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In mammalian mitochondria, mRNAs are cotranscriptionally stabilized by the protein factor LRPPRC (leucine-rich pentatricopeptide repeat-containing protein). Here, we characterize LRPPRC as an mRNA delivery factor and report its cryo-electron microscopy structure in complex with SLIRP (SRA stem-loop-interacting RNA-binding protein), mRNA and the mitoribosome. The structure shows that LRPPRC associates with the mitoribosomal proteins mS39 and the N terminus of mS31 through recognition of the LRPPRC helical repeats. Together, the proteins form a corridor for handoff of the mRNA. The mRNA is directly bound to SLIRP, which also has a stabilizing function for LRPPRC. To delineate the effect of LRPPRC on individual mitochondrial transcripts, we used RNA sequencing, metabolic labeling and mitoribosome profiling, which showed a transcript-specific influence on mRNA translation efficiency, with cytochrome c oxidase subunit 1 and 2 translation being the most affected. Our data suggest that LRPPRC–SLIRP acts in recruitment of mitochondrial mRNAs to modulate their translation. Collectively, the data define LRPPRC–SLIRP as a regulator of the mitochondrial gene expression system.

Introduction Symptomatic gastroesophageal reflux (GER) affects nearly half of all infants to the extent that their parents regard it as 'a problem.' (1,2) Regurgitation comprises the primary symptom; associated symptoms [...], To evaluate a pre-thickened formula (Enfamil AR®) for regurgitant gastroesophageal reflux, 104 infants were enrolled in a 5-week, multicenter, double-blind, randomized, placebo-controlled parallel group trial. The Enfamil AR group showed greater symptom reduction by the end of the first week: percent feedings with any regurgitation (p=0.045), total regurgitation volume score (p=0.035), and percent feedings with choke-gag-cough (p=0.004). The most symptomatic infants at baseline had a reduction in trouble sleeping significantly with Enfamil AR by the end of the study (p=0.030). This formula flows through a standard nipple, reduces regurgitation and choking-gagging-coughing within a week, and improves sleep in the most symptomatic babies by 5 weeks, without causing constipation.

ABSTRACTThe email of contemporary literary figures is ripe for research by scholars, and of broad interest to the general public, but can also present many challenges to cultural memory institutions that seek to appraise, process and provide access to this rich archival material. This article explores how five institutions across the United States, United Kingdom and New Zealand are using ePADD, free and open source software developed by Stanford Libraries that incorporates artificial intelligence and machine learning to help meet these challenges for email in contemporary English‐language literary collections. Authors and institutions represented include British poet Wendy Cope (The British Library), British novelist Ian McEwan (Harry Ransom Center, University of Texas at Austin), British Indian novelist and essayist Salman Rushdie (Emory University), American poet Robert Creeley (Stanford University) and New Zealand poet and critic Ian Wedde (National Library of New Zealand). The use cases are followed by a discussion identifying lessons learned and areas for further research.

A. Quarles, RN and J. Moran, MD; Duke University Medical Center, Durham, [...], Hypotension and cramping are common adverse events during hemodialysis treatment, frequently occurring together. Relative hypovolemia, delayed vascular refill and osmolality shifts have been implicated among other possible mechanisms in the pathophysiology of these events, although full understanding is lacking. We report a lower incidence of these side effects in patients treated with a new subcutaneous vascular access device (LifeSite System, Vasca, Inc., Tewksbury, MA) in a randomized prospective controlled trial. 36 patients were treated with the LifeSite device (LS), 34 patients with a Tesio-Cath (T) catheter (Medcomp, Harleysville, PA). Patients from 8 different sites in the U.S. were included, who were awaiting the placement or maturation of a permanent access (AV fistula or graft). All were treated with volumetric machines and bicarbonate dialysate. Hypotension occurred in the LifeSite group in 24/36 of the patients (66.7%) and in 26/34 patients (76.5%) in the Tesio group (p=0.43). However the rate of hypotension was 0.96 events per patient month in the LS group versus 1.88 in the T group (p=0.07). Cramping also occurred less frequently in the LS group: 15/36 patients (41.7%) versus 21/34 patients (61.8%) in the T group (p= 0.10). This represented a significantly lower incidence in events/patients months at risk in the LifeSite patients with 0.32 (30/93.7) versus 0.77 (70/90.4) in the Tesio group (p=0.013). The study was undertaken to test the LifeSite device as a new alternative for vascular access in HD patients. The lower incidence of hypotension and cramping is unexpected and unexplained, especially as the LifeSite group achieved higher blood flow rates and therefore might have been more susceptible to these side effects. Further investigation is needed to explain these findings.

There is a direct relationship between bodyweight and risk of diabetes. Lorcaserin, a selective serotonin 2C receptor agonist that suppresses appetite, has been shown to facilitate sustained weight loss in obese or overweight patients. We aimed to evaluate the long-term effects of lorcaserin on diabetes prevention and remission.

ObjectiveTo identify areas of priority and activity for international sportsfederations (IFs) with respect to athlete health and safety, and global health. Results serve to direct the work of the Association of Summer Olympic IF Medical and Scientific Consultative Group, the International Olympic Committee and to influence IFs’ planning and priorities.MethodsThe 28 IFs participating in the Summer Olympic Games (2016) were asked to rank the relative importance of 11 health-related topics and to report their activities or research initiatives on 27 identified topics using an electronic survey. A comparison with a similar survey (2012) was made.ResultsThe response rate was 100%. In general, the ‘fight against doping’ had the highest priority followed by ‘image as a safe sport’. The topics with the lowest importance ratings were ‘increasing the number of elite athletes’, and ‘health of the general population’. Despite ranking ‘health of your athletes,’ as a top priority, IFs are not addressing all aspects of athlete health. In comparison with 2012, there was a significant decrease in priority for IFs is ‘health of the general population’.ConclusionDespite the widespread knowledge of the importance of the promotion of physical activity (sport) on global health, the decreasing priority and programming of the IFs on physical activity promotion is concerning. Although IFs have prioritised the protection of the health of elite athletes, there are gaps in programming demonstrating that IFs are missing important areas of athlete health. Improving recreational athlete health programming could also benefit population health as well as improve IF fan base and sport participation.

Many active pharmaceutical ingredients (APIs) face the challenge of palatability when administered orally. Tastemasking technologies often utilize coatings to help palatability but these coatings or agglomerations can negatively impact bioavailability. Orbis Biosciences, Inc. (Orbis) has developed a novel taste-masking technology that has previously been demonstrated to have virtually complete taste-masking of the extremely bitter API, prednisone. The next facet of development was to assess the pharmacokinetics (PK) and relative bioequivalence (BE) of prednisone from this new formulation. Presented here is a randomized, open-label, two products, two period and crossover study in fasted adults comparing 10 mg prednisone taste-masked microspheres to a 10 mg prednisone tablet. Fourteen (14) post-dose plasma concentrations obtained over a 12 h period were analyzed for prednisone and its metabolite, prednisolone, using a validated HPLC/MS/MS method. Bioavailability was assessed according to current United States' Food and Drug Administration (FDA) criteria. Results indicated that for both Cmax (90% CI; 0.81-1.10) and AUCtotal (0.94-1.18), the microsphere formulation met bioavailability criteria for prednisone. For prednisolone, only AUCtotal met criteria for bioavailability. Cmax was lower (90% confidence interval of 0.647-0.938 for log transformed data) and time of Cmax (Tmax) was delayed (2.9 ± 0.5 vs. 1.8 ± 1.0 h, p=0.02) in the microsphere relative to the tablet formulation. In conclusion, the relative bioavailability of the novel microsphere formulation of prednisone was evident as compared to a commercially available tableted formulation of the drug. [ABSTRACT FROM AUTHOR]

The antipsychotic clozapine is uniquely effective in the management of schizophrenia; however, its use is limited by its potential to induce agranulocytosis. The causes of this, and of its precursor neutropenia, are largely unknown, although genetic factors have an important role. We sought risk alleles for clozapine-associated neutropenia in a sample of 66 cases and 5583 clozapine-treated controls, through a genome-wide association study (GWAS), imputed human leukocyte antigen (HLA) alleles, exome array and copy-number variation (CNV) analyses. We then combined associated variants in a meta-analysis with data from the Clozapine-Induced Agranulocytosis Consortium (up to 163 cases and 7970 controls). In the largest combined sample to date, we identified a novel association with rs149104283 (odds ratio (OR)=4.32, P=1.79 × 10−8), intronic to transcripts of SLCO1B3 and SLCO1B7, members of a family of hepatic transporter genes previously implicated in adverse drug reactions including simvastatin-induced myopathy and docetaxel-induced neutropenia. Exome array analysis identified gene-wide associations of uncommon non-synonymous variants within UBAP2 and STARD9. We additionally provide independent replication of a previously identified variant in HLA-DQB1 (OR=15.6, P=0.015, positive predictive value=35.1%). These results implicate biological pathways through which clozapine may act to cause this serious adverse effect.

Aims.We present molecular line observations of the molecular core associated with IRAS 16547-4247, which have allowed us to determine its physical and kinematical properties at angular resolutions of ~18´´.

Context.We report new simultaneous near-infrared/sub-millimeter/X-ray observations of the Sgr A* counterpart associated with the massive $3{-}4\times10^6$$M_{\odot}$black hole at the Galactic Center.

Lithium is the mainstay prophylactic treatment for bipolar disorder (BD), but treatment response varies considerably across individuals. Patients who respond well to lithium treatment might represent a relatively homogeneous subtype of this genetically and phenotypically diverse disorder. Here, we performed genome-wide association studies (GWAS) to identify (i) specific genetic variations influencing lithium response and (ii) genetic variants associated with risk for lithium-responsive BD. Patients with BD and controls were recruited from Sweden and the United Kingdom. GWAS were performed on 2698 patients with subjectively defined (self-reported) lithium response and 1176 patients with objectively defined (clinically documented) lithium response. We next conducted GWAS comparing lithium responders with healthy controls (1639 subjective responders and 8899 controls; 323 objective responders and 6684 controls). Meta-analyses of Swedish and UK results revealed no significant associations with lithium response within the bipolar subjects. However, when comparing lithium-responsive patients with controls, two imputed markers attained genome-wide significant associations, among which one was validated in confirmatory genotyping (rs116323614, P=2.74 × 10−8). It is an intronic single-nucleotide polymorphism (SNP) on chromosome 2q31.2 in the gene SEC14 and spectrin domains 1 (SESTD1), which encodes a protein involved in regulation of phospholipids. Phospholipids have been strongly implicated as lithium treatment targets. Furthermore, we estimated the proportion of variance for lithium-responsive BD explained by common variants (‘SNP heritability’) as 0.25 and 0.29 using two definitions of lithium response. Our results revealed a genetic variant in SESTD1 associated with risk for lithium-responsive BD, suggesting that the understanding of BD etiology could be furthered by focusing on this subtype of BD.

The genetic architecture of schizophrenia is complex, involving risk alleles ranging from common alleles of weak effect to rare alleles of large effect, the best exemplar of the latter being large copy number variants (CNVs). It is currently unknown whether pathophysiology in those with defined rare mutations overlaps with that in other individuals with the disorder who do not share the same rare mutation. Under an extreme heterogeneity model, carriers of specific high-penetrance mutations form distinct subgroups. In contrast, under a polygenic threshold model, high-penetrance rare allele carriers possess many risk factors, of which the rare allele is the only one, albeit an important, factor. Under the latter model, cases with rare mutations can be expected to share some common risk alleles, and therefore pathophysiological mechanisms, with cases without the same mutation. Here we show that, compared with controls, individuals with schizophrenia who have known pathogenic CNVs carry an excess burden of common risk alleles (P=2.25 × 10−17) defined from a genome-wide association study largely based on individuals without known CNVs. Our finding is not consistent with an extreme heterogeneity model for CNV carriers, but does offer support for the polygenic threshold model of schizophrenia. That this is so provides support for the notion that studies aiming to model the effects of rare variation may uncover pathophysiological mechanisms of relevance to those with the disorder more widely.

Background: Oxidative phosphorylation (OXPHOS) complexes consist of nuclear and mitochondrial DNA-encoded subunits. Their biogenesis requires cross-compartment gene regulation to mitigate the accumulation of disproportionate subunits. To determine how human cells coordinate mitochondrial and nuclear gene expression processes, we tailored ribosome profiling for the unique features of the human mitoribosome. Results: We resolve features of mitochondrial translation initiation and identify a small ORF in the 3′ UTR of MT-ND5. Analysis of ribosome footprints in five cell types reveals that average mitochondrial synthesis levels correspond precisely to cytosolic levels across OXPHOS complexes, and these average rates reflect the relative abundances of the complexes. Balanced mitochondrial and cytosolic synthesis does not rely on rapid feedback between the two translation systems, and imbalance caused by mitochondrial translation deficiency is associated with the induction of proteotoxicity pathways. Conclusions: Based on our findings, we propose that human OXPHOS complexes are synthesized proportionally to each other, with mitonuclear balance relying on the regulation of OXPHOS subunit translation across cellular compartments, which may represent a proteostasis vulnerability.

Large (>100 kb), rare (<1% in the population) copy number variants (CNVs) have been shown to confer risk for schizophrenia (SZ), but the findings for bipolar disorder (BD) are less clear. In a new BD sample from the United Kingdom (n=2591), we have examined the occurrence of CNVs and compared this with previously reported samples of 6882 SZ and 8842 control subjects. When combined with previous data, we find evidence for a contribution to BD for three SZ-associated CNV loci: duplications at 1q21.1 (P=0.022), deletions at 3q29 (P=0.03) and duplications at 16p11.2 (P=2.3 × 10−4). The latter survives multiple-testing correction for the number of recurrent large CNV loci in the genome. Genes in 20 regions (total of 55 genes) were enriched for rare exonic CNVs among BD cases, but none of these survives correction for multiple testing. Finally, our data provide strong support for the hypothesis of a lesser contribution of very large (>500 kb) CNVs in BD compared with SZ, most notably for deletions >1 Mb (P=9 × 10−4).

We present 15 images from the global mm-VLBI sessions in 1990 April at 100 GHz and 1993 April at 86 GHz. These observations probe the central engines of the 16 observed AGN's with up to 50 μas resolution. Among other sources previously observed with λ3 mm VLBI we present the first λ3 mm maps of 0735+178, 0748+126, 1055+018, 2145+067, and CTA 102, in total we have been able to image 13 out of the 16 observed sources. 6 out of the 13 imaged sources observed exhibit curvature and rapid structural changes, although the low dynamic range in two thirds of the maps limits the detection of weak features. Most of the sources have unresolved cores even at this high resolution. There is substantial evidence that the observed sources can be grouped into two general groups: A misaligned population with parsec scale jets in the form of low pitch helices and an aligned population with straight jets with small changes in PA due to intrinsic bends.

Transversus abdominis plane block is an effective postoperative analgesic technique after abdominal surgery, but no study has compared continuous transversus abdominis plane block with continuous epidural analgesia.We designed a randomised controlled trial comparing these techniques for major abdominal surgery. Patients in the epidural group received a bolus of 8 to 15 ml of ropivacaine 0.2% and an infusion of 5 to 15 ml/hour and the transversus abdominis plane block group a bolus dose of 20 ml of ropivacaine 0.375% bilaterally and an infusion of 0.2% ropivacaine 8 ml/hour bilaterally, for three days. Both groups received paracetamol and patient controlled analgesia with fentanyl for three days. Primary outcomes were numerical rating scores for pain (rest and dynamic over 72 hours) and total fentanyl use; complications and satisfaction scores were also noted.The study was terminated early after 42 patients had been randomised (epidural n=19; transversus abdominis plane block n=22; one excluded). No differences were found in regards to point pain scores or scores over time, either immediately postoperatively or in surgical wards; total fentanyl requirement and Likert satisfaction scores were also similar in both groups. In this underpowered study we found comparable results between continuous transversus abdominis plane technique and epidural analgesia in regard to pain, analgesic use and satisfaction after abdominal surgery. To confirm this finding, randomised trials with larger numbers of participants are needed.

Hypokalaemia is a common problem in critically ill patients, which if untreated, can result in dysrhythmia or another adverse outcome. We assessed the safety and efficacy of a continuous infusion of potassium chloride versus an existing intermittent infusion regimen. In this open-label randomised parallel-arm active-controlled pilot study, critically ill adults with plasma potassium concentration between 2.5 and 3.8 mmol/l were randomised to receive either a continuous infusion or intermittent infusions of potassium chloride for establishment and maintenance of normokalaemia. The primary outcome was the mean difference in plasma potassium concentration over time between the two study arms as assessed by a linear mixed-effects model. Although a statistically significant difference was observed (0.22 mmol/l; 95% confidence interval 0.17, 0.27; P<0.0001), this did not reach the pre-determined level indicative of a treatment effect (0.5 mmol/l). The continuous group demonstrated less variance in (mean) plasma potassium as reflected in narrower confidence intervals in a prediction-by-time model. The incidence rate ratio of dysrhythmia, assessed by a mixed-effects Poisson model, was similar in each group (0.62; 95% confidence interval 0.32, 1.21; P=0.16). We recorded no adverse events directly attributable to infusion of potassium chloride in either study arm. Although titrated continuous infusion did not demonstrate a clinically important difference by comparison with intermittent infusions for the maintenance of normokalaemia, there was more consistent control of plasma potassium with no observed complications or adverse events. Therefore, this trial showed an acceptable efficacy and safety profile for the continuous infusion regimen, suggesting scope for further study.

Mortality and cost outcomes of elderly intensive care unit (ICU) trauma patients were characterised in a retrospective cohort study from an Australian tertiary ICU. Trauma patients admitted between January 2000 and December 2005 were grouped into three major age categories: aged ≥65 years admitted into ICU (n=272); aged ≥65 years admitted into general ward (n=610) and aged <65 years admitted into ICU (n = 1617). Hospital mortality predictors were characterised as odds ratios (OR) using logistic regression. The impact of predictor variables on (log) total hospital-stay costs was determined using least squares regression. An alternate treatment-effects regression model estimated the mortality cost-effect as an endogenous variable. Mortality predictors (P ≤0.0001, comparator: ICU ≥65 years, ventilated) were: ICU <65 not-ventilated (OR 0.014); ICU <65 ventilated (OR 0.090); ICU age ≥65 not-ventilated (OR 0.061) and ward ≥65 (OR 0.086); increasing injury severity score and increased Charlson comorbidity index of 1 and 2, compared with zero (OR 2.21 [1.40 to 3.48] and OR 2.57 [1.45 to 4.55]). The raw mean daily ICU and hospital costs in A$ 2005 (US$) for age <65 and ≥65 to ICU, and ≥65 to the ward were; for year 2000: ICU, $2717 (1462) and $2777 (1494); hospital, $1837 (988) and $1590 (855); ward $933 (502); for year 2005: ICU, $3202 (2393) and $3086 (2307); hospital, $1938 (1449) and $1914 (1431); ward $1180 (882). Cost increments were predicted by age ≥65 and ICU admission, increasing injury severity score, mechanical ventilation, Charlson comorbidity index increments and hospital survival. Mortality cost-effect was estimated at −63% by least squares regression and −82% by treatment-effects regression model. Patient demographic factors, injury severity and its consequences predict both cost and survival in trauma. The cost mortality effect was biased upwards by conventional least squares regression estimation.

Intraoperative hypothermia is a known consequence of general anaesthesia. Forced air warming devices are commonly used to prevent hypothermia in anaesthesia, but there are limited data on the use of radiant warming devices. Previous trials comparing the efficacy of forced air and radiant warming devices have reported discordant results. The current study evaluated the efficacy of these devices during elective laparoscopic cholecystectomy, where surgery was expected to last >60 minutes. Twenty-nine patients were randomised to either a forced air warming device (Warm-touch™; group 1, n=15) or a radiant warming device applied to the face (Sun-touch™; group 2, n=14). All fluids were given via a standardised fluid warmer set at 41°C. Oesophageal temperature was measured every 15 minutes until the end of the procedure. Between-group, over-time temperatures and interaction were analysed using a linear mixed model. Statistical significance was ascribed at P ≤0.05. The median (range) time of surgery was 90 (60 to 180) minutes. Mean (SD) oesophageal temperatures in the Warm-touch and Sun-touch groups were at 15 minutes 36.2 (0.30)°C and 36.2 (0.57)°C, and at 90 minutes 36.2 (0.44)°C and 35.9 (0.29)°C respectively. There was no statistically significant temperature difference between groups (P=0.69) or over time (P=0.61), and no interaction between time and treatment group (P=0.97). Postoperative headache was recorded in four Sun-touch and no Warm-touch patients (P=0.04). No difference in the efficacy of the Sun-touch warming device compared with the Warm-touch was demonstrated. Operational-mode side-effects may limit the use of the Sun-touch device.

Organophosphate poisoning is common in developing countries. The morbidity and mortality with organophosphate poisoning is relatively high despite the use of atropine as specific antidotal therapy and oximes to reactivate acetylcholinesterase. Several adjunct and alternative therapies have been explored in animal and human studies. We reviewed the literature to ascertain if there was evidence of benefit of such therapies. Adjunct and alternative therapies included treatments to reduce poison absorption by topical application of creams, enhance toxin elimination by haemoperfusion or bioremediation and neutralise the poison by scavenging free organophosphate with cholinesterase-rich human plasma. In addition, magnesium, clonidine, diazepam, N-acetyl cysteine and adenosine receptor agonists have also been used to counteract poison effects. Detailed assessment was limited by the paucity of trials on adjunct/alternative therapies. The limited evidence from the review process suggested potential benefit from the use of human plasma infusion, early initiation of haemoperfusion and intravenous magnesium, in addition to standard therapy with atropine and pralidoxime. There appeared to be no additional benefit with alkalinisation or use of glycopyrrolate instead of atropine in human trials. Diazepam administration has been advocated by military authorities if symptoms developed following exposure to organophosphate. Bioremediation, clonidine, N-acetyl cysteine and adenosine receptor agonists have been evaluated only in animal models. The impact of adjunct and alternate therapies on outcomes in human poisoning needs to be further explored before implementation as standard treatment.

The role of Extra corporeal membrane oxygenation (ECMO) has not been formally validated for patients with adult respiratory distress syndrome. In anticipation of publication of the conventional ventilation versus ECMO in severe adult respiratory failure (CESAR) trial, the role of ECMO in this setting was reviewed.An electronic search for studies reporting the use of ECMO for the treatment of adult respiratory distress syndrome revealed two randomised controlled trials and three non-controlled trials. Bayesian analysis on the two randomised controlled trials produced an odds ratio mortality of 1.28 (credible interval 0.24 to 6.55) demonstrating no significant harm or benefit. Pooling was not possible for the non-controlled studies because of differing admission status and ECMO selection criteria and an inability to control for these differences in the absence of individual patient data. A large number (n=35) of case series have been published with generally more positive results. We also present a comprehensive narrative commentary on the history, current practice and future for ECMO.ECMO, as rescue therapy for adult respiratory distress syndrome, appears to be an unvalidated rescue treatment option. Analysis and review of trial data does not support its application; however the body of reported cases suggests otherwise. Until the CESAR trial provides an authoritative answer ECMO will continue to be offered on a case by case basis.

Mycobacterium tuberculosis complex species survive and replicate in phagosomes of the host cell. Cell death (CD) has been highlighted as one of the probable outcomes in this host-pathogen interaction. Previously, our group demonstrated macrophage apoptosis as a consequence of Mycobacterium bovis infection. In this study, we aimed to identify the contribution of apoptotic effector elements in M. bovis-induced CD. Bovine macrophages were either infected with M. bovis (multiplicity of infection, 10:1) or treated with an M. bovis cell extract (CFE). Structural changes compatible with CD were evaluated. Chromatin condensation was increased three times by the CFE. On the other hand, a terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling (TUNEL) assay demonstrated that levels of DNA fragmentation induced by M. bovis and CFE were 53.7% ± 24% and 38.9% ± 14%, respectively, whereas control cells had a basal proportion of 8.9% ± 4.1%. Rates of DNA fragmentation were unaffected by the presence of the pan-caspase inhibitor N-benzyloxycarbonyl-Val-Ala-Asp (z-VAD). Cells treated with 100 µg of CFE for 12 h had a fivefold decrease in the level of mitochondrial outer membrane permeabilization compared to that of untreated cells. Neither M. bovis infection nor CFE treatment induced activation of caspase 3, 8, or 9. Translocation of apoptosis-inducing factor (AIF) to the nucleus was identified in 32% ± 3.5% and 26.3% ± 4.9% of M. bovis-infected and CFE-treated cells, respectively. Incubation of macrophages with z-VAD prior to infection did not alter the percentage of cells showing AIF translocation. Our data suggest that M. bovis-induced CD in bovine macrophages is caspase independent with AIF participation.

Thermal loads can result in significant increases in grain pressure in silos. Eurocode 1 part 4 recognizes this action, but does not propose a calculation method for its measurement. The purpose of this study is to analyze and compare classical models for thermal load calculation with finite element models developed by the authors. [ABSTRACT FROM AUTHOR]

The risk factors for time to mortality, censored at 30 days, of patients admitted to an adult teaching hospital ICU with haematological and solid malignancies were assessed in a retrospective cohort study.Patients, demographics and daily ICU patient data, from admission to day 8, were identified from a prospective computerized database and casenote review in consecutive admissions to ICU with haematological and solid tumours over a 10-year period (1989–99). The cohort, 108 ICU admissions in 89 patients was of mean age (±SD) 55±14 years; 43% were female. Patient diagnoses were leukaemia (35%), lymphoma (38%) and solid tumours (27%). Median time from hospital to ICU admission was five days (range 0–67). On ICU admission, 50% had septic shock and first day APACHE II score was 28±9. Forty-six per cent of patients were ventilated. ICU and 30-day mortality were 39% and 54% respectively. Multivariate Cox model predictors (P<0.05), using only ICU admission day data were: Charlson comorbidity index (CCI), time to ICU admission (days) and mechanical ventilation. For daily data (admission through day 8), predictors were: cohort effect (2nd vs 1st five-year period); CCI; time to ICU admission (days); APACHE II score and mechanical ventilation.Outcomes were considered appropriate for severity of illness and demonstrated improvement over time. Ventilation was an independent outcome determinant. Controlling for other factors, mortality has improved over time (1st vs 2nd five year period). Analysis restricted to admission data alone may be insensitive to particular covariate effects.

The ability of various proxy cost measures, including therapeutic activity scores (TISS and Omega) and cumulative daily severity of illness scores, to predict individual ICU patient costs was assessed in a prospective “ground-up” utilization costing study over a six month period in 1991.Daily activity (TISS and Omega scores) and utilization in consecutive admissions to three adult university associated ICUs was recorded by dedicated data collectors. Cost prediction used linear regression with determination (80%) and validation (20%) data sets. The cohort, 1333 patients, had a mean (SD) age 57.5 (19.4) years, (41% female) and admission APACHE III score of 58 (27). ICU length of stay and mortality were 3.9 (6.1) days and 17.6% respectively. Mean total TISS and Omega scores were 117 (157) and 72 (113) respectively. Mean patient costs per ICU episode (1991 ÄS) were $6801 ($10311), with median costs of $2534, range $106 to $95,602. Dominant cost fractions were nursing 43.3% and overheads 16.9%. Inflation adjusted year 2002 (mean) costs were $9343 ($ AUS). Total costs in survivors were predicted by Omega score, summed APACHE III score and ICU length of stay; determination R2, 0.91; validation 0.88. Omega was the preferred activity score. Without the Omega score, predictors were age, summed APACHE III score and ICU length of stay; determination R2, 0.73; validation 0.73. In non-survivors, predictors were age and ICU length of stay (plus interaction), and Omega score (determination R2, 0.97; validation 0.91).Patient costs may be predicted by a combination of ICU activity indices and severity scores.

Variables predicting thirty-day outcome from Acute Respiratory Distress Syndrome (ARDS) were analysed using Cox regression structured for time-varying covariates. Over a three-year period, 1996–1998, consecutive patients with ARDS (bilateral chest X-ray opacities, PaO2/FiO2 ratio of <200 and an acute precipitating event) were identified using a prospective computerized data base in a university teaching hospital ICU.The cohort, 106 mechanically ventilated patients, was of mean (SD) age 63.5 (15.5) years and 37% were female. Primary lung injury occurred in 45% and 24% were postoperative. ICU-admission day APACHE II score was 25 (8); ARDS onset time from ICU admission was 1 day (median: range 0-16) and 30 day mortality was 41% (95% CI: 33%-51%). At ARDS onset, PaO2/FiO2 ratio was 92 (31), 81% had four-quadrant chest X-ray opacification and lung injury score was 2.75 (0.45). Average mechanical ventilator tidal volume was 10.3 ml/ predicted kg weight. Cox model mortality predictors (hazard ratio, 95% CI) were: APACHE II score, 1.15 (1.09-1.21); ARDS lag time (days), 0.72 (0.58-0.89); direct versus indirect injury, 2.89 (1.45-5.76); PaO2/FiO2 ratio, 0.98 (0.97-0.99); operative versus non-operative category, 0.24 (0.09-0.63). Time-varying effects were evident for PaO2/FiO2 ratio, operative versus non-operative category and ventilator tidal volume assessed as a categorical predictor with a cut-point of 8 ml/kg predicted weight (mean tidal volumes, 7.1 (1.9) vs 10.7 (1.6) ml/kg predicted weight). Thirty-day survival was improved for patients ventilated with lower tidal volumes.Survival predictors in ARDS were multifactorial and related to patient-injury-time interaction and level of mechanical ventilator tidal volume.

This prospective cohort analysis compared the efficiency of time-based discharge criteria (Group 1) to a modified clinical scoring system (Group 2), incorporating the assessment of pain and temperature, in the post anaesthesia care unit (PACU). Two consecutive series of patients (n=292) were assessed following general anaesthesia for various surgical procedures. The time taken for patients to satisfy their respective discharge criteria was recorded as PACU length of stay (LOS). Patient group and other factors that may have influenced PACU-LOS were examined using time-to-event analysis. The raw PACU-LOS was not shown to be different between the two groups (log rank test, P=0.12). Covariate adjusted estimates were used to compare the two discharge criteria and also to identify other factors influencing PACU-LOS. The Cox regression model was poorly specified and a log-logistic accelerated failure time model was found to be the most parsimonious predictive model.Predictors of decreased PACU-LOS were the treatment group (Group 2 versus Group 1) and the covariate recording anaesthetic airway choice (no endotracheal tube (ETT) versus ETT). Surgical time, as a linear function, intra- and postoperative opioid administration, as well as postoperative antiemetic use were predictors of increased PACU-LOS. Patient age, gender, urgency of surgery, and ASA classification were not predictive of PACU-LOS. Using covariate adjusted estimates, the new PACU discharge criteria, based on the Aldrete's scoring system, was associated with a significantly reduced PACU-LOS in comparison with time-based criteria.

Hybrid sorghum [Sorghum bicolor(L.) Moench] seed production relies exclusively on cytoplasmic male sterility (CMS) systems and almost all hybrid sorghum seed is produced using the A1 CMS system. However, the reliance on a single CMS system increases the vulnerability of the crop to diseases and stresses that may attack that particular CMS system. Alternative CMS systems have been described and even used on a limited basis for hybrid seed production, but a direct comparison of the agronomic effects of different cytoplasms has not been possible because male‐sterile lines with a common genetic background (and different cytoplasm) were not available. The recent development of isocytoplasmic A‐lines allows more direct comparison of cytoplasmic effect on agronomic performance. The purpose of this study was to determine by means of a set of isocytoplasmic hybrids if cytoplasm per se influences agronomic performance. Twelve hybrid genotypes were created in three different cytoplasms (A1, A2, and A3 for a total of 36 hybrids), and they were evaluated for plant height, days to anthesis, and grain yield at Weslaco and College Station, TX, in 1998 and 1999. As expected, significant differences existed among hybrids for plant height, days to anthesis, and grain yield. Cytoplasm type had no effect on plant height and was of minimal practical effect on days to anthesis, but a significant reduction in yield was observed in A3 cytoplasm hybrids as compared with A1 and A2 cytoplasm hybrids. The specific reason for the reduced yield of A3 hybrids is not known, but seed set data indicated that it was not associated with fertility restoration. The results indicate that hybrids created in A2 cytoplasm yield comparably to the commonly used A1 cytoplasm and therefore, the A2 system will provide a suitable alternative for hybrid seed production should problems be encountered in the A1 CMS system.

In order to study the immune response elicited by asymptomatic carriage of Neisseria meningitidis, samples of serum, peripheral blood mononuclear cells (PBMCs), and saliva were collected from a cohort of more than 200 undergraduate students in Nottingham, United Kingdom, who were subject to high rates of acquisition and carriage of meningococci. Serum immunoglobulin G levels were elevated following increases in the rate of carriage, and these responses were specific for the colonizing strains. In order to investigate T-cell responses, PBMCs from 15 individuals were stimulated with a whole-cell lysate of the H44/76 meningococcal strain (B:15:P1.7,16), stained to detect cell surface markers and intracellular cytokines, and examined by flow cytometry. The cells were analyzed for expression of CD69 (to indicate activation), gamma interferon (IFN-gamma) (a representative T-helper 1 subset [Th1]-associated cytokine), and interleukin-5 (IL-5) (a Th2-associated cytokine). Following a brief meningococcal stimulation, the numbers of CD69(+) IFN-gamma(+) CD56/16(+) NK cells were much higher than cytokine-positive CD4(+) events. Both IFN-gamma(+) and IL-5(+) events were detected among the CD69(+) CD4(+) population, leading to the conclusion that an unbiased T-helper subset response was elicited by meningococcal carriage.

Hyperglycemia alters the inflammatory response to infection and ischemia. We hypothesize that perioperative glycemic control could also influence the risk for allograft rejection.

Conclusion: Clearly much more can be achieved in preparing Plant Industries and Quarantine Agecies to deal with incursions of soilborne pathogens and pests. Awareness and preparedness strategies for prioritised lists of soil pathogens are required to enhance competencies of stakeholders in knowing what to look for. More sensitive diagnostic tools are needed for risk management to confirm preserice or absence of the target organism. Optimising containment and eradicant treatments should be a priority with the imminent demise of methyl bromide. Finally, pre-emptive breeding strategies that incorporate resistance genes into commercial cultivars deserve more attention. When successful, this is one of the most cost effective and environmentally acceptable methods of incursion management. The question of whether current resources, infrastructure and arrangements for quarantine management of incursions of exotic pests and diseases in Australia is a matter receiving close scrutiny by government and industry. Compensation is perhaps the most difficult and contentious issue. Farmers need to know they will not be financially disadvantaged by quarantine action otherwise there is no incentive to report suspicious symptoms, and then it’s too late!

Linoleic acid monoepoxides have been correlated with many pathological conditions. Studies using insect cells derived from Spodoptera frugiperda (Sf-21 cells) have suggested that conversion of the epoxides to the diols is required for toxicity. However, more recent studies using rabbit renal proximal tubules have suggested that linoleic acid monoepoxides are direct mitochondrial toxins. To better understand these discrepancies, we compared the toxicity of these linoleic acid metabolites in Sf-21 cells using mitochondrial respiration as an end point. Linoleic acid (100 μM) and 12,13-epoxy-9-octadecenoic acid (12,13-EOA, 100 μM) increased the rate of oligomycin-insensitive respiration by approximately 3.5- and 3-fold, respectively, decreased the rate of oligomycin-sensitive respiration by approximately 52 and 68%, respectively, and had no effect on the integrity of the electron transport chain. These effects were concentration-dependent, occurred within 1 min, and recovered to basal levels within 45 min. 12,13-Dihydroxy-9-octadecenoic acid (12,13-DHOA, 100 μM) had no effect on oligomycin-insensitive respiration but decreased the rate of oligomycin-sensitive respiration and uncoupled respiration in a concentration-dependent manner. Approximately 79 and 68% of oligomycin-sensitive respiration and uncoupled respiration was inhibited by 12,13-DHOA (100 μM), respectively. These effects occurred within 1 min and were not reversible in 6 h. Effects similar to those induced by 12,13-DHOA (100 μM) were observed using 12,13-EOA (100 μM) in Sf-21 cells expressing human soluble epoxide hydrolase. These data suggest that in this Sf-21 model linoleic acid and linoleic monoepoxides have transient uncoupling effects, whereas the primary mechanism of toxicity for linoleic acid diols in this model is inhibition of the electron transport chain.

The thiol tripeptides glutathione (GSH) and homoglutathione (hGSH) are very abundant in legume root nodules and their synthesis is catalyzed by the enzymes gamma-glutamylcysteine synthetase (gammaECS), GSH synthetase (GSHS), and hGSH synthetase (hGSHS). As an essential step to elucidate the role of thiols in N(2) fixation we have isolated cDNAs encoding the three enzymes and have quantified the transcripts in nodules. Assay of enzyme activities in highly purified nodule organelles revealed that gammaECS is localized in the plastids, hGSHS in the cytosol, and GSHS in the cytosol and mitochondria. These results are consistent with sequence analyses. Subcellular fractionation of nodules also showed that bacteroids contain high thiol concentrations and high specific gammaECS and GSHS activities. Results emphasize the role of nodule plastids in antioxidant protection and in control of thiol synthesis, and suggest that plastids may be important in the stress response of nodules. Overall, our results provide further evidence that thiol synthesis is critical for nodule functioning.

We present images and spectra of the active jet and anomalous arms on subparsec through kiloparsec scales in the LINER/Seyfert galaxy NGC 4258 (M106). New VLBA and multiconfiguration VLA images show that, on 0.3-300 pc scales, the jet in projection aligns with (1) the spin axis of the underlying accretion disk and (2) two radio hot spots 24'' S (840 pc) and 49'' N (1.7 kpc) from the nucleus. Hubble Space TelescopeWFPC2 [N II] ?6583 + H? images locate interactions between the jet and the interstellar medium (ISM). The most prominent is a pair of emission line arcs whose apices face away from the galaxy nucleus and envelop the leading edges of the radio hot spots. Ground-based (WHT) spectra with 2 Å resolution confirm that the gaseous kinematics and excitation of both arcs have the spatio-kinematic structure expected for jet working surfaces with a shock velocity 350 ± 100 km s-1. The north shock is oblique and may lie in a nuclear ionization cone. The south shock shows a detached, putative Mach disk. Models suggest that the S shock is a bow shock around a jet whose progress toward us through the galaxy ISM has stalled. This is notable because the inferred outflow axis is misaligned by ~65° (in three dimensions) with the spin axis of the accretion disk. Our emission line ratios and profiles diagnose the physical properties of the shocks, possible Mach disk, and thence the jets. The shocks lie at one end of a swath of kinematically disturbed gas that reaches back to the previously recognized spiral "anomalous arms," suggesting that they are linked dynamically by precession of the central engine; although claimed elsewhere to be bar shocks, the anomalous arms are probably a fossil record of changing jet activity in NGC 4258. Our results imply that the jet has recently moved a long way out of the plane of the galaxy. A deep Taurus Tunable Filter H? image shows that discrete strands in the anomalous arms persist to galactocentric radii of at least 4' (>8 kpc), indicating an ongoing ISM interaction.