Temporal shifts in prokaryotic metabolism in response to organic carbon dynamics in the mesopelagic ocean during an export event in the Southern ocean

As the major term in downward organic carbon flux attenuation, determining prokaryotic metabolism over depth in the mesopelagic ocean is crucial for constraining the efficiency of the gravitational biological carbon pump (BCP). We hypothesize that the enhancement of particulate organic carbon (POC) concentrations in the mesopelagic twilight zone during export events leads to a temporally dynamic prokaryotic metabolic response, which likely has consequences for the efficiency of the BCP. We tested this hypothesis by making repeated measurements of leucine assimilation and leucine respiration at in situ concentrations over six depths throughout the upper 500 m of the water column during the collapse of a large-scale Southern Ocean spring diatom bloom. Rates of prokaryotic leucine assimilation were used to indicate levels of prokaryotic heterotrophic production, and leucine assimilation efficiency (LAE; the proportion of leucine used for growth versus respiration) was taken as an indicator of prokaryotic growth efficiency. Thus, relative shifts in LAE are indicative of shifts in rates of prokaryotic production relative to respiration. The flux of POC through the oceans’ interior led to a dynamic prokaryotic response, characterized by a temporary elevation in mesopelagic prokaryote leucine assimilation rates, LAE and prokaryotic abundance. By the final measurement these changes had already begun to revert, despite POC concentrations still being enriched. As hypothesized, our data revealed distinctions in the phases of the mesopelagic system, likely due to an evolution in bulk prokaryotic metabolic status and the amount and composition of organic matter available. This indicates that estimating ocean carbon sequestration during export events necessitates a time course of measurements throughout the period of POC downward flux. Our findings also revealed distinctions in the ecophysiological prokaryotic responses to substrate regimes between the surface mixed layer and the mesopelagic. Specifically, in the latter in situ leucine concentrations appeared more significant in controlling prokaryote metabolism than POC concentration, and were more closely related to per cell leucine assimilation, than respiration. Whereas, in the mixed layer, the concentration of in situ leucine did not seem to drive rates of its assimilation, rather POC concentration was a strong negative driver of cell specific leucine respiration. These findings are suggestive of stronger levels of energy limitation in the deeper ocean. We surmised that ocean regions with sporadic substrate supply to the mesopelagic are likely to experience stronger energy limitation which favors prokaryotic respiration over production

Surgical site infection after gastrointestinal surgery in high-income, middle-income, and low-income countries: a prospective, international, multicentre cohort study

Background: Surgical site infection (SSI) is one of the most common infections associated with health care, but its importance as a global health priority is not fully understood. We quantified the burden of SSI after gastrointestinal surgery in countries in all parts of the world. Methods: This international, prospective, multicentre cohort study included consecutive patients undergoing elective or emergency gastrointestinal resection within 2-week time periods at any health-care facility in any country. Countries with participating centres were stratified into high-income, middle-income, and low-income groups according to the UN's Human Development Index (HDI). Data variables from the GlobalSurg 1 study and other studies that have been found to affect the likelihood of SSI were entered into risk adjustment models. The primary outcome measure was the 30-day SSI incidence (defined by US Centers for Disease Control and Prevention criteria for superficial and deep incisional SSI). Relationships with explanatory variables were examined using Bayesian multilevel logistic regression models. This trial is registered with ClinicalTrials.gov, number NCT02662231. Findings: Between Jan 4, 2016, and July 31, 2016, 13 265 records were submitted for analysis. 12 539 patients from 343 hospitals in 66 countries were included. 7339 (58·5%) patient were from high-HDI countries (193 hospitals in 30 countries), 3918 (31·2%) patients were from middle-HDI countries (82 hospitals in 18 countries), and 1282 (10·2%) patients were from low-HDI countries (68 hospitals in 18 countries). In total, 1538 (12·3%) patients had SSI within 30 days of surgery. The incidence of SSI varied between countries with high (691 [9·4%] of 7339 patients), middle (549 [14·0%] of 3918 patients), and low (298 [23·2%] of 1282) HDI (p < 0·001). The highest SSI incidence in each HDI group was after dirty surgery (102 [17·8%] of 574 patients in high-HDI countries; 74 [31·4%] of 236 patients in middle-HDI countries; 72 [39·8%] of 181 patients in low-HDI countries). Following risk factor adjustment, patients in low-HDI countries were at greatest risk of SSI (adjusted odds ratio 1·60, 95% credible interval 1·05–2·37; p=0·030). 132 (21·6%) of 610 patients with an SSI and a microbiology culture result had an infection that was resistant to the prophylactic antibiotic used. Resistant infections were detected in 49 (16·6%) of 295 patients in high-HDI countries, in 37 (19·8%) of 187 patients in middle-HDI countries, and in 46 (35·9%) of 128 patients in low-HDI countries (p < 0·001). Interpretation: Countries with a low HDI carry a disproportionately greater burden of SSI than countries with a middle or high HDI and might have higher rates of antibiotic resistance. In view of WHO recommendations on SSI prevention that highlight the absence of high-quality interventional research, urgent, pragmatic, randomised trials based in LMICs are needed to assess measures aiming to reduce this preventable complication

New models for the development of and access to CAR T-cell therapies for children and adolescents with cancer: an ACCELERATE multistakeholder analysis

Realising the potentially substantial benefits of chimeric antigen receptor (CAR) T-cell therapy for children with cancer is hindered by non-scientific barriers that are also relevant for other rare diseases. A solely commercial development model will not deliver optimally due to insufficient return on investment for pharmaceutical companies. Access to therapies is restricted for patients who might benefit and advancing innovation in the academic research setting is difficult. Challenges relating to CAR T-cell therapies in paediatric malignancies and how they might be addressed were discussed in a meeting convened by ACCELERATE—an international multistakeholder organisation aiming to advance the timely investigation of new anticancer drugs. New academic and biopharma hybrid development models could benefit rare populations and coordination of early development can promote synergy and avoid duplicative efforts. Following promising first-in-child trials, new models are needed to support pivotal trials, decentralised manufacturing, registration, and reduced costs. The European Medicines Agency and the US Food and Drug Administration encourage academic development and early discussions. A biotech company funded via a pooled investment vehicle could provide access to safe and effective products for children and adolescents with cancer through registration and reimbursement

Surgical site infection after gastrointestinal surgery in children : an international, multicentre, prospective cohort study

Introduction Surgical site infection (SSI) is one of the most common healthcare-associated infections (HAIs). However, there is a lack of data available about SSI in children worldwide, especially from low-income and middle-income countries. This study aimed to estimate the incidence of SSI in children and associations between SSI and morbidity across human development settings. Methods A multicentre, international, prospective, validated cohort study of children aged under 16 years undergoing clean-contaminated, contaminated or dirty gastrointestinal surgery. Any hospital in the world providing paediatric surgery was eligible to contribute data between January and July 2016. The primary outcome was the incidence of SSI by 30 days. Relationships between explanatory variables and SSI were examined using multilevel logistic regression. Countries were stratified into high development, middle development and low development groups using the United Nations Human Development Index (HDI). Results Of 1159 children across 181 hospitals in 51 countries, 523 (45 center dot 1%) children were from high HDI, 397 (34 center dot 2%) from middle HDI and 239 (20 center dot 6%) from low HDI countries. The 30-day SSI rate was 6.3% (33/523) in high HDI, 12 center dot 8% (51/397) in middle HDI and 24 center dot 7% (59/239) in low HDI countries. SSI was associated with higher incidence of 30-day mortality, intervention, organ-space infection and other HAIs, with the highest rates seen in low HDI countries. Median length of stay in patients who had an SSI was longer (7.0 days), compared with 3.0 days in patients who did not have an SSI. Use of laparoscopy was associated with significantly lower SSI rates, even after accounting for HDI. Conclusion The odds of SSI in children is nearly four times greater in low HDI compared with high HDI countries. Policies to reduce SSI should be prioritised as part of the wider global agenda.Peer reviewe

Tropospheric Aqueous-Phase Chemistry: Kinetics, Mechanisms, and Its Coupling to a Changing Gas Phase

[no abstract available

Development and external validation of the 'Global Surgical-Site Infection' (GloSSI) predictive model in adult patients undergoing gastrointestinal surgery

Background Identification of patients at high risk of surgical-site infections may allow surgeons to minimize associated morbidity. However, there are significant concerns regarding the methodological quality and transportability of models previously developed. The aim of this study was to develop a novel score to predict 30-day surgical-site infection risk after gastrointestinal surgery across a global context and externally validate against existing models. Methods This was a secondary analysis of two prospective international cohort studies: GlobalSurg-1 (July–November 2014) and GlobalSurg-2 (January–July 2016). Consecutive adults undergoing gastrointestinal surgery were eligible. Model development was performed using GlobalSurg-2 data, with novel and previous scores externally validated using GlobalSurg-1 data. The primary outcome was 30-day surgical-site infections, with two predictive techniques explored: penalized regression (least absolute shrinkage and selection operator (‘LASSO’)) and machine learning (extreme gradient boosting (‘XGBoost’)). Final model selection was based on prognostic accuracy and clinical utility. Results There were 14 019 patients (surgical-site infections = 12.3%) for derivation and 8464 patients (surgical-site infections = 11.4%) for external validation. The LASSO model was selected due to similar discrimination to extreme gradient boosting (AUC 0.738 (95% c.i. 0.725 to 0.750) versus 0.737 (95% c.i. 0.709 to 0.765)), but greater explainability. The final score included six variables: country income, ASA grade, diabetes, and operative contamination, approach, and duration. Model performance remained good on external validation (AUC 0.730 (95% c.i. 0.715 to 0.744); calibration intercept −0.098 and slope 1.008) and demonstrated superior performance to the external validation of all previous models. Conclusion The ‘Global Surgical-Site Infection’ score allows accurate prediction of the risk of surgical-site infections with six simple variables that are routinely available at the time of surgery across global settings. This can inform the use of intraoperative and postoperative interventions to modify the risk of surgical-site infections and minimize associated harm

The ASOS Surgical Risk Calculator: development and validation of a tool for identifying African surgical patients at risk of severe postoperative complications

Background: The African Surgical Outcomes Study (ASOS) showed that surgical patients in Africa have a mortality twice the global average. Existing risk assessment tools are not valid for use in this population because the pattern of risk for poor outcomes differs from high-income countries. The objective of this study was to derive and validate a simple, preoperative risk stratification tool to identify African surgical patients at risk for in-hospital postoperative mortality and severe complications. Methods: ASOS was a 7-day prospective cohort study of adult patients undergoing surgery in Africa. The ASOS Surgical Risk Calculator was constructed with a multivariable logistic regression model for the outcome of in-hospital mortality and severe postoperative complications. The following preoperative risk factors were entered into the model; age, sex, smoking status, ASA physical status, preoperative chronic comorbid conditions, indication for surgery, urgency, severity, and type of surgery. Results: The model was derived from 8799 patients from 168 African hospitals. The composite outcome of severe postoperative complications and death occurred in 423/8799 (4.8%) patients. The ASOS Surgical Risk Calculator includes the following risk factors: age, ASA physical status, indication for surgery, urgency, severity, and type of surgery. The model showed good discrimination with an area under the receiver operating characteristic curve of 0.805 and good calibration with c-statistic corrected for optimism of 0.784. Conclusions: This simple preoperative risk calculator could be used to identify high-risk surgical patients in African hospitals and facilitate increased postoperative surveillance. © 2018 British Journal of Anaesthesia. Published by Elsevier Ltd. All rights reserved.Medical Research Council of South Africa gran