Hospitalization Risk Among Older Adults with Sensory Impairments: Development of a Prognostic Model.

OBJECTIVES: To develop a prognostic model for hospital admissions over a 1-year period among community-dwelling older adults with self-reported hearing and/or vision impairments based on readily obtainable clinical predictors. DESIGN: Retrospective cohort study. SETTING: Medicare Current Beneficiary Survey from 1999 to 2006. PARTICIPANTS: Community-dwelling Medicare beneficiaries, aged 65 years and older, with self-reported hearing and/or vision impairment (N = 15,999). MEASUREMENTS: The primary outcome was any hospital admission over a predefined 1-year study period. Candidate predictors included demographic factors, prior healthcare utilization, comorbidities, functional impairment, and patient-level factors. We analyzed the association of all candidate predictors with any hospital admission over the 1-year study period using multivariable logistic regression. The final model was created using a penalized regression method known as the least absolute shrinkage and selection operator. Model performance was assessed by discrimination (concordance statistic (c-statistic)) and calibration (evaluated graphically). Internal validation was performed via bootstrapping, and results were adjusted for overoptimism. RESULTS: Of the 15,999 participants, the mean age was 78 years and 55% were female. A total of 2,567 participants (16.0%) had at least one hospital admission in the 1-year study period. The final model included seven variables independently associated with hospitalization: number of inpatient admissions in the previous year, number of emergency department visits in the previous year, activities of daily living difficulty score, poor self-rated health, and self-reported history of myocardial infarction, stroke, and nonskin cancer. The c-statistic of the final model was 0.717. The optimism-corrected c-statistic after bootstrap internal validation was 0.716. A calibration plot suggested that the model tended to overestimate risk among patients at the highest risk for hospitalization. CONCLUSION: This prognostic model can help identify which community-dwelling older adults with sensory impairments are at highest risk for hospitalization and may inform allocation of healthcare resources.

Regulation of Iron Homeostasis through Parkin-Mediated Lactoferrin Ubiquitylation.

Somatic mutations that perturb Parkin ubiquitin ligase activity and the misregulation of iron homeostasis have both been linked to Parkinson's disease. Lactotransferrin (LTF) is a member of the family of transferrin iron binding proteins that regulate iron homeostasis, and increased levels of LTF and its receptor have been observed in neurodegenerative disorders like Parkinson's disease. Here, we report that Parkin binds to LTF and ubiquitylates LTF to influence iron homeostasis. Parkin-dependent ubiquitylation of LTF occurred most often on lysines (K) 182 and 649. Substitution of K182 or K649 with alanine (K182A or K649A, respectively) led to a decrease in the level of LTF ubiquitylation, and substitution at both sites led to a major decrease in the level of LTF ubiquitylation. Importantly, Parkin-mediated ubiquitylation of LTF was critical for regulating intracellular iron levels as overexpression of LTF ubiquitylation site point mutants (K649A or K182A/K649A) led to an increase in intracellular iron levels measured by ICP-MS/MS. Consistently, RNAi-mediated depletion of Parkin led to an increase in intracellular iron levels in contrast to overexpression of Parkin that led to a decrease in intracellular iron levels. Together, these results indicate that Parkin binds to and ubiquitylates LTF to regulate intracellular iron levels. These results expand our understanding of the cellular processes that are perturbed when Parkin activity is disrupted and more broadly the mechanisms that contribute to Parkinson's disease.

Tctex1d2 associates with short-rib polydactyly syndrome proteins and is required for ciliogenesis.

Short-rib polydactyly syndromes (SRPS) arise from mutations in genes involved in retrograde intraflagellar transport (IFT) and basal body homeostasis, which are critical for cilia assembly and function. Recently, mutations in WDR34 or WDR60 (candidate dynein intermediate chains) were identified in SRPS. We have identified and characterized Tctex1d2, which associates with Wdr34, Wdr60 and other dynein complex 1 and 2 subunits. Tctex1d2 and Wdr60 localize to the base of the cilium and their depletion causes defects in ciliogenesis. We propose that Tctex1d2 is a novel dynein light chain important for trafficking to the cilium and potentially retrograde IFT and is a new molecular link to understanding SRPS pathology.