Establishing critical care nursing research priorities for three Australian regional public hospitals: A mixed method priority setting study.

OBJECTIVE: To determine key priorities for critical care nursing research in three Australian regional public hospitals, representing the shared priorities of healthcare professionals and patient representatives. METHODS: A three phase priority setting study, including consensus methods (nominal group), survey, qualitative interviews and focus groups were conducted between May 2021 and March 2022. Healthcare professionals and patient representatives from critical care units in regional public hospitals in Australia participated. A patient representative contributed to research design and co-authored this paper. RESULTS: In phase one, 29 research topics were generated. In phase two, during a nominal group ranking process, the top 5 priority areas for each site were identified. In the final phase, three themes from focus groups and interviews included patient flow through intensive care, patient care through intensive care journey and intensive care patient recovery. CONCLUSION: Identifying context specific research priorities through a priority setting exercise provides insight into the topics that are important to healthcare professionals and to patients in critical care. The top research priorities for nursing research in critical care in regional Australian hospitals include patient flow, patient recovery, and evidence based patient care through the intensive care journey, such as delirium management, pain and sedation, and mobilisation. These shared priorities will be used to guide future nursing research in critical care over the next 3-5 years. IMPLICATIONS FOR CLINICAL PRACTICE: The method we used in identifying the research priorities can be used by other researchers and clinicians; close collaboration among researchers and clinicians will be beneficial for practice improvement; and how we can be reassured that our practice is evidence based is worthy of attention.

Characteristics of Organ Donors Who Died From Suicide by Hanging in Australia and New Zealand: A Retrospective Study.

Background and objective The annual incidence of suicide by hanging in Australia and New Zealand has increased in the past decade, and a significant number of these individuals are becoming organ donors. The rates of organ donation following deaths from hanging is unknown and the characteristics of this cohort of donors have not been described in the literature. In light of this, we aimed to examine the trends in organ donation from individuals who had died from hanging, based on the solid organ donor data from the Australia and New Zealand Organ Donation (ANZOD) Registry. Methods We conducted a retrospective study that analyzed the ANZOD Registry donor data (2006-2015) to describe the characteristics of solid organ donors who had died by hanging (post-hanging group); these characteristics were compared to those of individuals who died by all other causes (non-hanging group). Results During the study period, the number and proportion of donors who died by suicide from hanging increased. Of the 4,024 consented organ donors, 226 had died by hanging and 3,798 had died from other causes. The probability that an individual who died by hanging would become an organ donor increased from 0.5 to 3%. Compared to donors who died by all other causes, post-hanging donors were younger (median age of 30 vs. 50 years), with fewer comorbidities, and a higher incidence of smoking. There was no significant difference in the proportion of those who indicated a prior intent to donate organs between post-hanging (34%) and non-hanging donors (38%). A higher proportion of post-hanging donors donated via the donation after the circulatory death pathway (36.3%) than non-hanging donors (24.2%). Individuals in the post-hanging cohort donated an average of 4.19 organs compared to 3.62 in the non-hanging cohort. Conclusion We believe the findings of this retrospective analysis will help inform clinical decision-making regarding organ donation, including the best approaches to obtaining donation consent. Our findings will help physicians provide care to patients and to families of individuals in this challenging group, where organ donation potential is high. Further investigations are required to determine which aspects of healthcare influence the donation rates in individuals who have died by hanging and the outcomes related to transplanted organs.

Sodium chloride or Plasmalyte-148 evaluation in severe diabetic ketoacidosis (SCOPE-DKA): a cluster, crossover, randomized, controlled trial.

PURPOSE: To determine whether treatment with Plasmalyte-148 (PL) compared to sodium chloride 0.9% (SC) results in faster resolution of diabetic ketoacidosis (DKA) and whether the acetate in PL potentiates ketosis. METHODS: We conducted a cluster, crossover, open-label, randomized, controlled Phase 2 trial at seven hospitals in adults admitted to intensive care unit (ICU) with severe DKA with hospital randomised to PL or SC as fluid therapy. The primary outcome, DKA resolution, was defined as a change in base excess to ≥ - 3 mEq/L at 48 h. RESULTS: Ninety-three patients were enrolled with 90 patients included in the modified-intention-to-treat population (PL n = 48, SC n = 42). At 48 h, mean fluid administration was 6798 ± 4850 ml vs 6574 ± 3123 ml, median anion gap 6 mEq/L (IQR 5-7) vs 7 mEq/L (IQR 5-7) and median blood ketones 0.3 mmol/L (IQR 0.1-0.5) vs 0.3 (IQR 0.1-0.5) in the PL and SC groups. DKA resolution at 48 h occurred in 96% (PL) and 86% (SC) of patients; odds ratio 3.93 (95% CI 0.73-21.16, p = 0.111). At 24 h, DKA resolution occurred in 69% (PL) and 36% (SC) of patients; odds ratio 4.24 (95% CI 1.68-10.72, p = 0.002). The median ICU and hospital lengths of stay were 49 h (IQR 23-72) vs 55 h (IQR 41-80) and 81 h (IQR 58-137) vs 98 h (IQR 65-195) in the PL and SC groups. CONCLUSION: Plasmalyte-148, compared to sodium chloride 0.9%, may lead to faster resolution of metabolic acidosis in patients with DKA without an increase in ketosis. These findings need confirmation in a large, Phase 3 trial.

Evaluating the influence of data collector training for predictive risk of death models: an observational study.

BACKGROUND: Severity-of-illness scoring systems are widely used for quality assurance and research. Although validated by trained data collectors, there is little data on the accuracy of real-world data collection practices. OBJECTIVE: To evaluate the influence of formal data collection training on the accuracy of scoring system data in intensive care units (ICUs). STUDY DESIGN AND METHODS: Quality assurance audit conducted using survey methodology principles. Between June and December 2018, an electronic document with details of three fictitious ICU patients was emailed to staff from 19 Australian ICUs who voluntarily submitted data on a web-based data entry form. Their entries were used to generate severity-of-illness scores and risks of death (RoDs) for four scoring systems. The primary outcome was the variation of severity-of-illness scores and RoDs from a reference standard. RESULTS: 50/83 staff (60.3%) submitted data. Using Bayesian multilevel analysis, severity-of-illness scores and RoDs were found to be significantly higher for untrained staff. The mean (95% high-density interval) overestimation in RoD due to training effect for patients 1, 2 and 3, respectively, were 0.24 (0.16, 0.31), 0.19 (0.09, 0.29) and 0.24 (0.1, 0.38) respectively (Bayesian factor >300, decisive evidence). Both groups (trained and untrained) had wide coefficients of variation up to 38.1%, indicating wide variability. Untrained staff made more errors in interpreting scoring system definitions. INTERPRETATION: In a fictitious patient dataset, data collection staff without formal training significantly overestimated the severity-of-illness scores and RoDs compared with trained staff. Both groups exhibited wide variability. Strategies to improve practice may include providing adequate training for all data collection staff, refresher training for previously trained staff and auditing the raw data submitted by individual ICUs. The results of this simulated study need revalidation on real patients.

Evaluation of cognitive load and emotional states during multidisciplinary critical care simulation sessions.

BACKGROUND: The simulation in critical care setting involves a heterogeneous group of participants with varied background and experience. Measuring the impacts of simulation on emotional state and cognitive load in this setting is not often performed. The feasibility of such measurement in the critical care setting needs further exploration. METHODS: Medical and nursing staff with varying levels of experience from a tertiary intensive care unit participated in a standardised clinical simulation scenario. The emotional state of each participant was assessed before and after completion of the scenario using a validated eight-item scale containing bipolar oppositional descriptors of emotion. The cognitive load of each participant was assessed after the completion of the scenario using a validated subjective rating tool. RESULTS: A total of 103 medical and nursing staff participated in the study. The participants felt more relaxed (-0.28±1.15 vs 0.14±1, P<0.005; d=0.39), excited (0.25±0.89 vs 0.55±0.92, P<0.005, d=0.35) and alert (0.85±0.87 vs 1.28±0.73, P<0.00001, d=0.54) following simulation. There was no difference in the mean scores for the remaining five items. The mean cognitive load for all participants was 6.67±1.41. There was no significant difference in the cognitive loads among medical staff versus nursing staff (6.61±2.3 vs 6.62±1.7; P>0.05). CONCLUSION: A well-designed complex high fidelity critical care simulation scenario can be evaluated to identify the relative cognitive load of the participants' experience and their emotional state. The movement of learners emotionally from a more negative state to a positive state suggests that simulation can be an effective tool for improved knowledge transfer and offers more opportunity for dynamic thinking.

Metabolic plasticity underpins innate and acquired resistance to LDHA inhibition.

Metabolic reprogramming in tumors represents a potential therapeutic target. Herein we used shRNA depletion and a novel lactate dehydrogenase (LDHA) inhibitor, GNE-140, to probe the role of LDHA in tumor growth in vitro and in vivo. In MIA PaCa-2 human pancreatic cells, LDHA inhibition rapidly affected global metabolism, although cell death only occurred after 2 d of continuous LDHA inhibition. Pancreatic cell lines that utilize oxidative phosphorylation (OXPHOS) rather than glycolysis were inherently resistant to GNE-140, but could be resensitized to GNE-140 with the OXPHOS inhibitor phenformin. Acquired resistance to GNE-140 was driven by activation of the AMPK-mTOR-S6K signaling pathway, which led to increased OXPHOS, and inhibitors targeting this pathway could prevent resistance. Thus, combining an LDHA inhibitor with compounds targeting the mitochondrial or AMPK-S6K signaling axis may not only broaden the clinical utility of LDHA inhibitors beyond glycolytically dependent tumors but also reduce the emergence of resistance to LDHA inhibition.

mTORC1-Dependent Metabolic Reprogramming Underlies Escape from Glycolysis Addiction in Cancer Cells.

Although glycolysis is substantially elevated in many tumors, therapeutic targeting of glycolysis in cancer patients has not yet been successful, potentially reflecting the metabolic plasticity of tumor cells. In various cancer cells exposed to a continuous glycolytic block, we identified a recurrent reprogramming mechanism involving sustained mTORC1 signaling that underlies escape from glycolytic addiction. Active mTORC1 directs increased glucose flux via the pentose phosphate pathway back into glycolysis, thereby circumventing a glycolysis block and ensuring adequate ATP and biomass production. Combined inhibition of glycolysis and mTORC1 signaling disrupted metabolic reprogramming in tumor cells and inhibited their growth in vitro and in vivo. These findings reveal novel combinatorial therapeutic strategies to realize the potential benefit from targeting the Warburg effect.

Acquired resistance of non-small cell lung cancer cells to MET kinase inhibition is mediated by a switch to epidermal growth factor receptor dependency.

Cancer cells harboring MET amplification display striking sensitivity to selective small molecule inhibitors of MET kinase, prompting their clinical evaluation. Similar to the experience with traditional therapeutics, most patients responding to treatment with such molecular targeted therapeutics ultimately relapse with drug-resistant disease. In this study we modeled acquired resistance to experimental MET kinase inhibitor PF2341066 in MET-amplified non-small cell lung carcinoma (NSCLC) cell lines to identify drug resistance mechanisms that may arise in clinic. We found that activation of the epidermal growth factor receptor (EGFR) pathway emerges as a resistance mechanism in MET-amplified cells after prolonged exposure to PF2341066. Whereas combined inhibition of MET and EGFR kinases in MET-dependent NSCLC cells did not enhance their initial sensitivity to PF2341066, this combination dramatically suppressed the eventual emergence of drug-resistant clones after prolonged drug exposure. Conversely, activation of the EGFR pathway increased the yield of PF2341066-resistant clones, confirming the significance of this pathway in conferring resistance. Our findings support an intimate relationship between the EGFR and MET signaling pathways in NSCLC, and they suggest that combination treatment with MET and EGFR kinase inhibitors may be beneficial in MET-amplified NSCLC by reducing selection for drug resistant clones.

E2F2 suppresses Myc-induced proliferation and tumorigenesis.

Deregulation of E2F transcriptional activity as a result of alterations in the p16-cyclin D-Rb pathway is a hallmark of cancer. However, the roles of the different E2F family members in the process of tumorigenesis are still being elucidated. Studies in mice and humans suggest that E2F2 functions as a tumor suppressor. Here we demonstrate that E2f2 inactivation cooperates with transgenic expression of Myc to enhance tumor development in the skin and oral cavity. In fact, hemizygosity at the E2f2 locus was sufficient to increase tumor incidence in this model. Loss of E2F2 enhanced proliferation in Myc transgenic tissue but did not affect Myc-induced apoptosis. E2F2 did not behave as a simple activator of transcription in epidermal keratinocytes but instead appeared to differentially regulate gene expression dependent on the individual target. E2f2 inactivation also altered the changes in gene expression in Myc transgenic cells by enhancing the increase of some genes, such as cyclin E, and reversing the repression of other genes. These findings demonstrate that E2F2 can function as a tumor suppressor in epithelial tissues, perhaps by limiting proliferation in response to Myc.

Respiratory changes during spinal anaesthesia for gynaecological laparoscopic surgery.

BACKGROUND: It is currently presumed that spinal anaesthesia can compromise respiratory muscle function during carbon dioxide (CO2) pneumoperitoneum. This observational study was designed to delineate the respiratory effects of CO2 pneumoperitoneum under spinal anaesthesia. PATIENTS #ENTITYSTARTX00026; METHODS: Forty one patients undergoing elective gynecological laparoscopy were administered spinal anaesthesia with 15 mg heavy bupivacaine and 50 mcg of fentanyl. Heart rare, blood pressure, tidal volume, respiratory rate and end tidal CO2 were serially recorded before, during and after the pneumoperitoneum. Arterial blood gas analysis was done before and 20 min after initiation of pneumoperitoneum. RESULTS: The mean heart rate and blood pressure decreased by less than 20% of the preoperative value. The mean tidal volume decreased from 353 ± 81(Standard Deviation) to 299±95 ml, p = 0.032, over the first 9 min after the pneumoperitoneum with a complete recovery towards the base line, 340 ± 72 ml, within 30 min during the surgery. The maximal inspiratory capacity declined from 1308±324 ml to 1067±296 ml at 20 min and recovered to 1187±267 ml, 5min after decompression. There was no observed change in the respiratory rate. Similarly, increase in the end tidal CO2 from 31.68±4.13 to 37.62±4.21 mmHg, p = 0.000, reached a plateau around 15 min and declined after decompression. Arterial carbon dioxide showed a corresponding increase at 20 min without change in arterial to end tidal CO2 difference. All observed changes were within the physiological limits. CONCLUSION: In a conscious patient undergoing laparoscopy with pneumoperitoneum, under spinal anaesthesia, the preserved inspiratory diaphragmatic activity maintains ventilation and, the gas exchange within physiological limits. Hence it is a safe alternative to general anaesthesia.

Oncogenes and the DNA damage response: Myc and E2F1 engage the ATM signaling pathway to activate p53 and induce apoptosis.

Activation of the ATM DNA damage response pathway is commonly observed in a variety of early-stage neoplasias. It has been proposed that this checkpoint response functions to suppress the development of cancer. A recent report from our laboratory demonstrates that ATM does indeed function to suppress tumorigenesis by responding to at least some oncogenic stresses. Transgenic expression of Myc is found to cause DNA damage in vivo and ATM is shown to respond to this damage by inducing the accumulation and phosphorylation of p53. In the absence of ATM, p53-dependent apoptosis is reduced and epithelial tumorigenesis is accelerated in Myc transgenic mice. Deregulated expression of the E2F1 transcription factor also elicits an ATM-dependent checkpoint response that activates p53 and promotes apoptosis, although the mechanism by which E2F1 and Myc stimulate ATM may differ. These findings have relevance for understanding why the ATM pathway is activated in many human cancers, what generates the selective pressure for p53 inactivation during tumorigenesis, and why AT patients and carriers are predisposed to developing cancer.

ATM promotes apoptosis and suppresses tumorigenesis in response to Myc.

Overexpression of the c-myc oncogene contributes to the development of a significant number of human cancers. In response to deregulated Myc activity, the p53 tumor suppressor is activated to promote apoptosis and inhibit tumor formation. Here we demonstrate that p53 induction in response to Myc overexpression requires the ataxia-telangiectasia mutated (ATM) kinase, a major regulator of the cellular response to DNA double-strand breaks. In a transgenic mouse model overexpressing Myc in squamous epithelial tissues, inactivation of Atm suppresses apoptosis and accelerates tumorigenesis. Deregulated Myc expression induces DNA damage in primary transgenic keratinocytes and the formation of gammaH2AX and phospho-SMC1 foci in transgenic tissue. These findings suggest that Myc overexpression causes DNA damage in vivo and that the ATM-dependent response to this damage is critical for p53 activation, apoptosis, and the suppression of tumor development.

Hepatitis B vaccination in premature and low birth weight (LBW) babies.

OBJECTIVE: To assess the immune response of preterm and low birth weight babies (LBW) to hepatitis B (HB) vaccine. SETTING: Neonatal Intensive Care Unit (NICU), postnatal ward and follow up clinics of KEM Hospital, Pune. DESIGN: Open trial. METHODS: 100 babies were enrolled in four study groups. Group I - preterm, gestational age (GA) < 34 weeks; Group II - GA 34 to 36 weeks; Group III full term <2.5 kg (LBW babies); and Group IV full term >2.5 kg (controls). A recombinant DNA HB vaccine was given at 0, 1, 2 and 12 month schedule. The first injection was administered as soon as the neonate was stabilized. Immune response in terms of anti HBs titres (AUSAB EIA Diagnostic kit) was measured one month after each of the first three injections and at the time of one year booster. Adverse events were monitored. RESULTS: 88 and 62 babies completed the study till the third dose and one year booster dose respectively. Immune response of HB vaccine was uniformly good in all the study groups with 100 % sero-conversion after the second dose itself. By one year (i.e. before the booster dose), very high titres were recorded in all 100%, with 85% demonstrating titres >1000 mIU/ml. Preterm and LBW babies had higher GMT as compared to full term babies till one month after third dose. By one year (before booster), full term babies had higher GMT than preterm and LBW babies. However, these differences were not statistically significant. The vaccine was well tolerated and safe and there were no adverse reactions. CONCLUSION: Immune response of preterm, LBW and full term babies to the new generation recombinant DNA HB vaccine was uniformly good. High and long term seroprotective levels were achieved after the second dose itself.