Diversity-oriented synthesis encoded by deoxyoligonucleotides.

Diversity-oriented synthesis (DOS) is a powerful strategy to prepare molecules with underrepresented features in commercial screening collections, resulting in the elucidation of novel biological mechanisms. In parallel to the development of DOS, DNA-encoded libraries (DELs) have emerged as an effective, efficient screening strategy to identify protein binders. Despite recent advancements in this field, most DEL syntheses are limited by the presence of sensitive DNA-based constructs. Here, we describe the design, synthesis, and validation experiments performed for a 3.7 million-member DEL, generated using diverse skeleton architectures with varying exit vectors and derived from DOS, to achieve structural diversity beyond what is possible by varying appendages alone. We also show screening results for three diverse protein targets. We will make this DEL available to the academic scientific community to increase access to novel structural features and accelerate early-phase drug discovery.

Labour market status and depression in Russia: A longitudinal study, 2011-2017.

AIMS: This is the first longitudinal study to examine the relationship between depression and the labour market in Russia. Using data from 2011 to 2017, we identify the impact that not being in employment has on mental distress, and we explore the mechanism underlying the observed association. METHODS: Using data from the Russia Longitudinal Monitoring Survey - Higher School of Economics, we employ random-effects regression models to estimate the impact of employment conditions on the likelihood of reporting mental distress in Russia. This method allows us to distinguish between the selection effect associated with mental distress and direct causation. RESULTS: Controlling for a range of socio-economic and demographic characteristics, we find that unemployment and labour market inactivity are strong predictors of the likelihood of reporting depression and serious nervous breakdown. However, we find that rather than negative labour market events giving rise to mental distress, the selection effect actually dominates, and the direction of causality therefore operates in reverse. CONCLUSIONS: Knowledge of the underlying mechanism that links unfavourable labour market outcomes with mental distress is crucial for designing policies that can address this link. We argue that our findings provide grounds for the initiation of anti-stigma campaigns among employers, policymakers, health practitioners and politicians as well as the general population. Eradication of the perception that mental disorders are somehow different to 'real' illnesses will not only prevent Russians from self-selection into unemployment but may also transform outdated approaches to mental health care in Russia.

Machine Learning on DNA-Encoded Library Count Data Using an Uncertainty-Aware Probabilistic Loss Function.

DNA-encoded library (DEL) screening and quantitative structure-activity relationship (QSAR) modeling are two techniques used in drug discovery to find novel small molecules that bind a protein target. Applying QSAR modeling to DEL selection data can facilitate the selection of compounds for off-DNA synthesis and evaluation. Such a combined approach has been done recently by training binary classifiers to learn DEL enrichments of aggregated "disynthons" in order to accommodate the sparse and noisy nature of DEL data. However, a binary classification model cannot distinguish between different levels of enrichment, and information is potentially lost during disynthon aggregation. Here, we demonstrate a regression approach to learning DEL enrichments of individual molecules, using a custom negative-log-likelihood loss function that effectively denoises DEL data and introduces opportunities for visualization of learned structure-activity relationships. Our approach explicitly models the Poisson statistics of the sequencing process used in the DEL experimental workflow under a frequentist view. We illustrate this approach on a DEL dataset of 108,528 compounds screened against carbonic anhydrase (CAIX), and a dataset of 5,655,000 compounds screened against soluble epoxide hydrolase (sEH) and SIRT2. Due to the treatment of uncertainty in the data through the negative-log-likelihood loss used during training, the models can ignore low-confidence outliers. While our approach does not demonstrate a benefit for extrapolation to novel structures, we expect our denoising and visualization pipeline to be useful in identifying structure-activity trends and highly enriched pharmacophores in DEL data. Further, this approach to uncertainty-aware regression modeling is applicable to other sparse or noisy datasets where the nature of stochasticity is known or can be modeled; in particular, the Poisson enrichment ratio metric we use can apply to other settings that compare sequencing count data between two experimental conditions.

First population norms for the EQ-5D-3L in the Russian Federation.

PURPOSE: The EQ-5D survey instrument is routinely applied to general and patient specific populations in many countries, as a means of measuring Health Related Quality of Life (HRQOL) and/or informing Health Technology Assessment. The instrument is the subject of growing interest in the Russian Federation, as too is Health Technology Assessment. This research is the first to systematically present the EQ-5D-3L nationally representative population norms and to examine the socioeconomic and socio-demographic characteristics of the instrument among a representative sample of the Russian population. METHODS: Based on a nationally representative health and well-being survey of the Russian population, conducted in November 2017, we establish the descriptive results, including the EQ-VAS and the EQ-5D Index, by age and gender, examine the correspondence between the EQ-5D health classifications and the separate EQ-VAS scores, and draw on a set of augmented logistic regressions to evaluate the association between the presence of problems in each dimension and various socio-economic and health-related characteristics. RESULTS: We find strong evidence that the EQ-5D instrument is sensitive to underlying observed and latent health experiences, that it mirrors many of the characteristics familiar from other settings but that there are Russian specificities which merit further research, particularly with respect to the anxiety/depression dimension of the instrument. CONCLUSION: This research represents an important landmark for HRQOL studies in Russia as well as for the prospects of continuing to develop the scholarly and practical infrastructure necessary for Russian Health Technology Assessment to advance.

Voluntary private health insurance, health-related behaviours and health outcomes: evidence from Russia.

This paper contributes to the discussion around ex-post (increased utilisation of health care) and ex-ante (changes in health behaviours) moral hazard in supplemental private health insurance. Applying a range of methodologies to data from the Russian Longitudinal Monitoring Survey-Higher School of Economics we exploit a selection mechanism in the data to compare the impact of workplace provided and individually purchased supplemental health insurance on the utilisation of health care, on a range of health behaviours and on self-assessed health. We find compelling policy-relevant evidence of ex-post moral hazard that confirms a theoretical prediction and empirical regularity found in other settings. In contrast to other empirical findings though, our data reveals evidence of ex-ante moral hazard demonstrated by clear behavioural differences between those with self-funded supplemental health insurance and those for whom the workplace finances the additional insurance. We find no evidence that either form of insurance is related to improved self-assessed health.

Unifying principles of bifunctional, proximity-inducing small molecules.

Nature uses a variety of tools to mediate the flow of information in cells, many of which control distances between key biomacromolecules. Researchers have thus generated compounds whose activities stem from interactions with two (or more) proteins simultaneously. In this Perspective, we describe how these 'bifunctional' small molecules facilitate the study of an increasingly wide range of complex biological phenomena and enable the drugging of otherwise challenging therapeutic targets and processes. Despite their structural and functional differences, all bifunctional molecules employ Nature's strategy of altering interactomes and inducing proximity to modulate biology. They therefore exhibit a shared set of chemical and biophysical principles that have not yet been appreciated fully. By highlighting these commonalities-and their wide-ranging consequences-we hope to chip away at the artificial barriers that threaten to constrain this interdisciplinary field. Doing so promises to yield remarkable benefits for biological research and therapeutics discovery.

Recent achievements and current trajectories of diversity-oriented synthesis.

For two decades, diversity-oriented synthesis (DOS) has facilitated the assembly of small-molecule libraries comprising a variety of complex molecular architectures. Here, we describe some of the recent achievements in this field, many of which promise to contribute to the development of new chemical probes and drug leads. In particular, we report progress along several avenues of bioactive discovery that leverage topographically complex compounds generated using DOS and other methods. We also discuss advances in DNA-compatible chemistry that enable syntheses of more three-dimensionally complex and diverse DNA-encoded libraries. Continual innovation in organic chemistry will be required to both expand and exploit our understanding of biological systems.

Valuing Health States in Russia: A First Feasibility Study.

OBJECTIVE: The aim of this study was to explore the feasibility of different health-related quality-of-life valuation methods in a new setting. Based on a small feasibility study of 100 young Russians, we trialed different methodologies and identified key differences that have implications for the development of health technology assessment in Russia. METHODS: In face-to-face interviews, respondents completed a series of health self-assessments based on a modified version of the EQ-5D-3L, visual analogue scale, time tradeoff, standard gamble, and best-worst scaling methodologies, covering actual and hypothetical health states. RESULTS: We found that (1) the visual analogue scale produced lower health valuations and fewer logical inconsistencies than either time trade-off or standard gamble methodologies; (2) initial health states can be decisive in determining values assigned to health improvements; (3) respondents evaluate abstract health states more positively than their own actual health states; (4) there is evidence consistent with the hypothesis that actual and hypothetical health state valuation, using EQ-5D-3L, is an artifact of understanding rather than preference and that the incorporation of additional levels may therefore be no panacea if the dimensions themselves overlook important attributes; and (5) the country context is important in determining how respondents relate to the survey tools and how those survey tools are translated and delivered. CONCLUSIONS: Russia is commencing its health technology assessment journey and should proceed cautiously as it moves toward the valuation of health benefits. These results suggest a useful framework for a more in-depth development of health valuation methodologies in Russia.

DNA Barcoding a Complete Matrix of Stereoisomeric Small Molecules.

It is challenging to incorporate stereochemical diversity and topographic complexity into DNA-encoded libraries (DELs) because DEL syntheses cannot fully exploit the capabilities of modern synthetic organic chemistry. Here, we describe the design, construction, and validation of DOS-DEL-1, a library of 107 616 DNA-barcoded chiral 2,3-disubsituted azetidines and pyrrolidines. We used stereospecific C-H arylation chemistry to furnish complex scaffolds primed for DEL synthesis, and we developed an improved on-DNA Suzuki reaction to maximize library quality. We then studied both the structural diversity of the library and the physicochemical properties of individual compounds using Tanimoto multifusion similarity analysis, among other techniques. These analyses revealed not only that most DOS-DEL-1 members have "drug-like" properties, but also that the library more closely resembles compound collections derived from diversity synthesis than those from other sources (e.g., commercial vendors). Finally, we performed validation screens against horseradish peroxidase and carbonic anhydrase IX, and we developed a novel, Poisson-based statistical framework to analyze the results. A set of assay positives were successfully translated into potent carbonic anhydrase inhibitors (IC50 = 20.1-68.7 nM), which confirmed the success of the synthesis and screening procedures. These results establish a strategy to synthesize DELs with scaffold-based stereochemical diversity and complexity that does not require the development of novel DNA-compatible chemistry.

DNA-Compatible [3 + 2] Nitrone-Olefin Cycloaddition Suitable for DEL Syntheses.

The limited scope of DNA-compatible chemistry restricts the types of chemical features that can be incorporated into DNA-encoded libraries (DELs). Here, a method to synthesize DNA-conjugated polycyclic isoxazolidines via a [3 + 2] nitrone-olefin cycloaddition is described. The reaction is compatible with many olefin-containing substrates and diverse N-alkylhydroxylamines. The ability to perform subsequent DNA ligation and PCR amplification was also confirmed. This methodology facilitates the synthesis of DELs containing topographically complex compounds with underexplored chemical features.

Attitudes to reform: Could a cooperative health insurance scheme work in Russia?

As for all health systems, in Russia, the demand for medical care is greater than its health system is able to guarantee the supply of. In this context, removing services from the state guaranteed package is an option that is receiving serious consideration. In this paper, we examine the attitudes of the Russian population to such a reform. Exploiting a widely-used methodology, we explore the population's willingness to pay for cooperative health insurance. Distinguishing between socioeconomic and demographic factors, health-related indicators and risk aversion we find, consistent with other literature, positive income and risk aversion effects. We interpret the former as evidence that the Russian population is not opposed to the idea of progressive redistribution, to pool the costs of health-related risks; and the latter as evidence that risk-averse individuals demand more insurance coverage. In exploring these results further, we show that cognitive bias is important: overestimating the benefits leads to the purchase of additional insurance, while underestimating lowers demand for insurance. Our overall conclusion is that the introduction of a supplementary cooperative health insurance scheme in Russia could increase the accessibility of healthcare, lower the tendency for informal payments, incentivize the personal maintenance of good health and create a new source of funding for public healthcare.

Convergence or Divergence? Life Expectancy Patterns in Post-communist Countries, 1959-2010.

In the 1960s and 1970s, the countries of Central and Eastern Europe and the Soviet Union experienced an unanticipated stagnation in the process of mortality reduction that was accelerating in the west. This was followed by even starker fluctuations and overall declines in life expectancy during the 1980s and 1990s. We identify statistically the extent to which, since the 1990s, the countries of the post-communist region have converged as a group towards other regional or cross-regional geopolitical blocks, or whether there are now multiple steady-states ('convergence clubs') emerging among these countries. We apply a complex convergence club methodology, including a recursive analysis, to data on 30 OECD countries (including 11 post-communist countries) drawn from the Human Mortality Database and spanning the period 1959-2010. We find that, rather than converging uniformly on western life expectancy levels, the post-communist countries have diverged into multiple clubs, with the lowest seemingly stuck in low-level equilibria, while the best performers (e.g. Czech Republic) show signs of catching-up with the leading OECD countries. As the post-communist period has progressed, the group of transition countries themselves has become more heterogeneous and it is noticeable that distinctive gender and age patterns have emerged. We are the first to employ an empirical convergence club methodology to help understand the complex long-run patterns of life expectancy within the post-communist region, one of very few papers to situate such an analysis in the context of the OECD countries, and one of relatively few to interpret the dynamics over the long-term.

Chemical probes and drug leads from advances in synthetic planning and methodology.

Screening of small-molecule libraries is a productive method for identifying both chemical probes of disease-related targets and potential starting points for drug discovery. In this article, we focus on strategies such as diversity-oriented synthesis that aim to explore novel areas of chemical space efficiently by populating small-molecule libraries with compounds containing structural features that are typically under-represented in commercially available screening collections. Drawing from more than a decade's worth of examples, we highlight how the design and synthesis of such libraries have been enabled by modern synthetic chemistry, and we illustrate the impact of the resultant chemical probes and drug leads in a wide range of diseases.

The effect of chronic conditions and multi-morbidity on self-assessed health in Russia.

AIMS: Chronic disorders, such as cardiovascular disease, cancer, respiratory diseases and diabetes, are the leading cause of mortality globally, representing 68% of all recorded deaths. The incidence of chronic disease and multiple chronic disease is rising across the world, but relatively little is known about the impact of multi-morbidities on the life experiences of those individuals who encounter them. In this paper, we examine and quantify the relationship between chronic illness, multi-morbidity and the individual self-assessed health of the Russian population using individual-level Russian data and a novel quantitative technique. METHODS: We apply a partial proportional odds framework to a rich data set incorporating demographic, socio-economic and health indicators in Russia. RESULTS: We find that individuals with chronic conditions report significantly lower levels of health than those without chronic conditions, but that the strength of the effect is much more pronounced for males than for females (e.g. neurological disease: odds ratio [OR]=4.81 for men; OR=1.86 for women)). As the number of co-morbidities increases, there is a dramatic decrease in the likelihood of reporting good health for both males and females, but for males there is a greater increase in the likelihood of reporting bad health (OR=49.31 for males with ≥5 diseases; OR=28.05 for females). CONCLUSIONS: More than 40% of Russians currently live with multi-morbidity, and this group is at the highest risk of reporting poor self-rated health. This research adds to the body of evidence demonstrating the challenges facing health-care systems as new patterns of disease take hold in contemporary society.

Too many and too few: The paradoxical case of physicians in the Russian Federation.

There is a paradox characterising the Russian health workforce. By international standards, Russia has a very high number of physicians per capita but at the same time is confronted by chronic real shortages of qualified physicians. This paper explores the reasons for this paradox by examining the structural characteristics of health workforce development in the context of the Soviet legacy and the comparative performance of other European countries. The paper uses data on comparative health workforce dynamics to argue that Russia is a European laggard, before then evaluating recent and current policies within that context. The health workforce challenges facing all low- and middle-income countries are acute, and this paper confirms this IS the case for Russia-Europe's largest country. The paper argues that the physician shortage is driven by the model of health workforce development inherited from the Soviet period, with its emphasis on quantitative rather than structural indicators. We find that, in contrast to most European Union countries, Russia's stalled reform process leaves it facing a chronic shortage of appropriately trained physicians. We document the costs of failed and slow reforms during the last 2 decades, while cautiously welcoming some recent policy initiatives.

Reforming voluntary drug insurance in Russian healthcare: does social solidarity matter?

With low take-up of both private health insurance and the existing public drug reimbursement scheme, it is thought that less than 5% of the Russian population have access to free outpatient drug treatment. This represents a major policy challenge for a country grappling with reforms of its healthcare system and experiencing low or no economic growth and significant associated reductions in spending on social services. In this paper, we draw on data from a 2011 Levada-Center survey to examine the attitudes and social solidarity of the Russian population towards drug policies in general and towards the introduction of a proposed voluntary drug insurance system in particular. In addition to being among the first to explore these important questions in the post-Communist setting, we make three important contributions to the emerging policy debates. First, we find that, if introduced immediately and without careful planning and preparation, Russia's voluntary drug insurance scheme is likely to collapse financially due to the over-representation of high-risk unhealthy individuals opting in to the scheme. Second, the negative attitude of higher income groups towards the redistribution of wealth to the poor may further impede government efforts to introduce voluntary drug insurance. Finally, we argue that Russia currently lacks the breadth and depth of social solidarity necessary for implementing this form of health financing.

Social inequalities in self-rated health in Ukraine in 2007: the role of psychosocial, material and behavioural factors.

Background: Despite Ukraine's large population, few studies have examined social inequalities in health. This study describes Ukrainian educational inequalities in self-rated health and assesses how far psychosocial, material and behavioural factors account for the education gradient in health. Methods: Data were analyzed from the 2007 wave of the Ukrainian Longitudinal Monitoring Survey. Education was categorized as: lower secondary or less, upper secondary and tertiary. In logistic regressions of 5451 complete cases, stratified by gender, declaring less than average health was regressed on education, before and after adjusting for psychosocial, material and behavioural factors. Results: In analyses adjusted for socio-demographic characteristics, compared with those educated up to lower secondary level, tertiary education was associated with lower risk of less than average health for both men and women. Including material factors (income quintiles, housing assets, labour market status) reduced the association between education and health by 55-64% in men and 35-47% in women. Inclusion of health behaviours (physical activity, smoking, alcohol consumption and body mass index) reduced the associations by 27-30% in men and 19-27% in women; in most cases including psychosocial factors (marital status, living alone, trust in family and friends) did not reduce the size of the associations. Including all potential explanatory factors reduced the associations by 68-84% in men and 43-60% in women. Conclusions: The education gradient in self-rated health in Ukraine was partly accounted for by material and behavioural factors. In addition to health behaviours, policymakers should consider upstream determinants of health inequalities, such as joblessness and poverty.