Integrated care at the emergency department: an investment for better health.

It is crucial that policy makers, healthcare providers and relevant stakeholders understand how integrated care may be improved at our emergency departments (EDs) and what benefits that would bring. The potential that exists for right-siting care of special patient groups who could be managed in an ambulatory setting with the integration of a variety of hospital-based and community-based clinical support services is tremendous. This review describes the best practice and value of integrated care at the EDs. Local evidence is cited and compared with findings from overseas. The opportunities of care transition interventions among discharged patients are outlined, including that for paediatric patients, palliative care patients and patients with chronic diseases. This review also suggests ways to move forward to meet the aim of providing holistic care at EDs through integrated care programmes, innovation and research.

A network meta-analysis of 12,116 individuals from randomized controlled trials in the treatment of depression after acute coronary syndrome.

BACKGROUND: Post-acute coronary syndrome (ACS) depression is a common but not well understood complication experienced by ACS patients. Research on the effectiveness of various therapies remains limited. Hence, we sought to conduct a network meta-analysis to assess the efficacy of different interventions for post-ACS depression in improving patient outcomes. METHODS AND FINDINGS: Three electronic databases were searched for randomised controlled trials describing different depression treatment modalities in post-ACS patients. Each article was screened based on inclusion criteria and relevant data were extracted. A bivariate analysis and a network meta-analysis was performed using risk ratios (RR) and standardized mean differences (SMD) for binary and continuous outcomes, respectively. A total of 30 articles were included in our analysis. Compared to standard care, psychosocial therapy was associated with the greatest reduction in depression scores (SMD:-1.21, 95% CI: -1.81 to -0.61, p<0.001), followed by cognitive behavioural therapy (CBT) (SMD: -0.75, 95% CI: -0.99 to -0.52, p<0.001), antidepressants (SMD: -0.73, 95% CI: -1.14 to -0.31, p<0.001), and lastly, combination therapy (SMD: -0.15, 95% CI: -0.28 to -0.03, p = 0.016). No treatment modalities was found to be more effective in reducing depression scores when compared to one another. Additional analysis showed that these treatment modalities did not have significant impact on the overall mortality, cardiac mortality and recurrent myocardial infarction. CONCLUSION: This network meta-analysis found that the treatment effect of the various psychological modalities on depression severity were similar. Future trials on psychological interventions assessing clinical outcomes and improvement in adherence to ACS-specific interventions are needed.

Raf Kinase Inhibitory Protein regulates the cAMP-dependent protein kinase signaling pathway through a positive feedback loop.

Raf Kinase Inhibitory Protein (RKIP) maintains cellular robustness and prevents the progression of diseases such as cancer and heart disease by regulating key kinase cascades including MAP kinase and protein kinase A (PKA). Phosphorylation of RKIP at S153 by Protein Kinase C (PKC) triggers a switch from inhibition of Raf to inhibition of the G protein coupled receptor kinase 2 (GRK2), enhancing signaling by the ß-adrenergic receptor (ß-AR) that activates PKA. Here we report that PKA-phosphorylated RKIP promotes ß-AR-activated PKA signaling. Using biochemical, genetic, and biophysical approaches, we show that PKA phosphorylates RKIP at S51, increasing S153 phosphorylation by PKC and thereby triggering feedback activation of PKA. The S51V mutation blocks the ability of RKIP to activate PKA in prostate cancer cells and to induce contraction in primary cardiac myocytes in response to the ß-AR activator isoproterenol, illustrating the functional importance of this positive feedback circuit. As previously shown for other kinases, phosphorylation of RKIP at S51 by PKA is enhanced upon RKIP destabilization by the P74L mutation. These results suggest that PKA phosphorylation at S51 may lead to allosteric changes associated with a higher-energy RKIP state that potentiates phosphorylation of RKIP at other key sites. This allosteric regulatory mechanism may have therapeutic potential for regulating PKA signaling in disease states.

Preparing for the silver boom: A falls prevention tool for older adults in the emergency department.

Geriatric falls presenting to the emergency department (ED) are rising due to our rapidly ageing population. As part of a group of geriatric-focused emergency medicine practitioners, we describe a multidisciplinary falls prevention tool using the acronym.

Effectiveness of a post-emergency department discharge multidisciplinary bundle in reducing acute hospital admissions for the elderly.

OBJECTIVE: We evaluated the effectiveness of the Subacute Ambulatory care for the Functionally challenged and Elderly (SAFE) programme, a post-emergency department (ED) discharge intervention for elderly and functionally challenged patients, in reducing acute hospital admissions. METHODS: This study was a 32-month retrospective quasi-experimental study comparing patients with at least one of six diagnostic classifications who underwent SAFE intervention with those who were eligible but declined and received usual ED care (control). The primary outcomes were rates of first acute hospital admission at 30 and 60 days post-ED discharge. Secondary outcomes were 20-day withdrawal rate and 60-day mortality. The difference in primary outcome between the two groups was compared using a Cox proportional hazards model. We reported adjusted hazard ratios (HRs) with their 95% confidence intervals (CIs) adjusting for predefined factors of age, sex, triage risk assessment tool scores and baseline ED utilization and acute hospital admission rates in the past year. RESULTS: There were 438 and 209 patients in the intervention and control groups, respectively. The intervention group had reduced risk of first acute hospital admission at 30 days (10 vs. 27%, HR=0.34, 95% CI: 0.22-0.52) and 60 days (18 vs. 33%, HR=0.48, 95% CI: 0.34-0.69) compared with the control. The 20-day withdrawal rate was 3.2%. Both groups did not differ in 60-day mortality rates. CONCLUSION: The SAFE programme was effective in reducing first acute hospital admissions in selected elderly and functionally challenged patients after ED discharge at 30 and 60 days compared with usual ED discharge care.

Conserved salt-bridge competition triggered by phosphorylation regulates the protein interactome.

Phosphorylation is a major regulator of protein interactions; however, the mechanisms by which regulation occurs are not well understood. Here we identify a salt-bridge competition or "theft" mechanism that enables a phospho-triggered swap of protein partners by Raf Kinase Inhibitory Protein (RKIP). RKIP transitions from inhibiting Raf-1 to inhibiting G-protein-coupled receptor kinase 2 upon phosphorylation, thereby bridging MAP kinase and G-Protein-Coupled Receptor signaling. NMR and crystallography indicate that a phosphoserine, but not a phosphomimetic, competes for a lysine from a preexisting salt bridge, initiating a partial unfolding event and promoting new protein interactions. Structural elements underlying the theft occurred early in evolution and are found in 10% of homo-oligomers and 30% of hetero-oligomers including Bax, Troponin C, and Early Endosome Antigen 1. In contrast to a direct recognition of phosphorylated residues by binding partners, the salt-bridge theft mechanism represents a facile strategy for promoting or disrupting protein interactions using solvent-accessible residues, and it can provide additional specificity at protein interfaces through local unfolding or conformational change.

Regulation of progranulin expression in myeloid cells.

Progranulin (pgrn; granulin-epithelin precursor, PC-cell-derived growth factor, or acrogranin) is a multifunctional secreted glycoprotein implicated in tumorigenesis, development, inflammation, and repair. It is highly expressed in macrophage and monocyte-derived dendritic cells. Here we investigate its regulation in myeloid cells. All-trans retinoic acid (ATRA) increased pgrn mRNA levels in myelomonocytic cells (CD34(+) progenitors; monoblastic U-937; monocytic THP-1; progranulocytic HL-60; macrophage RAW 264.7) but not in nonmyeloid cells tested. Interleukin-4 impaired basal expression of pgrn in U-937. Differentiation agents DMSO, and, in U-937 only, phorbol ester [phorbol 12-myristate,13-acetate (PMA)] elevated pgrn mRNA expression late in differentiation, suggestive of roles for pgrn in more mature terminally differentiated granulocyte/monocytes rather than during growth or differentiation. The response of pgrn mRNA to ATRA differs in U-937 and HL-60 lineages. In U-937, ATRA and chemical differentiation agents greatly increased pgrn mRNA stability, whereas, in HL-60, ATRA accelerated pgrn mRNA turnover. The initial upregulation of pgrn mRNA after stimulation with ATRA was independent of de novo protein synthesis in U-937 but not HL-60. Chemical blockade of nuclear factor-kappaB (NF-kappaB) activation impaired ATRA-stimulated pgrn expression in HL-60 but not U-937, whereas in U-937 it blocked PMA-induced pgrn mRNA expression, suggestive of cell-specific roles for NF-kappaB in determining pgrn mRNA levels. We propose that: 1) ATRA regulates pgrn mRNA levels in myelomonocytic cells; 2) ATRA acts in a cell-specific manner involving the differential control of mRNA stability and differential requirement for NF-kappaB signaling; and 3) elevated pgrn mRNA expression is characteristic of more mature cells and does not stimulate differentiation.

Progranulin is a mediator of the wound response.

Annually, 1.25 million individuals suffer burns in the United States and 6.5 million experience chronic skin ulcers, often from diabetes, pressure or venous stasis. Growth factors are essential mediators of wound repair, but their success as therapeutics in wound treatment has, so far, been limited. Therefore, there is a need to identify new wound-response regulatory factors, but few have appeared in recent years. Progranulin (also called granulin or epithelin precursor, acrogranin or PC-derived growth factor) is a growth factor involved in tumorigenesis and development. Peptides derived from progranulin have been isolated from inflammatory cells, which led to suggestions that progranulin gene products are involved in the wound response, but this remains undemonstrated. We report that in murine transcutaneous puncture wounds, progranulin mRNA is expressed in the inflammatory infiltrate and is highly induced in dermal fibroblasts and endothelia following injury. When applied to a cutaneous wound, progranulin increased the accumulation of neutrophils, macrophages, blood vessels and fibroblasts in the wound. It acts directly on isolated dermal fibroblasts and endothelial cells to promote division, migration and the formation of capillary-like tubule structures. Progranulin is, therefore, a probable wound-related growth factor.

Stage IV CD30+ anaplastic large cell lymphoma: response to acitretin and interferon-alpha.

Retinoids and interferon (IFN)-alpha induce differentiation, affect cell proliferation and alter various immune parameters. In combination, their effects may be additive or even synergistic in the treatment of malignancy. We present a 53-year-old woman with stage IV CD30+ anaplastic large cell lymphoma with brain, lung and skin involvement. The patient had been on methotrexate for rheumatoid arthritis. After a combination of oral acitretin 50 mg daily and IFN-alpha 3 million units subcutaneously 3 times per week, the skin lesions cleared within 2 months, lung lesions by 5 months and brain lesions by 7 months. Although we cannot exclude that methotrexate played a role in the development of this lymphoma and that its withdrawal contributed to the clearance of lesions, we propose that the patient's disease responded to the combination of acitretin and IFN-alpha.