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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.

A modified Delphi study was conducted to (1) identify intervention elements that are considered by geriatricians to be important in optimizing prescribing for older adults with multimorbidity, and (2) to select the accompanying behavior change techniques to be incorporated into a context-relevant intervention to support prescribing. Intervention elements such as medication review identified by the Delphi panel mirrored results from a previous scoping review. Statements involving roles of pharmacists selected by the panel validated findings in the literature that pharmacists play important collaborative roles to help reduce potentially inappropriate prescribing among older adults with multimorbidity. We identified relevant intervention elements and their accompanying behavior change techniques to aid in the development of a context-specific intervention. 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. 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. 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. 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.

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., Eleven barrier statements reached consensus with high importance according to the Delphi panel. Linking the barriers to Theoretical Domains Framework and intervention functions revealed strategic directions for the development of an intervention to address the barriers and optimize prescribing.

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.

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 evaluatein vivosignificance, 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 inhibitorl-NAME or by the DMT1-selective blocker ebselen. Lentiviral knockdown of DMT1 abolished LPS-induced dopaminergic neuron loss.SIGNIFICANCE STATEMENTNeuroinflammation 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 usingl-NAME, a NO synthase inhibitor, or by ebselen, a DMT1-selective blocker.