Aquatic Exercise Compared to Contrast Therapy With Shallow Water Treadmill Running to Assist Recovery in Elite Australian Rules Footballers

The purpose of this pilot exploratory study was to determine any immediate effects of a session of aquatic exercise (AE) compared to contrast therapy shallow water treadmill running (CSWR). Twenty-nine elite footballers were allocated randomly to AE or CSWR, 48 hours after a practice match. Outcome measures included maximum vertical jump height; visual analogue scale (VAS) for pain; the squeeze test for adductor strength, sit and reach test, plus ankle and hip range of movement. A significant difference between groups was found for maximum vertical jump height with the AE group being able to jump higher after the intervention (95% CI [-8.63 to -1.28]). No other significant differences between groups were detected for any outcome. Significant within group effects were found for the CSWR group in improving sit and reach (p = 0.04), and reducing pain when performing the squeeze test (p = 0.02). Both interventions may have improved aspects of performance; however, more highly powered trials, incorporating a control group, need to be conducted

IgG light chain-independent secretion of heavy chain dimers: consequence for therapeutic antibody production and design

Rodent monoclonal antibodies with specificity towards important biological targets are developed for therapeutic use by a process of humanisation. This process involves the creation of molecules, which retain the specificity of the rodent antibody but contain predominantly human coding sequence. Here we show that some humanised heavy chains can fold, form dimers and be secreted even in the absence of light chain. Quality control of recombinant antibody assembly in vivo is thought to rely upon folding of the heavy chain CH1 domain. This domain acts as a switch for secretion, only folding upon interaction with the light chain CL domain. We show that the secreted heavy-chain dimers contain folded CH1 domains and contribute to the heterogeneity of antibody species secreted during the expression of therapeutic antibodies. This subversion of the normal quality control process is dependent upon the heavy chain variable domain, is prevalent with engineered antibodies and can occur when only the Fab fragments are expressed. This discovery will impact on the efficient production of both humanised antibodies as well as the design of novel antibody formats

The rational design of affinity attenuated OmCI for the purification of Complement C5

Complement component C5 is the target of the monoclonal antibody Eculizumab, and the focus of a sustained drug discovery effort to prevent complement-induced inflammation in a range of autoimmune diseases. The immune evasion protein OmCI binds to, and potently inactivates, C5; this tight-binding interaction can be exploited to affinity-purify C5 protein from serum, offering a vastly simplified protocol compared to existing methods. However, breaking the high-affinity interaction requires conditions which risk denaturing or activating C5. We performed structure-guided in silico mutagenesis to identify prospective OmCI residues that contribute significantly to the binding affinity. We tested our predictions in vitro, using site directed mutagenesis, and characterised mutants using a range of biophysical techniques as well as functional assays. Our biophysical analyses suggest the C5-OmCI interaction is complex with potential for multiple binding modes.We present single mutations that lower the affinity of OmCI for C5 and combinations of mutations that significantly decrease, or entirely abrogate, formation of the complex. The affinity attenuated forms of OmCI are suitable for affinity purification and allow elution under mild conditions that are non-denaturing or activating to C5. We present the rational design, biophysical characterisation and experimental validation of affinity reduced forms of OmCI as tool reagents to enable the affinity purification of C5.</p

Experimental study of the hydrodynamic behaviour of slug flow in a horizontal pipe

This paper investigates the unsteady hydrodynamic behaviour of slug flow occurring within an air–silicone oil mixture, within a horizontal 67 mm internal diameter pipe. A series of slug flow regime experiments were performed for a range of injected air superficial velocities (0.29–1.4 m s−1) and for liquid flows with superficial velocities of between 0.05–0.47 m s−1. A pair of Electrical Capacitance Tomography (ECT) probes was used to determine: the slug translational velocities of the elongated bubbles and liquid slugs, the slug frequencies, the lengths of elongated bubbles and the liquid slugs, the void fractions within the elongated bubbles and liquid slugs. The pressure drop experienced along the pipe was measured using a differential pressure transducer cell (DP cell). A comparative analysis of the current experimental data and that previously published experimental confirms good agreement

Cystatin C is glucocorticoid responsive, directs recruitment of Trem2+ macrophages, and predicts failure of cancer immunotherapy

Cystatin C (CyC), a secreted cysteine protease inhibitor, has unclear biological functions. Many patients exhibit elevated plasma CyC levels, particularly during glucocorticoid (GC) treatment. This study links GCs with CyC’s systemic regulation by utilizing genome-wide association and structural equation modeling to determine CyC production genetics in the UK Biobank. Both CyC production and a polygenic score (PGS) capturing predisposition to CyC production were associated with increased all-cause and cancer-specific mortality. We found that the GC receptor directly targets CyC, leading to GC-responsive CyC secretion in macrophages and cancer cells. CyC-knockout tumors displayed significantly reduced growth and diminished recruitment of TREM2+ macrophages, which have been connected to cancer immunotherapy failure. Furthermore, the CyC-production PGS predicted checkpoint immunotherapy failure in 685 patients with metastatic cancer from combined clinical trial cohorts. In conclusion, CyC may act as a GC effector pathway via TREM2+ macrophage recruitment and may be a potential target for combination cancer immunotherapy.publishedVersio

Human Resource and Funding Constraints for Essential Surgery in District Hospitals in Africa: A Retrospective Cross-Sectional Survey

In the second of two papers investigating surgical provision in eight district hospitals in Saharan African countries, Margaret Kruk and colleagues describe the range of providers of surgical care and anesthesia and estimate the related costs

Effect of hydrogen addition on criteria and greenhouse gas emissions for a marine diesel engine

Hydrogen remains an attractive alternative fuel to petroleum and a number of investigators claim that adding hydrogen to the air intake manifold of a diesel engine will reduce criteria emissions and diesel fuel consumption. Such claims are appealing when trying to simultaneously reduce petroleum consumption, greenhouse gases and criteria pollutants. The goal of this research was to measure the change in criteria emissions (CO, NOx, and PM 2.5) and greenhouse gases such as carbon dioxide (CO2), using standard test methods for a wide range of hydrogen addition rates. A two-stroke Detroit Diesel Corporation 12V-71TI marine diesel engine was mounted on an engine dynamometer and tested at three out of the four loads specified in the ISO 8178-4 E3 emission test cycle and at idle. The engine operated on CARB ultra-low sulfur #2 diesel with hydrogen added at flow rates of 0, 22 and 220 SLPM. As compared with the base case without hydrogen, measurements showed that hydrogen injection at 22 and 220 SLPM had negligible influence on the overall carbon dioxide specific emission, EFCO2. However, in examining data at each load the data revealed that at idle EFCO2 was reduced by 21% at 22 SLPM (6.9% of the added fuel energy was from hydrogen) and 37.3% at 220 SLPM (103.1% of the added fuel energy was from hydrogen). At all other loads, the influence of added hydrogen was insignificant. Specific emissions for nitrogen oxides, EFNOx, and fine particulate matters, EFPM 2.5, showed a trade-off relationship at idle. At idle, EFNO x was reduced by 28% and 41% with increasing hydrogen flow rates, whilst EFPM2.5 increased by 41% and 86% respectively. For other engine loads, EFNOx and EFPM2.5 did not change significantly with varying hydrogen flow rates. One of the main reasons for the greater impact of hydrogen at idle is that the contribution of hydrogen to the total fuel energy is much higher at idle as compared to the other loads. The final examination in this paper was the system energy balance when hydrogen is produced by an on-board electrolysis unit. An analysis at 75% engine load showed that hydrogen production increased the overall equivalent fuel consumption by 2.6% at 22 SLPM and 17.7% at 220 SLPM. © 2014, Hydrogen Energy Publications, LLC. Published by Elsevier Ltd. All rights reserved

Laparoscopy in management of appendicitis in high-, middle-, and low-income countries: a multicenter, prospective, cohort study.

BACKGROUND: Appendicitis is the most common abdominal surgical emergency worldwide. Differences between high- and low-income settings in the availability of laparoscopic appendectomy, alternative management choices, and outcomes are poorly described. The aim was to identify variation in surgical management and outcomes of appendicitis within low-, middle-, and high-Human Development Index (HDI) countries worldwide. METHODS: This is a multicenter, international prospective cohort study. Consecutive sampling of patients undergoing emergency appendectomy over 6 months was conducted. Follow-up lasted 30 days. RESULTS: 4546 patients from 52 countries underwent appendectomy (2499 high-, 1540 middle-, and 507 low-HDI groups). Surgical site infection (SSI) rates were higher in low-HDI (OR 2.57, 95% CI 1.33-4.99, p = 0.005) but not middle-HDI countries (OR 1.38, 95% CI 0.76-2.52, p = 0.291), compared with high-HDI countries after adjustment. A laparoscopic approach was common in high-HDI countries (1693/2499, 67.7%), but infrequent in low-HDI (41/507, 8.1%) and middle-HDI (132/1540, 8.6%) groups. After accounting for case-mix, laparoscopy was still associated with fewer overall complications (OR 0.55, 95% CI 0.42-0.71, p < 0.001) and SSIs (OR 0.22, 95% CI 0.14-0.33, p < 0.001). In propensity-score matched groups within low-/middle-HDI countries, laparoscopy was still associated with fewer overall complications (OR 0.23 95% CI 0.11-0.44) and SSI (OR 0.21 95% CI 0.09-0.45). CONCLUSION: A laparoscopic approach is associated with better outcomes and availability appears to differ by country HDI. Despite the profound clinical, operational, and financial barriers to its widespread introduction, laparoscopy could significantly improve outcomes for patients in low-resource environments. TRIAL REGISTRATION: NCT02179112

The development and validation of a scoring tool to predict the operative duration of elective laparoscopic cholecystectomy

Background: The ability to accurately predict operative duration has the potential to optimise theatre efficiency and utilisation, thus reducing costs and increasing staff and patient satisfaction. With laparoscopic cholecystectomy being one of the most commonly performed procedures worldwide, a tool to predict operative duration could be extremely beneficial to healthcare organisations. Methods: Data collected from the CholeS study on patients undergoing cholecystectomy in UK and Irish hospitals between 04/2014 and 05/2014 were used to study operative duration. A multivariable binary logistic regression model was produced in order to identify significant independent predictors of long (> 90 min) operations. The resulting model was converted to a risk score, which was subsequently validated on second cohort of patients using ROC curves. Results: After exclusions, data were available for 7227 patients in the derivation (CholeS) cohort. The median operative duration was 60 min (interquartile range 45–85), with 17.7% of operations lasting longer than 90 min. Ten factors were found to be significant independent predictors of operative durations > 90 min, including ASA, age, previous surgical admissions, BMI, gallbladder wall thickness and CBD diameter. A risk score was then produced from these factors, and applied to a cohort of 2405 patients from a tertiary centre for external validation. This returned an area under the ROC curve of 0.708 (SE = 0.013, p  90 min increasing more than eightfold from 5.1 to 41.8% in the extremes of the score. Conclusion: The scoring tool produced in this study was found to be significantly predictive of long operative durations on validation in an external cohort. As such, the tool may have the potential to enable organisations to better organise theatre lists and deliver greater efficiencies in care

Pooled analysis of WHO Surgical Safety Checklist use and mortality after emergency laparotomy

Background The World Health Organization (WHO) Surgical Safety Checklist has fostered safe practice for 10 years, yet its place in emergency surgery has not been assessed on a global scale. The aim of this study was to evaluate reported checklist use in emergency settings and examine the relationship with perioperative mortality in patients who had emergency laparotomy. Methods In two multinational cohort studies, adults undergoing emergency laparotomy were compared with those having elective gastrointestinal surgery. Relationships between reported checklist use and mortality were determined using multivariable logistic regression and bootstrapped simulation. Results Of 12 296 patients included from 76 countries, 4843 underwent emergency laparotomy. After adjusting for patient and disease factors, checklist use before emergency laparotomy was more common in countries with a high Human Development Index (HDI) (2455 of 2741, 89.6 per cent) compared with that in countries with a middle (753 of 1242, 60.6 per cent; odds ratio (OR) 0.17, 95 per cent c.i. 0.14 to 0.21, P <0001) or low (363 of 860, 422 per cent; OR 008, 007 to 010, P <0.001) HDI. Checklist use was less common in elective surgery than for emergency laparotomy in high-HDI countries (risk difference -94 (95 per cent c.i. -11.9 to -6.9) per cent; P <0001), but the relationship was reversed in low-HDI countries (+121 (+7.0 to +173) per cent; P <0001). In multivariable models, checklist use was associated with a lower 30-day perioperative mortality (OR 0.60, 0.50 to 073; P <0.001). The greatest absolute benefit was seen for emergency surgery in low- and middle-HDI countries. Conclusion Checklist use in emergency laparotomy was associated with a significantly lower perioperative mortality rate. Checklist use in low-HDI countries was half that in high-HDI countries.Peer reviewe