A critical role for IRF5 in regulating allergic airway inflammation.

Interferon regulatory factor 5 (IRF5) is a key transcription factor involved in the control of the expression of proinflammatory cytokine and responses to infection, but its role in regulating pulmonary immune responses to allergen is unknown. We used genetic ablation, adenoviral vector-driven overexpression, and adoptive transfer approaches to interrogate the role of IRF5 in pulmonary immunity and during challenge with the aeroallergen, house dust mite. Global IRF5 deficiency resulted in impaired lung function and extracellular matrix (ECM) deposition. IRF5 was also essential for effective responses to inhaled allergen, controlling airway hyperresponsiveness, mucus secretion, and eosinophilic inflammation. Adoptive transfer of IRF5-deficient alveolar macrophages into the wild-type pulmonary milieu was sufficient to drive airway hyperreactivity, at baseline or following antigen challenge. These data identify IRF5-expressing macrophages as a key component of the immune defense of the airways. Manipulation of IRF5 activity in the lung could therefore be a viable strategy for the redirection of pulmonary immune responses and, thus, the treatment of lung disorders.

Vulnerability in elderly patients with gastrointestinal cancer--translation, cultural adaptation and validation of the European Portuguese version of the Vulnerable Elders Survey (VES-13).

BACKGROUND: "Vulnerable Elders Survey" (VES-13) is a questionnaire accurate in predicting functional decline and highly correlated with comprehensive geriatric assessment in identifying vulnerable elderly. The purpose of this study was to translate, cultural adapt and validate the first Portuguese cross-cultural version of VES-13 and to estimate the prevalence of vulnerability in Portuguese elderly gastrointestinal (GI) cancer patients. METHODS: VES-13 European Portuguese translation and cultural adaptation was developed according to internationally accepted guidelines. Test-retest reliability and internal consistency were assessed by calculating the Kappa statistic and by analyzing the inter-item and item-total correlation matrices and calculation of Cronbach's alpha coefficients, respectively. Construct and criterion validity was assessed by Spearman's correlation coefficient between VES-13 and each EQ-5D-5 L dimension, clinical judgment and performance status. RESULTS: The translated and culturally adapted version of VES-13 revealed high test-retest reliability (test-retest Kappa ≥ 0.612; p < 0.001) in the pilot study (n = 22). For the validation phase 206 patients with GI cancer were recruited (median age: 73 years; colo-rectal cancer: 63 %). Criterion validity was confirmed by adequate correlations between VES-13 and clinical judgment of vulnerability, ECOG and KPS scores. Construct validity was confirmed by moderate correlations with most of EQ-5D-5 L dimensions. Cronbach's alpha of the questionnaire was 0.848. The estimated prevalence of vulnerability is 50 % (CI95% 0.43-0.56). CONCLUSIONS: The European Portuguese version of VES-13 is a valid and reliable approach to screening elderly cancer patients for geriatric needs. In our setting, one in two elderly patients was likely to be vulnerable or frail which stresses the importance of their correct identification to better inform cancer management.

KAP1/TRIM28: an inhibitor of IRF5 function in inflammatory macrophages.

IRF5 plays a key role in the induction of pro-inflammatory cytokines, contributing to the plasticity and polarisation of macrophages to an M1 phenotype and initiation of a potent T(H)1-T(H)17 response. To better understand the means of IRF5 transcriptional action, we conducted a screen for IRF5-interacting partners by affinity purification coupled to mass spectrometry and identified KAP1/TRIM28 as a novel protein-protein interaction partner of IRF5. KAP1 acts as a transcriptional co-repressor, chiefly via recruitment of complexes involved in chromatin silencing, such as histone deacetylases and methyltransferases. We mapped the N-terminus of IRF5, encompassing its DNA-binding domain together with a highly intrinsically disordered region, as crucial for the IRF5-KAP1 interaction interface, and demonstrated that IRF5 can also form complexes with the methyltransferase SETDB1. Knockdown of KAP1 (TRIM28) gene expression in human M1 macrophages potentiated IRF5-mediated expression of TNF and other M1 macrophage markers. This effect may be linked to methyltransferase activity of SETDB1, such as trimethylation of lysine 9 of histone 3 (H3K9me3), deposition of which was decreased at the human TNF locus upon KAP1 knockdown. Our study furthers an understanding of the complex molecular interactions between the TRIM and IRF protein families, and highlights a role of the inhibitory properties of KAP1 in association with IRF5-mediated gene expression.

The Vulnerable Elders Survey: a tool for identifying vulnerable older people in the community.

OBJECTIVES: To develop a simple method for identifying community-dwelling vulnerable older people, defined as persons age 65 and older at increased risk of death or functional decline. To assess whether self-reported diagnoses and conditions add predictive ability to a function-based survey. DESIGN: Analysis of longitudinal survey data. SETTING: A nationally representative community-based survey. PARTICIPANTS: Six thousand two hundred five Medicare beneficiaries age 65 and older. MEASUREMENTS: Bivariate and multivariate analyses of the Medicare Current Beneficiary Survey; development and comparison of scoring systems that use age, function, and self-reported diagnoses to predict future death and functional decline. RESULTS: A multivariate model using function, self-rated health, and age to predict death or functional decline was only slightly improved when self-reported diagnoses and conditions were included as predictors and was significantly better than a model using age plus self-reported diagnoses alone. These analyses provide the basis for a 13-item function-based scoring system that considers age, self-rated health, limitation in physical function, and functional disabilities. A score of >or=3 targeted 32% of this nationally representative sample as vulnerable. This targeted group had 4.2 times the risk of death or functional decline over a 2-year period compared with those with scores <3. The receiver operating characteristics curve had an area of.78. An alternative scoring system that included self-reported diagnoses did not substantially improve predictive ability when compared with a function-based scoring system. CONCLUSIONS: A function-based targeting system effectively and efficiently identifies older people at risk of functional decline and death. Self-reported diagnoses and conditions, when added to the system, do not enhance predictive ability. The function-based targeting system relies on self-report and is easily transported across care settings.

Identifying a short functional disability screen for older persons.

BACKGROUND: Disability in instrumental activities of daily living (IADLs) or activities of daily living (ADLs) is an indicator of health risk. The inclusion of these items in population screens may be limited by variation in item performance across gender and age groups. Further, identification of shortened lists may encourage inclusion of these items in screens. METHODS: We applied item response theory (IRT) methods to assess the responses of 9865 community-dwelling elders in the 1993 Medicare Current Beneficiary Survey to 11 IADL/ADL items. Items were classified as "receive help/not receive help" for the overall population and stratified by age and gender. We assessed the same IADL/ADL items using responses classified as "difficulty/no difficulty." After eliminating items that performed poorly, we performed all-subsets analyses to identify abbreviated sets of items that would select the highest proportion of persons with IADL/ADL disability. RESULTS: Responses classified in receive help format showed consistency by gender and age group. Changing the response classification to difficulty/no difficulty influenced the reported order and relationship of IADL/ADL items. Receipt of help for any one of five items--shopping, doing light housework, walking, bathing, or managing finances--identified 93% of individuals receiving help with any IADL/ADL. A slightly different set of five items--walking, shopping, transferring, doing light housework, or bathing--identified 91% of persons reporting difficulty with any IADL or ADL. CONCLUSIONS: The relationship of IADL and ADL items to the underlying construct of disability was similar for men and women. The relationship was also similar for oldest-old and younger-old individuals. This study also identified abbreviated lists of disability items that can be used to efficiently screen community-dwelling elders for the presence of IADL/ADL disability.

Selecting target conditions for quality of care improvement in vulnerable older adults.

OBJECTIVE: To identify a set of geriatric conditions as optimal targets for quality improvement to be used in a quality measurement system for vulnerable older adults. DESIGN: Discussion and two rounds of ranking of conditions by a panel of geriatric clinical experts informed by literature reviews. METHODS: A list of 78 conditions common among vulnerable older people was reduced to 35 on the basis of their (1) prevalence, (2) impact on health and quality of life, (3) effectiveness of interventions in improving mortality and quality of life, (4) disparity in the quality of care across providers and geographic areas, and (5) feasibility of obtaining the data needed to test compliance with quality indicators. A panel of 12 experts in geriatric care discussed and then ranked the 35 conditions on the basis of the same five criteria. We then selected 21 conditions, based on panelists' iterative rankings. Using available national data, we compiled information about prevalence of the selected conditions for community-dwelling older people and older nursing home residents and estimated the proportion of inpatient and outpatient care attributable to the selected conditions. RESULTS: The 21 conditions selected as targets for quality improvement among vulnerable older adults include (in rank order): pharmacologic management; depression; dementia; heart failure; stroke (and atrial fibrillation); hospitalization and surgery; falls and mobility disorders; diabetes mellitus; end-of-life care; ischemic heart disease; hypertension; pressure ulcers; osteoporosis; urinary incontinence; pain management; preventive services; hearing impairment; pneumonia and influenza; vision impairment; malnutrition; and osteoarthritis. The selected conditions had mean rank scores from 1.2 to 3.8, and those excluded from 4.6 to 6.9, on a scale from 1 (highest ranking) to 7 (lowest ranking). Prevalence of the selected conditions ranges from 10 to 50% among community-dwelling older adults and from 25 to 80% in nursing home residents for the six most common selected conditions. The 21 target conditions account for at least 43% of all acute hospital discharges and 33% of physician office visits among persons 65 years of age and older. Actual figures must be higher because several of the selected conditions (e.g., end-of-life care) are not recorded as diagnoses. CONCLUSIONS: Twenty-one conditions were selected as targets for quality improvement in vulnerable older people for use in a quality measurement system. The 21 geriatric conditions selected are highly prevalent in this group and likely account for more than half of the care provided to this group in hospital and ambulatory settings.

Appropriateness of the decision to transfer nursing facility residents to the hospital.

OBJECTIVES: To develop and test a standardized instrument, the purpose of which is to assess (1) whether skilled nursing facilities (SNFs) transfer residents to emergency departments (ED) inappropriately, (2) whether residents are admitted to hospitals inappropriately, (3) and factors associated with inappropriate transfers. DESIGN: A structured implicit review (SIR) of medical records. SETTING AND PARTICIPANTS: Using nested random sampling in eight community SNFs, we identified SNF and hospital records of 100 unscheduled transfers to one of 10 hospitals. MEASUREMENTS: Seven trained physician reviewers assessed appropriateness using a SIR form designed for this study (2 independent reviews per record, 200 total reviews). We measured interrater reliability with kappa statistics and used bivariate analysis to identify factors associated with assessment that transfer was inappropriate. RESULTS: In 36% of ED transfers and 40% of hospital admissions, both reviewers agreed that transfer/admit was inappropriate, meaning the resident could have been cared for safely at a lower level of care. Agreement was high for both ED (percent agreement 84%, kappa .678) and hospital (percent agreement 89%, kappa .779). When advance directives were considered, both reviewers rated 44% of ED transfers and 45% of admissions inappropriate. Factors associated with inappropriateness included the perceptions that: (1) poor quality of care contributed to transfer need, (2) needed services would typically be available in outpatient settings, and (3) the chief complaint did not warrant hospitalization. CONCLUSIONS: Inappropriate transfers are a potentially large problem. Some inappropriate transfers may be associated with poor quality of care in SNFs. This study demonstrates that structured implicit review meets criteria for reliable assessment of inappropriate transfer rates. Structured implicit review may be a valuable tool for identifying inappropriate transfers from SNFs to EDs and hospitals.