Case Definition and Design Sensitivity

In a case-referent study, cases of disease are compared to noncases with respect to their antecedent exposure to a treatment in an effort to determine whether exposure causes some cases of the disease. Because exposure is not randomly assigned in the population, as it would be if the population were a vast randomized trial, exposed and unexposed subjects may differ prior to exposure with respect to covariates that may or may not have been measured. After controlling for measured preexposure differences, for instance by matching, a sensitivity analysis asks about the magnitude of bias from unmeasured covariates that would need to be present to alter the conclusions of a study that presumed matching for observed covariates removes all bias. The definition of a case of disease affects sensitivity to unmeasured bias. We explore this issue using: (i) an asymptotic tool, the design sensitivity, (ii) a simulation for finite samples, and (iii) an example. Under favorable circumstances, a narrower case definition can yield an increase in the design sensitivity, and hence an increase in the power of a sensitivity analysis. Also, we discuss an adaptive method that seeks to discover the best case definition from the data at hand while controlling for multiple testing. An implementation in R is available as SensitivityCaseControl

On which timescales do gas transfer velocities control North Atlantic CO2 flux variability?

The North Atlantic is an important basin for the global ocean's uptake of anthropogenic and natural carbon dioxide (CO2), but the mechanisms controlling this carbon flux are not fully understood. The air-sea flux of CO2, F, is the product of a gas transfer velocity, k, the air-sea CO2 concentration gradient, ΔpCO2, and the temperature and salinity-dependent solubility coefficient, α. k is difficult to constrain, representing the dominant uncertainty in F on short (instantaneous to interannual) timescales. Previous work shows that in the North Atlantic, ΔpCO2 and k both contribute significantly to interannual F variability, but that k is unimportant for multidecadal variability. On some timescale between interannual and multidecadal, gas transfer velocity variability and its associated uncertainty become negligible. Here, we quantify this critical timescale for the first time. Using an ocean model, we determine the importance of k, ΔpCO2 and α on a range of timescales. On interannual and shorter timescales, both ΔpCO2 and k are important controls on F. In contrast, pentadal to multidecadal North Atlantic flux variability is driven almost entirely by ΔpCO2; k contributes less than 25%. Finally, we explore how accurately one can estimate North Atlantic F without a knowledge of non-seasonal k variability, finding it possible for interannual and longer timescales. These findings suggest that continued efforts to better constrain gas transfer velocities are necessary to quantify interannual variability in the North Atlantic carbon sink. However, uncertainty in k variability is unlikely to limit the accuracy of estimates of longer term flux variability

Fabrication and experimental characterization of d31 telescopic piezoelectric actuators

A popular and useful piezoelectric actuator is the stack. Unfortunately with this type of actuation architecture the long lengths normally required to obtain necessary displacements can pose packaging and buckling problems. To overcome these limitations, a new architecture for piezoelectric actuators has been developed called telescopic. The basic design consists of concentric shells interconnected by end-caps which alternate in placement between the two axial ends of the shells. This leads to a linear displacement amplification at the cost of force; yet the force remains at the same magnitude as a stack and significantly higher than bender type architectures. This paper describes the fabrication and experimental characterization of three different telescopic prototypes. The actuator prototypes discussed in this paper mark a definitive step forward in fabrication techniques for complex piezoceramic structures. Materials Systems, Inc. has adapted injection molding for the fabrication of net shape piezoceramic actuators. Injection molding provides several advantages over conventional fabrication techniques, including: high production rate, uniform part dimensions, uniform piezoelectric properties, and reduced fabrication and assembly costs. Acrylate polymerization, developed at the University of Michigan, is similar to gelcasting, but uses a nonaqueous slurry which facilitates the production of large, tall, complex components such as the telescopic actuator, and is ideal for the rapid manufacture of unique or small batch structures. To demonstrate these fabrication processes a five tube telescopic actuator was injection molded along with a very tall three tube actuator that was cast using the acrylate polymerization method. As a benchmark, a third actuator was built from off-the-shelf tubes that were joined with aluminum end-caps. Each prototype's free deflection behavior was experimentally characterized and the results of the testing are presented within this paper.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/44767/1/10853_2004_Article_382116.pd

Aerosols implicated as a prime driver of twentieth-century North Atlantic climate variability

Systematic climate shifts have been linked to multidecadal variability in observed sea surface temperatures in the North Atlantic Ocean1. These links are extensive, influencing a range of climate processes such as hurricane activity2 and African Sahel3, 4, 5 and Amazonian5 droughts. The variability is distinct from historical global-mean temperature changes and is commonly attributed to natural ocean oscillations6, 7, 8, 9, 10. A number of studies have provided evidence that aerosols can influence long-term changes in sea surface temperatures11, 12, but climate models have so far failed to reproduce these interactions6, 9 and the role of aerosols in decadal variability remains unclear. Here we use a state-of-the-art Earth system climate model to show that aerosol emissions and periods of volcanic activity explain 76 per cent of the simulated multidecadal variance in detrended 1860–2005 North Atlantic sea surface temperatures. After 1950, simulated variability is within observational estimates; our estimates for 1910–1940 capture twice the warming of previous generation models but do not explain the entire observed trend. Other processes, such as ocean circulation, may also have contributed to variability in the early twentieth century. Mechanistically, we find that inclusion of aerosol–cloud microphysical effects, which were included in few previous multimodel ensembles, dominates the magnitude (80 per cent) and the spatial pattern of the total surface aerosol forcing in the North Atlantic. Our findings suggest that anthropogenic aerosol emissions influenced a range of societally important historical climate events such as peaks in hurricane activity and Sahel drought. Decadal-scale model predictions of regional Atlantic climate will probably be improved by incorporating aerosol–cloud microphysical interactions and estimates of future concentrations of aerosols, emissions of which are directly addressable by policy actions

Avoiding Coral Reef Functional Collapse Requires Local and Global Action

oral reefs face multiple anthropogenic threats, from pollution and overfishing to the dual effects of greenhouse gas emissions: rising sea temperature and ocean acidification [1]. While the abundance of coral has declined in recent decades [2, 3], the implications for humanity are difficult to quantify because they depend on ecosystem function rather than the corals themselves. Most reef functions and ecosystem services are founded on the ability of reefs to maintain their three-dimensional structure through net carbonate accumulation [4]. Coral growth only constitutes part of a reef's carbonate budget; bioerosion processes are influential in determining the balance between net structural growth and disintegration [5, 6]. Here, we combine ecological models with carbonate budgets and drive the dynamics of Caribbean reefs with the latest generation of climate models. Budget reconstructions using documented ecological perturbations drive shallow (6-10 m) Caribbean forereefs toward an increasingly fragile carbonate balance. We then projected carbonate budgets toward 2080 and contrasted the benefits of local conservation and global action on climate change. Local management of fisheries (specifically, no-take marine reserves) and the watershed can delay reef loss by at least a decade under "business-as-usual" rises in greenhouse gas emissions. However, local action must be combined with a low-carbon economy to prevent degradation of reef structures and associated ecosystem services

Influenza Outbreak during Sydney World Youth Day 2008: The Utility of Laboratory Testing and Case Definitions on Mass Gathering Outbreak Containment

BACKGROUND:Influenza causes annual epidemics and often results in extensive outbreaks in closed communities. To minimize transmission, a range of interventions have been suggested. For these to be effective, an accurate and timely diagnosis of influenza is required. This is confirmed by a positive laboratory test result in an individual whose symptoms are consistent with a predefined clinical case definition. However, the utility of these clinical case definitions and laboratory testing in mass gathering outbreaks remains unknown. METHODS AND RESULTS:An influenza outbreak was identified during World Youth Day 2008 in Sydney. From the data collected on pilgrims presenting to a single clinic, a Markov model was developed and validated against the actual epidemic curve. Simulations were performed to examine the utility of different clinical case definitions and laboratory testing strategies for containment of influenza outbreaks. Clinical case definitions were found to have the greatest impact on averting further cases with no added benefit when combined with any laboratory test. Although nucleic acid testing (NAT) demonstrated higher utility than indirect immunofluorescence antigen or on-site point-of-care testing, this effect was lost when laboratory NAT turnaround times was included. The main benefit of laboratory confirmation was limited to identification of true influenza cases amenable to interventions such as antiviral therapy. CONCLUSIONS:Continuous re-evaluation of case definitions and laboratory testing strategies are essential for effective management of influenza outbreaks during mass gatherings

Comparison of adjuvant gemcitabine and capecitabine with gemcitabine monotherapy in patients with resected pancreatic cancer (ESPAC-4): a multicentre, open-label, randomised, phase 3 trial

BACKGROUND: The ESPAC-3 trial showed that adjuvant gemcitabine is the standard of care based on similar survival to and less toxicity than adjuvant 5-fluorouracil/folinic acid in patients with resected pancreatic cancer. Other clinical trials have shown better survival and tumour response with gemcitabine and capecitabine than with gemcitabine alone in advanced or metastatic pancreatic cancer. We aimed to determine the efficacy and safety of gemcitabine and capecitabine compared with gemcitabine monotherapy for resected pancreatic cancer. METHODS: We did a phase 3, two-group, open-label, multicentre, randomised clinical trial at 92 hospitals in England, Scotland, Wales, Germany, France, and Sweden. Eligible patients were aged 18 years or older and had undergone complete macroscopic resection for ductal adenocarcinoma of the pancreas (R0 or R1 resection). We randomly assigned patients (1:1) within 12 weeks of surgery to receive six cycles of either 1000 mg/m(2) gemcitabine alone administered once a week for three of every 4 weeks (one cycle) or with 1660 mg/m(2) oral capecitabine administered for 21 days followed by 7 days' rest (one cycle). Randomisation was based on a minimisation routine, and country was used as a stratification factor. The primary endpoint was overall survival, measured as the time from randomisation until death from any cause, and assessed in the intention-to-treat population. Toxicity was analysed in all patients who received trial treatment. This trial was registered with the EudraCT, number 2007-004299-38, and ISRCTN, number ISRCTN96397434. FINDINGS: Of 732 patients enrolled, 730 were included in the final analysis. Of these, 366 were randomly assigned to receive gemcitabine and 364 to gemcitabine plus capecitabine. The Independent Data and Safety Monitoring Committee requested reporting of the results after there were 458 (95%) of a target of 480 deaths. The median overall survival for patients in the gemcitabine plus capecitabine group was 28·0 months (95% CI 23·5-31·5) compared with 25·5 months (22·7-27·9) in the gemcitabine group (hazard ratio 0·82 [95% CI 0·68-0·98], p=0·032). 608 grade 3-4 adverse events were reported by 226 of 359 patients in the gemcitabine plus capecitabine group compared with 481 grade 3-4 adverse events in 196 of 366 patients in the gemcitabine group. INTERPRETATION: The adjuvant combination of gemcitabine and capecitabine should be the new standard of care following resection for pancreatic ductal adenocarcinoma

Biotic and Human Vulnerability to Projected Changes in Ocean Biogeochemistry over the 21st Century

Ongoing greenhouse gas emissions can modify climate processes and induce shifts in ocean temperature, pH, oxygen concentration, and productivity, which in turn could alter biological and social systems. Here, we provide a synoptic global assessment of the simultaneous changes in future ocean biogeochemical variables over marine biota and their broader implications for people. We analyzed modern Earth System Models forced by greenhouse gas concentration pathways until 2100 and showed that the entire world's ocean surface will be simultaneously impacted by varying intensities of ocean warming, acidification, oxygen depletion, or shortfalls in productivity. In contrast, only a small fraction of the world's ocean surface, mostly in polar regions, will experience increased oxygenation and productivity, while almost nowhere will there be ocean cooling or pH elevation. We compiled the global distribution of 32 marine habitats and biodiversity hotspots and found that they would all experience simultaneous exposure to changes in multiple biogeochemical variables. This superposition highlights the high risk for synergistic ecosystem responses, the suite of physiological adaptations needed to cope with future climate change, and the potential for reorganization of global biodiversity patterns. If co-occurring biogeochemical changes influence the delivery of ocean goods and services, then they could also have a considerable effect on human welfare. Approximately 470 to 870 million of the poorest people in the world rely heavily on the ocean for food, jobs, and revenues and live in countries that will be most affected by simultaneous changes in ocean biogeochemistry. These results highlight the high risk of degradation of marine ecosystems and associated human hardship expected in a future following current trends in anthropogenic greenhouse gas emissions