Appropriate Prescribing for older adults with Multimorbidity (Pro-M): protocol for a feasibility study.

BACKGROUND: Potentially inappropriate prescribing is common among older adults with multimorbidity due to various reasons, from concurrent application of multiple single-disease clinical guidelines to fragmentation of care. Interventions such as medication review have been implemented worldwide to reduce inappropriate prescribing for older adults. However, the implementability of such interventions are underexplored in the outpatient clinics in Singapore's public hospitals. Hence, the Pro-M study aims to assess the feasibility of implementing a physician-pharmacist collaborative care intervention in geriatric medicine outpatient clinics to facilitate appropriate prescribing for older adults in Singapore. METHODS: This is a single-arm, non-randomised feasibility study using a pre-post evaluation design. This study consists of two parts: (1) implementation phase of the intervention (6 months) and an (2) evaluation phase (3 months). Eligible patients will be recruited from geriatric medicine outpatient clinics at two public hospitals in Singapore through convenience sampling. The main components of the Pro-M intervention are: (1) pharmacist-facilitated medication reviews with feedback on any medication issues and potential recommendations to physicians, and (2) physicians communicating changes to other relevant prescribers. The evaluation phase will involve surveying and interviewing physicians and pharmacists involved in the implementation of the intervention. A mixed-method approach will be employed for data collection and analysis. The quantitative and qualitative findings will be triangulated and reported using Proctor's implementation outcomes: appropriateness, penetration, acceptability, fidelity, feasibility, and sustainability. A basic cost analysis will be conducted alongside the study. DISCUSSION: This is a phase 2 study to test the feasibility of implementing an intervention that was co-created with stakeholders during phase 1 development of an intervention to optimise prescribing for older adults with multimorbidity. The implementation will be assessed using Proctor's implementation outcomes to provide insights on the process and the feasibility of implementing medication reviews for older adults with multimorbidity as a routine practice in outpatient clinics. Data collected from this study will inform a subsequent scale-up study. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT05756478. Registered on 06 March 2023.

Using multiple approaches to develop a physician-pharmacist collaborative care intervention to facilitate appropriate prescribing for older adults with multimorbidity.

BACKGROUND AND OBJECTIVES: This article discusses the development process of an intervention to facilitate appropriate prescribing for older adults with multimorbidity at geriatric medicine outpatient clinics. Both effectiveness and implementability were key aims, which were achieved by a systematic combination of different approaches guided by published guidance. METHODS: Various frameworks and tools were used to guide the intervention development. They include The Medical Research Council Framework for complex health interventions as the overarching framework, supplemented by the Framework of Actions for Intervention Development and a taxonomy of intervention development approaches. RESULTS: A combination of theory and evidence-based-, implementation-based and partnership approaches were used to develop the intervention. The Behaviour Change Wheel and Theoretical Domains Framework were used for intervention design. Three scoping reviews and two modified Delphi studies were conducted to build an evidence base on prescribing-related barriers and existing interventions. The findings were synthesised, assessed for implementability, and culminated in a co-creation exercise with physicians and pharmacists. The final intervention aims to facilitate collaboration between physicians and pharmacists and to improve communication and documentation of prescribing decisions. CONCLUSIONS: Multiple approaches may be required when developing interventions that are effective and implementable. The study team's experiences in using published guidance, integrating different approaches, and co-creating the intervention with healthcare professionals provide a useful case study with lessons and insights for developers of complex interventions. Furthermore, systematic reporting of such research-based efforts would contribute to advancement of intervention development in healthcare and reducing research waste.

Effects of Exercise Interventions on Physical Performance and Activities of Daily Living in Oldest-Old and Frail Older Adults: A Review of the Literature.

ABSTRACT: This review examined and compared the effects of exercise interventions using portable exercise equipment on muscle strength, balance, and ability to perform activities of daily living in the oldest-old and frail. We also examined the differences in the intervention characteristics between these two groups. The CINAHL, MEDLINE, and Cochrane databases were searched using specific text words and MeSH for randomized controlled trials published from 2000 to 2021, which involved exercise interventions for either oldest-old (≥75 yrs) or physically frail (reduced muscular strength, endurance, and physiological function) older adults. A total of 76 articles were included in this review, in which 61 studies involved oldest-old adults and 15 studies examined frail adults. Subgroup reviews of community dwelling and institutionalized adults were performed. The empirical evidence suggests that single-component and multicomponent exercise interventions produced positive effects for both older adult groups on muscle strength and balance, respectively. The effects of multicomponent interventions on muscular strength could be dependent on the number of exercise components per session. The effects of exercises on activities of daily living enhancement were less clear. We advocate for single intervention resistance training in all oldest-old and frail seniors to improve strength, if compliance to exercise duration is an issue.

Development and validation of a predictive model for patients with post-extubation dysphagia.

BACKGROUND: Swallowing disorder is a common clinical symptom that can lead to a series of complications, including aspiration, aspiration pneumonia, and malnutrition. This study aimed to investigate risk factors of post-extubation dysphagia (PED) in intensive care unit (ICU) patients with endotracheal intubation, and to develop a risk-predictive model for PED, which could serve as an assessment tool for the prevention and control of PED. METHODS: Patients retrospectively selected from June to December 2021 in a tertiary hospital served as the derivation cohort. Patients recruited from the same hospital from March to June 2022 served as the external validation cohort for the predictive model. We used a combination of variable screening and least absolute shrinkage and selection operator (LASSO) regression to select the most useful candidate predictors and checked the multicollinearity of independent variables using the variance inflation factor method. Multivariate logistic regression analysis was performed to calculate the odds ratio (OR; 95% confidence interval [95% CI]) and P-value for each variable to predict diagnosis. The screened risk factors were introduced into R software to build a nomogram model. The performance of the model, including discrimination ability, calibration, and clinical benefit, was evaluated by plotting the receiver operating characteristic (ROC), calibration, and decision curves. RESULTS: A total of 305 patients were included in this study. Among them, 235 patients (53 PED vs. 182 non-PED) were enrolled in the derivation cohort, while 70 patients (17 PED vs. 53 non-PED) were enrolled in the validation cohort. The independent predictors included age, pause of sedatives, level of consciousness, activities of daily living (ADL) score, nasogastric tube, sore throat, and voice disorder. These predictors were used to establish the predictive nomogram model. The model demonstrated good discriminative ability, and the area under the ROC curve (AUC) was 0.945 (95% CI 0.904-0.970). Applying the predictive model to the validation cohort demonstrated good discrimination with an AUC of 0.907 (95% CI 0.831-0.983) and good calibration. The decision-curve analysis of this nomogram showed a net benefit of the model. CONCLUSION: A predictive model that incorporates age, pause of sedatives, level of consciousness, ADL score, nasogastric tube, sore throat, and voice disorder may have the potential to predict PED in ICU patients.

SFPQ promotes RAS-mutant cancer cell growth by modulating 5'-UTR mediated translational control of CK1α.

Oncogenic mutations in the RAS family of small GTPases are commonly found in human cancers and they promote tumorigenesis by altering gene expression networks. We previously demonstrated that Casein Kinase 1α (CK1α), a member of the CK1 family of serine/threonine kinases, is post-transcriptionally upregulated by oncogenic RAS signaling. Here, we report that the CK1α mRNA contains an exceptionally long 5'-untranslated region (UTR) harbouring several translational control elements, implicating its involvement in translational regulation. We demonstrate that the CK1α 5'-UTR functions as an IRES element in HCT-116 colon cancer cells to promote cap-independent translation. Using tobramycin-affinity RNA-pulldown assays coupled with identification via mass spectrometry, we identified several CK1α 5'-UTR-binding proteins, including SFPQ. We show that RNA interference targeting SFPQ reduced CK1α protein abundance and partially blocked RAS-mutant colon cancer cell growth. Importantly, transcript and protein levels of SFPQ and other CK1α 5'-UTR-associated RNA-binding proteins (RBPs) are found to be elevated in early stages of RAS-mutant cancers, including colorectal and lung adenocarcinoma. Taken together, our study uncovers a previously unappreciated role of RBPs in promoting RAS-mutant cancer cell growth and their potential to serve as promising biomarkers as well as tractable therapeutic targets in cancers driven by oncogenic RAS.

Intervention elements and behavior change techniques to improve prescribing for older adults with multimorbidity in Singapore: a modified Delphi study.

PURPOSE: Potentially inappropriate prescribing among older adults is a rising concern, attributed mainly by polypharmacy and multimorbidity. We aimed to identify key components and strategies for construction of a context-relevant intervention to facilitate appropriate prescribing in outpatient clinics in Singapore. METHODS: The modified Delphi study was conducted in two rounds with 20 geriatricians from seven public hospitals in Singapore. Round one survey presented 69 statements formulated from a scoping review, while round two presented 23 statements with some modifications based on round one comments. The statements were rated against a 7-point Likert scale on their importance and impact on prescribing for older adults with multimorbidty. RESULTS: Consensus were achieved for 90% of the statements. Seven intervention elements were identified as being important: medication review, training, medication therapy management, shared decision making, patient interview, medication reconciliation, comprehensive geriatric assessment. In addition, some commonly identified behavior change techniques included goal setting (behavior), goal setting (outcome) and problem solving. CONCLUSIONS: This study identified important intervention elements and their potential strategies that could be adopted in an intervention to optimize appropriate prescribing for older adults with multimorbidity.

Barriers to appropriate prescribing in older adults with multimorbidity: A modified Delphi study.

OBJECTIVES: We aimed to understand the barriers experienced by physicians when prescribing for older adults with multimorbidity in specialist outpatient clinics in Singapore. METHODS: A modified Delphi study was conducted via email with 20 panel experts in the field of geriatric medicine. Barriers identified from an earlier scoping review were presented as statements to the panel. RESULTS: Eleven barrier statements reached consensus with high importance according to the Delphi panel. Of these statements, seven (64%) belong to the domain of Environmental context and resources in the Theoretical Domains Framework (TDF), while the remaining barriers belong to the domains of skills, knowledge, intentions, and professional/social role and identity. The barriers are further linked to intervention functions in the Behaviour Change Wheel (BCW). CONCLUSION: Linking the TDF domains to intervention functions revealed strategic directions for the development of an intervention to address the barriers and optimize prescribing.

S-Nitrosylation of Divalent Metal Transporter 1 Enhances Iron Uptake to Mediate Loss of Dopaminergic Neurons and Motoric Deficit.

Elevated iron deposition has been reported in Parkinson's disease (PD). However, the route of iron uptake leading to high deposition in the substantia nigra is unresolved. Here, we show a mechanism in enhanced Fe2+ uptake via S-nitrosylation of divalent metal transporter 1 (DMT1). While DMT1 could be S-nitrosylated by exogenous nitric oxide donors, in human PD brains, endogenously S-nitrosylated DMT1 was detected in postmortem substantia nigra. Patch-clamp electrophysiological recordings and iron uptake assays confirmed increased Mn2+ or Fe2+ uptake through S-nitrosylated DMT1. We identified two major S-nitrosylation sites, C23 and C540, by mass spectrometry, and DMT1 C23A or C540A substitutions abolished nitric oxide (NO)-mediated DMT1 current increase. To evaluate in vivo significance, lipopolysaccharide (LPS) was stereotaxically injected into the substantia nigra of female and male mice to induce inflammation and production of NO. The intranigral LPS injection resulted in corresponding increase in Fe2+ deposition, JNK activation, dopaminergic neuronal loss and deficit in motoric activity, and these were rescued by the NO synthase inhibitor l-NAME or by the DMT1-selective blocker ebselen. Lentiviral knockdown of DMT1 abolished LPS-induced dopaminergic neuron loss.SIGNIFICANCE STATEMENT Neuroinflammation and high cytoplasmic Fe2+ levels have been implicated in the initiation and progression of neurodegenerative diseases. Here, we report the unexpected enhancement of the functional activity of transmembrane divalent metal transporter 1 (DMT1) by S-nitrosylation. We demonstrated that S-nitrosylation increased DMT1-mediated Fe2+ uptake, and two cysteines were identified by mass spectrometry to be the sites for S-nitrosylation and for enhanced iron uptake. One conceptual advance is that while DMT1 activity could be increased by external acidification because the gating of the DMT1 transporter is proton motive, we discovered that DMT1 activity could also be enhanced by S-nitrosylation. Significantly, lipopolysaccharide-induced nitric oxide (NO)-mediated neuronal death in the substantia nigra could be ameliorated by using l-NAME, a NO synthase inhibitor, or by ebselen, a DMT1-selective blocker.