Obstetric admissions to intensive care units in Australia and New Zealand: a registry-based cohort study.

OBJECTIVE: Describe the epidemiology of obstetric patients admitted to an Intensive Care Unit (ICU). DESIGN: Registry-based cohort study. SETTING: One hundred and eighty-three ICUs in Australia and New Zealand. POPULATION: Women aged 15-49 years, admitted to ICU between 2008 and 2017, classified as pregnant, postpartum or with an obstetric-related diagnosis. METHODS: Data were extracted from the Australia and New Zealand Intensive Care Society (ANZICS) Adult Patient Database and national agencies. MAIN OUTCOME MEASURES: Incidence of ICU admission, cohort characteristics, maternal outcomes and changes over time. RESULTS: The cohort comprised 16 063 patients. The annual number of obstetric ICU admissions increased, whereas their proportion of total ICU admissions (1.3%) did not change (odds ratio 1.02, 95% CI 0.99-1.04, P = 0.14). There were 10 518 (65%) with an obstetric-related ICU diagnosis, and 5545 (35%) with a non-obstetric ICU diagnosis. Mean (SD) age was 31 (6.4) years, 1463 (9.1%) were Indigenous, 2305 (14%) were transferred from another hospital, and 3008 (19%) received mechanical ventilation. Median [IQR] length of stay in hospital was 5.2 [3.1-7.9] days, which included 1.1 [0.7-1.8] days in ICU. There were 108 (0.7%) maternal deaths, most (n = 97, 90%) having a non-obstetric diagnosis. There was no change in risk-adjusted length of stay or mortality over time. CONCLUSIONS: Obstetric patients account for a stable proportion of ICU admissions in Australia and New Zealand. These patients typically have a short length of ICU stay and low hospital mortality. TWEETABLE ABSTRACT: Obstetric patients in Australia/New Zealand ICUs have a short length of ICU stay and low mortality.

Patients retrieved to intensive care via a dedicated retrieval service do not have increased hospital mortality compared with propensity-matched controls.

This study was performed to estimate the effect of the retrieval process on mortality for patients admitted to a mixed adult intensive care unit (ICU) compared with propensity-matched, non-retrieved controls. Patients retrieved to the Royal Adelaide Hospital (RAH) ICU between 2011 and 2015 were propensity-score matched for age, gender, Aboriginal and Torres Strait Islander status, Acute Physiology and Chronic Health Evaluation (APACHE) III score and diagnostic group with non-retrieved ICU patients to estimate the average treatment effect of retrieval on hospital mortality. Factors associated with mortality in those retrieved were assessed by multiple logistic regression. Retrieved patients comprised 1,597 (14%) of 11,641 index ICU admissions; this group were younger, mean (standard deviation) 53 (18.5) versus 59 (17.7) years, had higher APACHE III scores, 61 (30.3) versus 56 (27.5), were more likely to be Indigenous (5.1% versus 3.7%) and to have sustained trauma (34% versus 9%). The average treatment effect for retrieval on hospital mortality, risk difference (95% confidence interval), was -0.7% (-2.8% to 1.3%), P=0.50. Variables independently associated with hospital mortality in those retrieved included age, APACHE III score and diagnostic category. Time from retrieval team activation to arrival with the patient, rural location, radial distance from the RAH and population size at the retrieval location were not significantly associated with mortality. The hospital mortality for retrieved patients was not significantly different when compared with propensity-matched controls. Mortality in those retrieved was associated with increasing age, APACHE III score and diagnostic category; however, was independent of time from team activation to arrival with the patient.

The challenges of hydrogen and metals.

The Royal Society Scientific Discussion Meeting 'The challenges of hydrogen and metals' was held in Carlton House Terrace, London, UK, on 16-18 January 2017. This is the introductory article to the discussion meeting issue which includes contributed papers and seven discussion papers. Here, we introduce the motivation to hold the Meeting and give a brief overview of the contents. We conclude with acknowledgements.This article is part of the themed issue 'The challenges of hydrogen and metals'.

Occult upper gastrointestinal mucosal abnormalities in critically ill patients.

BACKGROUND: The objectives of this study were to estimate the frequency of occult upper gastrointestinal abnormalities, presence of gastric acid as a contributing factor, and associations with clinical outcomes. METHODS: Data were extracted for study participants at a single centre who had an endoscopy performed purely for research purposes and in whom treating physicians were not suspecting gastrointestinal bleeding. Endoscopic data were independently adjudicated by two gastroenterologists who rated the likelihood that observed pathological abnormalities were related to gastric acid secretion using a 3-point ordinal scale (unlikely, possible or probable). RESULTS: Endoscopy reports were extracted for 74 patients [age 52 (37, 65) years] undergoing endoscopy on day 5 [3, 9] of ICU admission. Abnormalities were found in 25 (34%) subjects: gastritis/erosions in 10 (14%), nasogastric tube trauma in 8 (11%), oesophagitis in 4 (5%) and non-bleeding duodenal ulceration in 3 (4%). The contribution of acid secretion to observed pathology was rated 'probable' in six subjects (rater #1) and five subjects (rater #2). Prior to endoscopy, 39 (53%) patients were receiving acid-suppressive therapy. The use of acid-suppressive therapy was not associated with the presence of an endoscopic abnormality (present 15/25 (60%) vs. absent 24/49 (49%); P = 0.46). Haemoglobin concentrations, packed red cells transfused and mortality were not associated with mucosal abnormalities (P = 0.83, P > 0.9 and P > 0.9 respectively). CONCLUSIONS: Occult mucosal abnormalities were observed in one-third of subjects. The presence of mucosal abnormalities appeared to be independent of prior acid-suppressive therapy and was not associated with reduced haemoglobin concentrations, increased transfusion requirements, or mortality.

Plasmonic ELISA for the detection of gp120 at ultralow concentrations with the naked eye.

The technique of plasmonic ELISA is utilised here to detect the HIV-1 protein gp120 with the ultralow limit of detection of 8 × 10(-20) M (10(-17) g mL(-1)) in an independent laboratory. It was corroborated that changes in the concentration of hydrogen peroxide as small as 0.05 µM could lead to nanoparticle solutions of completely different tonality.

Screening and cell-based assessment of mutations in the Aristaless-related homeobox (ARX) gene.

ARX mutations cause a diverse spectrum of human disorders, ranging from severe brain and genital malformations to non-syndromic intellectual disability (ID). ARX is a transcription factor with multiple domains that include four polyalanine (pA) tracts, the first two of which are frequently expanded by mutations. We progressively screened DNA samples from 613 individuals with ID initially for the most frequent ARX mutations (c.304ins(GCG)(7)'expansion' of pA1 and c.429_452dup 'dup24bp' of pA2). Five hundred samples without pA1 or pA2 mutations had the entire ARX ORF screened by single stranded polymorphism conformation (SSCP) and/or denaturing high pressure liquid chromatography (dHPLC) analysis. Overall, eight families with six mutations in ARX were identified (1.31%): five duplication mutations in pA2 (0.82%) with three new clinical reports of families with the dup24bp and two duplications larger than the dup24bp mutation discovered (dup27bp, dup33bp); and three point mutations (0.6%), including one novel mutation in the homeodomain (c.1074G>T). Four ultraconserved regions distal to ARX (uc466-469) were also screened in a subset of 94 patients, with three unique nucleotide changes identified in two (uc466, uc467). The subcellular localization of full length ARX proteins was assessed for 11 variants. Protein mislocalization increased as a function of pA2 tract length and phenotypic severity, as has been previously suggested for pA1. Similarly, protein mislocalization of the homeodomain mutations also correlated with clinical severity, suggesting an emerging genotype vs cellular phenotype correlation.

Aristaless-related homeobox gene, the gene responsible for West syndrome and related disorders, is a Groucho/transducin-like enhancer of split dependent transcriptional repressor.

Aristaless-related homeobox gene (ARX) is an important paired-type homeobox gene involved in the development of human brain. The ARX gene mutations are a significant contributor to various forms of X-chromosome-linked mental retardation with and without additional features including epilepsy, lissencephaly with abnormal genitalia, hand dystonia or autism. Here we demonstrate that the human ARX protein is a potent transcriptional repressor, which binds to Groucho/transducin-like enhancer of split (TLE) co-factor proteins and the TLE1 in particular through its octapeptide (Engrailed homology repressor domain (eh-1) homology) domain. We show that the transcription repression activity of ARX is modulated by two strong repression domains, one located within the octapeptide domain and the second in the region of the polyalanine tract 4, and one activator domain, the aristaless domain. Importantly, we show that the transcription repression activity of ARX is affected by various naturally occurring mutations. The introduction of the c.98T>C (p.L33P) mutation results in the lack of binding to TLE1 protein and relaxed transcription repression. The introduction of the two most frequent ARX polyalanine tract expansion mutations increases the repression activity in a manner dependent on the number of extra alanines. Interestingly, deletions of alanine residues within polyalanine tracts 1 and 2 show low or no effect. In summary we demonstrate that the ARX protein is a strong transcription repressor, we identify novel ARX interacting proteins (TLE) and offer an explanation of a molecular pathogenesis of some ARX mutations, including the most frequent ARX mutations, the polyalanine tract expansion mutations, c.304ins(GCG)7 and c.428_451dup.

Cefazolin does not accelerate gastric emptying in the critically ill.

OBJECTIVE: To evaluate the effect of intravenous cefazolin on gastric emptying measured by the C-13 octanoic acid breath test. DESIGN: Prospective, double-blind, cross-over, randomised, placebo-controlled trial. SETTING: Mixed multidisciplinary intensive care unit in a university hospital. PATIENTS: Fourteen critically ill, mechanically ventilated patients. INTERVENTIONS: After a 4-h fast patients received either 50 mg cefazolin or 20 ml saline over 20 min immediately prior to measurement of gastric emptying. The next day the study was repeated with the alternative therapy. MEASUREMENTS AND RESULTS: Breath samples were analysed for the concentration of (13)CO2 by mass spectrometer, and the gastric emptying coefficient (GEC) and half-emptying time (t(50)) were calculated. Results are mean (standard deviation). Data were analysed with the paired t-test (saline vs cefazolin). Two patients were excluded for technical problems. Twelve patients remained (six male/six female), aged 57 (+/-16) years, with an APACHE II score of 20 (+/-8). Both GEC and t(50) were unchanged after administration of cefazolin compared with placebo (t(50) cefazolin, 138 (+/-54) vs saline 122 (+/-46) min, P=0.32; GEC cefazolin 3.27 (+/-0.83) vs saline 3.55 (+/-0.6), P=0.24). Two patients had abnormal t(50) after saline and five after cefazolin. There was no order effect of the study day. CONCLUSION: In mechanically ventilated patients, cefazolin had no effect on gastric emptying. These data do not support the use of low-dose cefazolin as a pro-kinetic agent in critically ill patients.

Morphological analysis of the effects of ions and ultraviolet light on colloidal monolayers at the air-water interface.

The formation of fractal aggregates under the external influence of ions or ultraviolet light has been observed in colloidal monolayers trapped at the air-water interface. A morphological analysis of this is reported in this paper. These fractals have many characteristics similar to those observed in other experiments where electrolyte was added to the bulk. However, they exhibit behavior, such as restructuring, particular to the external influence. In most cases the aggregating system displayed scaling analogous to spinodal decomposition, but with the measured fractal dimension (which depends slightly on the external influence) entering in place of the usual spatial dimension.

Pattern Formation in Colloidal Monolayers at the Air-Water Interface.

Using video-microscopic techniques, single layers (monolayers) of charged colloidal particles of 1- and 3-&mgr;m diameter were studied at an air-water interface. The particles normally arranged themselves in an ordered lattice-like array. However, occasionally, the monolayer formed loosely bonded crystallite clusters, here called mesostructures. The monolayer was exposed to a number of external influences: ions, electric current, and ultraviolet light. Depending on the perturbation applied, the lattice-like structure formed fractal aggregates, clusters (mesostructures), and two other particular structures, here referred to as striations and loops. The mechanisms of formation and implications of the different patterns are discussed. Copyright 2001 Academic Press.

Enteral nutrition in the critically ill: a prospective survey in an Australian intensive care unit.

Nutritional support is routine practice in critically ill patients and enteral feeding is preferred to the parenteral route. However this direct delivery of nutrients to the gut is potentially ineffective for a variety of reasons. We performed a prospective audit of 40 consecutive intensive care patients to determine whether enteral feeding met the nutritional requirements of our patients. The ideal requirements for each patient were calculated using the Harris-Benedict equation with an adjustment determined by the patient's diagnosis. We compared the amount of feed delivered with the daily requirements over a seven-day period Successful feeding was defined as the achievement of 90% of the ideal calorie requirement for two consecutive days. The mean calculated (+/- SD) energy requirement was 9,566 kJ (+/- 2,586). Patients received only 51% (SD 38) of their energy requirements throughout the study period. Only 10 patients (25%) were successfully fed for at least any two-day period in the seven days. Feeding was limited mainly by gastrointestinal dysfunction or by the need to fast the patient for medical, surgical and airway procedures. Success of feeding was not related to the use of sedative orparalysing agents and had no correlation with plasma albumin concentration. There was no difference in the volume of feed delivered to patients who survived or died. Prokinetic agents were used in 25 patients and in these patients there was a trend towards improved delivery of feed.

Surface stoichiometry and the initial oxidation of NiAl(110).

Selective oxidation of the surface of an ordered alloy requires redistribution of the atomic species in the vicinity of the surface. This process can be understood in terms of the formation and movements of point defects in the compound. On the basis of ab initio density-functional calculation we found both the creation of exchange defects near the NiAl surface and segregation of Ni vacancies to the top layer to be extremely favorable in the presence of oxygen. Scenarios for the initial oxidation of NiAl are suggested which demonstrate the appearance of an additional energy barrier on the Ni-rich side compared to the Al-rich side. The expulsion of Ni from the oxide layer as it forms is the driving force for its stability.

Common chromosomal fragile site FRA16D sequence: identification of the FOR gene spanning FRA16D and homozygous deletions and translocation breakpoints in cancer cells.

Fluorescence in situ hybridization of a tile path of DNA subclones has previously enabled the cyto-genetic definition of the minimal DNA sequence which spans the FRA16D common chromosomal fragile site, located at 16q23.2. Homozygous deletion of the FRA16D locus has been reported in adenocarcinomas of stomach, colon, lung and ovary. We have sequenced the 270 kb containing the FRA16D fragile site and the minimal homozygously deleted region in tumour cells. This sequence enabled localization of some of the tumour cell breakpoints to regions which contain AT-rich secondary structures similar to those associated with the FRA10B and FRA16B rare fragile sites. The FRA16D DNA sequence also led to the identification of an alternatively spliced gene, named FOR (fragile site FRA16D oxidoreductase), exons of which span both the fragile site and the minimal region of homozygous deletion. In addition, the complete DNA sequence of the FRA16D-containing FOR intron reveals no evidence of additional authentic transcripts. Alternatively spliced FOR transcripts (FOR I, FOR II and FOR III) encode proteins which share N-terminal WW domains and differ at their C-terminus, with FOR III having a truncated oxidoreductase domain. FRA16D-associated deletions selectively affect the FOR gene transcripts. Three out of five previously mapped translocation breakpoints in multiple myeloma are also located within the FOR gene. FOR is therefore the principle genetic target for DNA instability at 16q23.2 and perturbation of FOR function is likely to contribute to the biological consequences of DNA instability at FRA16D in cancer cells.

Developmental expression of dermatan sulfate proteoglycans in the elastic bovine nuchal ligament.

The nuchal ligament of bovines is a useful system in which to study elastic fibre formation since it contains up to 83% elastin and undergoes a period of rapid elastinogenesis during the last trimester of fetal development and in the first four post-natal months. To identify proteoglycans (PGs) which may be involved in this process we initially investigated changes in the glycosaminoglycan (GAG) profiles during nuchal ligament development. In contrast to the collagenous Achilles tendon, nuchal ligament exhibited: (a) elevated hyaluronan (HA) levels in the peak period of elastin-associated microfibril (fibrillin) synthesis (130-200 days) which precedes elastinogenesis; and (b) markedly increased synthesis of a glucuronate-rich copolymeric form of dermatan sulfate (DS) in the period corresponding to elastin formation (200-270 days). Analysis of DSPGs isolated from 230-day nuchal ligament showed that this copolymer was predominantly associated with a glycoform of biglycan which was specifically elevated at this stage in development. This finding was consistent with Northern blot analysis which showed that steady-state biglycan mRNA levels increased significantly during the elastinogenic period. In contrast, the mRNA levels for decorin, the only other DSPG detected in this tissue, declined rapidly after 140 days of fetal development. In conclusion, the results suggest that HA may play a role in microfibril assembly and that a specific glycoform of biglycan may be associated with the elastinogenic phase of elastic fibre formation.

Chromosomal fragile site FRA16D and DNA instability in cancer.

It has been proposed that common aphidicolin-inducible fragile sites, in general, predispose to specific chromosomal breakage associated with deletion, amplification, and/or translocation in certain forms of cancer. Although this appears to be the case for the fragile site FRA3B and may be the case for FRA7G, it is not yet clear whether this association is a general property of this class of fragile site. The major aim of the present study was to determine whether the FRA16D chromosomal fragile site locus has a role to play in predisposing DNA sequences within and adjacent to the fragile site to DNA instability (such as deletion or translocation), which could lead to or be associated with neoplasia. We report the localization of FRA16D within a contig of cloned DNA and demonstrate that this fragile site coincides with a region of homozygous deletion in a gastric adenocarcinoma cell line and is bracketed by translocation breakpoints in multiple myeloma, as reported previously (Chesi, M., et al., Blood, 91: 4457-4463, 1998). Therefore, given similar findings at the FRA3B and FRA7G fragile sites, it is likely that common aphidicolin-inducible fragile sites exhibit the general property of localized DNA instability in cancer cells.

Microfibril-associated glycoprotein-2 (MAGP-2) is specifically associated with fibrillin-containing microfibrils but exhibits more restricted patterns of tissue localization and developmental expression than its structural relative MAGP-1.

We developed an affinity-purified anti-MAGP-2 peptide antibody that specifically identified MAGP-2 on Western blots of purified matrix proteins and extracts of nuchal ligament. Immunolocalization studies on tissues from a 210-day-old fetus and a mature bovine showed that MAGP-2 was located in similar regions to MAGP-1 and fibrillin-1 but that the distribution of MAGP-2 was more restricted. In fetal nuchal ligament, skeletal muscle, and spleen the distribution of MAGP-2 was indistinguishable from that of MAGP-1. In contrast to MAGP-1, MAGP-2 was not detected in the medial layer of fetal thoracic aorta and in much of the peritubular matrix of fetal and mature kidney and in the mature ocular zonule. Some differences in the immunolocalization patterns were also evident in fetal lung, cartilage, skin, and heart. Immunoelectron microscopy confirmed that MAGP-2 was specifically associated with fibrillin-containing microfibrils in nuchal ligament, dermis, adventitia of aorta, glomerular mesangium and perimysium. Northern blotting of RNA from tissues of a 210-day-old fetus indicated that steady-state MAGP-2 mRNA levels were highest in nuchal ligament. Significant expression was also detected in lung, heart, skeletal muscle, skin, and Achilles tendon. The tissue pattern of MAGP-2 expression differed significantly from that of MAGP-1. MAGP-2 expression appeared to be higher in nuchal ligament, heart, and skeletal muscle and lower in aorta and kidney. In nuchal ligament, MAGP-2 mRNA expression appeared to peak around 180 days of fetal development, which correlates with the period of onset of elastinogenesis in this tissue. Overall, the immunolocalization and expression patterns of MAGP-2 appeared to be distinct from those of other microfibrillar components. This is consistent with the view that MAGP-2 plays a unique role in the biology of the microfibrils, perhaps by mediating their interaction with cell surfaces at specific stages of development and differentiation. (J Histochem Cytochem 46:871-885, 1998)

Microfibril-associated glycoprotein-1 (MAGP-1) binds to the pepsin-resistant domain of the alpha3(VI) chain of type VI collagen.

The interactions of type VI collagen have been investigated, using solid phase binding assays, with two components of the fibrillin-containing microfibrils, the elastin-binding protein, MAGP-1 and its structural relative MAGP-2. Both native and pepsin-treated forms of type VI collagen specifically bound to MAGP-1 but not to MAGP-2. Pepsin type VI collagen was shown to block the binding of MAGP-1 to native type VI collagen indicating that the major MAGP-1-binding site was in the triple-helical region of the molecule. MAGP-1 was found not to bind to collagens I, III, and V. Affinity blotting of pepsin-treated type VI collagen showed that MAGP-1 binding was specific for the collagenous domain of the alpha3(VI) chain. Decorin and biglycan were found not to inhibit the interaction of pepsin-treated type VI collagen with MAGP-1, indicating that its binding site on the collagen is not close to that for the proteoglycans. Reduction and alkylation of disulfide bonds in MAGP-1 did not destroy its type VI collagen-binding properties, indicating that the binding site was likely to be in the cysteine-free, N-terminal domain of MAGP-1. Interestingly, the interaction of MAGP-1 with type VI collagen was inhibited by tropoelastin, suggesting that the binding sites for tropoelastin and type VI collagen may be in the same domain of MAGP-1. A peptide, corresponding to amino acids 29-38 of MAGP-1, was found to inhibit the interactions of MAGP-1 with type VI collagen and tropoelastin. The results suggest that the peptide may contain the binding sequences for both type VI collagen and tropoelastin, and thus that these two proteins may share the same binding site on MAGP-1. The interactions of MAGP-1 with type VI collagen and tropoelastin were both determined to be of moderately high affinity, with Kd values of 5.6 x 10(-7) M and 2.6 x 10(-7) M, respectively. The findings indicate that MAGP-1 may mediate a molecular interaction between type VI collagen microfibrils and fibrillin-containing microfibrils, structures which are often found in close proximity to each other in a wide range of extracellular matrices.