The African football legends provided inspiration for many during their playing days ......

Physical and chemical DNA-damaging agents are used widely in the treatment of cancer. Double-strand break (DSB) lesions in DNA are the most deleterious form of damage and, if left unrepaired, can effectively kill cancer cells. DNA-dependent protein kinase (DNA-PK) is a critical component of nonhomologous end joining (NHEJ), one of the two major pathways for DSB repair. Although DNA-PK has been considered an attractive target for cancer therapy, the development of pharmacologic DNA-PK inhibitors for clinical use has been lagging. Here, we report the discovery and characterization of a potent, selective, and orally bioavailable DNA-PK inhibitor, M3814 (peposertib), and provide in vivo proof of principle for DNA-PK inhibition as a novel approach to combination radiotherapy. M3814 potently inhibits DNA-PK catalytic activity and sensitizes multiple cancer cell lines to ionizing radiation (IR) and DSB-inducing agents. Inhibition of DNA-PK autophosphorylation in cancer cells or xenograft tumors led to an increased number of persistent DSBs. Oral administration of M3814 to two xenograft models of human cancer, using a clinically established 6-week fractionated radiation schedule, strongly potentiated the antitumor activity of IR and led to complete tumor regression at nontoxic doses. Our results strongly support DNA-PK inhibition as a novel approach for the combination radiotherapy of cancer. M3814 is currently under investigation in combination with radiotherapy in clinical trials.

Age-at-onset is one of the critical traits in cohort studies of age-related diseases. Large-scale genome-wide association studies (GWAS) of age-at-onset traits can provide more insights into genetic effects on disease progression and transitions between stages. Moreover, proportional hazards (or Cox) regression models can achieve higher statistical power in a cohort study than a case-control trait using logistic regression. Although mixed-effects models are widely used in GWAS to correct for sample dependence, application of Cox mixed-effects models (CMEMs) to large-scale GWAS is so far hindered by intractable computational cost. In this work, we propose COXMEG, an efficient R package for conducting GWAS of age-at-onset traits using CMEMs. COXMEG introduces fast estimation algorithms for general sparse relatedness matrices including, but not limited to, block-diagonal pedigree-based matrices. COXMEG also introduces a fast and powerful score test for dense relatedness matrices, accounting for both population stratification and family structure. In addition, COXMEG generalizes existing algorithms to support positive semidefinite relatedness matrices, which are common in twin and family studies. Our simulation studies suggest that COXMEG, depending on the structure of the relatedness matrix, is orders of magnitude computationally more efficient than coxme and coxph with frailty for GWAS. We found that using sparse approximation of relatedness matrices yielded highly comparable results in controlling false-positive rate and retaining statistical power for an ethnically homogeneous family-based sample. By applying COXMEG to a study of Alzheimer’s disease (AD) with a Late-Onset Alzheimer’s Disease Family Study from the National Institute on Aging sample comprising 3456 non-Hispanic whites and 287 African Americans, we identified the APOE 4 variant with strong statistical power (P = 1e–101), far more significant than that reported in a previous study using a transformed variable and a marginal Cox model. Furthermore, we identified novel SNP rs36051450 (P = 2e–9) near GRAMD1B, the minor allele of which significantly reduced the hazards of AD in both genders. These results demonstrated that COXMEG greatly facilitates the application of CMEMs in GWAS of age-at-onset traits.

Key Points

Technology in bioanalysis, -omics, and computation have evolved over the past half century to allow for comprehensive assessments of the molecular to whole body pharmacology of diverse corticosteroids. Such studies have advanced pharmacokinetic and pharmacodynamic (PK/PD) concepts and models that often generalize across various classes of drugs. These models encompass the "pillars" of pharmacology, namely PK and target drug exposure, the mass-law interactions of drugs with receptors/targets, and the consequent turnover and homeostatic control of genes, biomarkers, physiologic responses, and disease symptoms. Pharmacokinetic methodology utilizes noncompartmental, compartmental, reversible, physiologic [full physiologically based pharmacokinetic (PBPK) and minimal PBPK], and target-mediated drug disposition models using a growing array of pharmacometric considerations and software. Basic PK/PD models have emerged (simple direct, biophase, slow receptor binding, indirect response, irreversible, turnover with inactivation, and transduction models) that place emphasis on parsimony, are mechanistic in nature, and serve as highly useful "top-down" methods of quantitating the actions of diverse drugs. These are often components of more complex quantitative systems pharmacology (QSP) models that explain the array of responses to various drugs, including corticosteroids. Progressively deeper mechanistic appreciation of PBPK, drug-target interactions, and systems physiology from the molecular (genomic, proteomic, metabolomic) to cellular to whole body levels provides the foundation for enhanced PK/PD to comprehensive QSP models. Our research based on cell, animal, clinical, and theoretical studies with corticosteroids have provided ideas and quantitative methods that have broadly advanced the fields of PK/PD and QSP modeling and illustrates the transition toward a global, systems understanding of actions of diverse drugs.

Doxycycline, an FDA-approved tetracycline, is used in tuberculosis in vivo models for the temporal control of mycobacterial gene expression. In these models, animals are infected with recombinant Mycobacterium tuberculosis carrying genes of interest under transcriptional control of the doxycycline-responsive TetR-tetO unit. To minimize fluctuations of plasma levels, doxycycline is usually administered in the diet. However, tissue penetration studies to identify the minimum doxycycline content in food achieving complete repression of TetR-controlled genes in tuberculosis (TB)-infected organs and lesions have not been conducted. Here, we first determined the tetracycline concentrations required to achieve silencing of M. tuberculosis target genes in vitro. Next, we measured doxycycline concentrations in plasma, major organs, and lung lesions in TB-infected mice and rabbits and compared these values to silencing concentrations measured in vitro. We found that 2,000 ppm doxycycline supplemented in mouse and rabbit feed is sufficient to reach target concentrations in TB lesions. In rabbit chow, the calcium content had to be reduced 5-fold to minimize chelation of doxycycline and deliver adequate oral bioavailability. Clearance kinetics from major organs and lung lesions revealed that doxycycline levels fall below concentrations that repress tet promoters within 7 to 14 days after doxycycline is removed from the diet. In summary, we have shown that 2,000 ppm doxycycline supplemented in standard mouse diet and in low-calcium rabbit diet delivers concentrations adequate to achieve full repression of tet promoters in infected tissues of mice and rabbits.

Animal models of bacterial infection have been widely used to explore the in vivo activity of antibacterial drugs. These data are often submitted to the U.S. Food and Drug Administration to support human use in an investigational new drug application (IND). To better understand the range and scientific use of animal models in regulatory submissions, a database was created surveying recent pneumonia models submitted as part of IND application packages. The IND studies were compared to animal models of bacterial pneumonia published in the scientific literature over the same period of time. In this review, we analyze the key experimental design elements, such as animal species, immune status, pathogens selected, and route of administration, and study endpoints.

Hepatitis C virus (HCV) is an important and underreported infectious disease, causing chronic infection in ~71 million people worldwide. The limited host range of HCV, which robustly infects only humans and chimpanzees, has made studying this virus in vivo challenging and hampered the development of a desperately needed vaccine. The restrictions and ethical concerns surrounding biomedical research in chimpanzees has made the search for an animal model all the more important. In this review, we discuss different approaches that are being pursued toward creating small animal models for HCV infection. Although efforts to use a nonhuman primate species besides chimpanzees have proven challenging, important advances have been achieved in a variety of humanized mouse models. However, such models still fall short of the overarching goal to have an immunocompetent, inheritably susceptible in vivo platform in which the immunopathology of HCV could be studied and putative vaccines development. Alternatives to overcome this include virus adaptation, such as murine-tropic HCV strains, or the use of related hepaciviruses, of which many have been recently identified. Of the latter, the rodent/rat hepacivirus from Rattus norvegicus species-1 (RHV-rn1) holds promise as a surrogate virus in fully immunocompetent rats that can inform our understanding of the interaction between the immune response and viral outcomes (i.e., clearance vs. persistence). However, further characterization of these animal models is necessary before their use for gaining new insights into the immunopathogenesis of HCV and for conceptualizing HCV vaccines.

Shannon's said: “OCRO HLI RGWR NMIELWIS”

A new process to harness multiple disease models for outbreak management has been developed by an international team of researchers. The team will immediately implement the process to help inform policy decisions for the COVID-19 outbreak.

First and last names, email addresses, gender and sexual orientation, and credit card information of models and users was left on an insecure server

Statistical models used by IMD will still be used for monsoon forecast, but the ministry of earth sciences is putting more emphasis on dynamic models.

In the COVID-19 pandemic, numerous models are being used to predict the future. But as helpful as they are, they cannot make sense of themselves. They rely on epidemiologists and other modelers to interpret them. Trouble is, making predictions in a pandemic is also a philosophical exercise. We need to think about hypothetical worlds, causation, evidence, and the relationship between models and reality.1,2

The value of philosophy in this crisis is that although the pandemic is unique, many of the challenges of prediction, evidence, and modeling are general problems. Philosophers like myself are trained to see the most general contours of problems—the view from the clouds. They can help interpret scientific results and claims and offer clarity in times of uncertainty, bringing their insights down to Earth. When it comes to predicting in an outbreak, building a model is only half the battle. The other half is making sense of what it shows, what it leaves out, and what else we need to know to predict the future of COVID-19.

Prediction is about forecasting the future, or, when comparing scenarios, projecting several hypothetical futures. Because epidemiology informs public health directives, predicting is central to the field. Epidemiologists compare hypothetical worlds to help governments decide whether to implement lockdowns and social distancing measures—and when to lift them. To make this comparison, they use models to predict the evolution of the outbreak under various simulated scenarios. However, some of these simulated worlds may turn out to misrepresent the real world, and then our prediction might be off.

In his book Philosophy of Epidemiology, Alex Broadbent, a philosopher at the University of Johannesburg, argues that good epidemiological prediction requires asking, “What could possibly go wrong?” He elaborated in an interview with Nautilus, “To predict well is to be able to explain why what you predict will happen rather than the most likely hypothetical alternatives. You consider the way the world would have to be for your prediction to be true, then consider worlds in which the prediction is false.” By ruling out hypothetical worlds in which they are wrong, epidemiologists can increase their confidence that they are right. For instance, by using antibody tests to estimate previous infections in the population, public health authorities could rule out the hypothetical possibility (modeled by a team at Oxford) that the coronavirus has circulated much more widely than we think.3

One reason the dynamics of an outbreak are often more complicated than a traditional model can predict is that they result from human behavior and not just biology.

Broadbent is concerned that governments across Africa are not thinking carefully enough about what could possibly go wrong, having for the most part implemented coronavirus policies in line with the rest of the world. He believes a one-size-fits-all approach to the pandemic could prove fatal.4 The same interventions that might have worked elsewhere could have very different effects in the African context. For instance, the economic impacts of social distancing policies on all-cause mortality might be worse because so many people on the continent suffer increased food insecurity and malnutrition in an economic downturn.5 Epidemic models only represent the spread of the infection. They leave out important elements of the social world.

Another limitation of epidemic models is that they model the effect of behaviors on the spread of infection, but not the effect of a public health policy on behaviors. The latter requires understanding how a policy works. Nancy Cartwright, a philosopher at Durham University and the University of California, San Diego, suggests that “the road from ‘It works somewhere’ to ‘It will work for us’ is often long and tortuous.”6 The kinds of causal principles that make policies effective, she says, “are both local and fragile.” Principles can break in transit from one place to the other. Take the principle, “Stay-at-home policies reduce the number of social interactions.” This might be true in Wuhan, China, but might not be true in a South African township in which the policies are infeasible or in which homes are crowded. Simple extrapolation from one context to another is risky. A pandemic is global, but prediction should be local.

Predictions require assumptions that in turn require evidence. Cartwright and Jeremy Hardie, an economist and research associate at the Center for Philosophy of Natural and Social Science at the London School of Economics, represent evidence-based policy predictions using a pyramid, where each assumption is a building block.7 If evidence for any assumption is missing, the pyramid might topple. I have represented evidence-based medicine predictions using a chain of inferences, where each link in the chain is made of an alloy containing assumptions.8 If any assumption comes apart, the chain might break.

An assumption can involve, for example, the various factors supporting an intervention. Cartwright writes that “policy variables are rarely sufficient to produce a contribution [to some outcome]; they need an appropriate support team if they are to act at all.” A policy is only one slice of a complete causal pie.9 Take age, an important support factor in causal principles of social distancing. If social distancing prevents deaths primarily by preventing infections among older individuals, wherever there are fewer older individuals there may be fewer deaths to prevent—and social distancing will be less effective. This matters because South Africa and other African countries have younger populations than do Italy or China.10

The lesson that assumptions need evidence can sound obvious, but it is especially important to bear in mind when modeling. Most epidemic modeling makes assumptions about the reproductive number, the size of the susceptible population, and the infection-fatality ratio, among other parameters. The evidence for these assumptions comes from data that, in a pandemic, is often rough, especially in early days. It has been argued that nonrepresentative diagnostic testing early in the COVID-19 pandemic led to unreliable estimates of important inputs in our epidemic modeling.11

Epidemic models also don’t model all the influences of the pathogen and of our policy interventions on health and survival. For example, what matters most when comparing deaths among hypothetical worlds is how different the death toll is overall, not just the difference in deaths due to the direct physiological effects of a virus. The new coronavirus can overwhelm health systems and consume health resources needed to save non-COVID-19 patients if left unchecked. On the other hand, our policies have independent effects on financial welfare and access to regular healthcare that might in turn influence survival.

A surprising difficulty with predicting in a pandemic is that the same pathogen can behave differently in different settings. Infection fatality ratios and outbreak dynamics are not intrinsic properties of a pathogen; these things emerge from the three-way interaction among pathogen, population, and place. Understanding more about each point in this triangle can help in predicting the local trajectory of an outbreak.

In April, an influential data-driven model, developed by the Institute for Health Metrics and Evaluation (IHME) at the University of Washington, which uses a curve-fitting approach, came under criticism for its volatile projections and questionable assumption that the trajectory of COVID-19 deaths in American states can be extrapolated from curves in other countries.12,13 In a curve-fitting approach, the infection curve representing a local outbreak is extrapolated from data collected locally along with data regarding the trajectory of the outbreak elsewhere. The curve is drawn to fit the data. However, the true trajectory of the local outbreak, including the number of infections and deaths, depends upon characteristics of the local population as well as policies and behaviors adopted locally, not just upon the virus.

Predictions require assumptions that in turn require evidence.

Many of the other epidemic models in the coronavirus pandemic are SIR-type models, a more traditional modelling approach for infectious-disease epidemiology. SIR-type models represent the dynamics of an outbreak, the transition of individuals in the population from a state of being susceptible to infection (S) to one of being infectious to others (I) and, finally, recovered from infection (R). These models simulate the real world. In contrast to the data-driven approach, SIR models are more theory-driven. The theory that underwrites them includes the mathematical theory of outbreaks developed in the 1920s and 1930s, and the qualitative germ theory pioneered in the 1800s. Epidemiologic theories impart SIR-type models with the know-how to make good predictions in different contexts.

For instance, they represent the transmission of the virus as a factor of patterns of social contact as well as viral transmissibility, which depend on local behaviors and local infection control measures, respectively. The drawback of these more theoretical models is that without good data to support their assumptions they might misrepresent reality and make unreliable projections for the future.

One reason why the dynamics of an outbreak are often more complicated than a traditional model can predict, or an infectious-disease epidemiology theory can explain, is that the dynamics of an outbreak result from human behavior and not just human biology. Yet more sophisticated disease-behavior models can represent the behavioral dynamics of an outbreak by modeling the spread of opinions or the choices individuals make.14,15 Individual behaviors are influenced by the trajectory of the epidemic, which is in turn influenced by individual behaviors.

“There are important feedback loops that are readily represented by disease-behavior models,” Bert Baumgartner, a philosopher who has helped develop some of these models, explains. “As a very simple example, people may start to socially distance as disease spreads, then as disease consequently declines people may stop social distancing, which leads to the disease increasing again.” These looping effects of disease-behavior models are yet another challenge to predicting.

It is a highly complex and daunting challenge we face. That’s nothing unusual for doctors and public health experts, who are used to grappling with uncertainty. I remember what that uncertainty felt like when I was training in medicine. It can be discomforting, especially when confronted with a deadly disease. However, uncertainty need not be paralyzing. By spotting the gaps in our models and understanding, we can often narrow those gaps or at least navigate around them. Doing so requires clarifying and questioning our ideas and assumptions. In other words, we must think like a philosopher.

Jonathan Fuller is an assistant professor in the Department of History and Philosophy of Science at the University of Pittsburgh. He draws on his dual training in philosophy and in medicine to answer fundamental questions about the nature of contemporary disease, evidence, and reasoning in healthcare, and theory and methods in epidemiology and medical science.

References

1. Walker, P., et al. The global impact of COVID-19 and strategies for mitigation and suppression. Imperial College London (2020).

2. Flaxman, S., et al. Estimating the number of infections and the impact of non-pharmaceutical interventions on COVID-19 in 11 European countries. Imperial College London (2020).

3. Lourenco, J., et al. Fundamental principles of epidemic spread highlight the immediate need for large-scale serological surveys to assess the stage of the SARS-CoV-2 epidemic. medRxiv:10.1101/2020.03.24.20042291 (2020).

4. Broadbent, A., & Smart, B. Why a one-size-fits-all approach to COVID-19 could have lethal consequences. TheConversation.com (2020).

5. United Nations. Global recession increases malnutrition for the most vulnerable people in developing countries. United Nations Standing Committee on Nutrition (2009).

6. Cartwright, N. Will this policy work for you? Predicting effectiveness better: How philosophy helps. Philosophy of Science 79, 973-989 (2012).

7. Cartwright, N. & Hardie, J. Evidence-Based Policy: A Practical Guide to Doing it Better Oxford University Press, New York, New York (2012).

8. Fuller, J., & Flores, L. The Risk GP Model: The standard model of prediction in medicine. Studies in History and Philosophy of Biological and Biomedical Sciences 54, 49-61 (2015).

9. Rothman, K., & Greenland, S. Causation and causal inference in epidemiology. American Journal Public Health 95, S144-S50 (2005).

10. Dowd, J. et al. Demographic science aids in understanding the spread and fatality rates of COVID-19. Proceedings of the National Academy of Sciences 117, 9696-9698 (2020).

11. Ioannidis, J. Coronavirus disease 2019: The harms of exaggerated information and non‐evidence‐based measures. European Journal of Clinical Investigation 50, e13222 (2020).

12. COVID-19 Projections. Healthdata.org. https://covid19.healthdata.org/united-states-of-america.

13. Jewell, N., et al. Caution warranted: Using the Institute for Health metrics and evaluation model for predicting the course of the COVID-19 pandemic. Annals of Internal Medicine (2020).

14. Nardin, L., et al. Planning horizon affects prophylactic decision-making and epidemic dynamics. PeerJ 4:e2678 (2016).

15. Tyson, R., et al. The timing and nature of behavioural responses affect the course of an epidemic. Bulletin of Mathematical Biology 82, 14 (2020).

Lead image: yucelyilmaz / Shutterstock

But the streaming gaming revolution "is not going to happen overnight."

With many families getting priced out of junior football, one club in Perth is waiving fees, and it could signal a new direction for grassroots sport in Australia, writes Samantha Lewis.

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