Back-of-the-envelope Research Articles

Agent-Based Models Help Interpret Patterns of Clinical Drug Resistance by Contextualizing Competition Between Distinct Drug Failure Modes

Modern targeted cancer therapies are carefully crafted small molecules. These exquisite technologies exhibit an astonishing diversity of observed failure modes (drug resistance mechanisms) in the clinic. This diversity is surprising because back of the envelope calculations and classic modeling results in evolutionary dynamics suggest that the diversity in the modes of clinical drug resistance should be considerably smaller than what is observed. These same calculations suggest that the outgrowth of strong pre-existing genetic resistance mutations within a tumor should be ubiquitous.Yet, clinically relevantdrug resistance occurs in the absence of obvious resistance conferring genetic alterations. Quantitatively, understanding the underlying biological mechanisms of failure mode diversity may improve the next generation of targeted anticancer therapies. It also provides insights into how intratumoral heterogeneity might shape interpatient diversity during clinical relapse. We employed spatial agent-based models to explore regimes where spatial constraintsenable wild type cells (that encounter beneficial microenvironments)tocompete against genetically resistant subclones in the presence of therapy. In order to parameterize a model of microenvironmental resistance, BT20 cells were cultured in the presence and absence of fibroblasts from 16different tissues. The degree of resistance conferred by cancer associated fibroblasts in the tumor microenvironment was quantified by treating mono- and co-cultures with letrozole and then measuring the death rates. Our simulations indicate that, even when a mutation is more drug resistant, its outgrowth can be delayed byabundant,low magnitude microenvironmental resistance across large regions of a tumor that lack genetic resistance.These observations hold fordifferent modes of microenvironmental resistance, including juxtacrine signaling, soluble secreted factors,and remodeled ECM.This result helps to explain the remarkable diversity of resistance mechanisms observed in solid tumors, which subverts the presumption that the failure mode that causes the quantitatively fastest growth in the presence of drug should occur most often in the clinic. Our model results demonstrate that spatial effects can interact with low magnitude of resistance microenvironmental effects to successfully compete against genetic resistance that is orders of magnitude larger. Clinical outcomes of solid tumors are intrinsically connected to their spatial structure, and the tractability of spatial agent-based models like the ones presented here enable us to understand this relationship more completely.

REVIEW: Multiple voices shed new light on New Zealand Wars

Voices from the New Zealand Wars. He Reo nō ngā pakanga o Aotearoa, by Vincent O’Malley. Wellington, NZ: Bridget Williams Books. 2021, 420 pages. ISBN 9781988587790.
 HISTORY and journalism are two very closely linked art forms. Journalism has often been described as the first draft of history, especially war, although veteran BBC journalist John Simpson is credited with saying that it is more like some rough notes scribbled on the back of a napkin that is then thrown out of the window while the restaurant is under fire.

Molecular hydrogen from organic sources in geological systems

We have recently shown that molecular hydrogen generation from organic matter occurs at high maturity levels (vitrinite reflectance 3–5%) in Lower Cretaceous shales of the Songliao Basin. To evaluate and extend these implications to a wider range of source rock types and organofacies, we report on two Paleozoic maturity suites from Australia, namely the Permian Patchawarra Formation (fluviodeltaic; Type-III; Cooper Basin) and the middle Cambrian Arthur Creek Formation (marine; Type-II; Georgina Basin), and additional mature marine source rocks from Europe and the USA.It can be inferred from high resolution mass spectrometry that rapid growth of aromatic ring systems is the major pathway for the formation of thermogenic molecular hydrogen from all organic matter types. Extensive open system pyrolysis experiments indicate that the main generation pulse occurs in the vitrinite reflectance range 3.5–5.0%. Kinetic parameters were constructed by subtracting the hydrogen associated with hydrocarbon formation from total hydrogen in the open-system experiments via adjustment factors defined by the relative yields of CH4 and H2. A cumulative H2 potential of 20 mg/g TOC is found with maximum rates of generation that are sufficient for feeding the deep biosphere. Back of the envelope calculations indicate ∼3.5E+10 tonnes of in-place accessible H2 globally, which is an order of magnitude lower than in-place shale gas resource estimates. Regionally, inferred here for the Patchawarra Formation in the Nappamerri Trough (Cooper Basin), yields per unit rock volume resemble those of economic shale gas in the Barnett Shale, Fort Worth Basin, USA.Organic particles are, at the SEM-scale (>30 nm), barren of secondary porosity in the case of terrigenous samples at all maturity stages, but show sponge-like porosity in the investigated marine source rocks exhibiting vitrinite reflectance >∼2.0%. Presence of such meso- and macropores is crucial for H2 storage in marine shales, as microporosity (<2 nm) yielding sorptive storage space for H2, is usually much higher in mature terrigenous kerogens.

Future Perfect

Future Perfect

Back of the envelope

Back-of-the-envelope calculations are a powerful professional practice.

The "Great Lockdown": Inactive workers and mortality by Covid-19.

In response to the Covid‐19 outbreak, the Italian Government imposed an economic lockdown on March 22, 2020, and ordered the closing of all non‐essential economic activities. This paper estimates the causal effects of this measure on mortality by Covid‐19 and on mobility patterns. The identification of the causal effects exploits the variation in the active population across municipalities induced by the economic lockdown. The difference‐in‐differences empirical design compares outcomes in municipalities above and below the median variation in the share of active population before and after the lockdown within a province, also controlling for municipality‐specific dynamics, daily shocks at the provincial level, and municipal unobserved characteristics. Our results show that the intensity of the economic lockdown is associated with a statistically significant reduction in mortality by Covid‐19 and, in particular, for age groups between 40 and 64 and older (with larger and more significant effects for individuals above 50). Back of the envelope calculations indicate that 4793 deaths were avoided, in the 26 days between April 5 and April 30, in the 3518 municipalities which experienced a more intense lockdown. Several robustness checks corroborate our empirical findings.

Back of the envelope calculations of marginal effects in some binary choice models

Back of the envelope calculations of marginal effects in some binary choice models

Eliciting Individuals’ Financial Decision-Making Approaches with Verbal Protocols

How do individuals approach financial decisions? Do they apply sophisticated formulas, 'back of the envelope'-math, do they guess, or something completely different? We show that the verbal protocol method – i.e., having individuals explain their approaches – generates new insights to answer these questions. Our findings on approaches discovered are reliable within sample and have predictive power out of sample. Among other things, we find that when assessing the value of an annuity, 40% of individuals use some math, and some even use formulas similar to actuaries; the other 60% seem to guess. Valuation approaches used predict valuation outcomes and valuation precision, explain puzzling findings reported in earlier literature, and predict a behavioral reaction to an anchoring intervention designed to match one of the approaches discovered. The verbal protocol method opens new pathways to understand financial decision-making as well as to design effective policy interventions.

The 'Great Lockdown': Inactive Workers and Mortality by COVID-19

In response to the COVID-19 outbreak the Italian Government imposed an economic lockdown on March 22, 2020 and ordered the closing of all non-essential economic activities. This paper estimates the causal effects of this measure on mortality by COVID-19 and on mobility patterns. The identification of the causal effects exploits the variation in the active population across municipalities induced by the economic lockdown. The difference-in-differences empirical design compares outcomes in municipalities above and below the median variation in the share of active population before and after the lockdown within a province, also controlling for municipality-specific dynamics, daily-shocks at the provincial level and municipal unobserved characteristics. Our results show that the intensity of the economic lockdown is associated with a statistically significant reduction in mortality by Covid-19 and, in particular, for age groups between 40-64 and older (with larger and more significant effects for individuals above 50). Back of the envelope calculations indicate that 4,793 deaths were avoided, in the 26 days between April 5 to April 30, in the 3,518 municipalities which experienced a more intense lockdown. Several robustness checks corroborate our empirical findings.

Payments for agrobiodiversity conservation services: An overview of Latin American experiences, lessons learned and upscaling challenges

Many developing countries face a major challenge today: how to safeguard the biodiversity maintained in the fields of the rural poor - which constitute a national and global public good - whilst meeting those same people's development needs and rights? A solution to this dilemma has thus been sought in adapting the design and implementation of Payments for Ecosystem Services (PES) concepts to the conservation of agrobiodiversity.Here we review the application of nine such Payments for Agrobiodiversity Conservation (PACS) schemes that have been applied to date in four Latin American countries over the period 2010–2018. These covered 130 threatened varieties across a number of major food crops, and involved over 100 farming communities and 1,100 farmers (45 % of which were women). Conservation service offers were received through a competitive tender mechanism. Average bid offers revealed high heterogeneity, varying between US$675/ha. to ten times as much.In relation to issues identified as key to PES, such as spatial targeting, differentiated payments and conditionality, the underlying design of the PACS schemes may be considered solid. PACS-related prioritisation processes allow for the a priori identification of sites with high ecosystem service densities and high threat levels. The use of competitive tenders permits accounting for cost heterogeneity in the provision of conservation services and for payments to be differentiated. Conditionality is strong.In terms of implementation, a “back of the envelope” calculation based on the results of the competitive tenders suggests that conservation costs are modest. For a priority conservation portfolio of 100 varieties (which may be from different crops) each with a target area of five hectares, costs would amount to just under US$860,000 over twenty years or US$70,000 p.a. at a 5 % discount rate. The small-scale and one-off nature of the interventions realised to date, along with threatened crop variety seed availability constraints, have however meant that environmental effectiveness has been incomplete in the short-term (area cultivated with specific threatened varieties increased, but still below the “not at risk” threshold). The establishment of systematic monitoring systems is required to determine longer-term impacts and inform more regular PACS interventions within a dynamically evolving systems context.

Green Solvent: Green Shadow on Chemical Synthesis.

The natural beauty and purity of our planet has been contaminated deeply due to human selfish activities such as pollution, improper waste management, and various industrial and commercial discharges of untreated toxic by-products into the lap of nature. The collective impact of these hazardous suspensions into the natural habitat is very deadly. Challenges due to human activity on the environment have become ubiquitous. The chemical industry has a major role in human evolution and, predictably, opened gates of increased risk of pollution if the production is not done sustainably. In these circumstances, the notion of Green Chemistry has been identified as the efficient medium of synthesis of chemicals and procedures to eradicate the toxic production of harmful substances. Principles of Green Chemistry guide the scientist in their hunt towards chemical synthesis which requires the use of solvents. These solvents contaminate our air, water, land and surrounding due to its toxic properties. Even though sufficient precautions are taken for proper disposal of these solvents but it is difficult to be recycled. In order to preserve our future and coming generation from the adverse impacts associated with solvents it is very important to find alternative of this which will be easy to use, reusable and also eco-friendly. Solvents are used daily in various industrial processes as reaction medium, as diluters, and in separation procedures. As reaction medium, the role of solvent is to bring catalysts and reactants together and to release heat thus affecting activity and selectivity. The proper selection of the solvent considering its biological, physical and chemical properties is very necessary for product separation, environmental, safety handling and economic factors. Green solvents are the boon in this context. They are not only environmentally benign but also cost effective. The biggest challenge faced by the chemists is adaptation of methods and selection of solvents during chemical synthesis which will give negligible waste product and will remain human and nature friendly. During designing compounds for a particular reaction it is difficult to give assurance regarding the toxicity and biodegradability of the method. Chemists are still far away from predicting the various chemical and biological effects of the compounds on the back of the envelope. To achieve that point is formidable task but it will definitely act as inspiration for the coming generation of chemists. The green solvents are undoubtedly a far better approach to eliminate the negative impacts and aftermath of any chemical synthesis on the environment. Our study in this review covers an overview of green solvents, their role in safer chemical synthesis with reference to some of the important green solvents and their detail summarization.

Comment on “The Household Channel of Monetary Policy in the Euro Area: A Back of the Envelope Calculation”

This paper presents a model of investment in a duopoly with firms that choose the scale and timing of investment. Decision-making flexibility and the costs saved by investing in large steps rather than sequences of small steps determine an incumbent’s ability to deter entry by a potential competitor. Entry occurs when these cost savings are very small or very large, because the effect of increased industry capacity on the incumbent’s assets-in-place is the same regardless of which firm invests. In intermediate cases, the incumbent is able to deter entry by making a smaller, earlier investment than the potential entrant. The smaller investment scale protects the incumbent’s assets-in-place, which offsets the incumbent’s cost disadvantage from investing in smaller steps than the entrant would choose. Nevertheless, the threat of entry constrains the incumbent’s investment behavior and limits its profitability. The model is solved using a combination of best-response iteration and the projected successive over-relaxation method.

Exchange rate forecasting on a napkin

This paper shows that there are two regularities in foreign exchange markets in advanced countries with flexible regimes. First, real exchange rates are mean-reverting, as implied by the Purchasing Power Parity model. Second, the adjustment takes place via nominal exchange rates. These features of the data can be exploited, even on the back of a napkin, to generate nominal exchange rate forecasts that outperform the random walk. The secret is to avoid estimating the pace of mean reversion and assume that relative prices are unchanged. Direct forecasting, panel data techniques and non-linear models can outperform the random walk, but fail to beat this simple calibrated model.

The 'Great Lockdown': Inactive Workers and Mortality by COVID-19

In response to the Covid-19 outbreak the Italian Government imposed an economic lockdown on March 22, 2020 and ordered the closing of all non-essential economic activities. This paper estimates the causal effects of this measure on mortality by Covid-19 and on mobility patterns. The identification of the causal effects exploits the variation in the active population across municipalities induced by the economic lockdown. The difference-in-differences empirical design compares outcomes in municipalities above and below the median variation in the share of active population before and after the lockdown within a province, also controlling for municipality-specific dynamics, daily-shocks at the provincial level and municipal unobserved characteristics. Our results show that the intensity of the economic lockdown is associated with a statistically significant reduction in mortality by Covid-19 and, in particular, for age groups between 40-64 and older (with larger and more significant effects for individuals above 50). Back of the envelope calculations indicate that 4,793 deaths were avoided, in the 26 days between April 5 to April 30, in the 3,518 municipalities which experienced a more intense lockdown. Several robustness checks corroborate our empirical findings.

Acknowledgments

The ideas in this book began as a few notes on the back of a napkin, scribbled together with Alison Phipps, whom I must thank first for our rich and rewarding years of friendship, for her collegiality and support, for her sharp mind, brilliant ideas, and deep humanity, for helping to draw the occasional bright idea out of me, for the inspiration and motivation to think beyond the narrow confines of the language classroom in order to help recognize the potential of language teaching and learning, for showing me that understanding the complexities of language and learning is useless unless it serves the larger purpose of fostering human capabilities, creativity, and compassion. I also want to offer Heidi Byrnes tausend Dank, for encouraging the writing of this monograph beyond the confines of an academic article. Her feedback and guidance early in the project were essential for seeing the big picture of what the book should be about. Thank you to Wander Lowie for his encouragement and support throughout the writing process, and his patience with my delays and many questions. I am also very grateful to David Block and Rick Kern for their rich and detailed feedback and instructions for revising the first draft; I did my best to address all of their concerns and wishes. Thanks, too, to Kate Miller for her skillful editing of the manuscript, and to Shalini Chawla for her patience and attention to detail in the production phase. I am inexpressibly grateful to Bridget Swanson for her keen and brutally honest reading and editing of drafts of this monograph, for what I call her bird's-eye perspective of issues of language teaching, and for her unwavering encouragement throughout! I want to thank Monika Böhme for the many insightful and inspiring conversations we had about language teaching and language learners, which were helpful in focusing many of the discussions in these chapters, as well as keeping them grounded in what teachers actually do, or can do, with their students. Likewise, the many discussions I had on the topics in these chapters were invaluable, and so I am very grateful to Claire Kramsch, Christina Frei, Hiram Maxim, Cori Crane, Chantelle Warner, Steve Thorne, David Gramling, Susanne Rott, Barbara Schmenk, Thor Sawin, Julio Torres, Lisa Parkes, Jerry Won Lee, Bettina Matthias, Carl Blyth, Dave Malinowski, Heather Willis Allen, Friederike Tebben, Per Urlaub, Rosemarie Tracy, Stephan Breidbach, Tessa Wegener, and Sébastien Dubreil. I am forever grateful to all of the graduate students I have had the pleasure to work with over many years, who provided both inspiration and insights through our many interactions about language teaching and my many visits to their classes. Thanks to Eric Blankenship, Kristin Brehm, Patrick Carlson, Matt Cooper, Natalie Eppelsheimer, Jonathan Fine, Friederike Kaufel, Rose Jones, Erin Kelly, Franz Kuzay, David Lamme, Alex Lotz, Susan Morse, Simona Moti, Steven Nave, Yao Pei, Mohammed Rafi, Jaime Roots, Rebecca Schuman, Henrik Sponsel, Jacob Schaubs, Xuxu Song, Magda Tarnawska Senel, Jessica Wood, and Jason Wilby. Also, without the amazing friendship, hospitality, and support of Gail Hart and Dennis Perchak, I am certain I would not have had the peace and quiet I needed at crucial stages of the work. Finally, I want to thank Ursula Levine for the support and encouragement through the years I worked on this book. While writing is a solitary activity, her belief in me was crucial. Just as much, I am grateful to my children, Hanna, Annika, and Sam, especially for their understanding for the many days I was gone in order to research and write. To all of those who gave feedback and comments on parts or all of the book, the usual disclaimer applies: Any shortcomings of the work are entirely on me. Glenn Levine Irvine, California, October 26, 2019

An increasing gasoline price elasticity in the United States?

Abstract Drawing on the 2009 and 2017 waves of the National Household Transportation Survey, this paper is concerned with modeling the fuel price elasticity, allowing for differential estimates in its magnitude over time and across households. We find an elasticity close to zero for the year 2009, which increases to upwards of −0.3 by the year 2017. We explore the robustness of this result to different model specifications and estimation techniques, including instrumental variable estimation to account for the possible endogeneity of fuel prices, as well as quantile regression to account for heterogeneity according to driving intensity. While a similar pattern of increasing elasticity over time emerges across all these models, the quantile model suggests an inverse relationship between the magnitude of the elasticity and miles driven in 2017. As demonstrated with a back of the envelope calculation, one implication of this pattern is a more muted effectiveness of fuel taxation than implied by the estimates of a standard mean regression.

An Increasing Gasoline Price Elasticity in the United States?

Drawing on the 2009 and 2017 waves of the National Household Transportation Survey, this paper is concerned with modeling the fuel price elasticity, allowing for differential estimates in its magnitude over time and across households. We find a small but statistically significant mean elasticity of about -0.05 for the year 2009, which increases over fivefold to -0.26 by the year 2017. We explore the robustness of this result to different model specifications and estimation techniques, including instrumental variable estimation to account for the possible endogeneity of fuel prices, as well as quantile regression to account for heterogeneity according to driving intensity. While a similar pattern of substantially increasing elasticity emerges across all these models, the quantile model suggests an inverse relationship between the magnitude of the elasticity and miles driven in 2017. As demonstrated with a back of the envelope calculation, one implication of this pattern is a more muted effectiveness of fuel taxation than implied by the estimates of a standard mean regression.

Back-of-the-envelope image quality estimation using the national image interpretability rating scale: erratum.

This paper corrects several errata in Appl. Opt.58, 6586 (2019)APOPAI0003-693510.1364/AO.58.006586.

Love in the Time of Dementia

Love in the Time of Dementia

Bistatic sonobuoy deployment strategies for detecting stationary and mobile underwater targets

The problem of determining effective allocation schemes of underwater sensors for surveillance, search, detection, and tracking purposes is a fundamental research area in military operations research. Among the various sensor types, multistatic sonobuoy systems are a promising development in submerged target detection systems. These systems consist of sources (active sensors) and receivers (passive sensors), which need not be collocated. A multistatic sonobuoy system consisting of a single source and receiver is called a bistatic system. The sensing zone of this fundamental system is defined by Cassini ovals. The unique properties and unusual geometrical profile of these ovals distinguish the bistatic sensor allocation problem from conventional sonar placement problems. This study is aimed at supporting decision makers in making the best use of bistatic sonobuoys to detect stationary and mobile targets transiting through an area of interest. We use integral geometry and geometric probability concepts to derive analytic expressions for the optimal source and receiver separation distances to maximize the detection probability of a submerged target. We corroborate our analytic results using Monte Carlo simulation. Our approach constitutes a valuable “back of the envelope” method for the important and difficult problem of analyzing bistatic sonar performance.