Publications by authors named "Mark Plummer"

94 Publications

Dynamic Heterogeneity Shapes Patterns of Spiral Ganglion Activity.

J Neurosci 2021 10 22;41(43):8859-8875. Epub 2021 Sep 22.

Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, New Jersey 08854

Neural response properties that typify primary sensory afferents are critical to fully appreciate because they establish and, ultimately represent, the fundamental coding design used for higher-level processing. Studies illuminating the center-surround receptive fields of retinal ganglion cells, for example, were ground-breaking because they determined the foundation of visual form detection. For the auditory system, a basic organizing principle of the spiral ganglion afferents is their extensive electrophysiological heterogeneity establishing diverse intrinsic firing properties in neurons throughout the spiral ganglion. Moreover, these neurons display an impressively large array of neurotransmitter receptor types that are responsive to efferent feedback. Thus, electrophysiological diversity and its neuromodulation are a fundamental encoding mechanism contributed by the primary afferents in the auditory system. To place these features into context, we evaluated the effects of hyperpolarization and cAMP on threshold level as indicators of overall afferent responsiveness in CBA/CaJ mice of either sex. Hyperpolarization modified threshold gradients such that distinct voltage protocols could shift the relationship between sensitivity and stimulus input to reshape resolution. This resulted in an "accordion effect" that appeared to stretch, compress, or maintain responsivity across the gradient of afferent thresholds. cAMP targeted threshold and kinetic shifts to rapidly adapting neurons, thus revealing multiple cochleotopic properties that could potentially be independently regulated. These examples of dynamic heterogeneity in primary auditory afferents not only have the capacity to shift the range, sensitivity, and resolution, but to do so in a coordinated manner that appears to orchestrate changes with a seemingly unlimited repertoire. How do we discriminate the more nuanced qualities of the sound around us? Beyond the basics of pitch and loudness, aspects, such as pattern, distance, velocity, and location, are all attributes that must be used to encode acoustic sensations effectively. While higher-level processing is required for perception, it would not be unexpected if the primary auditory afferents optimized receptor input to expedite neural encoding. The findings reported herein are consistent with this design. Neuromodulation compressed, expanded, shifted, or realigned intrinsic electrophysiological heterogeneity to alter neuronal responses selectively and dynamically. This suggests that diverse spiral ganglion phenotypes provide a rich substrate to support an almost limitless array of coding strategies within the first neural element of the auditory pathway.
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http://dx.doi.org/10.1523/JNEUROSCI.0924-20.2021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8549539PMC
October 2021

Considering intervention intensity in habitat restoration planning: An application to Pacific salmon.

J Environ Manage 2021 Dec 6;299:113536. Epub 2021 Sep 6.

Northwest Fisheries Science Center, 2725 Montlake Blvd. East, Seattle, WA, 98112, USA; Pacific Marine Environmental Laboratory, 7600 Sand Point Way NE, Seattle, WA, 98115, USA.

Habitat restoration is a key strategy for recovering imperiled species, and planning habitat restoration activities cost effectively can help advance recovery objectives. Habitat restoration planning involves decisions about where and when to undertake restoration, and what type of restoration to undertake. This article focuses on decisions about the amount of restoration to undertake for a given type, location, and time, termed intervention intensity. A return on investment framework is developed for incorporating intervention intensity into habitat restoration planning. The framework is then applied in the context of planning habitat restoration for Pacific salmon recovery as a case study. Results showed that no single intervention type or location dominated, and several returns to scale relationships emerged across the candidate interventions. Scenarios that considered interventions across multiple intensities outperformed single-intensity scenarios in terms of total benefits and cost effectiveness. These findings highlight the usefulness of exploratory return on investment analysis for prioritizing habitat restoration interventions, and underscore the importance of systematically considering how much restoration to undertake, in addition to what to do and where.
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http://dx.doi.org/10.1016/j.jenvman.2021.113536DOI Listing
December 2021

Perioperative Neutrophil-Lymphocyte Ratio Predicts Mortality After Cardiac Surgery: Systematic Review and Meta-Analysis.

J Cardiothorac Vasc Anesth 2021 Jul 9. Epub 2021 Jul 9.

Department of Surgery, Monash University, Clayton, Australia; School of Clinical Sciences, Monash Health, Clayton, Australia.

Objectives: Neutrophil-lymphocyte ratio (NLR) is an inflammatory biomarker that has been evaluated across a variety of surgical disciplines and is widely predictive of poor postoperative outcome, but its value in cardiac surgery is unclear. The authors did this systematic review and meta-analysis to determine the impact of elevated perioperative NLR on survival after cardiac surgery.

Design: Systematic review and meta-analysis of study-level data.

Setting: Multiple hospitals involved in an international pool of studies.

Participants: Adults undergoing cardiac surgery.

Interventions: None.

Measurements And Main Results: The authors searched multiple databases from inception until November 2020. They generated summary hazard ratios (HR) and odds ratios (OR) for the association of elevated preoperative NLR with long-term and short-term mortality following cardiac surgery. They separately reported on elevated postoperative NLR. Between-study heterogeneity was explored using metaregression. The authors included 12 studies involving 13,262 patients undergoing cardiac surgery. Elevated preoperative NLR was associated with worse long-term (>30 days) (hazard ratio [HR] 1.56; 95% CI [confidence interval], 1.18-2.06; 8 studies) and short-term (<30 days) mortality (OR 3.18; 95% CI, 1.90-5.30; 7 studies). One study reported the association of elevated postoperative NLR with long-term mortality (HR 8.58; 95% CI, 2.55-28.85). There was considerable between-study heterogeneity for the analysis of long-term mortality (I statistic 94.39%), which mostly was explained by study-level variables, such as the number of variables adjusted for by included studies and how many of these significantly increased the risk of long-term mortality, high risk of bias, and number of study centers, as well as participant level factors, such as average participant age and hypertension prevalence.

Conclusions: Perioperative NLR is an independent predictor of short-term and long-term postoperative mortality following cardiac surgery. Further research is required to determine which patient-level factors modify the prognostic value of NLR and to evaluate its role in routine clinical practice.
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http://dx.doi.org/10.1053/j.jvca.2021.07.001DOI Listing
July 2021

A multicenter randomized clinical trial of pharmacological vitamin B1 administration to critically ill patients who develop hypophosphatemia during enteral nutrition (The THIAMINE 4 HYPOPHOSPHATEMIA trial).

Clin Nutr 2021 08 24;40(8):5047-5052. Epub 2021 Jul 24.

The University of Melbourne, Department of Critical Care, Melbourne Medical School, Melbourne, Australia; Intensive Care Unit, Royal Melbourne Hospital, Melbourne, Australia.

Background: Hypophosphatemia may be a useful biomarker to identify thiamine deficiency in critically ill enterally-fed patients. The objective was to determine whether intravenous thiamine affects blood lactate, biochemical and clinical outcomes in this group.

Method: This randomized clinical trial was conducted across 5 Intensive Care Units. Ninety critically ill adult patients with a serum phosphate ≤0.65 mmol/L within 72 h of commencing enteral nutrition were randomized to intravenous thiamine (200 mg every 12 h for up to 14 doses) or usual care (control). The primary outcome was blood lactate over time and data are median [IQR] unless specified.

Results: Baseline variables were well balanced (thiamine: lactate 1.2 [1.0, 1.6] mmol/L, phosphate 0.56 [0.44, 0.64] mmol/L vs. control: lactate 1.0 [0.8, 1.3], phosphate 0.54 [0.44, 0.61]). Patients randomized to the intervention received a median of 11 [7.5, 13.5] doses for a total of 2200 [1500, 2700] mg of thiamine. Blood lactate over the entire 7 days of treatment was similar between groups (mean difference = -0.1 (95 % CI -0.2 to 0.1) mmol/L; P = 0.55). The percentage change from lactate pre-randomization to T = 24 h was not statistically different (thiamine: -32 (-39, -26) vs. control: -24 (-31, -16) percent, P = 0.09). Clinical outcomes were not statistically different (days of vasopressor administration: thiamine 2 [1, 4] vs. control 2 [0, 5.5] days; P = 0.37, and deaths 9 (21 %) vs. 5 (11 %); P = 0.25).

Conclusions: In critically ill enterally-fed patients who developed hypophosphatemia, intravenous thiamine did not cause measurable differences in blood lactate or clinical outcomes.

Trial Registration: Australian and New Zealand Clinical Trials Registry (ACTRN12619000121167).
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http://dx.doi.org/10.1016/j.clnu.2021.07.024DOI Listing
August 2021

Creation of a new class of radiosensitizers for glioblastoma based on the mibefradil pharmacophore.

Oncotarget 2021 Apr 27;12(9):891-906. Epub 2021 Apr 27.

Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, CT 06510-8034, USA.

Glioblastoma (GBM) is the most common primary malignant tumor of the central nervous system with a dismal prognosis. Locoregional failure is common despite high doses of radiation therapy, which has prompted great interest in developing novel strategies to radiosensitize these cancers. Our group previously identified a calcium channel blocker (CCB), mibefradil, as a potential GBM radiosensitizer. We discovered that mibefradil selectively inhibits a key DNA repair pathway, alternative non-homologous end joining. We then initiated a phase I clinical trial that revealed promising initial efficacy of mibefradil, but further development was hampered by dose-limiting toxicities, including CCB-related cardiotoxicity, off-target hERG channel and cytochrome P450 enzymes (CYPs) interactions. Here, we show that mibefradil inhibits DNA repair independent of its CCB activity, and report a series of mibefradil analogues which lack CCB activity and demonstrate reduced hERG and CYP activity while retaining potency as DNA repair inhibitors. We present pharmacokinetic studies of the top analogues with evidence of brain penetration. We also report a targeted siRNA-based screen which suggests a possible role for mTOR and Akt in DNA repair inhibition by this class of drugs. Taken together, these data reveal a new class of mibefradil-based DNA repair inhibitors which can be further advanced into pre-clinical testing and eventually clinical trials, as potential GBM radiosensitizers.
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http://dx.doi.org/10.18632/oncotarget.27933DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8092340PMC
April 2021

A γ-lactam siderophore antibiotic effective against multidrug-resistant Pseudomonas aeruginosa, Klebsiella pneumoniae, and Acinetobacter spp.

Eur J Med Chem 2021 Aug 8;220:113436. Epub 2021 Apr 8.

Research Service, Louis Stokes Cleveland Department of Veterans Affairs Medical Center, Cleveland, OH, 44106, USA; Department of Biochemistry, Case Western Reserve University, Cleveland, OH, 44106, USA; Department of Medicine, Case Western Reserve University, Cleveland, OH, 44106, USA; Geriatric Research, Education and Clinical Center, Louis Stokes Cleveland Department of Veterans Affairs Medical Center, Cleveland, OH, 44106, USA; Departments of Pharmacology, Molecular Biology & Microbiology, And Proteomics & Bioinformatics, Case Western Reserve University, Cleveland, OH, 44106, USA; CWRU-Cleveland VAMC Center for Antimicrobial Resistance and Epidemiology (Case VA CARES), Cleveland, OH, 44106, USA. Electronic address:

Serious infections caused by multidrug-resistant (MDR) organisms (Klebsiella pneumoniae, Pseudomonas aeruginosa, Acinetobacter baumannii) present a critical need for innovative drug development. Herein, we describe the preclinical evaluation of YU253911, 2, a novel γ-lactam siderophore antibiotic with potent antimicrobial activity against MDR Gram-negative pathogens. Penicillin-binding protein (PBP) 3 was shown to be a target of 2 using a binding assay with purified P. aeruginosa PBP3. The specific binding interactions with P. aeruginosa were further characterized with a high-resolution (2.0 Å) X-ray structure of the compound's acylation product in P. aeruginosa PBP3. Compound 2 was shown to have a concentration >1 μg/ml at the 6 h time point when administered intravenously or subcutaneously in mice. Employing a meropenem resistant strain of P. aeruginosa, 2 was shown to have dose-dependent efficacy at 50 and 100 mg/kg q6h dosing in a mouse thigh infection model. Lastly, we showed that a novel γ-lactam and β-lactamase inhibitor (BLI) combination can effectively lower minimum inhibitory concentrations (MICs) against carbapenem resistant Acinetobacter spp. that demonstrated decreased susceptibility to 2 alone.
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http://dx.doi.org/10.1016/j.ejmech.2021.113436DOI Listing
August 2021

Pharmacological Management of Paroxysmal Sympathetic Hyperactivity: A Scoping Review.

J Neurotrauma 2021 Aug 20;38(16):2221-2237. Epub 2021 May 20.

Department of Intensive Care, Royal Melbourne Hospital, Melbourne, Australia.

Paroxysmal sympathetic hyperactivity (PSH) occurs in ∼10% of patients following acute severe brain injury. While PSH is associated with worse outcomes, there are no clinical practice guidelines to inform treatment. We aimed to systematically review the literature on the pharmacological management of PSH. MEDLINE, Embase, and Cochrane library databases were searched from inception to August 2020. Eligible studies met the following criteria: 1) randomized controlled trials, non-randomized controlled trials (case control or controlled cohort), observational studies, case series, and case reports; 2) study population of adult and pediatric patients; 3) exposure to an acute neurological insult complicated by PSH (or historic synonym); 4) description of pharmacological treatment of PSH. Our search retrieved 2729 citations with 83 articles assessed for inclusion. After full text extraction, 56 manuscripts inclusive of 459 patients met eligibility criteria. We identified 31 case reports, 15 case series (152 patients), seven retrospective case control or cohort studies (212 patients), and three prospective observational studies (52 patients). Traumatic brain injury was the most common precipitating insult (407 patients), followed by hypoxic encephalopathy (72 patients) and intracranial hemorrhage (10 patients). There were 48 drugs from 22 classes prescribed for the management of PSH. The most frequently prescribed agents were benzodiazepines, β-blockers, opioids, α-2 agonists, and baclofen. However, route and dose of drug and subsequent outcome were inconsistently reported, such that no summary was possible. While a wide variety of drugs have been reported to treat PSH, there is a lack of even moderate-quality evidence to inform clinical decision making.
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http://dx.doi.org/10.1089/neu.2020.7597DOI Listing
August 2021

Urinary and renal oxygenation during dexmedetomidine infusion in critically ill adults with mechanistic insights from an ovine model.

J Crit Care 2021 08 24;64:74-81. Epub 2021 Mar 24.

Department of Intensive Care, Royal Melbourne Hospital, 300 Grattan Street Parkville, Melbourne, Australia; Department of Critical Care, University of Melbourne, Melbourne, Australia. Electronic address:

Purpose: Examine effects of dexmedetomidine on bladder urinary oxygen tension (PuO) in critically ill patients and delineate mechanisms in an ovine model.

Materials And Methods: In 12 critically ill patients: oxygen-sensing probe inserted in the bladder catheter and dexmedetomidine infusion at a mean (SD) rate of 0.9 ± 0.3 μg/kg/h for 24-h. In 9 sheep: implantation of flow probes around the renal and pulmonary arteries, and oxygen-sensing probes in the renal cortex, renal medulla and bladder catheter; dexmedetomidine infusion at 0.5 μg/kg/h for 4-h and 1.0 μg/kg/h for 4-h then 16 h observation.

Results: In patients, dexmedetomidine decreased bladder PuOat 2 (-Δ11 (95% CI 7-16)mmHg), 8 (-Δ 7 (0.1-13)mmHg) and 24 h (-Δ 11 (0.4-21)mmHg). In sheep, dexmedetomidine at 1 μg/kg/h reduced renal medullary oxygenation (-Δ 19 (14-24)mmHg) and bladder PuO (-Δ 12 (7-17)mmHg). There was moderate correlation between renal medullary oxygenation and bladder PuO; intraclass correlation co-efficient 0.59 (0.34-0.80). Reductions in renal medullary oxygenation were associated with reductions in blood pressure, cardiac output and renal blood flow (P < 0.01).

Conclusions: Dexmedetomidine decreases PuOin critically ill patients and in sheep. In sheep this reflects a decrease in renal medullary oxygenation, associated with reductions in cardiac output, blood pressure and renal blood flow.
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http://dx.doi.org/10.1016/j.jcrc.2021.03.004DOI Listing
August 2021

Postprandial rise of essential amino acids is impaired during critical illness and unrelated to small-intestinal function.

JPEN J Parenter Enteral Nutr 2021 Mar 5. Epub 2021 Mar 5.

Department of Surgery, NUTRIM School for Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, The Netherlands.

Background: Postprandial rise of plasma essential amino acids (EAAs) determines the anabolic effect of dietary protein. Disturbed gastrointestinal function could impair the anabolic response in critically ill patients. Aim was to investigate the postprandial EAA response in critically ill patients and its relation to small-intestinal function.

Methods: Twenty-one mechanically ventilated patients and 9 healthy controls received a bolus containing 100 ml of a formula feed (Ensure) and 2 g of 3-O-Methyl-d-glucose (3-OMG) via postpyloric feeding tube. Fasting and postprandial plasma concentrations of EAAs, 3-OMG, total bile salts, and the gut-released hormone fibroblast growth factor 19 (FGF19) were measured over a 4-hour period. Changes over time and between groups were assessed with linear mixed-effects analysis. Early (0-60 minutes) and total postprandial responses are summarized as the incremental area under the curve (iAUC).

Results: At baseline, fasting EAA levels were similar in both groups: 1181 (1055-1276) vs 1150 (1065-1334) μmol·L-1, P = .87. The early postprandial rise in EAA was not apparent in critically ill patients compared with healthy controls (iAUC , -4858 [-6859 to 2886] vs 5406 [3099-16,853] µmol·L ·60 minutes; P = .039). Impaired EAA response did not correlate with impaired 3-OMG response (Spearman ρ 0.32, P = .09). There was a limited increase in total bile salts but no relevant FGF19 response in either group.

Conclusion: Postprandial rise of EAA is blunted in critically ill patients and unrelated to glucose absorption measured with 3-OMG. Future studies should aim to delineate governing mechanisms of macronutrient malabsorption.
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http://dx.doi.org/10.1002/jpen.2103DOI Listing
March 2021

Neuroprotective Properties of Vitamin C: A Scoping Review of Pre-Clinical and Clinical Studies.

J Neurotrauma 2021 Aug 8;38(16):2194-2205. Epub 2021 Mar 8.

Department of Intensive Care, Royal Melbourne Hospital, Parkville, Victoria, Australia.

There is a need for novel neuroprotective therapies. We aimed to review the evidence for exogenous vitamin C as a neuroprotective agent. MEDLINE, Embase, and Cochrane library databases were searched from inception to May 2020. Pre-clinical and clinical reports evaluating vitamin C for acute neurological injury were included. Twenty-two pre-clinical and 11 clinical studies were eligible for inclusion. Pre-clinical studies included models of traumatic and hypoxic brain injury, subarachnoid and intracerebral hemorrhage, and ischemic stroke. The median [IQR] maximum daily dose of vitamin C in animal studies was 120 [50-500] mg/kg. Twenty-one animal studies reported improvements in biomarkers, functional outcome, or both. Clinical studies included single reports in neonatal hypoxic encephalopathy, traumatic brain injury, and subarachnoid hemorrhage and eight studies in ischemic stroke. The median maximum daily dose of vitamin C was 750 [500-1000] mg, or ∼10 mg/kg for an average-size adult male. Apart from one case series of intracisternal vitamin C administration in subarachnoid hemorrhage, clinical studies reported no patient-centered benefit. Although pre-clinical trials suggest that exogenous vitamin C improves biomarkers of neuroprotection, functional outcome, and mortality, these results have not translated to humans. However, clinical trials used approximately one tenth of the vitamin C dose of animal studies.
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http://dx.doi.org/10.1089/neu.2020.7443DOI Listing
August 2021

Gut dysfunction in the ICU: diagnosis and management.

Curr Opin Crit Care 2021 04;27(2):141-146

Intensive Care Unit, Royal Adelaide Hospital.

Purpose Of Review: Progress has been made in our understanding of gut dysfunction in critical illness. This review will outline new findings and give perspectives based on previous knowledge and concurrent advances in nutrition.

Recent Findings: The relationship between gut dysfunction and poor outcomes in critical illness has received considerable interest. It remains uncertain whether gut dysfunction is merely a marker of illness severity or if it is directly responsible for prolonged critical illness and increased mortality. This relationship is difficult to ascertain given there is no agreed method for identification and quantification; biomarkers such as intestinal fatty acid binding protein and citrulline show promise but require further study. Recent studies have investigated strategies to deliver enteral nutrition targets with impacts on gut function, including high calorie or protein formulae, intermittent regimes and novel prokinetics.

Summary: Gut dysfunction is associated with poor outcomes, but it remains uncertain whether strategies to improve gut function will influence survival and recovery.
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http://dx.doi.org/10.1097/MCC.0000000000000813DOI Listing
April 2021

Emerging benefits and drawbacks of α -adrenoceptor agonists in the management of sepsis and critical illness.

Br J Pharmacol 2021 03 15;178(6):1407-1425. Epub 2021 Feb 15.

Preclinical Critical Care Unit, Florey Institute of Neuroscience and Mental Health, Melbourne, Victoria, Australia.

Agonists of α -adrenoceptors are increasingly being used for the provision of comfort, sedation and the management of delirium in critically ill patients, with and without sepsis. In this context, increased sympathetic and inflammatory activity are common pathophysiological features linked to multi-organ dysfunction, particularly in patients with sepsis or those undergoing cardiac surgery requiring cardiopulmonary bypass. Experimental and clinical studies support the notion that the α -adrenoceptor agonists, dexmedetomidine and clonidine, mitigate sympathetic and inflammatory overactivity in sepsis and cardiac surgery requiring cardiopulmonary bypass. These effects can protect vital organs, including the cardiovascular system, kidneys, heart and brain. We review the pharmacodynamic mechanisms by which α -adrenoceptor agonists might mitigate multi-organ dysfunction arising from pathophysiological conditions associated with excessive inflammatory and adrenergic stress in experimental studies. We also outline recent clinical trials that have examined the use of dexmedetomidine in critically ill patients with and without sepsis and in patients undergoing cardiac surgery.
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http://dx.doi.org/10.1111/bph.15363DOI Listing
March 2021

Comparison of Critical Care Occupancy and Outcomes of Critically Ill Patients during the 2020 COVID-19 Winter Surge and 2009 H1N1 Influenza Pandemic in Australia.

Ann Am Thorac Soc 2021 08;18(8):1380-1389

Australian and New Zealand Intensive Care Research Centre, School of Public Health and Preventive Medicine, Monash University, Melbourne, Victoria, Australia.

Both 2009 pandemic influenza A (H1N1) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are transmitted by respiratory secretions and in severe cases result in a viral pneumonitis, requiring intensive care unit (ICU) admission. However, no studies have compared the clinical characteristics and outcomes of such patients. To report and compare the demographic characteristics, treatments, use of critical care resources, and outcomes of patients admitted to an Australian ICU with H1N1 influenza during the winter of 2009, and SARS-CoV-2 during the winter of 2020. This was a multicenter project, using national data from previous and ongoing epidemiological studies concerning severe acute respiratory infections in Australia. All ICUs admitting patients with H1N1 or coronavirus disease (COVID-19) were included and contributed data. We compared clinical characteristics and outcomes of patients with H1N1 admitted to ICU in the winter of 2009 versus patients with COVID-19 admitted to ICU in the winter of 2020. The primary outcome was in-hospital mortality. Potential years of life lost (PYLL) were calculated according to sex-adjusted life expectancy in Australia. Across the two epochs, 861 patients were admitted to ICUs; 236 (27.4%) with COVID-19 and 625 (72.6%) with H1N1 influenza. The number of ICU admissions and bed-days occupied were higher with 2009 H1N1 influenza. Patients with COVID-19 were older, more often male and overweight, and had lower Acute Physiology and Chronic Health Evaluation II scores at ICU admission. The highest age-specific incidence of ICU admission was among infants (0-1 yr of age) for H1N1, and among the elderly (≥65 yr) for COVID-19. Unadjusted in-hospital mortality was similar (11.5% in COVID-19 vs. 16.1% in H1N1; odds ratio, 0.68 [95% confidence interval (95% CI), 0.42-1.06];  = 0.10). The PYLL was greater with H1N1 influenza than with COVID-19 at 154.1 (95% CI, 148.7-159.4) versus 13.6 (95% CI, 12.2-15.1) PYLL per million inhabitants. In comparison with 2009 H1N1 influenza, COVID-19 admissions overwinter in Australia resulted in fewer ICU admissions, and lower bed-day occupancy. Crude in-hospital mortality was similar, but because of demographic differences in affected patients, deaths due to 2009 H1N1 influenza led to an 11-fold increase in the number of PYLL in critically ill patients.
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http://dx.doi.org/10.1513/AnnalsATS.202010-1311OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8513663PMC
August 2021

Outcomes for patients with COVID-19 admitted to Australian intensive care units during the first four months of the pandemic.

Med J Aust 2021 01 15;214(1):23-30. Epub 2020 Dec 15.

Australian and New Zealand Intensive Care Research Centre, Monash University, Melbourne, VIC.

Objectives: To describe the characteristics and outcomes of patients with COVID-19 admitted to intensive care units (ICUs) during the initial months of the pandemic in Australia.

Design, Setting: Prospective, observational cohort study in 77 ICUs across Australia.

Participants: Patients admitted to participating ICUs with laboratory-confirmed COVID-19 during 27 February - 30 June 2020.

Main Outcome Measures: ICU mortality and resource use (ICU length of stay, peak bed occupancy).

Results: The median age of the 204 patients with COVID-19 admitted to intensive care was 63.5 years (IQR, 53-72 years); 140 were men (69%). The most frequent comorbid conditions were obesity (40% of patients), diabetes (28%), hypertension treated with angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers (24%), and chronic cardiac disease (20%); 73 patients (36%) reported no comorbidity. The most frequent source of infection was overseas travel (114 patients, 56%). Median peak ICU bed occupancy was 14% (IQR, 9-16%). Invasive ventilation was provided for 119 patients (58%). Median length of ICU stay was greater for invasively ventilated patients than for non-ventilated patients (16 days; IQR, 9-28 days v 3 days; IQR, 2-5 days), as was ICU mortality (26 deaths, 22%; 95% CI, 15-31% v four deaths, 5%; 95% CI, 1-12%). Higher Acute Physiology and Chronic Health Evaluation II (APACHE-II) scores on ICU day 1 (adjusted hazard ratio [aHR], 1.15; 95% CI, 1.09-1.21) and chronic cardiac disease (aHR, 3.38; 95% CI, 1.46-7.83) were each associated with higher ICU mortality.

Conclusion: Until the end of June 2020, mortality among patients with COVID-19 who required invasive ventilation in Australian ICUs was lower and their ICU stay longer than reported overseas. Our findings highlight the importance of ensuring adequate local ICU capacity, particularly as the pandemic has not yet ended.
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http://dx.doi.org/10.5694/mja2.50883DOI Listing
January 2021

Are Classic Bedside Exam Findings Required to Initiate Enteral Nutrition in Critically Ill Patients: Emphasis on Bowel Sounds and Abdominal Distension.

Nutr Clin Pract 2021 Feb 9;36(1):67-75. Epub 2020 Dec 9.

Department of Anaesthesiology and Intensive Care, University of Tartu, Tartu, Estonia.

The general physical examination of a patient is an axiom of critical care medicine, but evidence to support this practice remains sparse. Given the lack of evidence for a comprehensive physical examination of the entire patient on admission to the intensive care unit, which most clinicians consider an essential part of care, should clinicians continue the practice of a specialized gastrointestinal system physical examination when commencing enteral nutrition in critically ill patients? In this review of literature related to gastrointestinal system examination in critically ill patients, the focus is on gastrointestinal sounds and abdominal distension. There is a summary of what these physical features represent, an evaluation of the evidence regarding use of these physical features in patients after abdominal surgery, exploration of the rationale for and against using the physical findings in routine practice, and detail regarding what is known about each feature in critically ill patients. Based on the available evidence, it is recommended that an isolated symptom, sign, or bedside test does not provide meaningful information. However, it is submitted that a comprehensive physical assessment of the gastrointestinal system still has a role when initiating or administering enteral nutrition: specifically, when multiple features are present, clinicians should consider further investigation or intervention.
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http://dx.doi.org/10.1002/ncp.10610DOI Listing
February 2021

Global Impact of Coronavirus Disease 2019 Infection Requiring Admission to the ICU: A Systematic Review and Meta-analysis.

Chest 2021 02 15;159(2):524-536. Epub 2020 Oct 15.

Intensive Care Unit, Royal Melbourne Hospital, Parkville, VIC, Australia; University of Melbourne, Melbourne Medical School, Department of Medicine and Radiology, Royal Melbourne Hospital, Parkville, VIC, Australia.

Background: The coronavirus disease 2019 (COVID-19) pandemic has placed unprecedented burden on the delivery of intensive care services worldwide.

Research Question: What is the global point estimate of deaths and risk factors for patients who are admitted to ICUs with severe COVID-19?

Study Design And Methods: In this systematic review and meta-analysis Medline, Embase, and the Cochrane library were searched up to August 1, 2020. Pooled prevalence of participant characteristics, clinical features, and outcome data was calculated with the use of random effects models. Subgroup analyses were based on geographic distribution, study type, quality assessment, sample size, end date, and patient disposition. Studies that reported in-hospital mortality rate of adult patients (age >18 years) with confirmed COVID-19 admitted to an ICU met study eligibility criteria. Critical evaluation was performed with the Newcastle Ottawa Scale for nonrandomized studies.

Results: Forty-five studies with 16,561 patients from 17 countries across four continents were included. Patients with COVID-19 who were admitted to ICUs had a mean age of 62.6 years (95% CI, 60.4-64.7). Common comorbidities included hypertension (49.5%; 95% CI, 44.9-54.0) and diabetes mellitus (26.6%; 95% CI, 22.7-30.8). More than three-quarters of cases experienced the development of ARDS (76.1%; 95% CI, 65.7-85.2). Invasive mechanical ventilation was required in 67.7% (95% CI, 59.1-75.7) of case, vasopressor support in 65.9% (95% CI, 52.4-78.4) of cases, renal replacement therapy in 16.9% (95% CI, 12.1-22.2) of cases, and extracorporeal membrane oxygenation in 6.4% (95% CI, 4.1-9.1) of cases. The duration of ICU and hospital admission was 10.8 days (95% CI, 9.3-18.4) and 19.1 days (95% CI, 16.3-21.9), respectively, with in-hospital mortality rate of 28.1% (95% CI, 23.4-33.0; I = 96%). No significant subgroup effect was observed.

Interpretation: Critically ill patients with COVID-19 who are admitted to the ICU require substantial organ support and prolonged ICU and hospital level care. The pooled estimate of global death from severe COVID-19 is <1 in 3.
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http://dx.doi.org/10.1016/j.chest.2020.10.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7557272PMC
February 2021

Smoking in critically ill patients with COVID-19: the Australian experience.

Crit Care Resusc 2020 09;22(3):281-283

Department of Intensive Care and Hyperbaric Medicine, The Alfred Hospital, Melbourne, VIC, Australia.

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September 2020

Smoking in critically ill patients with COVID-19: the Australian experience.

Crit Care Resusc 2020 Jul 8. Epub 2020 Jul 8.

Department of Intensive Care and Hyperbaric Medicine, The Alfred Hospital, Melbourne, VIC, Australia.

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July 2020

A γ-Lactam Siderophore Antibiotic Effective against Multidrug-Resistant Gram-Negative Bacilli.

J Med Chem 2020 06 2;63(11):5990-6002. Epub 2020 Jun 2.

Department of Biochemistry, Case Western Reserve University, Cleveland, Ohio 44106, United States.

Treatment of multidrug-resistant Gram-negative bacterial pathogens represents a critical clinical need. Here, we report a novel γ-lactam pyrazolidinone that targets penicillin-binding proteins (PBPs) and incorporates a siderophore moiety to facilitate uptake into the periplasm. The MIC values of γ-lactam YU253434, , are reported along with the finding that is resistant to hydrolysis by all four classes of β-lactamases. The druglike characteristics and mouse PK data are described along with the X-ray crystal structure of binding to its target PBP3.
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http://dx.doi.org/10.1021/acs.jmedchem.0c00255DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7590959PMC
June 2020

Gallbladder Dyskinesia Is Associated With an Impaired Postprandial Fibroblast Growth Factor 19 Response in Critically Ill Patients.

Hepatology 2019 07 5;70(1):308-318. Epub 2019 Jun 5.

Department of Surgery, Maastricht University Medical Center and NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, the Netherlands.

Critical illness is associated with a disturbed regulation of gastrointestinal hormones resulting in functional and metabolic anomalies. Fibroblast growth factor 19 (FGF19) is an ileum-derived metabolic hormone induced by bile salts upon gallbladder emptying after enteral nutrient stimulation. Our aim was to study the nutrient-stimulated FGF19 response in 24 patients admitted to the intensive care unit (ICU) compared with 12 healthy controls. All subjects received intraduodenal high-lipid nutrient infusion for 120 minutes. Blood was collected every 30 minutes until 1 hour after infusion, and gallbladder emptying was studied by ultrasound. Serum levels of bile salts and FGF19 were assessed. ICU patients had significantly higher fasting bile salt serum levels compared with controls, whereas FGF19 serum levels were similar. In both groups, nutrient infusion elicited substantial bile salt elevations (P < 0.001), peaking at 90 minutes, albeit with a significantly lower peak in the ICU patients (P = 0.029). In controls, FGF19 was significantly elevated relative to baseline from 120 minutes onward (P < 0.001). In ICU patients, the FGF19 response was blunted, as reflected by significantly lower FGF19 elevations at 120, 150, and 180 minutes (P < 0.05) and significantly lower area under the curve (AUC) values compared with controls (P < 0.001). Gallbladder dysmotility was associated with the impaired FGF19 response in critical illness. The gallbladder ejection fraction correlated positively with FGF19 AUC values (ρ = +0.34, P = 0.045). In 10 of 24 ICU patients, gallbladder emptying was disturbed. These patients had significantly lower FGF19 AUC values (P < 0.001). Gallbladder emptying and the FGF19 response were respectively disturbed or absent in patients receiving norepinephrine. Conclusion: The nutrient-stimulated FGF19 response is impaired in ICU patients, which is mechanistically linked to gallbladder dysmotility in critical illness. This may contribute to disturbed liver metabolism in these patients and has potential as a nutritional biomarker.
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http://dx.doi.org/10.1002/hep.30629DOI Listing
July 2019

Gut dysmotility in the ICU: diagnosis and therapeutic options.

Curr Opin Crit Care 2019 04;25(2):138-144

Intensive Care Unit.

Purpose Of Review: To provide a comprehensive update of diagnosis and treatment of gastrointestinal dysmotility in the critically ill, with a focus on work published in the last 5 years.

Recent Findings: Symptoms and clinical features consistent with upper and/or lower gastrointestinal dysmotility occur frequently. Although features of gastrointestinal dysmotility are strongly associated with adverse outcomes, these associations may be because of unmeasured confounders. The use of ultrasonography to identify upper gastrointestinal dysmotility appears promising. Both nonpharmacological and pharmacological approaches to treat gastrointestinal dysmotility have recently been evaluated. These approaches include modification of macronutrient content and administration of promotility drugs, stool softeners or laxatives. Although these approaches may reduce features of gastrointestinal dysmotility, none have translated to patient-centred benefit.

Summary: 'Off-label' metoclopramide and/or erythromycin administration are effective for upper gastrointestinal dysmotility but have adverse effects. Trials of alternative or novel promotility drugs have not demonstrated superiority over current pharmacotherapies. Prophylactic laxative regimens to prevent non-defecation have been infrequently studied and there is no recent evidence to further inform treatment of established pseudo-obstruction. Further trials of nonpharmacological and pharmacological therapies to treat upper and lower gastrointestinal dysmotility are required and challenges in designing such trials are explored.
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http://dx.doi.org/10.1097/MCC.0000000000000581DOI Listing
April 2019

Incretin Physiology and Pharmacology in the Intensive Care Unit.

Crit Care Clin 2019 Apr 24;35(2):341-355. Epub 2019 Jan 24.

Intensive Care Unit, Royal Melbourne Hospital, 300 Grattan Street, Parkville, Victoria 3050, Australia; Intensive Care, University of Melbourne, 300 Grattan Street, Parkville, Victoria 3050, Australia.

In health, postprandial glycemic excursions are attenuated via stimulation of insulin secretion, suppression of glucagon secretion, and slowing of gastric emptying. The incretin hormones, glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide, are primary modulators of this response. Drugs have recently been developed that exploit the incretin-axis for the management of type 2 diabetes. There is burgeoning interest in the potential of incretin therapies for the management of acute hyperglycemia in the critically ill. This article outlines basic incretin physiology, highlights relevant pharmacology, and briefly summarizes the literature on incretins for glycemic control in the critically ill.
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http://dx.doi.org/10.1016/j.ccc.2018.11.011DOI Listing
April 2019

Systematic review of incretin therapy during peri-operative and intensive care.

Crit Care 2018 Nov 14;22(1):299. Epub 2018 Nov 14.

Department of Anaesthesiology, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, Postbus 22660, 1105 AZ, Amsterdam, the Netherlands.

Background: Glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP) are incretin hormones. By lowering blood glucose in a glucose-dependent manner, incretin-based therapies represent a novel and promising intervention to treat hyperglycaemia in hospital settings. We performed a systematic review of the literature for all current applications of incretin-based therapies in the peri-operative and critical care settings.

Methods: We searched MEDLINE, the Cochrane Library, and Embase databases for all randomised controlled trials using exogenous GLP-1, GLP-1 receptor agonists, exogenous GIP and dipeptidyl peptidase IV inhibitors in the setting of adult peri-operative care or intensive care. We defined no comparator treatment. Outcomes of interest included blood glucose, frequency of hypoglycaemia and insulin administration.

Results: Of the 1190 articles identified during the initial literature search, 38 fulfilled criteria for full-text review, and 19 single-centre studies were subsequently included in the qualitative review. Of the 18 studies reporting glycaemic control, improvement was reported in 15, defined as lower glucose concentrations in 12 and as reduced insulin administration (with similar glucose concentrations) in 3. Owing to heterogeneity, meta-analysis was possible only for the outcome of hypoglycaemia. This revealed an incidence of 7.4% in those receiving incretin-based therapies and 6.8% in comparator groups (P = 0.94).

Conclusions: In small, single-centre studies, incretin-based therapies lowered blood glucose and reduced insulin administration without increasing the incidence of hypoglycaemia.

Trial Registration: PROSPERO, CRD42017071926.
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http://dx.doi.org/10.1186/s13054-018-2197-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6236901PMC
November 2018

Incident Diabetes in Survivors of Critical Illness and Mechanisms Underlying Persistent Glucose Intolerance: A Prospective Cohort Study.

Crit Care Med 2019 02;47(2):e103-e111

Discipline of Acute Care Medicine, University of Adelaide, Adelaide, SA, Australia.

Objectives: Stress hyperglycemia occurs in critically ill patients and may be a risk factor for subsequent diabetes. The aims of this study were to determine incident diabetes and prevalent prediabetes in survivors of critical illness experiencing stress hyperglycemia and to explore underlying mechanisms.

Design: This was a prospective, single center, cohort study. At admission to ICU, hemoglobin A1c was measured in eligible patients. Participants returned at 3 and 12 months after ICU admission and underwent hemoglobin A1c testing and an oral glucose tolerance test. Blood was also collected for hormone concentrations, whereas gastric emptying was measured via an isotope breath test. β-cell function was modeled using standard techniques.

Setting: Tertiary-referral, mixed medical-surgical ICU.

Patients: Consecutively admitted patients who developed stress hyperglycemia and survived to hospital discharge were eligible.

Measurements And Main Results: Consent was obtained from 40 patients (mean age, 58 yr [SD, 10], hemoglobin A1c 36.8 mmol/mol [4.9 mmol/mol]) with 35 attending the 3-month and 26 the 12-month visits. At 3 months, 13 (37%) had diabetes and 15 (43%) had prediabetes. At 12 months, seven (27%) participants had diabetes, whereas 11 (42%) had prediabetes. Mean hemoglobin A1c increased from baseline during the study: +0.7 mmol/mol (-1.2 to 2.5 mmol/mol) at 3 months and +3.3 mmol/mol (0.98-5.59 mmol/mol) at 12 months (p = 0.02). Gastric emptying was not significantly different across groups at either 3 or 12 months.

Conclusions: Diabetes and prediabetes occur frequently in survivors of ICU experiencing stress hyperglycemia. Based on the occurrence rate observed in this cohort, structured screening and intervention programs appear warranted.
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http://dx.doi.org/10.1097/CCM.0000000000003524DOI Listing
February 2019

Cerebral metabolic effects of strict versus conventional glycaemic targets following severe traumatic brain injury.

Crit Care 2018 01 25;22(1):16. Epub 2018 Jan 25.

Neurosciences Critical Care Unit, Addenbrooke's Hospital, Cambridge, CB2 0QQ, UK.

Background: Optimal glycaemic targets for patients with severe traumatic brain injury remain unclear. The primary objective of this microdialysis study was to compare cerebral metabolism with strict versus conventional glycaemic control.

Methods: We performed a prospective single-centre randomised controlled within-subject crossover study of 20 adult patients admitted to an academic neurointensive care unit with severe traumatic brain injury. Patients underwent randomised, consecutive 24-h periods of strict (4-7 mmol/L; 72-126 mg/dl) and conventional (<10 mmol/L; 180 mg/dl) glycaemic control with microdialysis measurements performed hourly. The first 12 h of each study period was designated as a 'washout' period, with the subsequent 12 h being the period of interest.

Results: Cerebral glucose was lower during strict glycaemia than with conventional control (mean 1.05 [95% CI 0.58-1.51] mmol/L versus 1.28 [0.81-1.74] mmol/L; P = 0.03), as was lactate (3.07 [2.44-3.70] versus 3.56 [2.81-4.30]; P < 0.001). There were no significant differences in pyruvate or the lactate/pyruvate ratio between treatment phases. Strict glycaemia increased the frequency of low cerebral glucose (< 0.8 mmol/L; OR 1.91 [95% CI 1.01-3.65]; P < 0.05); however, there were no differences in the frequency of critically low glucose (< 0.2 mmol/L) or critically elevated lactate/pyruvate ratio between phases.

Conclusions: Compared with conventional glycaemic targets, strict blood glucose control was associated with lower mean levels of cerebral glucose and an increased frequency of abnormally low glucose levels. These data support conventional glycaemic targets following traumatic brain injury.

Trial Registration: ISRCTN, ISRCTN19146279 . Retrospectively registered on 2 May 2014.
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http://dx.doi.org/10.1186/s13054-017-1933-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5784688PMC
January 2018

Glycaemic control targets after traumatic brain injury: a systematic review and meta-analysis.

Crit Care 2018 01 19;22(1):11. Epub 2018 Jan 19.

Division of Anaesthesia, Department of Medicine, University of Cambridge, Addenbrooke's Hospital, Cambridge, CB2 0QQ, UK.

Background: Optimal glycaemic targets in traumatic brain injury (TBI) remain unclear. We performed a systematic review and meta-analysis of randomised controlled trials (RCTs) comparing intensive with conventional glycaemic control in TBI requiring admission to an intensive care unit (ICU).

Methods: We systematically searched MEDLINE, EMBASE and the Cochrane Central Register of Controlled Trials to November 2016. Outcomes of interest included ICU and in-hospital mortality, poor neurological outcome, the incidence of hypoglycaemia and infective complications. Data were analysed by pairwise random effects models with secondary analysis of differing levels of conventional glycaemic control.

Results: Ten RCTs, involving 1066 TBI patients were included. Three studies were conducted exclusively in a TBI population, whereas in seven trials, the TBI population was a sub-cohort of a mixed neurocritical or general ICU population. Glycaemic targets with intensive control ranged from 4.4 to 6.7 mmol/L, while conventional targets aimed to keep glucose levels below thresholds of 8.4-12 mmol/L. Conventional versus intensive control showed no association with ICU or hospital mortality (relative risk (RR) (95% CI) 0.93 (0.68-1.27), P = 0.64 and 1.07 (0.84-1.36), P = 0.62, respectively). The risk of a poor neurological outcome was higher with conventional control (RR (95% CI) = 1.10 (1.001-1.24), P = 0.047). However, severe hypoglycaemia occurred less frequently with conventional control (RR (95% CI) = 0.22 (0.09-0.52), P = 0.001).

Conclusions: This meta-analysis of intensive glycaemic control shows no association with reduced mortality in TBI. Intensive glucose control showed a borderline significant reduction in the risk of poor neurological outcome, but markedly increased the risk of hypoglycaemia. These contradictory findings should motivate further research.
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http://dx.doi.org/10.1186/s13054-017-1883-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5775599PMC
January 2018

Corrigendum: Glycemia Is Related to Impaired Cerebrovascular Autoregulation after Severe Pediatric Traumatic Brain Injury: A Retrospective Observational Study.

Front Pediatr 2017 24;5:245. Epub 2017 Nov 24.

Division of Academic Neurosurgery, Department of Clinical Neurosciences, Addenbrooke's Hospital, University of Cambridge, Cambridge, United Kingdom.

[This corrects the article on p. 205 in vol. 5, PMID: 28993802.].
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http://dx.doi.org/10.3389/fped.2017.00245DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5705618PMC
November 2017

Long-term mortality of critically ill patients with diabetes who survive admission to the intensive care unit.

Crit Care Resusc 2017 Dec;19(4):303-309

Discipline of Acute Care Medicine, University of Adelaide, Adelaide, SA, Australia.

Objective: Long-term outcomes of critically ill patients with diabetes are unknown. Our objectives were to evaluate the effect of diabetes on both long-term survival rates and the average number of years of life lost for patients admitted to an intensive care unit who survived to hospital discharge.

Design And Participants: A data linkage study evaluating all adult patients in South Australia between 2004 and 2011 who survived hospitalisation that required admission to a public hospital ICU.

Main Outcome Measures: All patients were evaluated using hospital coding for diabetes, which was crossreferenced with registration with the Australian National Diabetes Services Scheme for a diagnosis of diabetes. This dataset was then linked to the Australian National Death Index. Longitudinal survival was assessed using Cox proportional hazards regression. Life-years lost were calculated using age- and sex-specific life-tables from the Australian Bureau of Statistics.

Results: 5450 patients with diabetes and 17 023 patients without diabetes were included. Crude mortality rates were 105.5 per 1000 person-years (95% CI, 101.6-109.6 per 1000 person-years) for patients with diabetes, and 67.6 per 1000 person-years (95% CI, 65.9-69.3 per 1000 personyears) for patients without diabetes. Patients with diabetes were older and had higher illness severity scores on admission to the ICU, were more likely to die after hospital discharge (unadjusted hazard ratio [HR], 1.52 [95% CI, 1.45-1.59]; adjusted HR, 1.16 [95% CI, 1.10-1.21]; P < 0.0001) and suffered a greater number of average lifeyears lost.

Conclusions: Our study indicates that crude mortality for ICU survivors with pre-existing diabetes is considerable after hospital discharge, and the risk of mortality is greater than for survivors without diabetes.
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December 2017

The antimalarial activity of the pantothenamide α-PanAm is via inhibition of pantothenate phosphorylation.

Sci Rep 2017 10 27;7(1):14234. Epub 2017 Oct 27.

Section of Infectious Diseases, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut, USA.

The biosynthesis of the major acyl carrier Coenzyme A from pantothenic acid (PA) is critical for survival of Plasmodium falciparum within human erythrocytes. Accordingly, a PA analog α-PanAm showed potent activity against blood stage parasites in vitro; however, its efficacy in vivo and its mode of action remain unknown. We developed a new synthesis route for α-PanAm and showed that the compound is highly effective against blood stages of drug-sensitive and -resistant P. falciparum strains, inhibits development of P. berghei in hepatocytes, and at doses up to 100 mg/kg also inhibits blood stage development of P. chabaudi in mice. We used yeast and its pantothenate kinase Cab1 as models to characterize mode of action of α-PanAm and found that α-PanAm inhibits yeast growth in a PA-dependent manner, and its potency increases dramatically in a yeast mutant with defective pantothenate kinase activity. Biochemical analyses using C-PA as a substrate demonstrated that α-PanAm is a competitive inhibitor of Cab1. Interestingly, biochemical and mass spectrometry analyses also showed that the compound is phosphorylated by Cab1. Together, these data suggest that α-PanAm exerts its antimicrobial activity by direct competition with the natural substrate PA for phosphorylation by the pantothenate kinase.
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http://dx.doi.org/10.1038/s41598-017-14074-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5660193PMC
October 2017

Glycemia Is Related to Impaired Cerebrovascular Autoregulation after Severe Pediatric Traumatic Brain Injury: A Retrospective Observational Study.

Front Pediatr 2017 25;5:205. Epub 2017 Sep 25.

Division of Academic Neurosurgery, Department of Clinical Neurosciences, Addenbrooke's Hospital, University of Cambridge, Cambridge, United Kingdom.

Introduction: A strong association exists between hyperglycemia and outcome in pediatric traumatic brain injury (TBI). Herein, we describe observations of serum markers of glucose metabolism in a cohort of pediatric TBI patients and how these variables are related to parameters of intracranial pathophysiology.

Methods: A retrospective analysis was performed on pediatric severe TBI patients admitted to Addenbrookes Hospital Paediatric Intensive Care Unit (PICU) between January 2001 and December 2013. Demographic, outcome, systemic physiological, and cerebral autoregulatory data were extracted for patients who had received continuous invasive monitoring (ICM+, Cambridge Enterprise, Cambridge, UK). Data were analyzed using a mixed linear model.

Results: Forty-four patients with an average age of 12.2 years were admitted to the PICU with a TBI requiring invasive neurosurgical monitoring. Thirty-two patients (73%) survived, with favorable outcomes in 62%. The mean (SD) intracranial pressure (ICP) was 17.6 + 9.0 mmHg, MAP was 89.7 + 9.0 mmHg, and pressure-reactivity index (PRx) was -0.01 + 0.23 a.u. The mean (SD) serum lactate was 2.2 (3.3) mmol/L. and the mean (SD) serum glucose was 6.1 (1.6) mmol/L. Early hyperglycemia was strongly associated with both PRx (Pearson correlation 0.351,  < 0.001) and ICP (Pearson correlation 0.240,  = 0.002) death ( = 0.021) and impaired cerebral autoregulation ( = 0.02). There was a strong association between ICP and serum lactate ( = 0.001).

Conclusion: Increases in systemic glucose are associated with impaired cerebrovasular autoregulation after severe pediatric TBI. Moreover, deranged blood glucose is a marker of poor prognosis. Further studies are required to delineate putative mechanisms of hyperglycemia induced cerebral harm.
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http://dx.doi.org/10.3389/fped.2017.00205DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5622298PMC
September 2017
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