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Background: Modifications of FOLFIRINOX are widely used despite the absence of prospective data validating efficacy in metastatic disease (metastatic pancreatic cancer (MPC)) or locally advanced pancreatic cancer (LAPC). We conducted a multicentre phase II study of modified FOLFIRINOX in advanced pancreatic cancer to assess the impact of dose attenuation in MPC and efficacy in LAPC. Methods: Patients with untreated MPC or LAPC received modified FOLFIRINOX (irinotecan and bolus 5-fluorouracil reduced by 25%). Adverse events (AEs) were compared with full-dose FOLFIRINOX. Response rate (RR), median progression-free survival (PFS) and median overall survival (OS) were determined. Results: In total, 31 and 44 patients with LAPC and MPC were enrolled, respectively. In MPC, efficacy of modified FOLFIRINOX was comparable with FOLFIRINOX with RR 35.1%, OS 10.2 months (95% CI 7.65–14.32) and PFS 6.1 months (95% CI 5.19–8.31). In LAPC, efficacy was notable with RR 17.2%, resection rate 41.9%, PFS 17.8 months (95% CI 11.0–23.9) and OS 26.6 months (95% CI 16.7, NA). Neutropenia ( P <0.0001), vomiting ( P <0.001) and fatigue ( P =0.01) were significantly decreased. [ 18 F]-Fluorodeoxyglucose positron emission tomography imaging response did not correlate with PFS or OS. Conclusions: In this first prospective study of modified FOLFIRINOX in MPC and LAPC, we observed decreased AEs compared with historical control patients. In MPC, the efficacy appears comparable with FOLFIRINOX. In LAPC, PFS and OS were prolonged and support the continued use of FOLFIRINOX in this setting.

In response to concerns about the continued unrealized potential of IT in K-12 education, the National Research Council's Division of Behavioral and Social Sciences and Education, Center for Education (CFE), Board on Behavioral, Cognitive, and Sensory Sciences (BBCSS), and Computer Science and Telecommunications Board (CSTB) undertook a collaborative project to help the IT, education research, and practitioner communities work together to find ways of improving the use of IT in K-12 education for the benefit of all students.

Release of carbon previously locked in permafrost is a potentially important positive climate feedback. Now metagenomics reveal the vulnerability of active-layer soil carbon to warming-induced microbial decomposition in Alaskan tundra. Microbial decomposition of soil carbon in high-latitude tundra underlain with permafrost is one of the most important, but poorly understood, potential positive feedbacks of greenhouse gas emissions from terrestrial ecosystems into the atmosphere in a warmer world 1 , 2 , 3 , 4 . Using integrated metagenomic technologies, we showed that the microbial functional community structure in the active layer of tundra soil was significantly altered after only 1.5 years of warming, a rapid response demonstrating the high sensitivity of this ecosystem to warming. The abundances of microbial functional genes involved in both aerobic and anaerobic carbon decomposition were also markedly increased by this short-term warming. Consistent with this, ecosystem respiration ( R eco ) increased up to 38%. In addition, warming enhanced genes involved in nutrient cycling, which very likely contributed to an observed increase (30%) in gross primary productivity (GPP). However, the GPP increase did not offset the extra R eco , resulting in significantly more net carbon loss in warmed plots compared with control plots. Altogether, our results demonstrate the vulnerability of active-layer soil carbon in this permafrost-based tundra ecosystem to climate warming and the importance of microbial communities in mediating such vulnerability.

Estimation of the effective reproductive number R t is important for detecting changes in disease transmission over time. During the Coronavirus Disease 2019 (COVID-19) pandemic, policy makers and public health officials are using R t to assess the effectiveness of interventions and to inform policy. However, estimation of R t from available data presents several challenges, with critical implications for the interpretation of the course of the pandemic. The purpose of this document is to summarize these challenges, illustrate them with examples from synthetic data, and, where possible, make recommendations. For near real-time estimation of R t , we recommend the approach of Cori and colleagues, which uses data from before time t and empirical estimates of the distribution of time between infections. Methods that require data from after time t , such as Wallinga and Teunis, are conceptually and methodologically less suited for near real-time estimation, but may be appropriate for retrospective analyses of how individuals infected at different time points contributed to the spread. We advise caution when using methods derived from the approach of Bettencourt and Ribeiro, as the resulting R t estimates may be biased if the underlying structural assumptions are not met. Two key challenges common to all approaches are accurate specification of the generation interval and reconstruction of the time series of new infections from observations occurring long after the moment of transmission. Naive approaches for dealing with observation delays, such as subtracting delays sampled from a distribution, can introduce bias. We provide suggestions for how to mitigate this and other technical challenges and highlight open problems in R t estimation.

Understanding the influence of the changing Arctic on mid-latitude weather is complex, and a challenge for researchers. This Perspective considers current approaches and proposes a way forward based on accepting the chaotic nature of the atmospheric circulation. Are continuing changes in the Arctic influencing wind patterns and the occurrence of extreme weather events in northern mid-latitudes? The chaotic nature of atmospheric circulation precludes easy answers. The topic is a major science challenge, as continued Arctic temperature increases are an inevitable aspect of anthropogenic climate change. We propose a perspective that rejects simple cause-and-effect pathways and notes diagnostic challenges in interpreting atmospheric dynamics. We present a way forward based on understanding multiple processes that lead to uncertainties in Arctic and mid-latitude weather and climate linkages. We emphasize community coordination for both scientific progress and communication to a broader public.

We evaluate public health and climate impacts of low-sulphur fuels in global shipping. Using high-resolution emissions inventories, integrated atmospheric models, and health risk functions, we assess ship-related PM 2.5 pollution impacts in 2020 with and without the use of low-sulphur fuels. Cleaner marine fuels will reduce ship-related premature mortality and morbidity by 34 and 54%, respectively, representing a ~ 2.6% global reduction in PM 2.5 cardiovascular and lung cancer deaths and a ~3.6% global reduction in childhood asthma. Despite these reductions, low-sulphur marine fuels will still account for ~250k deaths and ~6.4 M childhood asthma cases annually, and more stringent standards beyond 2020 may provide additional health benefits. Lower sulphur fuels also reduce radiative cooling from ship aerosols by ~80%, equating to a ~3% increase in current estimates of total anthropogenic forcing. Therefore, stronger international shipping policies may need to achieve climate and health targets by jointly reducing greenhouse gases and air pollution. Aerosol pollution from shipping contributes to cooling but also leads to premature mortality and morbidity. Here the authors combine emission inventories, atmospheric models and health risk functions to show how cleaner marine fuels will reduce premature deaths and childhood asthma but results in larger warming.

Academic medical centers provide cutting edge acute care, train tomorrow's physicians, and carry out research that will expand the range of treatable and curable illnesses. But these centers themselves may need urgent care--experts generally agree that many are suffering acute--even life-threatening--financial distress. Many academic medical centers are suffering for several reasons: in-patient admissions are down, as many procedures that once required a hospital stay are now performed on an out-patient basis or in a physician's office ; managed care plans have negotiated discounted fees that cut hospital operating margins; the Balanced Budget Act of 1997 curtailed Medicare reimbursements, lowered margins and pushed some into the red; the revolution in information technology is imposing large new capital costs; and the character of medical education is receiving its most thorough review in decades. While there is a general consensus that medical centers are under pressure, experts disagree about the depth and pervasiveness of the current financial distress. Are they whining about financial pressures other, less-favored sectors find routine; or is the high quality American teaching hospital becoming an endangered species--that could face extinction if nothing is done. Because academic medical centers perform such important jobs, it is critical to determine the true nature and depth of their current financial problems--and then fashion analytically sound and politically sustainable solutions. This book brings together chief executive officers of major medical centers, university presidents, senior members of Congressional and executive office staffs, and leading analysts. These experts address the key issues and prescribe remedies both regulatory and legislative to ensure that the teaching hospital remains a picture of financial health. Contributors include Nancy Kane (Harvard School of Public Health), Jamie Reuter (Institute for Health Care Research P.