Epidemiology, prehospital care and outcomes of patients arriving by ambulance with dyspnoea: An observational study

Background: This study aimed to determine epidemiology and outcome for patients presenting to emergency departments (ED) with shortness of breath who were transported by ambulance. Methods: This was a planned sub-study of a prospective, interrupted time series cohort study conducted at three time points in 2014 and which included consecutive adult patients presenting to the ED with dyspnoea as a main symptom. For this sub-study, additional inclusion criteria were presentation to an ED in Australia or New Zealand and transport by ambulance. The primary outcomes of interest are the epidemiology and outcome of these patients. Analysis was by descriptive statistics and comparisons of proportions. Results: One thousand seven patients met inclusion criteria. Median age was 74 years (IQR 61-68) and 46.1 % were male. There was a high rate of co-morbidity and chronic medication use. The most common ED diagnoses were lower respiratory tract infection (including pneumonia, 22.7 %), cardiac failure (20.5%) and exacerbation of chronic obstructive pulmonary disease (19.7 %). ED disposition was hospital admission (including ICU) for 76.4 %, ICU admission for 5.6 % and death in ED in 0.9 %. Overall in-hospital mortality among admitted patients was 6.5 %. Discussion: Patients transported by ambulance with shortness of breath make up a significant proportion of ambulance caseload and have high comorbidity and high hospital admission rate. In this study, >60 % were accounted for by patients with heart failure, lower respiratory tract infection or COPD, but there were a wide range of diagnoses. This has implications for service planning, models of care and paramedic training. Conclusion: This study shows that patients transported to hospital by ambulance with shortness of breath are a complex and seriously ill group with a broad range of diagnoses. Understanding the characteristics of these patients, the range of diagnoses and their outcome can help inform training and planning of services

Prevalence, associated factors and outcomes of pressure injuries in adult intensive care unit patients: the DecubICUs study

Funder: European Society of Intensive Care Medicine; doi: http://dx.doi.org/10.13039/501100013347Funder: Flemish Society for Critical Care NursesAbstract: Purpose: Intensive care unit (ICU) patients are particularly susceptible to developing pressure injuries. Epidemiologic data is however unavailable. We aimed to provide an international picture of the extent of pressure injuries and factors associated with ICU-acquired pressure injuries in adult ICU patients. Methods: International 1-day point-prevalence study; follow-up for outcome assessment until hospital discharge (maximum 12 weeks). Factors associated with ICU-acquired pressure injury and hospital mortality were assessed by generalised linear mixed-effects regression analysis. Results: Data from 13,254 patients in 1117 ICUs (90 countries) revealed 6747 pressure injuries; 3997 (59.2%) were ICU-acquired. Overall prevalence was 26.6% (95% confidence interval [CI] 25.9–27.3). ICU-acquired prevalence was 16.2% (95% CI 15.6–16.8). Sacrum (37%) and heels (19.5%) were most affected. Factors independently associated with ICU-acquired pressure injuries were older age, male sex, being underweight, emergency surgery, higher Simplified Acute Physiology Score II, Braden score 3 days, comorbidities (chronic obstructive pulmonary disease, immunodeficiency), organ support (renal replacement, mechanical ventilation on ICU admission), and being in a low or lower-middle income-economy. Gradually increasing associations with mortality were identified for increasing severity of pressure injury: stage I (odds ratio [OR] 1.5; 95% CI 1.2–1.8), stage II (OR 1.6; 95% CI 1.4–1.9), and stage III or worse (OR 2.8; 95% CI 2.3–3.3). Conclusion: Pressure injuries are common in adult ICU patients. ICU-acquired pressure injuries are associated with mainly intrinsic factors and mortality. Optimal care standards, increased awareness, appropriate resource allocation, and further research into optimal prevention are pivotal to tackle this important patient safety threat

Correction to: Prevalence, associated factors and outcomes of pressure injuries in adult intensive care unit patients: the DecubICUs study

The original version of this article unfortunately contained a mistake

Prevalence, associated factors and outcomes of pressure injuries in adult intensive care unit patients: the DecubICUs study

Funder: European Society of Intensive Care Medicine; doi: http://dx.doi.org/10.13039/501100013347Funder: Flemish Society for Critical Care NursesAbstract: Purpose: Intensive care unit (ICU) patients are particularly susceptible to developing pressure injuries. Epidemiologic data is however unavailable. We aimed to provide an international picture of the extent of pressure injuries and factors associated with ICU-acquired pressure injuries in adult ICU patients. Methods: International 1-day point-prevalence study; follow-up for outcome assessment until hospital discharge (maximum 12 weeks). Factors associated with ICU-acquired pressure injury and hospital mortality were assessed by generalised linear mixed-effects regression analysis. Results: Data from 13,254 patients in 1117 ICUs (90 countries) revealed 6747 pressure injuries; 3997 (59.2%) were ICU-acquired. Overall prevalence was 26.6% (95% confidence interval [CI] 25.9–27.3). ICU-acquired prevalence was 16.2% (95% CI 15.6–16.8). Sacrum (37%) and heels (19.5%) were most affected. Factors independently associated with ICU-acquired pressure injuries were older age, male sex, being underweight, emergency surgery, higher Simplified Acute Physiology Score II, Braden score 3 days, comorbidities (chronic obstructive pulmonary disease, immunodeficiency), organ support (renal replacement, mechanical ventilation on ICU admission), and being in a low or lower-middle income-economy. Gradually increasing associations with mortality were identified for increasing severity of pressure injury: stage I (odds ratio [OR] 1.5; 95% CI 1.2–1.8), stage II (OR 1.6; 95% CI 1.4–1.9), and stage III or worse (OR 2.8; 95% CI 2.3–3.3). Conclusion: Pressure injuries are common in adult ICU patients. ICU-acquired pressure injuries are associated with mainly intrinsic factors and mortality. Optimal care standards, increased awareness, appropriate resource allocation, and further research into optimal prevention are pivotal to tackle this important patient safety threat

Role and mechanism of endothelin in the central nervous system in neuropathic pain

Neuropathic pain, with an estimated 1.5% pervasiveness in the worldwide population is now considered as a distinct clinical entity and treatment is frequently inadequate. Endothelin-1 (ET-1) emerges to be a therapeutic target for the treatment of neuropathic pain in recent decade, which has been implicated in a remarkable variety of pain related processes. ET-1 and its two receptors, ETAR and ETBR, are found across multiple levels in pain pathway from peripheral nociceptors to the central high end of pain perception. Although studies have illustrated the players in the endothelin system, the mechanism remains obscure, especially its function in the central nervous system (CNS) in neuropathic pain. Therefore, work in this thesis was designed to determine 1) the functional significance and 2) the regulatory mechanism of central ET-1 axis in neuropathic pain of peripheral origin, 3) whether ET-1 axis underlies neuropathic pain of central origin and mechanisms of current clinical treatments of neuropathic pain, namely ketamine and voluntary exercise. In the first study, sciatic nerve ligation (SNL)-induced neuropathic pain model was established in our unique transgenic mice which has selective over-expression of ET-1 in astrocyte. We found that persistent astrocytic over-expression of ET-1 exerted antiallodynic/ hyperalgesic effect via ETAR. However, opposite result was observed in nontransgenic mice that nociceptive behaviors were associated with up-regulated ET-1 and ETAR, suggesting a differential modification of ETAR under prolonged exposure to overexpressed astrocytic ET-1 in transgenic mice. We further showed that ET-1 modulates pain response by regulation of spinal excitatory amino acid transporter (EAAT2), which facilitates synaptic glutamate uptake. In the second study, we demonstrated that, in SNL-induced neuropathic pain, spinal mRNA expressions of ET-1 and ETAR were enhanced accompanied by elevated expressions of Pax2 and NFAT5, two transcription factors that facilitate ET-1 transcription. Gene silencing of Pax2, but not NFAT5, reduced spinal ET-1 expression while inhibition of Pax2, NFAT5 and ETAR attenuated neuropathic pain. Additionally, inhibition of ETAR also reduced mRNA expressions of post-SNL Pax2 and NFAT5, suggesting a novel signaling transduction by Pax2/ET-1/ETAR/NFAT5. To the best of our knowledge, this is the first study reporting a new function of Pax2 and NFAT5, indicating their significant functional regulatory role in ET-1 axis-mediated neuropathic pain. In the third study, we assessed the role of ET-1 axis in central neuropathic pain. In spinal cord injury (SCI)-induced neuropathic pain, up-regulation of ETAR and ETBR was associated with increased glutamate N-methyl-D-aspartate (NMDA) receptor and decreased EAAT2. Combination of multiday low dose ketamine and voluntary exercise reduced ET-1 receptors and subsequently corrected the dysregulation of glutamatergic transmission. In addition, joint treatment was superior in improving sensory and motor function than either ketamine or voluntary exercise alone. It is hoped that studies described in this thesis have advanced the knowledge concerning the role of ET-1 in neuropathic pain and its importance as a potential target in combating neuropathic pain. Findings observed in our research may facilitate the development of novel and effective therapies for the treatment of neuropathic pain and related functional deficits, which is common in chronic pain patients.published_or_final_versionAnaesthesiologyDoctoralDoctor of Philosoph

Involvement of astrocytic endothelin-1 in neuropathic pain processing: a pain-behavioural and gene expressionprofiling study

Neuropathic pain is becoming a disease of global burden with growing prevalence worldwide. It is difficult to treat and there is no assured cure for it so far. Patients have to live with it relying on combinations of drug treatments to ameliorate the effect. The cause of neuropathic pain is often considered as a dysfunction of the nervous system which involves both peripheral and central nervous system sensitization. However, the mechanism behind it remains poorly understood at the molecular level. In my thesis, I have investigated Endothelin-1 (ET-1), a potent vasoconstrictor and neuro-modulator, in the central pain-process in neuropathic pain. ET-1 induction has been reported in a variety of pathological states such as cancer, ischaemia, and neuropathic pain. The effect of central endogenous ET-1 in development of neuropathic pain has not been adequately studied. Therefore, in my first study, I evaluated the influence of endogenous ET-1 in neuropathic pain by antagonizing Endothelin Receptor type A (ETAR), which is documented as the receptor that ET-1 acts on to induce pain, in the CNS. BQ-123, an ETAR selective antagonist, was administered intrathecally to study the effect of central ET-1 in neuropathic pain induced by Peripheral Sciatic Ligation (PSL) in Sprague Dawley (SD) rat. I found that repeated administration of BQ-123 alleviated mechanical allodynia, which developed after PSL as a typical symptom of neuropathic pain. Thus, ET-1 and ETAR may involve in PSL- induced neuropathic pain. To the best of our knowledge, exogenous administration of ET-1 in the CNS has been shown to exert a pain-inhibiting effect in thermal and inflammatory pain, but the mechanism and the cellular origin of such pain-inhibiting nature remains elusive. Hence, I further investigated the effect of central ET-1 in neuropathic pain. Here, transgenic mouse overexpressing ET-1 in astrocytes (GET-1) was used as a model. I found that GET-1 mice exhibited 15-fold of ET-1 mRNA induction in the spinal cord by real-time PCR. However, GET-1 transgenic mice did not show altered mechanical threshold compared to non-transgenic (Ntg) mice at basal level under physiological condition. After PSL, I found that GET-1 transgenic mice did not show signs of neuropathic pain while age-matched Ntg mice had mechanical allodynia. High expression of ETAR observed only in Ntg mice after PSL supports the pain-alleviating effect of ETAR antagonist shown in our first study. Moreover, I explored the relationship between ET-1 and glial glutamate transporter EAAT2 which is responsible for major clearance of glutamate in the CNS. Interestingly, high expression level of EAAT2 was observed distinctively in GET-1 transgenic mice which did not develop PSL-induced neuropathic pain. Thus, EAAT2 may be the key factor in neuron protection from central sensitization by enhanced glutamate release in induction of neuropathic pain. These results suggest that endogenous central ET-1 may mediate neuropathic pain partially via ETAR. Taken together with the evidence that GET-1 did not develop neuropathic pain and showed high expression of EAAT2, I concluded that overexpressed astrocytic ET-1 in GET-1 mice exerted an analgesic effect in neuropathic pain by modulating expression of EAAT2.published_or_final_versionAnaesthesiologyMasterMaster of Philosoph

miRNA-23a/CXCR4 regulates neuropathic pain via directly targeting TXNIP/NLRP3 inflammasome axis

Abstract Background Chemokine CXC receptor 4 (CXCR4) in spinal glial cells has been implicated in neuropathic pain. However, the regulatory cascades of CXCR4 in neuropathic pain remain elusive. Here, we investigated the functional regulatory role of miRNAs in the pain process and its interplay with CXCR4 and its downstream signaling. Methods miRNAs and CXCR4 and its downstream signaling molecules were measured in the spinal cords of mice with sciatic nerve injury via partial sciatic nerve ligation (pSNL). Immunoblotting, immunofluorescence, immunoprecipitation, and mammal two-hybrid and behavioral tests were used to explore the downstream CXCR4-dependent signaling pathway. Results CXCR4 expression increased in spinal glial cells of mice with pSNL-induced neuropathic pain. Blocking CXCR4 alleviated the pain behavior; contrarily, overexpressing CXCR4 induced pain hypersensitivity. MicroRNA-23a-3p (miR-23a) directly bounds to 3′ UTR of CXCR4 mRNA. pSNL-induced neuropathic pain significantly reduced mRNA expression of miR-23a. Overexpression of miR-23a by intrathecal injection of miR-23a mimics or lentivirus reduced spinal CXCR4 and prevented pSNL-induced neuropathic pain. In contrast, knockdown of miR-23a by intrathecal injection of miR-23a inhibitor or lentivirus induced pain-like behavior, which was reduced by CXCR4 inhibition. Additionally, miR-23a knockdown or CXCR4 overexpression in naïve mice could increase the thioredoxin-interacting protein (TXNIP), which was associated with induction of NOD-like receptor protein 3 (NLRP3) inflammasome. Indeed, CXCR4 and TXNIP were co-expressed. The mammal two-hybrid assay revealed the direct interaction between CXCR4 and TXNIP, which was increased in the spinal cord of pSNL mice. In particular, inhibition of TXNIP reversed pain behavior elicited by pSNL, miR-23a knockdown, or CXCR4 overexpression. Moreover, miR-23a overexpression or CXCR4 knockdown inhibited the increase of TXNIP and NLRP3 inflammasome in pSNL mice. Conclusions miR-23a, by directly targeting CXCR4, regulates neuropathic pain via TXNIP/NLRP3 inflammasome axis in spinal glial cells. Epigenetic interventions against miR-23a, CXCR4, or TXNIP may potentially serve as novel therapeutic avenues in treating peripheral nerve injury-induced nociceptive hypersensitivity

Epigenetic Regulation of Optic Nerve Development, Protection, and Repair

Epigenetic factors are known to influence tissue development, functionality, and their response to pathophysiology. This review will focus on different types of epigenetic regulators and their associated molecular apparatus that affect the optic nerve. A comprehensive understanding of epigenetic regulation in optic nerve development and homeostasis will help us unravel novel molecular pathways and pave the way to design blueprints for effective therapeutics to address optic nerve protection, repair, and regeneration