Diabetes in residential aged care: Pharmacological management and concordance with clinical guidelines.

OBJECTIVE: Existing studies have highlighted suboptimal diabetes management in residential aged care facilities (RACFs). However, understanding of diabetes management in Australian metropolitan RACFs has been limited. This retrospective cohort study aimed to explore the pharmacological management of diabetes in 25 RACFs in Sydney Australia and assess concordance with clinical practice guidelines (CPGs). METHODS: Data from 231 permanent RACF residents aged ≥65 years and over with type 2 diabetes mellitus over the period from 1 July 2016 to 31 December 2019 were used. Concordance was measured by assessing the medications and medical history data for each individual resident for concordance with evidence-based CPGs. Multivariable logistic regression was used to estimate the effect of resident characteristics on concordance with CPGs. RESULTS: Of the 231 residents with diabetes, 87 (38%) were not taking any antidiabetic medication. Pharmacological management inconsistent with CPG recommendations was observed for 73 (32%) residents, with the most common reason for non-concordance being the use of medications with significant adverse effects in older adults (47, 2%). Residents with hypertension or other heart diseases in addition to their diabetes had greater odds of their diabetes management being non-concordant with CPGs (OR = 2.84 95% CI = 1.54, 5.3 and OR = 2.64, 95% CI = 1.07, 6.41, respectively). CONCLUSIONS: Pharmacological diabetes management in metropolitan Australian RACFs is suboptimal, with a high prevalence of inconsistency with CPGs (32%) observed. Additionally, having hypertension or heart diseases significantly increased the possibility of non-concordance among diabetic RACF residents. Further investigation into the underlying relationships with comorbidities is required to develop better strategies.

Spontaneous cerebrovascular reactivity at rest in older adults with and without mild cognitive impairment and memory deficits.

Background: Older adults with mild cognitive impairment (MCI) exhibit deficits in cerebrovascular reactivity (CVR), suggesting CVR is a biomarker for vascular contributions to MCI. This study examined if spontaneous CVR is associated with MCI and memory impairment. Methods: 161 older adults free of dementia or major neurological/psychiatric disorders were recruited. Participants underwent clinical interviews, cognitive testing, venipuncture for Alzheimer's biomarkers, and brain MRI. Spontaneous CVR was quantified during 5 minutes of rest. Results: Whole brain CVR was negatively associated with age, but not MCI. Lower CVR in the parahippocampal gyrus (PHG) was found in participants with MCI and was linked to worse memory performance on memory tests. Results remained significant after adjusting for Alzheimer's biomarkers and vascular risk factors. Conclusion: Spontaneous CVR deficits in the PHG are observed in older adults with MCI and memory impairment, indicating medial temporal microvascular dysfunction's role in cognitive decline.

Tailoring communication practices to support effective delivery of telehealth in general practice.

BACKGROUND: The unprecedented increase in telehealth use due to COVID-19 has changed general practitioners' (GP) and patients' engagement in healthcare. There is limited specific advice for effective communication when using telehealth. Examining telehealth use in practice in conjunction with perspectives on telehealth as they relate to communication allows opportunities to produce evidence-based guidance for optimal use of telehealth, while also offering practitioners the opportunity to reflect on elements of their communicative practice common to both styles of consultation. The objective of this research was to develop evidence-based resources to support effective, person-centred communication when GPs and patients use telehealth. This included examination of interactional practices of recorded telehealth consultations, exploration of GP and patient perspectives relating to telehealth, and identifying priorities for guidance informed by these analyses as well as participant co-design. METHODS: This study involved recording telehealth consultations (n = 42), conducting patient surveys (n = 153), and interviewing patients (n = 9) and GPs (n = 15). These were examined using interaction analytic methods, quantitative analysis, and thematic analyses, to create a robust, integrated picture of telehealth practice and perspectives. The process of research translation involved a co-design approach, engaging with providers, patients, and policy makers to facilitate development of evidence-based principles that focus on supporting effective communication when using telehealth. RESULTS: Three key themes relating to communication in telehealth were identified across the different analyses. These were relationship building, conversational flow, and safety netting. The draft best practice principles drawn from these themes were modified based on co-design feedback into five Best Practice Principles for Communication between GPs and Patients using Telehealth. CONCLUSIONS: Effective communication is supported through relationship building and attention to conversational flow in telehealth consultations, which in turn allows for safety netting to occur. In telehealth, GPs and patients recognise that not being co-present changes the consultation and use both intuitive and strategic interactional adjustments to support their exchange. The mixed-method examination of experiences through both a detailed analysis of telehealth consultations in practice and comparative exploration of GP and patient perspectives enabled the identification of principles that can support effective communication when using telehealth. Co-design helped ensure these principles are ready for implementation into practice.

A Longitudinal Study of the Use and Effects of Fall-Risk-Increasing Drugs in Residential Aged Care.

OBJECTIVES: Fall-risk-increasing drugs (FRIDs)-psychotropics and cardiovascular disease (CVD) drugs-may elevate the risk of falling, with strong evidence observed in psychotropic FRIDs, whereas findings from cardiovascular disease (CVD) FRIDs remain inconclusive. Existing studies on FRIDs and falls are often hampered by methodologic limitations. Leveraging longitudinal observational data, we aimed to determine the long-term patterns of FRID use and their association with falls in residential aged care (RAC) homes. DESIGN: A retrospective longitudinal cohort study. SETTING AND PARTICIPANTS: A total of 4207 permanent residents newly admitted to 27 RAC homes in Sydney, Australia. METHOD: The outcomes were incidence of all and injurious falls. We measured exposure to each FRID over 60 months using the Proportion of Days Covered (PDC) metric. We used group-based multitrajectory modeling to determine concurrent usage patterns of psychotropics and CVD FRIDs and applied negative binomial regression to assess their associations with the outcomes. RESULTS: A total of 83.6% (n = 3516) and 77.3% (n = 3254) residents used psychotropic and CVD FRIDs, respectively. The PDC values ranged from 67.3% (opioids) to 86.9% (antidepressants) for specific psychotropics and 79.0% (α-adrenoceptor antagonists) to 89.6% (ß blockers) for CVD FRIDs. We identified 4 groups: group 1, low psychotropics-low CVDs use (16.7%, n = 701); group 2, low psychotropics-high CVDs (25.0%, n = 1054); group 3, high psychotropics-high CVDs (41.0%, n = 1723); and group 4, high psychotropics-low CVDs (17.3%, n = 729). Group 4 had a significantly higher rate of falls than the other groups for both outcomes, including relative to group 3, in which exposure to both FRID classes was high. CONCLUSIONS AND IMPLICATIONS: Our findings reveal concerningly high FRID use in RAC homes and highlight a critical difference in the impact of the 2 major FRID classes on falls. Psychotropics were strongly associated with falls, whereas the studied CVD FRIDs did not elevate risk of falling.

Short-term blood pressure variability and brain functional network connectivity in older adults.

Background: Blood pressure variability is increasingly linked with cerebrovascular disease and Alzheimer's disease, independent of mean blood pressure levels. Elevated blood pressure variability is also associated with attenuated cerebrovascular reactivity, which may have implications for functional hyperemia underpinning brain network connectivity. It remains unclear whether blood pressure variability is related to functional network connectivity. We examined relationships between beat-to-beat blood pressure variability and functional connectivity in brain networks vulnerable to aging and Alzheimer's disease. Methods: 53 community-dwelling older adults (mean [SD] age = 69.9 [7.5] years, 62.3% female) without history of dementia or clinical stroke underwent continuous blood pressure monitoring and resting state fMRI scan. Blood pressure variability was calculated as variability independent of mean. Functional connectivity was determined by resting state fMRI for several brain networks: default, salience, dorsal attention, fronto-parietal, and language. Multiple linear regression examined relationships between short-term blood pressure variability and functional network connectivity. Results: Elevated short-term blood pressure variability was associated with lower functional connectivity in the default network (systolic: standardized ß = -0.30 [95% CI -0.59, -0.01], p = .04). There were no significant associations between blood pressure variability and connectivity in other functional networks or between mean blood pressure and functional connectivity in any network. Discussion: Older adults with elevated short-term blood pressure variability exhibit lower resting state functional connectivity in the default network. Findings support the role of blood pressure variability in neurovascular dysfunction and Alzheimer's disease. Blood pressure variability may represent an understudied early vascular risk factor for neurovascular dysfunction relevant to Alzheimer's disease, with potential therapeutic implications.

The interactive effect of intra-beat and inter-beat blood pressure variability on neurodegeneration in older adults.

Blood pressure variability (BPV) and arterial stiffness are age-related hemodynamic risk factors for neurodegenerative disease, but it remains unclear whether they exert independent or interactive effects on brain health. When combined with high inter-beat BPV, increased intra-beat BPV indicative of arterial stiffness could convey greater pressure wave fluctuations deeper into the cerebrovasculature, exacerbating neurodegeneration. This interactive effect was studied in older adults using multiple markers of neurodegeneration, including medial temporal lobe (MTL) volume, plasma neurofilament light (NfL) and glial fibrillary acidic protein (GFAP). Older adults (N=105) without major neurological or systemic disease were recruited and underwent brain MRI and continuous BP monitoring to quantify inter-beat BPV through systolic average real variability (ARV) and intra-beat variability through arterial stiffness index (ASI). Plasma NfL and GFAP were assessed. The interactive effect of ARV and ASI on MTL atrophy, plasma NfL, and GFAP was studied using hierarchical linear regression. Voxel-based morphometry (VBM) was used to confirm region-of-interest analysis findings. The interaction between higher ARV and higher ASI was significantly associated with left-sided MTL atrophy in both the region-of-interest and false discovery rate-corrected VBM analysis. The interactive effect was also significantly associated with increased plasma NfL, but not GFAP. The interaction between higher ARV and higher ASI is independently associated with increased neurodegenerative markers, including MTL atrophy and plasma NfL, in independently living older adults. Findings could suggest the increased risk for neurodegeneration associated with higher inter-beat BPV may be compounded by increased intra-beat variability due to arterial stiffness.

Perception of middle-aged and older adults towards mHealth apps: A comparative factor analysis between Australia and Germany.

OBJECTIVE: Although evidence of the global effectiveness and usability of mobile health (mHealth) apps as non-drug interventions is growing, older adults often demonstrate low adoption rates of these apps. This study aims to identify the perspectives of older adults on introducing and adopting mHealth apps in Australia and Germany. MATERIALS AND METHODS: We conducted two online cross-sectional surveys to examine factors from contextual, technological and personal perspectives that influence older adults in mHealth app adoption. Using descriptive statistics, chi-square tests and exploratory factor analysis, we identified the differences and similarities between respondents' perspectives across two countries. RESULTS: A total of 290 respondents (149, Australia; 141, Germany) completed the survey. Older adults' ability to use a mHealth app, the user-friendliness of the app, their positive self-efficacy regarding their health and resource availability for using mHealth apps were related to intended adoption. Differences between Germany and Australia were found in issues concerned with data sharing and empowerment by the doctor, while similarities were related to trust in the doctor and their treatment approaches. DISCUSSION AND CONCLUSION: This study highlights participants' perspectives and attitudes towards mHealth app use, unmet needs and barriers, and the facilitating influences in the two countries. These insights can be used to inform the development and implementation of mHealth apps and to construct tailored strategies to increase the adoption rates of mHealth apps among older adults and to maximise their potential benefits.

The relationship between participation in leisure activities and incidence of falls in residential aged care.

BACKGROUND: Active engagement in leisure activities has positive effects on individuals' health outcomes and social functioning; however, there is limited understanding of the link between participation in leisure activities, particularly non-exercise activities, and falls in older adults. This study aimed to determine the relationship between participation in leisure activities and the incidence of falls, and the variation of this relationship by dementia status in residential aged care facilities (RACFs). METHODS: A retrospective longitudinal cohort study utilising routinely collected data (January 2021-August 2022) from 25 RACFs in Sydney, Australia, was conducted. The cohort included 3,024 older permanent residents (1,493 with dementia and 1,531 without) aged ≥65 and with a stay of ≥1 week. The level of participation in leisure activities was measured using the number of leisure activities per 1,000 resident days and divided into quartiles. Outcome measures were the incidence rate of all falls and injurious falls (i.e., number of falls per 1,000 resident days). We used multilevel negative binary regression to examine the relationship between leisure participation and fall incidence. RESULTS: For the whole sample, leisure participation was significantly inversely associated with the incidence rate of all falls and injurious falls. For example, residents in the high leisure participation group were 26% less likely to experience a fall compared to those in the low leisure participation group after controlling for confounders (incidence rate ratio = 0.74, 95% confidence interval = 0.60, 0.91). Such inverse relationship was observed in both exercise and non-exercise activities and was stronger among residents without dementia. CONCLUSIONS: Leisure participation is associated with a lower rate of falls, a key quality indicator by which RACFs are benchmarked and funded in Australia and many other countries. More recognition and attention are needed for the currently underfunded leisure activities in RACFs in future funding arrangement.

Co-production processes for translation and validation of psychosocial assessments for older adults in aged care.

OBJECTIVE: Given the diverse ethnic backgrounds of aged care clients, there is a critical requirement to translate psychosocial assessment tools into various languages to effectively evaluate social engagement and quality of life in older adults receiving aged care services. This study aimed to translate psychosocial tools into Turkish, Korean and Mandarin, the primary languages spoken by clients of an Australian community aged care provider. METHODS: A co-development approach encompassing forward and backward translations of the Australian Community Participation Questionnaire and ICEpop CAPability measure for Older people tools, along with focus group discussions involving bilingual staff (n = 7) and clients (n = 16), was employed to ensure precision and cultural relevance. Multiple iterations were undertaken until linguistic, conceptual and scaling equivalence was achieved, with recorded sessions transcribed and analysed thematically. RESULTS: Cultural appropriateness significantly impacted the delivery of questions within the tools, emphasising translation challenges tied to specific queries. These difficulties included the lack of terms for unique places of worship, the use of outdated language (e.g., references to reading newspapers), and varying priorities in social and well-being matters between Western and Eastern/Asian cultures. Staff feedback identified that formal translated tool versions eased administration for culturally and linguistically diverse (CALD) clients, enabling them to independently interpret questions, resulting in improved questionnaire completion rates. CONCLUSIONS: Insights indicate the need for continued efforts in tailoring assessment tools to diverse cultural contexts to ensure accurate and meaningful data collection.

Adverse impacts in residential aged care facilities: The resident perspective.

OBJECTIVES: Inclusion of consumer perspectives is a key component to person-centred health-care approaches. While current residential aged care systems focus on recording adverse events to meet the requirements of regulatory reporting, little is known about the views of residents. The aim of this research was to explore residents' responses on the types of incidents that have an adverse impact on them and how they are affected by these incidents. METHODS: The study used a qualitative, inductive approach to derive themes from interviews with 20 permanent residents of aged care facilities in New South Wales and the Australian Capital Territory. RESULTS: Four main themes surrounding adverse incidents emerged: (i) social relationships and the adverse impacts of lack of meaningful interactions, (ii) adjustment to life in the residential aged care facility and the loss of residents' former life and self-determination, (iii) the impact of COVID-19 lockdowns which meant that residents were not able to go out or interact with others and (iv) acceptance, resignation and resilience in coping with adverse incidents. CONCLUSIONS: This research highlights the difference between health-care definition, used for incident management reporting and quality indicators, and the way residents respond when asked to describe an incident that has affected them. Resident responses discuss situations having an adverse effect on them in contrast to the way adverse events and incidents are reported and monitored. The findings suggest that within adverse event and incident management systems and resident governance systems, there is scope for incorporating periods of transitions and well-being measures that capture elements that matter to older people.

Real-world utilization, patient characteristics, and treatment patterns among men with localized prostate cancer tested with the 17-gene genomic prostate score® (GPSTM) assay.

OBJECTIVES: Descriptive study focusing on real-world utilization and characteristics of men with prostate cancer tested with the 17-gene Genomic Prostate Score® (GPS™) assay by linking administrative claims and electronic health record (EHR) data with GPS results. METHODS: This retrospective, observational cohort study (January 1, 2013 to December 31, 2020) included men aged 40-80 years with localized prostate cancer claims, continuous enrollment in Optum's Integrated Claims data set, ≥1 day of EHR clinical activity, and a GPS result. Men were classified as undergoing definitive therapy (DT) (prostatectomy, radiation, or focal therapy) or active surveillance (AS). AS and DT distribution were analyzed across GPS results, National Comprehensive Cancer Network® (NCCN®) risk, and race. Costs were assessed 6 months after the first GPS result (index); clinical outcomes and AS persistence were assessed during the variable follow-up. All variables were analyzed descriptively. RESULTS: Of 834 men, 650 (77.9%) underwent AS and 184 (22.1%) DT. Most men had Quan-Charlson comorbidity scores of 1-2 and a tumor stage of T1c (index). The most common Gleason patterns were 3 + 3 (79.6%) (AS cohort) and 3 + 4 (55.9%) (DT cohort). The mean (standard deviation) GPS results at index were 23.2 (11.3) (AS) and 30.9 (12.9) (DT). AS decreased with increasing GPS result and NCCN risk. Differences between races were minimal. Total costs were substantially higher in the DT cohort. CONCLUSIONS: Most men with GPS-tested localized prostate cancer underwent AS, indicating the GPS result can inform clinical management. Decreasing AS with increasing GPS result and NCCN risk suggests the GPS complements NCCN risk stratification.

ORF48 is required for optimal lytic replication of Kaposi's Sarcoma-Associated Herpesvirus.

Kaposi's sarcoma-associated herpesvirus (KSHV) establishes persistent infection in the host by encoding a vast network of proteins that aid immune evasion. One of these targeted innate immunity pathways is the cGAS-STING pathway, which inhibits the reactivation of KSHV from latency. Previously, we identified multiple cGAS/STING inhibitors encoded by KSHV, suggesting that the counteractions of this pathway by viral proteins are critical for maintaining a successful KSHV life cycle. However, the detailed mechanisms of how these viral proteins block innate immunity and facilitate KSHV lytic replication remain largely unknown. In this study, we report that ORF48, a previously identified negative regulator of the cGAS/STING pathway, is required for optimal KSHV lytic replication. We used both siRNA and deletion-based systems to evaluate the importance of intact ORF48 in the KSHV lytic cycle. In both systems, loss of ORF48 resulted in defects in lytic gene transcription, lytic protein expression, viral genome replication and infectious virion production. ORF48 genome deletion caused more robust and global repression of the KSHV transcriptome, possibly due to the disruption of RTA promoter activity. Mechanistically, overexpressed ORF48 was found to interact with endogenous STING in HEK293 cells. Compared with the control cell line, HUVEC cells stably expressing ORF48 exhibited repressed STING-dependent innate immune signaling upon ISD or diABZI treatment. However, the loss of ORF48 in our iSLK-based lytic system failed to induce IFNß production, suggesting a redundant role of ORF48 on STING signaling during the KSHV lytic phase. Thus, ORF48 is required for optimal KSHV lytic replication through additional mechanisms that need to be further explored.

Effectiveness of fall prevention interventions in residential aged care and community settings: an umbrella review.

INTRODUCTION: Preventing falls is a priority for aged care providers. Research to date has focused on fall prevention strategies in single settings (e.g., residential aged care (RAC) or community settings). However, some aged care providers deliver care, including fall prevention interventions, across RAC and community settings. We conducted an umbrella review to identify what type of fall prevention interventions had the greatest impact on falls outcomes in RAC and community settings. METHODS: Five databases were searched for systematic reviews of falls prevention randomised control trials in older adults living in the community or RAC. Data extracted included systematic review methods, population characteristics, intervention characteristics, setting details (RAC or community), and fall-related outcomes (falls, people who have had a fall, fall-related hospitalisations, and fall-related fractures). Review quality was appraised using the Assessment of Multiple Systematic Reviews-2 tool. RESULTS: One-hundred and six systematic reviews were included; 63 and 19 of these stratified results by community and RAC settings respectively, the remainder looked at both settings. The most common intervention types discussed in reviews included 'exercise' (61%, n = 65), 'multifactorial' (two or more intervention types delivered together) (26%, n = 28), and 'vitamin D' (18%, n = 19). In RAC and community settings, 'exercise' interventions demonstrated the most consistent reduction in falls and people who have had a fall compared to other intervention types. 'Multifactorial' interventions were also beneficial in both settings however demonstrated more consistent reduction in falls and people who fall in RAC settings compared to community settings. 'Vitamin D' interventions may be beneficial in community-dwelling populations but not in RAC settings. It was not possible to stratify fall-related hospitalisation and fall-related fracture outcomes by setting due to limited number of RAC-specific reviews (n = 3 and 0 respectively). CONCLUSION: 'Exercise' interventions may be the most appropriate falls prevention intervention for older adults in RAC and community settings as it is beneficial for multiple fall-related outcomes (falls, fall-related fractures, and people who have had a fall). Augmenting 'exercise' interventions to become 'multifactorial' interventions may also improve the incidence of falls in both settings.

Utilising Mobile Health Apps - A Comparison of GP Perceptions Across Australia and Germany.

Germany became the first country to accept certain mobile health (mHealth) apps for prescription with costs covered by statutory health insurance. Yet, this option has only been used to a limited extent. To develop an international comparison, this study investigates GPs' perceptions of mHealth apps with a medical purpose in Germany and Australia. We conducted semi-structured interviews to examine their perspective on introducing and using mHealth apps and their awareness of their impact on patient adherence, empowerment, and health literacy. The results show that prescribing mHealth apps in general practice seems feasible in Australia and doctors are highly receptive to it.

Designing an Informatics Infrastructure for a National Aged Care Medication Roundtable.

In the residential aged care sector medication management has been identified as a major area of concern contributing to poor outcomes and quality of life for residents. Monitoring medication management in residential aged care in Australia has been highly reliant on small, internal audits. The introduction of electronic medication administration systems provides new opportunities to establish improved methods for ongoing, timely and efficient monitoring of a range of medication indicators, made more meaningful by linking medication data with resident characteristics and outcomes. Benchmarking contemporary medication indicators provides a further opportunity for improvement and is most effective when indicator data are adjusted to take account of confounding factors, such as residents' characteristics and health conditions. Roundtables provide a structure for sharing and discussing indicator data in a trusted and supportive environment and encourage the identification of strategies which may be effective in improving medication management. This paper describes a new project to establish, implement and evaluate a National Aged Care Medication Roundtable.

What would it take to improve the uptake and utilisation of mHealth applications among older Australians? A qualitative study.

Objective Health-related apps on mobile devices (mHealth apps) have become an effective self-management tool and treatment support for patients. There is limited research, however, on how older people (50 and over) perceive the opportunity of using mHealth apps. Our aim was to investigate the perceptions of older people in Australia regarding the opportunity of using prescribed or doctor-recommended mHealth apps and provide insights which can enhance their uptake of mHealth. Methods This was a qualitative study using semi-structured interviews involving 21 participants aged 51-82 years. Qualitative thematic analysis was used to categorise the factors that influence the adoption of mHealth apps by older adults. Results We show that beyond the prominent influencing factors from technology adoption research (such as performance and effort expectancy, social influence and facilitating conditions), health-specific factors such as a trusting doctor-patient relationship and strong health self-efficacy positively influence the intended adoption of mHealth apps among older adults. In addition, the IT security and accurate interpretation of participants' input in an mHealth app can present barriers to mHealth app adoption. Conclusion Our analyses provide additional insights complementing existing technology adoption research. Their successful adoption and utilisation require further empirical evidence on its effectiveness along with attention to the voices of those who are meant to use them. To address potential barriers, improve the quality and security of mHealth apps, and thus achieve greater patient safety, the involvement of consumers, regulators and health professionals is necessary.

Methylation of elongation factor 1A by yeast Efm4 or human eEF1A-KMT2 involves a beta-hairpin recognition motif and crosstalks with phosphorylation.

Translation elongation factor 1A (eEF1A) is an essential and highly conserved protein required for protein synthesis in eukaryotes. In both Saccharomyces cerevisiae and human, five different methyltransferases methylate specific residues on eEF1A, making eEF1A the eukaryotic protein targeted by the highest number of dedicated methyltransferases after histone H3. eEF1A methyltransferases are highly selective enzymes, only targeting eEF1A and each targeting just one or two specific residues in eEF1A. However, the mechanism of this selectivity remains poorly understood. To reveal how S. cerevisiae elongation factor methyltransferase 4 (Efm4) specifically methylates eEF1A at K316, we have used AlphaFold-Multimer modeling in combination with crosslinking mass spectrometry (XL-MS) and enzyme mutagenesis. We find that a unique beta-hairpin motif, which extends out from the core methyltransferase fold, is important for the methylation of eEF1A K316 in vitro. An alanine mutation of a single residue on this beta-hairpin, F212, significantly reduces Efm4 activity in vitro and in yeast cells. We show that the equivalent residue in human eEF1A-KMT2 (METTL10), F220, is also important for its activity towards eEF1A in vitro. We further show that the eEF1A guanine nucleotide exchange factor, eEF1Bα, inhibits Efm4 methylation of eEF1A in vitro, likely due to competitive binding. Lastly, we find that phosphorylation of eEF1A at S314 negatively crosstalks with Efm4-mediated methylation of K316. Our findings demonstrate how protein methyltransferases can be highly selective towards a single residue on a single protein in the cell.

Non-Interferon-Dependent Role of STING Signaling in Pulmonary Hypertension.

BACKGROUND: Patients with constitutive activation of DNA-sensing pathway through stimulator of IFN (interferon) genes (STING), such as those with STING-associated vasculopathy with onset in infancy, develop pulmonary hypertension (PH). However, the role of STING signaling in general PH patients is heretofore undescribed. Here, we seek to investigate the role of STING in PH development. METHODS: STING expression in patient lung samples was examined. PH was induced in global STING-deficient mice and global type I IFN receptor 1-deficient mice using bleomycin or chronic hypoxia exposure. PH development was evaluated by right ventricular systolic pressure and Fulton index, with additional histological and flow cytometric analysis. VEGF (vascular endothelial growth factor) expression on murine immune cells was quantified and evaluated with multiplex and flow cytometry. Human myeloid-derived cells were differentiated from peripheral blood mononuclear cells and treated with either STING agonist or STING antagonist for evaluation of VEGF secretion. RESULTS: Global STING deficiency protects mice from PH development, and STING-associated PH seems independent of type I IFN signaling. Furthermore, a role for STING-VEGF signaling pathway in PH development was demonstrated, with altered VEGF secretion in murine pulmonary infiltrated myeloid cells in a STING-dependent manner. In addition, pharmacological manipulation of STING in human myeloid-derived cells supports in vivo findings. Finally, a potential role of STING-VEGF-mediated apoptosis in disease development and progression was illustrated, providing a roadmap toward potential therapeutic applications. CONCLUSIONS: Overall, these data provide concrete evidence of STING involvement in PH, establishing biological plausibility for STING-related therapies in PH treatment.

Hospitalisations before and after entry into a residential aged care facility: An interrupted time series analysis.

OBJECTIVE: Hospitalisations are an important indicator of safety and quality of care in residential aged care facilities (RACFs). This study aimed to investigate changes in hospital use 12 months before and 12 months after RACF entry using routinely collected data from 25 Australian RACFs. METHODS: This was a retrospective longitudinal cohort study using linked aged care provider and hospital record data. The sample comprised 1029 residents living in an aged care facility between July 2014 and December 2019 who had stayed a minimum of 12 months in an RACF. The outcome measures were all-cause hospitalisations and fall-related hospitalisations. We applied an interrupted time series analysis using segmented regression to examine changes in both outcome measures over time. Stratified analyses were conducted by gender and dementia status. RESULTS: The rate of all-cause hospitalisations increased dramatically over the 12 months before RACF entry, from 97 per 1000 residents per month 12 months prior to RACF admission to 303 per 1000 residents at the second month prior to RACF entry. All-cause hospitalisations then decreased considerably to 55 per 1000 residents upon RACF admission and stabilised across the next 12 months. Such trajectories were also observed in fall-related hospitalisations and were consistent for gender and dementia status. CONCLUSIONS: In this study, hospitalisation rates decreased significantly after RACF entry, and such reductions were maintained for residents who stayed for 12 months in RACFs. Multiple hospital admissions are likely to precipitate entry into RACF. Additional investigation of how community-based services can be successful in reducing the escalating hospitalisations is needed.

Real-world use of inotuzumab ozogamicin is associated with lower health care costs than blinatumomab in patients with acute lymphoblastic leukemia in the first relapsed/refractory setting.

Aim: To compare all-cause and acute lymphoblastic leukemia (ALL)-related healthcare resource utilization (HCRU) and costs among patients receiving inotuzumab ozogamicin (InO) and blinatumomab (Blina) for ALL in the first relapsed/refractory (R/R) setting. Patients & methods: We studied retrospective claims for adult commercial and Medicare Advantage enrollees with ALL receiving InO (n = 29) or Blina (n = 23) from 1 January 2015 to 16 February 2021. Mean per-patient-per-month (PPPM) HCRU and total costs were described and multivariable-adjusted PPPM total all-cause and ALL-related predicted costs were calculated. Results: Mean monthly ALL-related hospitalizations were the same for patients receiving InO and Blina (PPPM = 0.8 stays); however, the length of ALL-related hospital stay was almost twice as long among patients receiving Blina versus InO (ALL-related: InO = 7.6 days; Blina = 14.1 days; p = 0.346). In multivariable models, total ALL-related costs were 43% lower for InO compared with Blina (PPPM costs: InO = $93,767; Blina = $163,470; p = 0.021). Conclusion: In the first R/R setting, patients who used InO had significantly lower all-cause and ALL-related costs compared with patients who used Blina, in part driven by hospitalization patterns.