There is a need for robust, clearly defined, patient-relevant outcome measures for use in randomised trials in perioperative medicine. Our objective was to establish standard outcome measures for ...postoperative pulmonary complications research.
A systematic literature search was conducted using MEDLINE, Web of Science, SciELO, and the Korean Journal Database. Definitions were extracted from included manuscripts. We then conducted a three-stage Delphi consensus process to select the optimal outcome measures in terms of methodological quality and overall suitability for perioperative trials.
From 2358 records, the full texts of 81 manuscripts were retrieved, of which 45 met the inclusion criteria. We identified three main categories of outcome measure specific to perioperative pulmonary outcomes: (i) composite outcome measures of multiple pulmonary outcomes (27 definitions); (ii) pneumonia (12 definitions); and (iii) respiratory failure (six definitions). These were rated by the group according to suitability for routine use. The majority of definitions were given a low score, and many were imprecise, difficult to apply consistently, or both, in large patient populations. A small number of highly rated definitions were identified as appropriate for widespread use. The group then recommended four outcome measures for future use, including one new definition.
A large number of postoperative pulmonary outcome measures have been used, but most are poorly defined. Our four recommended outcome measures include a new definition of postoperative pulmonary complications, incorporating an assessment of severity. These definitions will meet the needs of most clinical effectiveness trials of treatments to improve postoperative pulmonary outcomes.
Summary Background In pancreatic ductal adenocarcinoma, the CCL2–CCR2 chemokine axis is used to recruit tumour-associated macrophages for construction of an immunosuppressive tumour microenvironment. ...This pathway has prognostic implications in pancreatic cancer, and blockade of CCR2 restores anti-tumour immunity in preclinical models. We aimed to establish the safety, tolerability, and recommended phase 2 oral dose of the CCR2 inhibitor PF-04136309 in combination with FOLFIRINOX chemotherapy (oxaliplatin and irinotecan plus leucovorin and fluorouracil). Methods We did this open-label, dose-finding, non-randomised, phase 1b study at one centre in the USA. We enrolled treatment-naive patients aged 18 years or older with borderline resectable or locally advanced biopsy-proven pancreatic ductal adenocarcinoma, an Eastern Cooperative Oncology Group performance status of 1 or less, measurable disease as defined by Response Evaluation Criteria in Solid Tumors version 1.1, and normal end-organ function. Patients were allocated to receive either FOLFIRINOX alone (oxaliplatin 85 mg/m2 , irinotecan 180 mg/m2 , leucovorin 400 mg/m2 , and bolus fluorouracil 400 mg/m2 , followed by 2400 mg/m2 46-h continuous infusion), administered every 2 weeks for a total of six treatment cycles, or in combination with oral PF-04136309, administered at a starting dose of 500 mg twice daily in a standard 3 + 3 dose de-escalation design. Both FOLFIRINOX and PF-04136309 were simultaneously initiated with a total treatment duration of 12 weeks. The primary endpoints were the safety, tolerability, and recommended phase 2 dose of PF-04136309 plus FOLFIRINOX, with an expansion phase planned at the recommended dose. We analysed the primary outcome by intention to treat. This trial is registered with ClinicalTrials.gov , number NCT01413022. Results Between April 19, 2012, and Nov 12, 2014, we treated 47 patients with FOLFIRINOX alone (n=8) or with FOLFIRINOX plus PF-04136309 (n=39). One patient had a dose-limiting toxic effect in the dose de-escalation group receiving FOLFIRINOX plus PF-04136309 at 500 mg twice daily (n=6); this dose was established as the recommended phase 2 dose. We pooled patients in the expansion-phase group (n=33) with those in the dose de-escalation group that received PF-04136309 at the recommended phase 2 dose for assessment of treatment-related toxicity. Six (75%) of the eight patients receiving FOLFIRINOX alone were assessed for treatment toxicity, after exclusion of two (25%) patients due to insurance coverage issues. The median duration of follow-up for treatment toxicity was 72·0 days (IQR 49·5–89·0) in the FOLFIRINOX alone group and 77·0 days (70·0–90·5) in the FOLFIRINOX plus PF-04136309 group. No treatment-related deaths occurred. Two (5%) patients in the FOLFIRINOX plus PF-04136309 group stopped treatment earlier than planned due to treatment-related toxic effects. Grade 3 or higher adverse events reported in at least 10% of the patients receiving PF-04136309 included neutropenia (n=27), febrile neutropenia (n=7), lymphopenia (n=4), diarrhoea (n=6), and hypokalaemia (n=7). Grade 3 or higher adverse events reported in at least 10% of patients receiving FOLFIRINOX alone were neutropenia (n=6), febrile neutropenia (n=1), anaemia (n=2), lymphopenia (n=1), diarrhoea (n=2), hypoalbuminaemia (n=1), and hypokalaemia (n=3). Therapy was terminated because of treatment-related toxicity in one (17%) of the six patients receiving FOLFIRINOX alone. 16 (49%) of 33 patients receiving FOLFIRINOX plus PF-04136309 who had undergone repeat imaging achieved an objective tumour response, with local tumour control achieved in 32 (97%) patients. In the FOLFIRINOX alone group, none of the five patients with repeat imaging achieved an objective response, although four (80%) of those patients achieved stable disease. Interpretation CCR2-targeted therapy with PF-04136309 in combination with FOLFIRINOX is safe and tolerable. Funding Washington University–Pfizer Biomedical Collaborative.
The global nitrogen (N) cycle at the beginning of the 21st century has been shown to be strongly influenced by the inputs of reactive nitrogen (Nr) from human activities, including combustion-related ...NOx, industrial and agricultural N fixation, estimated to be 220 Tg N yr−1 in 2010, which is approximately equal to the sum of biological N fixation in unmanaged terrestrial and marine ecosystems. According to current projections, changes in climate and land use during the 21st century will increase both biological and anthropogenic fixation, bringing the total to approximately 600 Tg N yr−1 by around 2100. The fraction contributed directly by human activities is unlikely to increase substantially if increases in nitrogen use efficiency in agriculture are achieved and control measures on combustion-related emissions implemented. Some N-cycling processes emerge as particularly sensitive to climate change. One of the largest responses to climate in the processing of Nr is the emission to the atmosphere of NH3, which is estimated to increase from 65 Tg N yr−1 in 2008 to 93 Tg N yr−1 in 2100 assuming a change in global surface temperature of 5 °C in the absence of increased anthropogenic activity. With changes in emissions in response to increased demand for animal products the combined effect would be to increase NH3 emissions to 135 Tg N yr−1. Another major change is the effect of climate changes on aerosol composition and specifically the increased sublimation of NH4NO3 close to the ground to form HNO3 and NH3 in a warmer climate, which deposit more rapidly to terrestrial surfaces than aerosols. Inorganic aerosols over the polluted regions especially in Europe and North America were dominated by (NH4)2SO4 in the 1970s to 1980s, and large reductions in emissions of SO2 have removed most of the SO42− from the atmosphere in these regions. Inorganic aerosols from anthropogenic emissions are now dominated by NH4NO3, a volatile aerosol which contributes substantially to PM10 and human health effects globally as well as eutrophication and climate effects. The volatility of NH4NO3 and rapid dry deposition of the vapour phase dissociation products, HNO3 and NH3, is estimated to be reducing the transport distances, deposition footprints and inter-country exchange of Nr in these regions. There have been important policy initiatives on components of the global N cycle. These have been regional or country-based and have delivered substantial reductions of inputs of Nr to sensitive soils, waters and the atmosphere. To date there have been no attempts to develop a global strategy to regulate human inputs to the nitrogen cycle. However, considering the magnitude of global Nr use, potential future increases, and the very large leakage of Nr in many forms to soils, waters and the atmosphere, international action is required. Current legislation will not deliver the scale of reductions globally for recovery from the effects of Nr deposition on sensitive ecosystems, or a decline in N2O emissions to the global atmosphere. Such changes would require substantial improvements in nitrogen use efficiency across the global economy combined with optimization of transport and food consumption patterns. This would allow reductions in Nr use, inputs to the atmosphere and deposition to sensitive ecosystems. Such changes would offer substantial economic and environmental co-benefits which could help motivate the necessary actions.
Abstract Background & Aims We assessed the diagnostic performance of magnetic resonance imaging (MRI) proton density fat fraction (PDFF) in grading hepatic steatosis and change in hepatic steatosis ...in adults with nonalcoholic steatohepatitis (NASH) in a multi-center study, using central histology as reference. Methods We collected data from 113 adults with NASH participating in a multi-center, randomized, double-masked, placebo-controlled, phase 2b trial to compare the efficacy cross-sectionally and longitudinally of obeticholic acid vs placebo. Hepatic steatosis was assessed at baseline and after 72 weeks of obeticholic acid or placebo by liver biopsy and MRI (scanners from different manufacturers, at 1.5T or 3T). We compared steatosis estimates by PDFF vs histology. Histologic steatosis grade was scored in consensus by a pathology committee. Cross-validated receiver operating characteristic (ROC) analyses were performed. Results At baseline, 34% of subjects had steatosis grade 0 or 1, 39% had steatosis grade 2, and 27% had steatosis grade 3; corresponding mean PDFF values were 9.8%±3.7%, 18.1%±4.3%, and 30.1%±8.1%. PDFF classified steatosis grade 0–1 vs 2–3 with an area under the ROC curve (AUROC) of 0.95 (95% CI, 0.91–0.98), and grade 0–2 vs grade 3 steatosis with an AUROC of 0.96 (95% CI, 0.93–0.99). PDFF cut-off values at 90% specificity were 16.3% for grades 2–3 and 21.7% for grade 3, with corresponding sensitivities of 83% and 84%. After 72 weeks' of obeticholic vs. placebo, 42% of subjects had a reduced steatosis grade (mean reduction in PDFF from baseline of 7.4%±8.7%), 49% had no change in steatosis grade (mean increase in PDFF from baseline of 0.3%±6.3%), and 9% had an increased steatosis grade (mean increase in PDFF from baseline of 7.7%±6.0%). PDFF change identified subjects with reduced steatosis grade with an AUROC of 0.81 (95% CI, 0.71–0.91) and increased steatosis grade with an AUROC of 0.81 (95% CI, 0.63–0.99). A PDFF reduction of 5.15% identified subjects with reduced steatosis grade with 90% specificity and 58% sensitivity, whereas a PDFF increase of 5.6% identified those with increased steatosis grade with 90% specificity and 57% sensitivity. Conclusions Based on data from a phase 2 randomized controlled trial of adults with NASH, PDFF estimated by MRI scanners of different field strength and at different sites, accurately classifies grades and changes in hepatic steatosis when histologic analysis of biopsies is used as a reference.
Summary Background Multiple system atrophy (MSA) is a fatal and still poorly understood degenerative movement disorder that is characterised by autonomic failure, cerebellar ataxia, and parkinsonism ...in various combinations. Here we present the final analysis of a prospective multicentre study by the European MSA Study Group to investigate the natural history of MSA. Methods Patients with a clinical diagnosis of MSA were recruited and followed up clinically for 2 years. Vital status was ascertained 2 years after study completion. Disease progression was assessed using the unified MSA rating scale (UMSARS), a disease-specific questionnaire that enables the semiquantitative rating of autonomic and motor impairment in patients with MSA. Additional rating methods were applied to grade global disease severity, autonomic symptoms, and quality of life. Survival was calculated using a Kaplan-Meier analysis and predictors were identified in a Cox regression model. Group differences were analysed by parametric tests and non-parametric tests as appropriate. Sample size estimates were calculated using a paired two-group t test. Findings 141 patients with moderately severe disease fulfilled the consensus criteria for MSA. Mean age at symptom onset was 56·2 (SD 8·4) years. Median survival from symptom onset as determined by Kaplan-Meier analysis was 9·8 years (95% CI 8·1–11·4). The parkinsonian variant of MSA (hazard ratio HR 2·08, 95% CI 1·09–3·97; p=0·026) and incomplete bladder emptying (HR 2·10, 1·02–4·30; p=0·044) predicted shorter survival. 24-month progression rates of UMSARS activities of daily living, motor examination, and total scores were 49% (9·4 SD 5·9), 74% (12·9 8·5), and 57% (21·9 11·9), respectively, relative to baseline scores. Autonomic symptom scores progressed throughout the follow-up. Shorter symptom duration at baseline (OR 0·68, 0·5–0·9; p=0·006) and absent levodopa response (OR 3·4, 1·1–10·2; p=0·03) predicted rapid UMSARS progression. Sample size estimation showed that an interventional trial with 258 patients (129 per group) would be able to detect a 30% effect size in 1-year UMSARS motor examination decline rates at 80% power. Interpretation Our prospective dataset provides new insights into the evolution of MSA based on a follow-up period that exceeds that of previous studies. It also represents a useful resource for patient counselling and planning of multicentre trials. Funding Fifth Framework Programme of the European Union, the Oesterreichische Nationalbank, and the Austrian Science Fund.
Body mass index (BMI) and mortality in old adults from the general population have been related in a U‐shaped or J‐shaped curve. However, limited information is available for elderly nursing home ...populations, particularly about specific cause of death. A systematic PubMed/EMBASE/CINAHL/SCOPUS search until 31 May 2014 without language restrictions was conducted. As no published study reported mortality in standard BMI groups (<18.5, 18.5–24.9, 25–29.9, ≥30 kg/m²), the most adjusted hazard ratios (HRs) according to a pre‐defined list of covariates were obtained from authors and pooled by random‐effect model across each BMI category. Out of 342 hits, 20 studies including 19,538 older nursing home residents with 5,223 deaths during a median of 2 years of follow‐up were meta‐analysed. Compared with normal weight, all‐cause mortality HRs were 1.41 (95% CI = 1.26–1.58) for underweight, 0.85 (95% CI = 0.73–0.99) for overweight and 0.74 (95% CI = 0.57–0.96) for obesity. Underweight was a risk factor for higher mortality caused by infections (HR = 1.65 95% CI = 1.13–2.40). RR results corroborated primary HR results, with additionally lower infection‐related mortality in overweight and obese than in normal‐weight individuals. Like in the general population, underweight is a risk factor for mortality in old nursing home residents. However, uniquely, not only overweight but also obesity is protective, which has relevant nutritional goal implications in this population/setting.
Pediatric community-acquired pneumonia (CAP) is often treated with 10 days of antibiotics. Shorter treatment strategies may be effective and lead to less resistance. The impact of duration of ...treatment on the respiratory microbiome is unknown. Data are from children (
= 171), ages 6 to 71 months, enrolled in the SCOUT-CAP trial (NCT02891915). Children with CAP were randomized to a short (5 days) versus standard (10 days) beta-lactam treatment strategy. Throat swabs were collected at enrollment and the end of the study and used for shotgun metagenomic sequencing. The number of beta-lactam and multidrug efflux resistance genes per prokaryotic cell (RGPC) was significantly lower in children receiving the short compared to standard treatment strategy at the end of the study (Wilcoxon rank sum test,
< 0.05 for each). Wilcoxon effect sizes were small for beta-lactam (
: 0.15; 95% confidence interval CI, 0.01 to 0.29) and medium for multidrug efflux RGPC (
: 0.23; 95% CI, 0.09 to 0.37). Analyses comparing the resistome at the beginning and end of the trial indicated that in contrast to the standard strategy group, the resistome significantly differed in children receiving the short course strategy. Relative abundances of commensals such as Neisseria subflava were higher in children receiving the standard strategy, and
species and Veillonella parvula were higher in children receiving the short course strategy. We conclude that children receiving 5 days of beta-lactam therapy for CAP had a significantly lower abundance of antibiotic resistance determinants than those receiving standard 10-day treatment. These data provide an additional rationale for reductions in antibiotic use when feasible.
Antibiotic resistance is a major threat to public health. Treatment strategies involving shorter antibiotic courses have been proposed as a strategy to lower the potential for antibiotic resistance. We examined relationships between the duration of antibiotic treatment and its impact on resistance genes and bacteria in the respiratory microbiome using data from a randomized controlled trial of beta-lactam therapy for pediatric pneumonia. The randomized design provides reliable evidence of the effectiveness of interventions and minimizes the potential for confounding. Children receiving 5 days of therapy for pneumonia had a lower prevalence of two different types of resistance genes than did those receiving the 10-day treatment. Our data also suggest that children receiving longer durations of therapy have a greater abundance of antibiotic resistance genes for a longer period of time than do children receiving shorter durations of therapy. These data provide an additional rationale for reductions in antibiotic use.
The global nitrogen (N) cycle at the beginning of the 21st century has been shown to be strongly influenced by the inputs of reactive nitrogen (Nr) from human activities, including combustion-related ...NOx, industrial and agricultural N fixation, estimated to be 220 Tg N yr-1 in 2010, which is approximately equal to the sum of biological N fixation in unmanaged terrestrial and marine ecosystems. According to current projections, changes in climate and land use during the 21st century will increase both biological and anthropogenic fixation, bringing the total to approximately 600 Tg N yr-1 by around 2100. The fraction contributed directly by human activities is unlikely to increase substantially if increases in nitrogen use efficiency in agriculture are achieved and control measures on combustion-related emissions implemented. Some N-cycling processes emerge as particularly sensitive to climate change. One of the largest responses to climate in the processing of Nr is the emission to the atmosphere of NH3, which is estimated to increase from 65 Tg N yr-1 in 2008 to 93 Tg N yr-1 in 2100 assuming a change in global surface temperature of 5 degree C in the absence of increased anthropogenic activity. With changes in emissions in response to increased demand for animal products the combined effect would be to increase NH3 emissions to 135 Tg N yr-1. Another major change is the effect of climate changes on aerosol composition and specifically the increased sublimation of NH4NO3 close to the ground to form HNO3 and NH3 in a warmer climate, which deposit more rapidly to terrestrial surfaces than aerosols. Inorganic aerosols over the polluted regions especially in Europe and North America were dominated by (NH4)2SO4 in the 1970s to 1980s, and large reductions in emissions of SO2 have removed most of the SO42- from the atmosphere in these regions. Inorganic aerosols from anthropogenic emissions are now dominated by NH4NO3, a volatile aerosol which contributes substantially to PM10 and human health effects globally as well as eutrophication and climate effects. The volatility of NH4NO3 and rapid dry deposition of the vapour phase dissociation products, HNO3 and NH3, is estimated to be reducing the transport distances, deposition footprints and inter-country exchange of Nr in these regions. There have been important policy initiatives on components of the global N cycle. These have been regional or country-based and have delivered substantial reductions of inputs of Nr to sensitive soils, waters and the atmosphere. To date there have been no attempts to develop a global strategy to regulate human inputs to the nitrogen cycle. However, considering the magnitude of global Nr use, potential future increases, and the very large leakage of Nr in many forms to soils, waters and the atmosphere, international action is required. Current legislation will not deliver the scale of reductions globally for recovery from the effects of Nr deposition on sensitive ecosystems, or a decline in N2O emissions to the global atmosphere. Such changes would require substantial improvements in nitrogen use efficiency across the global economy combined with optimization of transport and food consumption patterns. This would allow reductions in Nr use, inputs to the atmosphere and deposition to sensitive ecosystems. Such changes would offer substantial economic and environmental co-benefits which could help motivate the necessary actions.
The literature on atmospheric particulate matter (PM), or atmospheric aerosol, has increased enormously over the last 2 decades and amounts now to some 1500-2000 papers per year in the refereed ...literature. This is in part due to the enormous advances in measurement technologies, which have allowed for an increasingly accurate understanding of the chemical composition and of the physical properties of atmospheric particles and of their processes in the atmosphere. The growing scientific interest in atmospheric aerosol particles is due to their high importance for environmental policy. In fact, particulate matter constitutes one of the most challenging problems both for air quality and for climate change policies. In this context, this paper reviews the most recent results within the atmospheric aerosol sciences and the policy needs, which have driven much of the increase in monitoring and mechanistic research over the last 2 decades. The synthesis reveals many new processes and developments in the science underpinning climate-aerosol interactions and effects of PM on human health and the environment. However, while airborne particulate matter is responsible for globally important influences on premature human mortality, we still do not know the relative importance of the different chemical components of PM for these effects. Likewise, the magnitude of the overall effects of PM on climate remains highly uncertain. Despite the uncertainty there are many things that could be done to mitigate local and global problems of atmospheric PM. Recent analyses have shown that reducing black carbon (BC) emissions, using known control measures, would reduce global warming and delay the time when anthropogenic effects on global temperature would exceed 2 °C. Likewise, cost-effective control measures on ammonia, an important agricultural precursor gas for secondary inorganic aerosols (SIA), would reduce regional eutrophication and PM concentrations in large areas of Europe, China and the USA. Thus, there is much that could be done to reduce the effects of atmospheric PM on the climate and the health of the environment and the human population. A prioritized list of actions to mitigate the full range of effects of PM is currently undeliverable due to shortcomings in the knowledge of aerosol science; among the shortcomings, the roles of PM in global climate and the relative roles of different PM precursor sources and their response to climate and land use change over the remaining decades of this century are prominent. In any case, the evidence from this paper strongly advocates for an integrated approach to air quality and climate policies.
Abstract Since their widespread introduction more than half a century ago, Intensive Care Units (ICUs) have become an integral part of the health care system. While most ICUs are found in high income ...countries, they are increasingly a feature of health care systems in low and middle income countries. The World Federation of Societies of Intensive and Critical Care Medicine (WFSICCM) convened a task force whose objective was to answer the question, “What is an ICU” in an internationally meaningful manner, and to develop a system for stratifying ICUs on the basis of the intensity of the care they provide. We undertook a scoping review of the peer-reviewed and grey literature to assemble existing models for ICU stratification. Based on these, and on discussions amongst task force members by teleconference and two face-to-face meetings, we present a proposed definition and classification of ICUs. An ICU is an organized system for the provision of care to critically ill patients that provides intensive and specialized medical and nursing care, an enhanced capacity for monitoring, and multiple modalities of physiologic organ support to sustain life during a period of life-threatening organ system insufficiency. While an ICU is based in a defined geographic area of a hospital, its activities often extend beyond the walls of the physical space to include the emergency department, hospital ward, and follow-up clinic. A Level One ICU is capable of providing oxygen, non-invasive monitoring, and more intensive nursing care than on a ward, while a Level Two ICU can provide invasive monitoring and basic life support for a short period of time. A Level Three ICU provides a full spectrum of monitoring and life support technologies, serves as a regional resource for the care of critically ill patients, and may play an active role in developing the specialty of intensive care through research and education. A formal definition and descriptive framework for ICUs can inform health care decision-makers in planning and measuring capacity, and provide clinicians and patients with a benchmark to evaluate the level of resources available for clinical care.