Comparative route of administration studies using therapeutic siRNAs show widespread gene modulation in Dorset sheep

siRNAs comprise a class of drugs that can be programmed to silence any target gene. Chemical engineering efforts resulted in development of divalent siRNAs (di-siRNAs), which support robust and long-term efficacy in rodent and nonhuman primate brains upon direct cerebrospinal fluid (CSF) administration. Oligonucleotide distribution in the CNS is nonuniform, limiting clinical applications. The contribution of CSF infusion placement and dosing regimen on relative accumulation, specifically in the context of large animals, is not well characterized. To our knowledge, we report the first systemic, comparative study investigating the effects of 3 routes of administration - intrastriatal (i.s.), i.c.v., and intrathecal catheter to the cisterna magna (ITC) - and 2 dosing regimens - single and repetitive via an implanted reservoir device - on di-siRNA distribution and accumulation in the CNS of Dorset sheep. CSF injections (i.c.v. and ITC) resulted in similar distribution and accumulation across brain regions. Repeated dosing increased homogeneity, with greater relative deep brain accumulation. Conversely, i.s. administration supported region-specific delivery. These results suggest that dosing regimen, not CSF infusion placement, may equalize siRNA accumulation and efficacy throughout the brain. These findings inform the planning and execution of preclinical and clinical studies using siRNA therapeutics in the CNS

Diabetes Alters Intracellular Calcium Transients in Cardiac Endothelial Cells

Diabetic cardiomyopathy (DCM) is a diabetic complication, which results in myocardial dysfunction independent of other etiological factors. Abnormal intracellular calcium ([Ca2+]i) homeostasis has been implicated in DCM and may precede clinical manifestation. Studies in cardiomyocytes have shown that diabetes results in impaired [Ca2+]i homeostasis due to altered sarcoplasmic reticulum Ca2+ ATPase (SERCA) and sodium-calcium exchanger (NCX) activity. Importantly, altered calcium homeostasis may also be involved in diabetes-associated endothelial dysfunction, including impaired endothelium-dependent relaxation and a diminished capacity to generate nitric oxide (NO), elevated cell adhesion molecules, and decreased angiogenic growth factors. However, the effect of diabetes on Ca2+ regulatory mechanisms in cardiac endothelial cells (CECs) remains unknown. The objective of this study was to determine the effect of diabetes on [Ca2+]i homeostasis in CECs in the rat model (streptozotocin-induced) of DCM. DCM-associated cardiac fibrosis was confirmed using picrosirius red staining of the myocardium. CECs isolated from the myocardium of diabetic and wild-type rats were loaded with Fura-2, and UTP-evoked [Ca2+]i transients were compared under various combinations of SERCA, sarcoplasmic reticulum Ca2+ ATPase (PMCA) and NCX inhibitors. Diabetes resulted in significant alterations in SERCA and NCX activities in CECs during [Ca2+]i sequestration and efflux, respectively, while no difference in PMCA activity between diabetic and wild-type cells was observed. These results improve our understanding of how diabetes affects calcium regulation in CECs, and may contribute to the development of new therapies for DCM treatment

Acuity and severity of patients attending 28 Queensland hospitals emergency departments in 2008-09

Overcrowding of hospital Emergency Departments (EDs) in Australia is a complex issue of high public and professional prominence, resulted from a combination of increasing demands, increased complexity of care and Access Block. The aim of this study is to describe the distribution of the acuity and severity of current Queensland ED patients to better understand ED users..

Imaging NF-kappaB activity in a murine model of early stage diabetes

Early pro-inflammatory signaling in the endocrine pancreas involves activation of NF-kappaB, which is believed to be important for determining the ultimate fate of beta-cells and hence progression of type 1 diabetes (T1D). Thus, early non-invasive detection of NF-kappaB in pancreatic islets may serve as a potential strategy for monitoring early changes in pancreatic endocrine cells eventually leading to T1D. We investigated the feasibility of optical imaging of NF-kappaB transcription factor activation induced by low-dose streptozocin (LD-STZ) treatment in the immunocompetent SKH1 mouse model of early stage diabetes. In this model, we showed that the levels of NF-kappaB may be visualized and measured by fluorescence intensity of specific near-infrared (NIR) fluorophore-labeled oligodeoxyribonucleotide duplex (ODND) probes. In addition, NF-kappaB activation following LD-STZ treatment was validated using immunofluorescence and transgenic animals expressing NF-kappaB inducible imaging reporter. We showed that LD-STZ-treated SKH1 mice had significantly higher (2-3 times, P \u3c .01) specific NIR FI in the nuclei and cytoplasm of islets cells than in non-treated control mice and this finding was corroborated by immunoblotting and electrophoretic mobility shift assays. Finally, using semi-quantitative confocal analysis of non-fixed pancreatic islet microscopy we demonstrated that ODND probes may be used to distinguish between the islets with high levels of NF-kappaB transcription factor and control islet cells

Private hospital emergency departments in Australia: Challenges and opportunities

Background: Public hospital EDs in Australia have become increasingly congested because of increasing demand and access block. Six percent of ED patients attend private hospital EDs whereas 45% of the population hold private health insurance. Objectives: This study describes the patients attending a small selection of four private hospital EDs in Queensland and Victoria, and tests the feasibility of a private ED database. Methods: De-identified routinely collected patient data were provided by the four participating private hospital and amalgamated into a single data set. Result: The mean age of private ED patients was 52 years. Males outnumbered females in all age groups except > 80 years. Attendance was higher on weekends and Mondays, and between 08.00 and 20.00 h. There were 6.6% of the patients triaged as categories 1 and 2, and 60% were categories 4 or 5. There were 36.4% that required hospital admission. Also, 96% of the patients had some kind of insurance. Furthermore, 72% were self-referred and 12% were referred by private medical practitioners. Approximately 25% arrived by ambulance. There were 69% that completed their ED treatment within 4h. Conclusion: This study is the first public description of patients attending private EDs in Australia. Private EDs have a significant role to play in acute medical care and in providing access to private hospitals which could alleviate pressure on public EDs. This study demonstrates the need for consolidated data based on a consistent data set and data dictionary to enable system-wide analysis, benchmarking and evaluation

Acceptability of emergency department triage nurse's advice for patients to attend general practice: A cross-sectional survey

OBJECTIVES: Demand for ED care is increasing at a rate higher than population growth. Strategies to attenuate ED demands include diverting low-acuity general practice-type ED attendees to alternate primary healthcare settings. The present study assessed the ED attendees' receptiveness to accept triage nurse's face-to-face advice to explore alternate options for medical care and what factors influence the level of acceptance.METHODS: The ED attendees of four major public hospital EDs in Brisbane were surveyed between August and October 2018, using a questionnaire informed by Health Belief Model's cues to action.RESULTS: Of the 514 valid responses, 81% of respondents were very likely/likely to accept the triage nurse's advice to see a general practitioner. Self-perceived urgency of presenting condition/s (odds ratio [OR] 0.87, 95% confidence interval [CI] 0.78-0.97), not having confidence in general practitioner (OR 0.37, 95% CI 0.21-0.66) and having a medical record at the hospital (OR 0.60, 95% CI 0.36-0.99) were negatively associated with the likelihood of accepting the advice. For every point increase in perceived seriousness, the odds of accepting the advice decreased by 16% (95% CI 6-25%).CONCLUSION: Most of the participants believed that EDs were for emergent care and they attended the ED because they perceived their presenting condition/s to be serious and/or urgent. The acceptability of face-to-face advice by triage nurse to seek help in general practice was influenced by perceived threats of the illness, and the underlying beliefs about availability, accessibility, suitability and affordability of the service.</p

[In Press] Acceptability of emergency department triage nurse's advice for patients to attend general practice : a cross-sectional survey

Objectives: Demand for ED care is increasing at a rate higher than population growth. Strategies to attenuate ED demands include diverting low-acuity general practice-type ED attendees to alternate primary healthcare settings. The present study assessed the ED attendees’ receptiveness to accept triage nurse’s face-to-face advice to explore alternate options for medical care and what factors influence the level of acceptance. Methods: The ED attendees of four major public hospital EDs in Brisbane were surveyed between August and October 2018, using a questionnaire informed by Health Belief Model’s cues to action. Results: Of the 514 valid responses, 81% of respondents were very likely/ likely to accept the triage nurse’s advice to see a general practitioner. Self-perceived urgency of presenting condition/s (odds ratio [OR] 0.87, 95% confidence interval [CI] 0.78–0.97), not having confidence in general practitioner (OR 0.37, 95% CI 0.21–0.66) and having a medical record at the hospital (OR 0.60, 95% CI 0.36–0.99) were negatively associated with the likelihood of accepting the advice. For every point increase in perceived seriousness, the odds of accepting the advice decreased by 16% (95% CI 6–25%). Conclusion: Most of the participants believed that EDs were for emergent care and they attended the ED because they perceived their presenting condition/s to be serious and/or urgent. The acceptability of face-to-face advice by triage nurse to seek help in general practice was influenced by perceived threats of the illness, and the underlying beliefs about availability, accessibility, suitability and affordability of the service

The Montreal heat response plan: evaluation of its implementation towards healthcare professionals and vulnerable populations

ObjectivesSince 2004, the Montreal heat response plan (MHRP) has been developed and implemented on the Island of Montreal to reduce heat-related health effects in the general population. In this paper, we aimed to assess the barriers and facilitators to implementation of the MHRP and evaluate the awareness of key elements of the plan by healthcare professionals and individuals from vulnerable populations.MethodsData were gathered from monitoring reports and a questionnaire administered to managers of healthcare institutions and healthcare workers in Montreal-area health and social services institutions. Individual interviews and focus groups with healthcare workers and with individuals with schizophrenia or suffering from drug or alcohol dependencies were performed. Data were categorized according to predefined subthemes. Coding matrices were then used to determine the most frequently occurring elements in the subthemes.ResultsOur results indicate that actions are progressively implemented each year in the healthcare network. Intensification of surveillance for signs of heat-related illness is the most frequently reported measure. Identification and prioritization of clientele and homecare patients are identified as a challenge, as is ensuring the availability of sufficient personnel during a heat wave. Analysis of practice and awareness in healthcare professionals reveals that preventive measures are known and applied by the personnel. Individuals from vulnerable population groups were not uniformly aware of preventive measures, and consequently, variability was observed in their application.ConclusionThe framework proposed in this study revealed valuable information that can be useful to improve plans aimed at reducing heat-related health effects in the population