Silva Zavarsek

Elf5 is essential for early embryogenesis and mammary gland development during pregnancy and lactation.

Elf5 is an epithelial‐specific ETS factor. Embryos with a null mutation in the Elf5 gene died before embryonic day 7.5, indicating that Elf5 is essential during mouse embryogenesis. Elf5 is also required for proliferation and differentiation of mouse mammary alveolar epithelial cells during pregnancy and lactation. The loss of one functional allele led to complete developmental arrest of the mammary gland in pregnant Elf5 heterozygous mice. A quantitative mRNA expression study and Western blot analysis revealed that decreased expression of Elf5 correlated with the downregulation of milk proteins in Elf5+/− mammary glands. Mammary gland transplants into Rag−/− mice demonstrated that Elf5+/− mammary alveolar buds failed to develop in an Elf5+/+ mammary fat pad during pregnancy, demonstrating an epithelial cell autonomous defect. Elf5 expression was reduced in Prolactin receptor (Prlr) heterozygous mammary glands, which phenocopy Elf5+/− glands, suggesting that Elf5 and Prlr are in the same pathway. Our data demonstrate that Elf5 is essential for developmental processes in the embryo and in the mammary gland during pregnancy.

The chromosome 21 transcription factor ETS2 transactivates the β-APP promoter: Implications for Down syndrome

The gene that codes for beta-amyloid precursor protein (beta-APP), a protein centrally involved in senile plaque formation in Down syndrome (DS) and Alzheimers disease (AD), is located on chromosome 21. In DS beta-APP expression is three- to fourfold higher than what is expected from the 1.5-fold increased gene load, suggesting that other genes on chromosome 21 directly or indirectly can further up-regulate beta-APP. Here we show that the chromosome 21 transcription factor ETS2 transactivates the beta-APP gene via specific Ets binding sites in the beta-APP promoter and, in this respect, cooperates with the transcription factor complex AP1. We further show that brains and primary neuronal cultures from Ets2 transgenic mice, as well as 3T3 fibroblasts that overexpress ETS2, display molecular abnormalities also seen in DS, such as elevated expression of beta-APP protein, an increase in presenilin-1 and increased beta-amyloid production. We conclude that ETS2 is a transcriptional regulator of beta-APP and that overexpression of ETS2 in DS may play a role in the pathogenesis of the brain abnormalities in DS and possibly AD.

6-PACK programme to decrease fall injuries in acute hospitals: cluster randomised controlled trial

Objective To evaluate the effect of the 6-PACK programme on falls and fall injuries in acute wards. Design Cluster randomised controlled trial. Setting Six Australian hospitals. Participants All patients admitted to 24 acute wards during the trial period. Interventions Participating wards were randomly assigned to receive either the nurse led 6-PACK programme or usual care over 12 months. The 6-PACK programme included a fall risk tool and individualised use of one or more of six interventions: “falls alert” sign, supervision of patients in the bathroom, ensuring patients’ walking aids are within reach, a toileting regimen, use of a low-low bed, and use of a bed/chair alarm. Main outcome measures The co-primary outcomes were falls and fall injuries per 1000 occupied bed days. Results During the trial, 46 245 admissions to 16 medical and eight surgical wards occurred. As many people were admitted more than once, this represented 31 411 individual patients. Patients’ characteristics and length of stay were similar for intervention and control wards. Use of 6-PACK programme components was higher on intervention wards than on control wards (incidence rate ratio 3.05, 95% confidence interval 2.14 to 4.34; P<0.001). In all, 1831 falls and 613 fall injuries occurred, and the rates of falls (incidence rate ratio 1.04, 0.78 to 1.37; P=0.796) and fall injuries (0.96, 0.72 to 1.27; P=0.766) were similar in intervention and control wards. Conclusions Positive changes in falls prevention practice occurred following the introduction of the 6-PACK programme. However, no difference was seen in falls or fall injuries between groups. High quality evidence showing the effectiveness of falls prevention interventions in acute wards remains absent. Novel solutions to the problem of in-hospital falls are urgently needed. Trial registration Australian New Zealand Clinical Trials Registry ACTRN12611000332921.

The extra resource burden of in-hospital falls: a cost of falls study

Objective: To quantify the additional hospital length of stay (LOS) and costs associated with in‐hospital falls and fall injuries in acute hospitals in Australia.

The 6-PACK programme to decrease fall-related injuries in acute hospitals: protocol for a cluster randomised controlled trial

Background and aims In-hospital fall-related injuries are a source of personal harm, preventable hospitalisation costs, and access block through increased length of stay. Despite increased fall prevention awareness and activity over the last decade, rates of reported fall-related fractures in hospitals appear not to have decreased. This cluster randomised controlled trial (RCT) aims to determine the efficacy of the 6-PACK programme for preventing fall-related injuries, and its generalisability to other acute hospitals. Methods 24 acute medical and surgical wards from six to eight hospitals throughout Australia will be recruited for the study. Wards will be matched by type and fall-related injury rates, then randomly allocated to the 6-PACK intervention (12 wards) or usual care control group (12 wards). The 6-PACK programme includes a nine-item fall risk assessment and six nursing interventions: ‘falls alert’ sign; supervision of patients in the bathroom; ensuring patients walking aids are within reach; establishment of a toileting regime; use of a low-low bed; and use of bed/chair alarm. Intervention wards will be supported by a structured implementation strategy. The primary outcomes are fall and fall-related injury rates 12 months following 6-PACK implementation. Discussion This study will involve approximately 16 000 patients, and as such is planned to be the largest hospital fall prevention RCT to be undertaken and the first to be powered for the important outcome of fall-related injuries. If effective, there is potential to implement the programme widely as part of daily patient care in acute hospital wards where fall-related injuries are a problem. Trial registration The protocol for this study is registered with the Australian New Zealand Clinical Trials Registry (ACTRN12611000332921).

Evaluating heterogeneity in cumulative meta-analyses

BackgroundRecently developed measures such as I2 and H allow the evaluation of the impact of heterogeneity in conventional meta-analyses. There has been no examination of the development of heterogeneity in the context of a cumulative meta-analysis.MethodsCumulative meta-analyses of five smoking cessation interventions (clonidine, nicotine replacement therapy using gum and patch, physician advice and acupuncture) were used to calculate I2 and H. These values were plotted by year of publication, control event rate and sample size to trace the development of heterogeneity over these covariates.ResultsThe cumulative evaluation of heterogeneity varied according to the measure of heterogeneity used and the basis of cumulation. Plots produced from the calculations revealed areas of heterogeneity useful in the consideration of potential sources for further study.ConclusionThe examination of heterogeneity in conjunction with summary effect estimates in a cumulative meta-analysis offered valuable insight into the evolution of variation. Such information is not available in the context of conventional meta-analysis and has the potential to lead to the development of a richer picture of the effectiveness of interventions.

The 6-PACK programme to decrease falls and fall-related injuries in acute hospitals: protocol for an economic evaluation alongside a cluster randomised controlled trial

Background Falls are a common hospital occurrence complicating the care of patients. From an economic perspective, the impact of in-hospital falls and related injuries is substantial. However, few studies have examined the economic implications of falls prevention interventions in an acute care setting. The 6-PACK programme is a targeted nurse delivered falls prevention programme designed specifically for acute hospital wards. It includes a risk assessment tool and six simple strategies that nurses apply to patients classified as high-risk by the tool. Objective To examine the incremental cost-effectiveness of the 6-PACK programme for the prevention of falls and fall-related injuries, compared with usual care practice, from an acute hospital perspective. Methods and design The 6-PACK project is a multicentre cluster randomised controlled trial (RCT) that includes 24 acute medical and surgical wards from six hospitals in Australia to investigate the efficacy of the 6-PACK programme. This economic evaluation will be conducted alongside the 6-PACK cluster RCT. Outcome and hospitalisation cost data will be prospectively collected on approximately 16 000 patients admitted to the participating wards during the 12-month trial period. The results of the economic evaluation will be expressed as ‘cost or saving per fall prevented’ and ‘cost or saving per fall-related injury prevented’ calculated from differences in mean costs and effects in the intervention and control groups, to generate an incremental cost-effectiveness ratio (ICER). Discussion This economic evaluation will provide an opportunity to explore the cost-effectiveness of a targeted nurse delivered falls prevention programme for reducing in-hospital falls and fall-related injuries. This protocol provides a detailed statement of a planned economic evaluation conducted alongside a cluster RCT to investigate the efficacy of the 6-PACK programme to prevent falls and fall-related injuries. Trial registration number The protocol for the cluster RCT is registered with the Australian New Zealand Clinical Trials Registry (ACTRN12611000332921).

In-hospital falls and fall-related injuries: a protocol for a cost of fall study

Background In-hospital falls are common and pose significant economic burden on the healthcare system. To date, few studies have quantified the additional cost of hospitalisation associated with an in-hospital fall or fall-related injury. The aim of this study is to determine the additional length of stay and hospitalisation costs associated with in-hospital falls and fall-related injuries, from the acute hospital perspective. Methods and design A multisite prospective study will be conducted as part of a larger falls-prevention clinical trial—the 6-PACK project. This study will involve 12 acute medical and surgical wards from six hospitals across Australia. Patient and admission characteristics, outcome and hospitalisation cost data will be prospectively collected on approximately 15 000 patients during the 15-month study period. A review of all in-hospital fall events will be conducted using a multimodal method (medical record review and daily verbal report from the nurse unit manager, triangulated with falls recorded in the hospital incident reporting and administrative database), to ensure complete case ascertainment. Hospital clinical costing data will be used to calculate patient-level hospitalisation costs incurred by a patient during their inpatient stay. Additional hospital and hospital resource utilisation costs attributable to in-hospital falls and fall-related injuries will be calculated using linear regression modelling, adjusting for a priori-defined potential confounding factors. Discussion This protocol provides the detailed statement of the planned analysis. The results from this study will be used to support healthcare planning, policy making and allocation of funding relating to falls prevention within acute hospitals.