What Do We Really Know About Cosmic Acceleration?

Essentially all of our knowledge of the acceleration history of the Universe - including the acceleration itself - is predicated upon the validity of general relativity. Without recourse to this assumption, we use SNeIa to analyze the expansion history and find (i) very strong (5 sigma) evidence for a period of acceleration, (ii) strong evidence that the acceleration has not been constant, (iii) evidence for an earlier period of deceleration and (iv) only weak evidence that the Universe has not been decelerating since z~0.3.Comment: 9 pages, 8 figure

Tanzania Livestock Master Plan: The Dairy Roadmap

Bill & Melinda Gates Foundatio

Tanzania livestock master plan—Key findings

Bill & Melinda Gates Foundatio

Defensive Investments and the Demand for Air Quality: Evidence from the NOx Budget Program and Ozone Reductions

Willingness to pay for air quality is a function of health and the costly defensive investments that contribute to health, but there is little research assessing the empirical importance of defensive investments. The setting for this paper is a large US emissions cap and trade market – the NOx Budget Trading Program (NBP) – that has greatly reduced NOx emissions since its initiation in 2003. Using rich quasi-experimental variation, we find that the reductions in NOx emissions decreased the number of summer days with high ozone levels by about 25%. The NBP also led to reductions in expenditures on prescription pharmaceutical expenditures of about 1.9%. Additionally, the summer mortality rate declined by approximately 0.5%, indicating that there were about 2,200 fewer premature deaths per summer, mainly among individuals 75 and older. The monetized value of the reductions in pharmaceutical purchases and mortality rates are each roughly $900 million annually, suggesting that defensive investments are a significant portion of willingness to pay for air quality. Finally, we cautiously conclude that the reductions in ozone are the primary channel for these reductions in defensive investments and mortality rates, which indicates that willingness to pay for ozone reductions is larger than previously understood

PCSK9 Inhibitors in Secondary Prevention – An Opportunity for Personalized Therapy

Atherosclerotic cardiovascular disease (ASCVD) remains the leading cause of death worldwide. Low-density lipoprotein cholesterol (LDL-C) is the primary cause of ASCVD and reducing LDL-C levels with statin therapy significantly reduces ASCVD risk; however, significant residual risk remains. Two monoclonal antibodies (mAbs), alirocumab and evolocumab, that target proprotein convertase subtilisin/kexin-type 9 (PCSK9), reduce LDL-C levels by up to 60% when used in combination with statins and significantly reduce the risk of recurrent ASCVD events in both stable secondary prevention and acute coronary syndrome populations. Pre-specified analyses of recent randomized controlled trials have shed light on how best to prioritize these therapies to maximize their value in select high risk groups. These data have also informed recent clinical practice guidelines and scientific statements resulting in an expanded role for PCSK9-mAbs compared to previous guidelines, albeit there are notable differences between these recommendations. Ongoing research is exploring the long-term safety of PCSK9-mAbs and their role in the acute setting as well as patients without prior myocardial infarction or stroke. Novel therapies that inhibit PCSK9 synthesis via small interfering RNA, such as inclisiran, are also in development and may reduce LDL-C levels similar to PCSK9-mAbs but with less frequent administration. Nonetheless, the PCSK9-mAbs are a breakthrough therapy and warrant consideration in very-high risk patients who are most likely to benefit. Such a personalized approach can help to ensure cost-effectiveness and maximize their value

Mutation of the co-chaperone Tsc1 in bladder cancer diminishes Hsp90 acetylation and reduces drug sensitivity and selectivity

The molecular chaperone Heat shock protein 90 (Hsp90) is essential for the folding, stability, and activity of several drivers of oncogenesis. Hsp90 inhibitors are currently under clinical evaluation for cancer treatment, however their efficacy is limited by lack of biomarkers to optimize patient selection. We have recently identified the tumor suppressor tuberous sclerosis complex 1 (Tsc1) as a new co-chaperone of Hsp90 that affects Hsp90 binding to its inhibitors. Highly variable mutations of TSC1 have been previously identified in bladder cancer and correlate with sensitivity to the Hsp90 inhibitors. Here we showed loss of TSC1 leads to hypoacetylation of Hsp90-K407/K419 and subsequent decreased binding to the Hsp90 inhibitor ganetespib. Pharmacologic inhibition of histone deacetylases (HDACs) restores acetylation of Hsp90 and sensitizes Tsc1-mutant bladder cancer cells to ganetespib, resulting in apoptosis. Our findings suggest that TSC1 status may predict response to Hsp90 inhibitors in patients with bladder cancer, and co-targeting HDACs can sensitize tumors with Tsc1 mutations to Hsp90 inhibitors

Coherent Control and Entanglement in the Attosecond Electron Recollision Dissociation of D2+

We examine the attosecond electron recollision dissociation of D2+ recently demonstrated experimentally [H. Niikura et al., Nature (London) 421, 826 (2003)] from a coherent control perspective. In this process, a strong laser field incident on D2 ionizes an electron, accelerates the electron in the laser field to eV energies, and then drives the electron to recollide with the parent ion, causing D2+ dissociation. A number of results are demonstrated. First, a full dimensional Strong Field Approximation (SFA) model is constructed and shown to be in agreement with the original experiment. This is then used to rigorously demonstrate that the experiment is an example of coherent pump-dump control. Second, extensions to bichromatic coherent control are proposed by considering dissociative recollision of molecules prepared in a coherent superposition of vibrational states. Third, by comparing the results to similar scenarios involving field-free attosecond scattering of independently prepared D2+ and electron wave packets, recollision dissociation is shown to provide an example of wave-packet coherent control of reactive scattering. Fourth, this analysis makes clear that it is the temporal correlations between the continuum electron and D2+ wave packet, and not entanglement, that are crucial for the sub-femtosecond probing resolution demonstrated in the experiment. This result clarifies some misconceptions regarding the importance of entanglement in the recollision probing of D2+. Finally, signatures of entanglement between the recollision electron and the atomic fragments, detectable via coincidence measurements, are identified

Adapting the Climate Change: The Remarkable Decline in the U.S. Temperature-Mortality Relationship Over the 20th Century

Adaptation is the only strategy that is guaranteed to be part of the world's climate strategy. Using the most comprehensive set of data files ever compiled on mortality and its determinants over the course of the 20th century, this paper makes two primary discoveries. First, we find that the mortality effect of an extremely hot day declined by about 80% between 1900-1959 and 1960-2004. As a consequence, days with temperatures exceeding 90°F were responsible for about 600 premature fatalities annually in the 1960-2004 period, compared to the approximately 3,600 premature fatalities that would have occurred if the temperature-mortality relationship from before 1960 still prevailed. Second, the adoption of residential air conditioning (AC) explains essentially the entire decline in the temperature-mortality relationship. In contrast, increased access to electricity and health care seem not to affect mortality on extremely hot days. Residential AC appears to be both the most promising technology to help poor countries mitigate the temperature related mortality impacts of climate change and, because fossil fuels are the least expensive source of energy, a technology whose proliferation will speed up the rate of climate change

Microfluidic chromatography for early stage evaluation of biopharmaceutical binding and separation conditions

Optimization of separation conditions for biopharmaceuticals requires evaluation of a large number of process variables. To miniaturize this evaluation a microfluidic column (1.5 mu L volume and 1cm height) was fabricated and packed with a typical process scale resin. The device was assessed by comparison to a protein separation at conventional laboratory scale. This was based upon measurement of the quality of packing and generation of breakthrough and elution curves. Dynamic binding capacities from the microfluidic column compared well with the laboratory scale. Microfluidic scale gradient elution separations also equated to the laboratory column three orders of magnitude larger in scale

Association Between Early Hyperoxia Exposure After Resuscitation From Cardiac Arrest and Neurological Disability: Prospective Multicenter Protocol-Directed Cohort Study

BACKGROUND: Studies examining the association between hyperoxia exposure after resuscitation from cardiac arrest and clinical outcomes have reported conflicting results. Our objective was to test the hypothesis that early postresuscitation hyperoxia is associated with poor neurological outcome. METHODS: This was a multicenter prospective cohort study. We included adult patients with cardiac arrest who were mechanically ventilated and received targeted temperature management after return of spontaneous circulation. We excluded patients with cardiac arrest caused by trauma or sepsis. Per protocol, partial pressure of arterial oxygen (Pao2) was measured at 1 and 6 hours after return of spontaneous circulation. Hyperoxia was defined as a Pao2 >300 mm Hg during the initial 6 hours after return of spontaneous circulation. The primary outcome was poor neurological function at hospital discharge, defined as a modified Rankin Scale score >3. Multivariable generalized linear regression with a log link was used to test the association between Pao2 and poor neurological outcome. To assess whether there was an association between other supranormal Pao2 levels and poor neurological outcome, we used other Pao2 cut points to define hyperoxia (ie, 100, 150, 200, 250, 350, 400 mm Hg). RESULTS: Of the 280 patients included, 105 (38%) had exposure to hyperoxia. Poor neurological function at hospital discharge occurred in 70% of patients in the entire cohort and in 77% versus 65% among patients with versus without exposure to hyperoxia respectively (absolute risk difference, 12%; 95% confidence interval, 1-23). Hyperoxia was independently associated with poor neurological function (relative risk, 1.23; 95% confidence interval, 1.11-1.35). On multivariable analysis, a 1-hour-longer duration of hyperoxia exposure was associated with a 3% increase in risk of poor neurological outcome (relative risk, 1.03; 95% confidence interval, 1.02-1.05). We found that the association with poor neurological outcome began at ≥300 mm Hg. CONCLUSIONS: Early hyperoxia exposure after resuscitation from cardiac arrest was independently associated with poor neurological function at hospital discharge