement Information System (PROMIS) depression and anxiety scales. To measure trait energy and trait fatigue, the Mental and Physical State and Trait Energy and Fatigue Scale (MPSTEFS) was used. Findings: There was a significant association between depression and energy (b=-0.46, t = -1.78, p < .001) and loneliness (b=1.38, t = 4.00, p < .001) and increased alcohol use (b=2.11, t = 2.04, p = .045). We also found that nurses with depression were significantly more likely to seek mental health counseling (b=-2.91, t = 2.54, p = 0.013), which was also the case for anxiety (b=3.13, t = 2.14, p = .036). Conclusions: Our study highlights the mental health burden among nurses who worked in the early phase of the COVID-19 pandemic and its association with increased alcohol use and loneliness. The findings may help healthcare leaders identify early signals of deterioration in nurses' well-being.

Transgenic ferret models define pulmonary ionocyte diversity and function.

Speciation leads to adaptive changes in organ cellular physiology and creates challenges for studying rare cell-type functions that diverge between humans and mice. Rare cystic fibrosis transmembrane conductance regulator (CFTR)-rich pulmonary ionocytes exist throughout the cartilaginous airways of humans1,2, but limited presence and divergent biology in the proximal trachea of mice has prevented the use of traditional transgenic models to elucidate ionocyte functions in the airway. Here we describe the creation and use of conditional genetic ferret models to dissect pulmonary ionocyte biology and function by enabling ionocyte lineage tracing (FOXI1-CreERT2::ROSA-TG), ionocyte ablation (FOXI1-KO) and ionocyte-specific deletion of CFTR (FOXI1-CreERT2::CFTRL/L). By comparing these models with cystic fibrosis ferrets3,4, we demonstrate that ionocytes control airway surface liquid absorption, secretion, pH and mucus viscosity-leading to reduced airway surface liquid volume and impaired mucociliary clearance in cystic fibrosis, FOXI1-KO and FOXI1-CreERT2::CFTRL/L ferrets. These processes are regulated by CFTR-dependent ionocyte transport of Cl- and HCO3-. Single-cell transcriptomics and in vivo lineage tracing revealed three subtypes of pulmonary ionocytes and a FOXI1-lineage common rare cell progenitor for ionocytes, tuft cells and neuroendocrine cells during airway development. Thus, rare pulmonary ionocytes perform critical CFTR-dependent functions in the proximal airway that are hallmark features of cystic fibrosis airway disease. These studies provide a road map for using conditional genetics in the first non-rodent mammal to address gene function, cell biology and disease processes that have greater evolutionary conservation between humans and ferrets.

A protocol for isolating and imaging large extracellular vesicles or midbody remnants from mammalian cell culture.

Traditionally, midbody remnants (MBRs) are isolated from cell culture medium using ultracentrifugation, which is expensive and time consuming. Here, we present a protocol for isolating MBRs or large extracellular vesicles (EVs) from mammalian cell culture using either 1.5% polyethylene glycol 6000 (PEG6000) or PEG5000-coated gold nanoparticles. We describe steps for growing cells, collecting media, and precipitating MBRs and EVs from cell culture medium. We then detail characterization of MBRs through immunofluorescent antibody staining and immunofluorescent imaging.

Inflammatory Activity of Epithelial Stem Cell Variants from Cystic Fibrosis Lungs Is Not Resolved by CFTR Modulators.

Rationale: CFTR (cystic fibrosis transmembrane conductance regulator) modulator drugs restore function to mutant channels in patients with cystic fibrosis (CF) and lead to improvements in body mass index and lung function. Although it is anticipated that early childhood treatment with CFTR modulators will significantly delay or even prevent the onset of advanced lung disease, lung neutrophils and inflammatory cytokines remain high in patients with CF with established lung disease despite modulator therapy, underscoring the need to identify and ultimately target the sources of this inflammation in CF lungs. Objectives: To determine whether CF lungs, like chronic obstructive pulmonary disease (COPD) lungs, harbor potentially pathogenic stem cell "variants" distinct from the normal p63/Krt5 lung stem cells devoted to alveolar fates, to identify specific variants that might contribute to the inflammatory state of CF lungs, and to assess the impact of CFTR genetic complementation or CFTR modulators on the inflammatory variants identified herein. Methods: Stem cell cloning technology developed to resolve pathogenic stem cell heterogeneity in COPD and idiopathic pulmonary fibrosis lungs was applied to end-stage lungs of patients with CF (three homozygous CFTR:F508D, one CFTR F508D/L1254X; FEV1, 14-30%) undergoing therapeutic lung transplantation. Single-cell-derived clones corresponding to the six stem cell clusters resolved by single-cell RNA sequencing of these libraries were assessed by RNA sequencing and xenografting to monitor inflammation, fibrosis, and mucin secretion. The impact of CFTR activity on these variants after CFTR gene complementation or exposure to CFTR modulators was assessed by molecular and functional studies. Measurements and Main Results: End-stage CF lungs display a stem cell heterogeneity marked by five predominant variants in addition to the normal lung stem cell, of which three are proinflammatory both at the level of gene expression and their ability to drive neutrophilic inflammation in xenografts in immunodeficient mice. The proinflammatory functions of these three variants were unallayed by genetic or pharmacological restoration of CFTR activity. Conclusions: The emergence of three proinflammatory stem cell variants in CF lungs may contribute to the persistence of lung inflammation in patients with CF with advanced disease undergoing CFTR modulator therapy.

Lost in Transition: Missed Opportunities for the 4 Ms to Support Post-Acute Care Transitions.

Thousands of health systems have adopted the 4 Ms framework, a set of evidence-based practices specific to older adults, as part of the Age-Friendly Health Systems (AFHS) initiative. However, implementation efforts have largely been setting-specific and approaches to achieve continuity of the 4 Ms during care transitions are nascent. Transitions from hospitals to skilled nursing facilities (SNFs) are one type of care transition that would greatly benefit from continuity of 4 Ms practices. Drawing from the authors' insights and 5 exploratory interviews at 3 health systems that implemented the 4 Ms in the inpatient setting, we describe a set of current-state challenges when trying to extend specific inpatient 4 Ms practices (eg, deprescribing of high-risk medications) as well as the nuanced understanding of the individual's clinical trajectory developed during an inpatient stay. We also offer concrete opportunities, such as developing 4 Ms-centric discharge summary templates, to address the challenges. With the large investment in AFHS transformation and associated efforts to implement the 4 Ms framework in all care settings used by older adults, it is critical to raise awareness of the specific obstacles to promoting continuity of successful 4 Ms practices during care transitions and work to overcome them. Our insights from hospital-to-SNF transitions offer a starting point.

College students with disabilities report higher rates of food insecurity.

BACKGROUND: Increased risk of food insecurity has been reported among both college students and persons with disabilities; however, food insecurity among college students with disabilities has not been explored. OBJECTIVE: This article aims to characterize the prevalence of food insecurity among college students with and without disabilities at a northeastern university. METHODS: Cross-sectional data were collected between 2018 and 2020at a public northeastern university as part of the ongoing College Health and Nutrition Assessment Survey. An online survey collected self-reported data, including food security and disability status. Chi-square and logistic regression analyses examined the differences in food insecurity among college students with and without disabilities. RESULTS: The sample (n = 880) was 61.6% female, predominately white (94.5%), and had a mean age of 19 ± 1.2 years. One out of eight participants (13.3%) reported a disability. Low or very low food security (13.3% and 5.5% respectively) was reported in one out of five participants, while 81.4% reported high or marginal food security (67.6% and 13.8%, respectively). Participants with a disability were more than twice as likely to report food insecurity than those without a disability (35.9% vs. 16.0%, p < 0.001). Among participants with a disability, 12.8% reported very low food security and 23.1% reported low food security, compared to 4.3% and 11.7%, respectively, among those students without disabilities (p < 0.001). CONCLUSIONS: College students with disabilities experienced disproportionally higher rates of food insecurity than students without disabilities. Further research in diverse institutions can help to better understand and develop targeted supports for this vulnerable segment of the college population.

Health system approaches and experiences implementing the 4Ms: Insights from 3 early adopter health systems.

BACKGROUND: Redesigning the healthcare system to consistently provide effective and tailored care to older adults is needed. The 4Ms (What Matters, Mobility, Medication, and Mentation) offer a framework to guide health systems' efforts to deliver Age-Friendly care. We use an implementation science framework to characterize and assess real-world implementation experiences with the 4Ms across varied health systems. METHODS: With expert input, we selected three health systems that were early adopters of the 4Ms and engaged in different implementation support models through the Institute for Healthcare Improvement. We conducted 29 semi-structured interviews with diverse stakeholders from each site. Stakeholders ranged from hospital leadership to frontline clinicians. Interviews covered each site's approach to and experiences with implementation, including facilitators and barriers. Interviews were recorded, transcribed, and deductively coded using the Consolidated Framework for Implementation Research. We characterized each site's implementation decisions and then inductively identified overarching themes and subthemes with supporting quotes. RESULTS: Health systems varied in their implementation approach, including the implementation order of each of the 4Ms. We identified three overarching themes: (1) the 4Ms offered a compelling conceptual framework for advancing Age-Friendly care, but implementation was complex and fragmented; (2) complete and sustained implementation of the 4Ms required multidisciplinary and multilevel leadership and engagement; (3) strategies that facilitate implementation success and support frontline culture change included top-down communication and infrastructure alongside hands-on clinical education and support. Common barriers are siloed implementation efforts across settings that impeded synergies and scaling; disengaged physicians; and difficulty implementing What Matters in a meaningful way. CONCLUSIONS: Similar to other implementation studies, we identified multifactorial domains impacting 4Ms implementation. To achieve Age-Friendly transformation, health systems must plan for and attend to multiple phases of implementation while ensuring that the work coheres under a unified vision that spans disciplines and settings.