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Objective: To quantify the potential time saved with pre‐hospital antibiotic therapy in sepsis. Methods: Study data for adult patients transported by Ambulance Victoria (AV), and enrolled into the Australasian Resuscitation In Sepsis Evaluation (ARISE), were linked with pre‐hospital electronic records. Results: An AV record was identified for 240 of 341 ARISE patients. The pre‐hospital case notes referred to potential infection in 165 patients. The median time to first antibiotic administration from loading the patient into the ambulance was 107 (74–160) min. Conclusions: ARISE patients in Victoria were frequently identified pre‐hospital. An opportunity exists to study the feasibility of pre‐hospital antibiotic therapy. [ABSTRACT FROM AUTHOR]

The article presents an examination into the relationship between unexpected accounting rates of return and abnormal returns between the 1965-1982. The intertemporal and cross-sectional variations of the financial reports are analyzed, suggesting an inflationary model of explanation. Data is presented from the Center for Research in Security Prices (CRSP) and measured through earnings deflated by opening net book value (ROCE) and by opening market value of ordinary share capital (ROVAL) paradigms.

A model for the interaction-induced polarizability of halide ions in condensed phases has been developed from ab initio electronic structure calculations. This model is incorporated into computer simulations of molten LiF, LiCl, and NaCl and used to calculate correlation functions of the polarizability in order to simulate the light scattering spectra. The results for the line shapes, frequency dependent depolarization ratio, and absolute intensity compare extremely well with the available experimental data. The relative importance of the contributions to the interaction-induced spectra from changes in the ionic polarizability caused by short-range overlap, ionic field-induced distortion, and dipole–induced dipole interactions is assessed and their distinctive spectral characteristics identified. [ABSTRACT FROM AUTHOR]

Understanding how defoliation affects soybean [Glycine max (L.) Merr.] yield during the seed-filling period will aid in making management recommendations for control of stresses that reduce yield through defoliation. Because previous research has studied defoliation effects at only one or two specific stages of seed filling, our objective was to gain a greater understanding of the mechanisms for yield reduction with defoliation at weekly intervals across the seed-filling period. Defoliations were conducted from the bottom of the canopy upward to mimic the progress of soybean rust. Two experiments, one in Kentucky (38° N lat) and the other in Louisiana (300 N lat), were conducted in randomized complete block designs in split-split plot arrangements with four replications. Main plots were two cultivars, split plots were defoliation timings at weekly intervals during seed filling, and split-split plots were defoliation levels of 0,33,66, and 100% leaf removal. Data were obtained on yield and several growth dynamic and yield component factors. Defoliation-induced yield losses corresponded more closely with percentage of light interception reductions than percentage of leaf area reductions. During the R5 to R6 period, defoliation levels sufficient to reduce light interception by 18 to 23% were required to cause yield loss. Yield losses from total defoliation were greatest at early seed filling (78%) but gradually diminished as seed filling progressed. Each 0.1 delay in developmental stage resulted in a 5% decline in yield loss. [ABSTRACT FROM AUTHOR]

In a bid to enhance clinical practice through the application of practice Jane Board discusses impact of tissue stretch and interstitial fluid flow on fibroblasts and collagen fibres in lymphoedema [ABSTRACT FROM AUTHOR]

Soybean rust (SBR; caused by Phakopsora pachyrhizi Syd. and P. Syd.) leads to premature leaf loss and yield reduction. The objectives of this study were to assess effects of SBR infection on soybean [Glycine max (L.) Merrill] yield and to identify causes for the yield reduction. Experiments were conducted in the 2005-2006 and 2006-2007 growing seasons at Londrina, Brazil. The five treatments were SBR infection beginning at either (i) the R2 or (ii) R5 growth stages; nondiseased defoliation treatments to mimic the leaf loss when SBR started at either (iii) the R2 or (iv) R5 growth stages; and (v) a disease-free, nondefoliated control. The control and defoliation treatments were protected against SBR by fungicide applications. Disease severity, lesion area, and leaf area were monitored from R2 to R7. Biomass and seed yield were measured at maturity. Mean SBR-induced yield reductions were 67% when infection started at R2 and 37% when infection started at R5. Leaf loss alone reduced yield significantly in only one year and only when defoliation treatments were begun at R2 (31% in 2005-2006). Soybean rust-induced yield loss was attributable to (i) premature leaf loss, (ii) reduction in canopy green leaf area due to SBR lesions, (iii) reduction in dry matter accumulation per unit absorbed radiation by the nonlesion green leaf area, and (iv) reduction in harvest index. The response of harvest index was attributable to reduced seed set and seed mass resulting likely from SBR-induced reductions in rate of dry matter accumulation. [ABSTRACT FROM AUTHOR]

Maize (Zea mays L.) containing the leafy (Lfy) gene has not been extensively used in genetic investigations because the gene has been patented. The objective of this study was to obtain genetic information on ear moisture loss rate (EMLR), leaf number above the ear, SPAD chlorophyll of leaves, and harvest index via use of a diallel cross (Griffing's Method 3) of seven leafy parents. Ear moisture loss rate was measured via an electronic probe device (EMLR-P) and the “oven method” (EMLR-O). General combining ability (GCA) was significant for EMLR-P and EMLR-O, but GCA × year interaction existed only for EMLR-O. Thus, multiple-year data are needed for investigations of EMLR-O, which increases evaluation cost. Additive genetic correlation between EMLR-P and EMLR-O was 0.96. Parents Mo17 and 914 had the desirable, negative GCA effects. The number of leaves above the ear was a complex, quantitatively inherited trait, as revealed by significant GCA, specific combining ability (SCA), nonmaternal (reciprocal), and SCA-by-years interaction effects. The cross Mo17 × 914 showed positive SCA effect and parental line B73 showed positive GCA effect for leaf number. For SPAD chlorophyll, GCA and SCA were significant, as were GCA × year and SCA × year interactions. Parents Mo17 and Hy had positive GCA effects and A619 had a negative GCA effect for SPAD chlorophyll. The cross A619 × 914 had undesirable negative SCA effect for SPAD chlorophyll. Harvest index (HI), stover, grain weight, and total dry matter (TDM) had significant GCA and reciprocal effects. To increase HI, B73 and 914 should be desirable parents. Parent Hy possessed favorable GCA and maternal factors to increase stover and TDM. A regression equation for grain weight (GWT) was: GWT = -643.0 + 0.28 TDMlinear + 2221.3 HIlinear (R2 = 90%), suggesting that grain weight can be improved by increasing TDM and HI in the leafy maize used here. [ABSTRACT FROM AUTHOR]

Maize (Zea mays L.) containing the leafy (Lfy) gene has not been extensively used in genetic investigations because the gene has been patented. The objective of this study was to obtain genetic information on ear moisture loss rate (EMLR), leaf number above the ear, SPAD chlorophyll of leaves, and harvest index via use of a diallel cross (Griffing's Method 3) of seven leafy parents. Ear moisture loss rate was measured via an electronic probe device (EMLR-P) and the “oven method” (EMLR-O). General combining ability (GCA) was significant for EMLR-P and EMLR-O, but GCA x year interaction existed only for EMLR-O. Thus, multiple-year data are needed for investigations of EMLR-O, which increases evaluation cost. Additive genetic correlation between EMLR-P and EMLR-O was 0.96. Parents Mo17 and 914 had the desirable, negative GCA effects. The number of leaves above the ear was a complex, quantitatively inherited trait, as revealed by significant GCA, specific combining ability (SCA), nonmaternal (reciprocal), and SCA-by-years interaction effects. The cross Mo17 x 914 showed positive SCA effect and parental line B73 showed positive GCA effect for leaf number. For SPAD chlorophyll, GCA and SCA were significant, as were GCA x year and SCA x year interactions. Parents Mo17 and Hy had positive GCA effects and A619 had a negative GCA effect for SPAD chlorophyll. The cross A619 x 914 had undesirable negative SCA effect for SPAD chlorophyll. Harvest index (HI), stover, grain weight, and total dry matter (TDM) had significant GCA and reciprocal effects. To increase HI, B73 and 914 should be desirable parents. Parent Hy possessed favorable GCA and maternal factors to increase stover and TDM. A regression equation for grain weight (GWT) was: GWT = -643.0 + 0.28 TDMlinear + 2221.3 HIlinear(R2 = 90%), suggesting that grain weight can be improved by increasing TDM and HI in the leafy maize used here. [ABSTRACT FROM PUBLISHER]

The third article in this series describes the treatment available to sufferers of lymphoedema in the UK. Lymphoedema is a condition that cannot be cured and requires lifelong treatment to control symptoms which, if left untreated, would progressively worsen. The aim of treatment is to stabilize the oedema and empower the patient with the necessary skills to undertake self-care. Four components of treatment are used to achieve this goal: care of the skin, compression and support, lymphatic massage and exercise. The purpose of each treatment will be explained and supported with research findings. Examination of the literature reveals a weak evidence base supporting treatment practice in this country. The majority of evidence relates to vascular insufficiency and findings from abroad. A brief account will be made of the reasons for this and how the trend is changing. [ABSTRACT FROM AUTHOR]

Writing call options against long positions in the underlying equities is the most popular options strategy. Since the variance is an inadequate measure of risk for options strategies, this paper uses a range of dominance criteria and four utility functions to compare the performance of partly and fully covered call strategies with that of the underlying equity portfolio. It is found that the dominance criteria are ineffective in choosing between strategies. However, all four utility functions (representing different combinations of absolute and relative risk aversion) find that the covered call strategy is preferable for the data period studied, supporting the widespread use of this strategy. [ABSTRACT FROM AUTHOR]

This article analyzes the effects of using averaged rather than unaveraged data on the mean-variance efficient set. If prices follow a particular type of random walk, the mean, variance and covariance of averaged data will differ from those of unaveraged data. The variances and covariances will be only two thirds of the correct value while the mean return will be biased downwards by one sixth of the true variance. This means that the efficient set constants and the investment proportions calculated using averaged data will differ from those using unaveraged data. Therefore, the use of averaged data to construct an efficient portfolio will lead to biased results. The theoretical results depend upon the random walk assumption and they do not quantify the sizes of the bias involved in the efficient set constants and the investment proportions. Therefore, an empirical analysis of international data was conducted to indicate the size of any bias and to investigate the extent to which the bias could be accounted for by the theoretical correction factors. This analysis used efficient sets both when short sales were permitted and when they were not. It was found that the biases involved in using averaged data were fairly large and that, so far as investment proportions are concerned, the adjustments could remove between zero and 40 per cent of this bias.

A common form of non-randomness in stock market returns for a number of countries is negative returns over the weekend. The presence of this effect in the UK is documented for the period 1962–1986. It is then shown that the system of Stock Exchange accounts in the UK provides a partial explanation for this apparent anomaly. Returns on Mondays which are the first day of the account were found to be positive, while the returns on other Mondays were negative. The net effect is a negative return for all Mondays. A trading rule based on these findings is not profitable, although it may be beneficial to alter the timing of transactions. [ABSTRACT FROM AUTHOR]

Objective: This qualitative study applies a community-based participatory research approach to elicit formative data on pediatric patient experiences of racism in the health care setting and to explore clinic-based opportunities for supporting pediatric patients experiencing racism., Methods: The study is situated within the outpatient practice of a large tertiary academic medical center in a midsize Midwestern city. Community partners were involved in all aspects of the research, including research protocol design, recruitment, data analysis, community dissemination, and manuscript preparation. Participants were youth between 11 and 18 years, in middle or high school, self-identifying as a person of color, Latinx or Indigenous who answered yes to the question "have you ever experienced race-related prejudice and discrimination?" Parent/guardians of youth meeting inclusion criteria participated in separate focus groups. Data were analyzed using an interpretative phenomenological analysis approach., Results: Major findings were divided into 2 categories: 1) racism-related experiences in the health care setting; and 2) patient and parent/guardian recommendations to support pediatric patients experiencing racism. Among health care setting experiences, primary emerging themes included racism experienced in the health care setting, patient-clinician communication around racism, patient-clinician concordance, and high-quality clinical care. Recommendations were presented within the 4 domains of racism: intrapersonal, interpersonal, structural, and institutional., Conclusions: Racism experiences worsen child biological, psychological, and behavioral functioning, yet research is lacking on how health care professionals may best support pediatric patients experiencing racism. Study findings suggest opportunities for providing safer and more supportive health care spaces for youth experiencing racism., Competing Interests: Declaration of Competing Interest None., (Copyright © 2024 Academic Pediatric Association. Published by Elsevier Inc. All rights reserved.)

RNA polymerase II (RNAPII) transcription initiates bidirectionally at many human protein-coding genes. Sense transcription usually dominates and leads to messenger RNA production, whereas antisense transcription rapidly terminates. The basis for this directionality is not fully understood. Here, we show that sense transcriptional initiation is more efficient than in the antisense direction, which establishes initial promoter directionality. After transcription begins, the opposing functions of the endonucleolytic subunit of Integrator, INTS11, and cyclin-dependent kinase 9 (CDK9) maintain directionality. Specifically, INTS11 terminates antisense transcription, whereas sense transcription is protected from INTS11-dependent attenuation by CDK9 activity. Strikingly, INTS11 attenuates transcription in both directions upon CDK9 inhibition, and the engineered recruitment of CDK9 desensitises transcription to INTS11. Therefore, the preferential initiation of sense transcription and the opposing activities of CDK9 and INTS11 explain mammalian promoter directionality., Competing Interests: JE, JB, LD, CE, SW No competing interests declared, (© 2024, Eaton, Board et al.)

Objectives: To determine the concordance between activated partial thromboplastin time (aPTT) and anti-factor-Xa (anti-Xa) in adults undergoing extracorporeal membrane oxygenation (ECMO) and to identify the factors associated with discordant paired aPTT/anti-Xa., Design: Pre-planned secondary analysis of the Low-Dose Heparin in Critically Ill Patients Undergoing Extracorporeal Membrane Oxygenation pilot randomized unblinded, parallel-group controlled trial., Setting: Two ICUs in two university hospitals., Patients: Thirty-two critically ill patients who underwent ECMO and who had at least one paired aPTT and anti-Xa assay performed at the same time., Interventions: We analyzed the concordance between aPTT and anti-Xa and identified factors associated with discordant paired aPTT/anti-Xa based on their respective therapeutic ranges. We also compared biological parameters between heparin resistance episode and no heparin resistance., Measurements and Main Results: Of the 32 patients who were included in this study, 24 (75%) had at least one discordant paired aPTT/anti-Xa. Of the 581 paired aPTT/anti-Xa that were analyzed, 202 were discordant. The aPTT was relatively lower than anti-Xa in 66 cases (32.7%) or relatively higher than anti-Xa in 136 cases (67.3%). Thirty-three heparin resistance episodes were identified in six patients (19%)., Conclusions: In these critically ill patients undergoing ECMO, one third of paired aPTT/anti-Xa measures was discordant. Coagulopathy and heparin resistance might be the reasons for discordance. Our results support the potential importance of routinely monitoring both tests in this setting., (Copyright © 2023 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of the Society of Critical Care Medicine.)

Cervical spinal cord injury (SCI) usually results in severe, long-term disability. Early therapeutic hypothermia (33-34°C) has been used to improve outcomes in preclinical studies, but previous clinical studies have commenced cooling after arrival at hospital. The objective of the study is to determine the feasibility and safety of early therapeutic hypothermia initiated by paramedics and maintained for up to 24 hours in hospital in patients with SCI. This is a pilot clinical study. The study was undertaken at Ambulance Victoria and The Alfred Hospital, Victoria, Australia. A total of 17 consecutive patients with suspected acute traumatic cervical SCI were enrolled. Patients with suspected cervical SCI were administered a bolus (up to 20 mL/kg) intravenous (IV) cold (4°C) normal saline in the prehospital phase of care. After hospital admission and spinal imaging, further cooling used IV catheter temperature control or surface cooling. Major complications and long-term outcomes were compared with historical controls admitted to the same center before the study. A decrease in core temperature of 1.1°C was achieved during prehospital care and the target temperature was achieved in 6 hours with mechanical temperature management devices in the hospital. There were no major safety concerns. Patients with motor complete SCI who underwent early decompressive surgery had a favorable rate of partial spinal cord recovery compared with historical controls. Therapeutic hypothermia induced using bolus, large-volume, ice-cold saline prehospital and maintained for 24 hours using mechanical devices appears to be feasible and safe in patients with SCI. Larger trials need to be undertaken to determine whether prehospital cooling combined with early decompressive surgery improves outcomes in patients with complete cervical SCI. Australian and New Zealand Clinical Trials Registry (ACTRN12616001086459).

Objectives: To investigate the association between plasma sodium concentrations and 6-month neurologic outcome in critically ill patients with aneurysmal subarachnoid hemorrhage., Design: Prospective cohort study., Setting: Eleven ICUs in Australia and New Zealand., Participants: Three-hundred fifty-six aneurysmal subarachnoid hemorrhage patients admitted to ICU between March 2016 and June 2018. The exposure variable was daily measured plasma sodium., Interventions: None., Measurements and Main Results: Six-month neurologic outcome as measured by the modified Rankin Scale. A poor outcome was defined as a modified Rankin Scale greater than or equal to 4. The mean age was 57 years (± 12.6 yr), 68% were female, and 32% ( n = 113) had a poor outcome. In multivariable analysis, including age, illness severity, and process of care measures as covariates, higher mean sodium concentrations (odds ratio, 1.17; 95% CI, 1.05-1.29), and greater overall variability-as measured by the sd (odds ratio, 1.53; 95% CI, 1.17-1.99)-were associated with a greater likelihood of a poor outcome. Multivariable generalized additive modeling demonstrated, specifically, that a high initial sodium concentration, followed by a gradual decline from day 3 onwards, was also associated with a poor outcome. Finally, greater variability in sodium concentrations was associated with a longer ICU and hospital length of stay: mean ICU length of stay ratio (1.13; 95% CI, 1.07-1.20) and mean hospital length of stay ratio (1.08; 95% CI, 1.01-1.15)., Conclusions: In critically ill aneurysmal subarachnoid hemorrhage patients, higher mean sodium concentrations and greater variability were associated with worse neurologic outcomes at 6 months, despite adjustment for known confounders. Interventional studies would be required to demonstrate a causal relationship., Competing Interests: The authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2021 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of the Society of Critical Care Medicine.)

Importance: Evidence regarding corticosteroid use for severe coronavirus disease 2019 (COVID-19) is limited., Objective: To determine whether hydrocortisone improves outcome for patients with severe COVID-19., Design, Setting, and Participants: An ongoing adaptive platform trial testing multiple interventions within multiple therapeutic domains, for example, antiviral agents, corticosteroids, or immunoglobulin. Between March 9 and June 17, 2020, 614 adult patients with suspected or confirmed COVID-19 were enrolled and randomized within at least 1 domain following admission to an intensive care unit (ICU) for respiratory or cardiovascular organ support at 121 sites in 8 countries. Of these, 403 were randomized to open-label interventions within the corticosteroid domain. The domain was halted after results from another trial were released. Follow-up ended August 12, 2020., Interventions: The corticosteroid domain randomized participants to a fixed 7-day course of intravenous hydrocortisone (50 mg or 100 mg every 6 hours) (n = 143), a shock-dependent course (50 mg every 6 hours when shock was clinically evident) (n = 152), or no hydrocortisone (n = 108)., Main Outcomes and Measures: The primary end point was organ support-free days (days alive and free of ICU-based respiratory or cardiovascular support) within 21 days, where patients who died were assigned -1 day. The primary analysis was a bayesian cumulative logistic model that included all patients enrolled with severe COVID-19, adjusting for age, sex, site, region, time, assignment to interventions within other domains, and domain and intervention eligibility. Superiority was defined as the posterior probability of an odds ratio greater than 1 (threshold for trial conclusion of superiority >99%)., Results: After excluding 19 participants who withdrew consent, there were 384 patients (mean age, 60 years; 29% female) randomized to the fixed-dose (n = 137), shock-dependent (n = 146), and no (n = 101) hydrocortisone groups; 379 (99%) completed the study and were included in the analysis. The mean age for the 3 groups ranged between 59.5 and 60.4 years; most patients were male (range, 70.6%-71.5%); mean body mass index ranged between 29.7 and 30.9; and patients receiving mechanical ventilation ranged between 50.0% and 63.5%. For the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively, the median organ support-free days were 0 (IQR, -1 to 15), 0 (IQR, -1 to 13), and 0 (-1 to 11) days (composed of 30%, 26%, and 33% mortality rates and 11.5, 9.5, and 6 median organ support-free days among survivors). The median adjusted odds ratio and bayesian probability of superiority were 1.43 (95% credible interval, 0.91-2.27) and 93% for fixed-dose hydrocortisone, respectively, and were 1.22 (95% credible interval, 0.76-1.94) and 80% for shock-dependent hydrocortisone compared with no hydrocortisone. Serious adverse events were reported in 4 (3%), 5 (3%), and 1 (1%) patients in the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively., Conclusions and Relevance: Among patients with severe COVID-19, treatment with a 7-day fixed-dose course of hydrocortisone or shock-dependent dosing of hydrocortisone, compared with no hydrocortisone, resulted in 93% and 80% probabilities of superiority with regard to the odds of improvement in organ support-free days within 21 days. However, the trial was stopped early and no treatment strategy met prespecified criteria for statistical superiority, precluding definitive conclusions., Trial Registration: ClinicalTrials.gov Identifier: NCT02735707.

Purpose: To determine the diagnostic and prognostic value of glial fibrillary acidic protein (GFAP) and S100B after traumatic brain injury (TBI) in an Erythropoietin (EPO) clinical trial and examine whether EPO therapy reduces biomarker concentrations., Materials and Methods: Forty-four patients with moderate-to-severe TBI were enrolled to a sub-study of the EPO-TBI trial. Patients were randomized to either Epoetin alfa 40,000 IU or 1 ml sodium chloride 0.9 as subcutaneous injection within 24 h of TBI., Results: GFAP and S100B were measured in serum by ELISA from D0 (within 24 h of injury, prior to EPO/vehicle administration) to D5. Biomarker concentrations were compared between injury severities, diffuse vs. focal TBI, 6-month outcome scores (GOS-E) and EPO or placebo treatments. At D0 GFAP was significantly higher than S100B (951 pg/mL vs. 476 pg/mL, p = 0.018). ROC analysis of S100B at 1D post-injury distinguished favorable vs. unfavorable outcomes (area under the curve = 0.73; p = 0.01). EPO did not reduce concentration of either biomarker., Conclusions: Elevated serum concentrations of GFAP and S100B after TBI reflect a robust, acute glial response to injury. Consistent with lack of improved outcome in TBI patients treated with EPO and prior findings on neuronal and axonal markers, glial biomarker concentrations and acute profiles were not affected by EPO., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: In critically ill patients, who require multiple blood gas assessments, agreement between arterial and venous blood gas values for pH and partial pressure of carbon dioxide, is not clear. Good agreement would mean that venous values could be used to assess ventilation and metabolic status of patients in intensive care unit., Methods: All adult patients admitted to Alfred intensive care unit, Melbourne, from February 2013 to January 2014, who were likely to have arterial and central venous lines for three days, were enrolled. Patients on extra-corporeal life support and pregnant women were excluded. After enrolment, near simultaneous arterial and central venous sampling and analysis were performed at least once per nursing shift till the lines were removed or the patient died. Bland-Altman analysis for repeated measures was performed to assess the agreement between arterio-venous pH and partial pressure of carbon dioxide., Results: A total of 394 paired blood gas analyses were performed from 59 participants. The median (IQR) number of samples per patient was 6 (5-9) with the median (IQR) sampling interval 9.4 (5.2-18.5) h. The mean bias for pH was  + 0.036 with 95% limits of agreement ranging from - 0.005 to + 0.078. For partial pressure of carbon dioxide, the values were -2.58 and -10.43 to + 5.27 mmHg, respectively., Conclusions: The arterio-venous agreement for pH in intensive care unit patients appears to be acceptable. However, the agreement for partial pressure of carbon dioxide was poor., (© The Intensive Care Society 2019.)

Purpose  This study aims to quantify the distances between the cortex of the distal radius and flexor and extensor tendons. Methods  We analyzed 50 magnetic resonance images (MRI) of intact wrist without pathology. The distances between the volar cortex and the flexor pollicis longs (FPL), index flexor digitorum profunduns (FDPi), flexor digitorum profundus (FDP), and flexor digitorum superficialis (FDS) were measured at the level of the watershed line and 3- and 6-mm proximal to this level. The distances between the dorsal cortex and the extensor carpi radialis longus (ECRL), extensor carpi radialis brevis (ECRB), extensor pollicis longus (EPL), extensor indicis proprius (EIP), and the extensor digitorum communis (EDC) were measured at the level of Lister's tubercle and 5-mm distal to this level. Analysis was descriptive. Results  At the watershed line, the FPL, FDPi, FDP, and FDS were located at an average of 3.1, 2.4, 3.6, and 5.1 mm, respectively, volar to the volar cortex. The distances of the FDP and FDS increased at 3-mm proximal to the watershed line and increased for all four tendons at 6-mm proximal to the watershed line. Dorsally, at Listers' tubercle the ECRL, ECRB, EPL, EIP, and EDC were identified at an average of 0.7, 0.5, 0.5, 2.6, and 3.2 mm, respectively, dorsal to the dorsal cortex of the distal radius. At 5-mm more distal, these tendons were located on average 1.2, 1.0, 0.7, 1.9, and 1.8 mm, respectively, dorsal to the dorsal cortex. Conclusion  On the volar side, on average there is enough room for a volar plate when staying proximal to the watershed line. On the dorsal side, there is virtually no room for protruding screws as physical anatomical space is limited to a maximum of 0.7 mm from cortex to the closest tendon (the FDP), with screw increments being 2 mm. Level of Evidence  This is a Level II Study., Competing Interests: Conflict of Interest None declared., (© Thieme Medical Publishers.)

Objectives: To determine whether randomization of patients undergoing extracorporeal membrane oxygenation to either therapeutic or a low-dose anticoagulation protocol results in a difference in activated partial thromboplastin time and anti-Xa., Design: Randomized, controlled, unblinded study., Setting: Two ICUs of two university hospitals., Patients: Patients admitted to the ICU, who required extracorporeal membrane oxygenation (venovenous or venoarterial) and who did not have a preexisting indication for therapeutic anticoagulation., Interventions: Therapeutic anticoagulation with heparin (target activated partial thromboplastin time between 50 and 70 s) or lower dose heparin (up to 12,000 U/24 hr aiming for activated partial thromboplastin time < 45 s)., Measurements and Main Results: Thirty-two patients were randomized into two study groups that were not significantly different in demographics and extracorporeal membrane oxygenation characteristics. There was a significant difference in the daily geometric mean heparin dose (11,742 U [95% CI, 8,601-16,031 U] vs 20,710 U [95% CI, 15,343-27,954 U]; p = 0.004), daily geometric mean activated partial thromboplastin time (48.1 s [95% CI, 43.5-53.2 s] vs 55.5 s [95% CI, 50.4-61.2 s]; p = 0.04), and daily geometric mean anti-Xa (0.11 international units/mL [95% CI, 0.07-0.18] vs 0.27 [95% CI, 0.17-0.42]; p = 0.01). We found similar results when considering only venovenous extracorporeal membrane oxygenation episodes; however, no difference in daily geometric mean activated partial thromboplastin time between groups when considering only venoarterial extracorporeal membrane oxygenation episodes., Conclusions: Allocating patients on extracorporeal membrane oxygenation to two different anticoagulation protocols led to a significant difference in mean daily activated partial thromboplastin time and anti-Xa levels between groups. When considering subgroups analyses, these results were consistent in patients on venovenous extracorporeal membrane oxygenation. Our results support the feasibility of a larger trial in patients undergoing venovenous extracorporeal membrane oxygenation to compare different anticoagulation protocols; however, this study does not provide evidence on the optimal anticoagulation protocol for patients undergoing extracorporeal membrane oxygenation.

A general synthesis of highly substituted 2-naphthols based on a new carbanionic reaction sequence is demonstrated. The reaction exploits the dual nature of lithium bases consisting of consecutive ring opening of readily available coumarins with either LiNEt 2 or LiNiPr 2 into Z-cinnamamides, thus generating a directing group in situ and allowing, by conformational freedom, a lateral directed remote metalation for ring closure to give the aryl 2-naphthols in good to excellent yields. These transformations can be combined to provide a more efficient one-pot process. Mechanistic insight into the remote lateral metalation step, demonstrating the requirement of Z-cinnamamide, is described. Application of this methodology to the synthesis of highly substituted 3,3'-diaryl BINOL ligands is also reported., (© 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Objective: To determine profiles of serum ubiquitin carboxy-terminal hydrolase L1 and phosphorylated neurofilament heavy-chain, examine whether erythropoietin administration reduce their concentrations, and whether biomarkers discriminate between erythropoietin and placebo treatment groups., Design: Single-center, prospective observational study., Setting: A sub-study of the erythropoietin-traumatic brain injury clinical trial, conducted at the Alfred Hospital, Melbourne, Australia., Patients: Forty-four patients with moderate-to-severe traumatic brain injury., Interventions: Epoetin alfa 40,000 IU or 1 mL sodium chloride 0.9 as subcutaneous injection within 24 hours of traumatic brain injury., Measurements and Main Results: Ubiquitin carboxy-terminal hydrolase L1, phosphorylated neurofilament heavy-chain, and erythropoietin concentrations were measured in serum by enzyme-linked immunosorbent assay from D0 (within 24 hr of injury, prior to erythropoietin/vehicle administration) to D5. Biomarker concentrations were compared between injury severities, diffuse versus focal traumatic brain injury and erythropoietin or placebo treatment groups. Ubiquitin carboxy-terminal hydrolase L1 peaked at 146.0 ng/mL on D0, significantly decreased to 84.30 ng/mL on D1, and declined thereafter. Phosphorylated neurofilament heavy-chain levels were lowest at D0 and peaked on D5 at 157.9 ng/mL. D0 ubiquitin carboxy-terminal hydrolase L1 concentrations were higher in diffuse traumatic brain injury. Peak phosphorylated neurofilament heavy-chain levels on D3 and D4 correlated with Glasgow Outcome Score-Extended, predicting poor outcome. Erythropoietin did not reduce concentrations of ubiquitin carboxy-terminal hydrolase L1 or phosphorylated neurofilament heavy-chain., Conclusions: Serum ubiquitin carboxy-terminal hydrolase L1 and phosphorylated neurofilament heavy-chain increase after traumatic brain injury reflecting early neuronal and progressive axonal injury. Consistent with lack of improved outcome in traumatic brain injury patients treated with erythropoietin, biomarker concentrations and profiles were not affected by erythropoietin. Pharmacokinetics of erythropoietin suggest that the dose given was possibly too low to exert neuroprotection.

A cascade reaction has been developed for the synthesis of lactonamycin. In this paper, we demonstrate that a transition-metal-free thermal ene-diyne cyclization can be used for the construction of the entire core of the antibiotic lactonamycin and anticancer agent lactonamycin Z.

Homology modelling can provide important insights into the structures of proteins when a related protein structure has already been solved. However, for many proteins, including a number of invertebrate-active toxins and accessory proteins, no such templates exist. In these cases, techniques of ab initio, template-independent modelling can be employed to generate models that may give insight into structure and function. In this overview, examples of both the problems and the potential benefits of ab initio techniques are illustrated. Consistent modelling results may indicate useful approximations to actual protein structures and can thus allow the generation of hypotheses regarding activity that can be tested experimentally., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: The Cry6 family of proteins from Bacillus thuringiensis represents a group of powerful toxins with great potential for use in the control of coleopteran insects and of nematode parasites of importance to agriculture. These proteins are unrelated to other insecticidal toxins at the level of their primary sequences and the structure and function of these proteins has been poorly studied to date. This has inhibited our understanding of these toxins and their mode of action, along with our ability to manipulate the proteins to alter their activity to our advantage. To increase our understanding of their mode of action and to facilitate further development of these proteins we have determined the structure of Cry6Aa in protoxin and trypsin-activated forms and demonstrated a pore-forming mechanism of action., Results: The two forms of the toxin were resolved to 2.7 Å and 2.0 Å respectively and showed very similar structures. Cry6Aa shows structural homology to a known class of pore-forming toxins including hemolysin E from Escherichia coli and two Bacillus cereus proteins: the hemolytic toxin HblB and the NheA component of the non-hemolytic toxin (pfam05791). Cry6Aa also shows atypical features compared to other members of this family, including internal repeat sequences and small loop regions within major alpha helices. Trypsin processing was found to result in the loss of some internal sequences while the C-terminal region remains disulfide-linked to the main core of the toxin. Based on the structural similarity of Cry6Aa to other toxins, the mechanism of action of the toxin was probed and its ability to form pores in vivo in Caenorhabditis elegans was demonstrated. A non-toxic mutant was also produced, consistent with the proposed pore-forming mode of action., Conclusions: Cry6 proteins are members of the alpha helical pore-forming toxins - a structural class not previously recognized among the Cry toxins of B. thuringiensis and representing a new paradigm for nematocidal and insecticidal proteins. Elucidation of both the structure and the pore-forming mechanism of action of Cry6Aa now opens the way to more detailed analysis of toxin specificity and the development of new toxin variants with novel activities.