Observation versus screening spinal MRI and pre-emptive treatment for spinal cord compression in patients with castration-resistant prostate cancer and spinal metastases in the UK (PROMPTS): an open-label, randomised, controlled, phase 3 trial.

BACKGROUND: Early diagnosis of malignant spinal cord compression (SCC) is crucial because pretreatment neurological status is the major determinant of outcome. In metastatic castration-resistant prostate cancer, SCC is a clinically significant cause of disease-related morbidity and mortality. We investigated whether screening for SCC with spinal MRI, and pre-emptive treatment if radiological SCC (rSCC) was detected, reduced the incidence of clinical SCC (cSCC) in asymptomatic patients with metastatic castration-resistant prostate cancer and spinal metastasis. METHODS: We did a parallel-group, open-label, randomised, controlled, phase 3, superiority trial. Patients with metastatic castration-resistant prostate cancer were recruited from 45 National Health Service hospitals in the UK. Eligible patients were aged at least 18 years, with an Eastern Co-operative Oncology Group performance status of 0-2, asymptomatic spinal metastasis, no previous SCC, and no spinal MRI in the past 12 months. Participants were randomly assigned (1:1), using a minimisation algorithm with a random element (balancing factors were treatment centre, alkaline phosphatase [normal vs raised, with the upper limit of normal being defined at each participating laboratory], number of previous systemic treatments [first-line vs second-line or later], previous spinal treatment, and imaging of thorax and abdomen), to no MRI (control group) or screening spinal MRI (intervention group). Serious adverse events were monitored in the 24 h after screening MRI in the intervention group. Participants with screen-detected rSCC were offered pre-emptive treatment (radiotherapy or surgical decompression was recommended per treating physician's recommendation) and 6-monthly spinal MRI. All patients were followed up every 3 months, and then at month 30 and 36. The primary endpoint was time to and incidence of confirmed cSCC in the intention-to-treat population (defined as all patients randomly assigned), with the primary timepoint of interest being 1 year after randomisation. The study is registered with ISRCTN, ISRCTN74112318, and is now complete. FINDINGS: Between Feb 26, 2013, and April 25, 2017, 420 patients were randomly assigned to the control (n=210) or screening MRI (n=210) groups. Median age was 74 years (IQR 68 to 79), 222 (53%) of 420 patients had normal alkaline phosphatase, and median prostate-specific antigen concentration was 48 ng/mL (IQR 17 to 162). Screening MRI detected rSCC in 61 (31%) of 200 patients with assessable scans in the intervention group. As of data cutoff (April 23, 2020), at a median follow-up of 22 months (IQR 13 to 31), time to cSCC was not significantly improved with screening (hazard ratio 0·64 [95% CI 0·37 to 1·11]; Gray's test p=0·12). 1-year cSCC rates were 6·7% (95% CI 3·8-10·6; 14 of 210 patients) for the control group and 4·3% (2·1-7·7; nine of 210 patients) for the intervention group (difference -2·4% [95% CI -4·2 to 0·1]). Median time to cSCC was not reached in either group. No serious adverse events were reported within 24 h of screening. INTERPRETATION: Despite the substantial incidence of rSCC detected in the intervention group, the rate of cSCC in both groups was low at a median of 22 months of follow-up. Routine use of screening MRI and pre-emptive treatment to prevent cSCC is not warranted in patients with asymptomatic castration-resistant prostate cancer with spinal metastasis. FUNDING: Cancer Research UK.

Route Designer: a retrosynthetic analysis tool utilizing automated retrosynthetic rule generation.

Route Designer, version 1.0, is a new retrosynthetic analysis package that generates complete synthetic routes for target molecules starting from readily available starting materials. Rules describing retrosynthetic transformations are automatically generated from reaction databases, which ensure that the rules can be easily updated to reflect the latest reaction literature. These rules are used to carry out an exhaustive retrosynthetic analysis of the target molecule, in which heuristics are used to mitigate the combinatorial explosion. Proposed routes are prioritized by an empirical rating algorithm to present a diverse profile of the most promising solutions. The program runs on a server with a web-based user interface. An overview of the system is presented together with examples that illustrate Route Designer's utility.

Should we worry about income inequality?

Liberals (in the European sense) argue that a liberal free-market economic policy regime-nationally and globally-is good for economic growth and poverty reduction and for keeping income inequality within tolerable limits. Second, they argue that substantial income inequality is desirable because of its good effects on other things, notably incentives, innovation, and panache; and conversely, they dismiss concerns about growing inequality as "the politics of envy." Third, they argue that the core liberal theory of capitalist political economy satisfactorily explains the central tendencies in the role of the state in advanced capitalist economies. This essay challenges all three arguments on both conceptual and empirical grounds. It then suggests why the arguments are nevertheless widely accepted, proposes criteria for deciding how much inequality is fair, and ends by suggesting ways for achieving higher salience for income redistribution (downwards) in political agendas.

The causes of increasing world poverty and inequality; or, why the Matthew effect prevails.

This article challenges the liberal (or "neoliberal") argument that free trade in goods and services (including financial services) makes for better overall economic performance at the level of the world economy and the level of national economies. Liberal champions infer that those who oppose the liberal prescriptions either fail to understand the theory or seek to protect vested interests, and hence regional bodies such as the European Commission and international bodies such as the World Bank and International Monetary Fund should properly push the liberal agenda under the banner of "the general interest." The author presents theoretical and empirical grounds on which to challenge the argument. He shows that Henry George's enigma--the association of poverty with progress--is still with us, and relates its persistence to the way that the positive feedback of the Matthew effect--"to him that hath shall be given"--dominates the negative feedback of neo-classical diminishing returns.

Is globalization reducing poverty and inequality?

Over the past 20 years or so, India, China, and the rest of East Asia experienced fast economic growth and falls in the poverty rate, Latin America stagnated, and the former Soviet Union, Central and Eastern Europe, and sub-Saharan Africa regressed. But what are the net trends? The neoliberal argument says that world poverty and income inequality fell over the past two decades for the first time in more than a century and a half, thanks to the rising density of economic integration across national borders. The evidence therefore confirms that globalization in the context of the world economic regime in place since the end of Bretton Woods generates more "mutual benefit" than "conflicting interests." This article questions the empirical basis of the neoliberal argument.

An enantioselective synthesis of (S)-(+)-3-aminomethyl-5-methylhexanoic acid via asymmetric hydrogenation.

A concise enantioselective synthesis of (S)-(+)-3-aminomethyl-5-methylhexanoic acid (1, Pregabalin) has been developed. The key step is the asymmetric hydrogenation of a 3-cyano-5-methylhex-3-enoic acid salt 2 with a rhodium Me-DuPHOS catalyst, providing the desired (S)-3-cyano-5-methylhexanoate 3 in very high ee. Subsequent hydrogenation of the nitrile 3 with a heterogeneous nickel catalyst provides Pregabalin 1 in excellent overall yield and purity.

The rising inequality of world income distribution

According to the author, evidence shows (in seven of eight different measures used) that world income distribution has varying degrees of increasing inequality in the past twenty years. The causes of this increasing inequality are multiple and difficult to establish, but two important ones are the debt trap and the concentration of technological change in high developed countries. It has important economic and social consequences. It also raises implications for reorienting international organizations such as the World Bank and the International Monetary Fund and the World Trade Organization. (December 2001, Volume 38, Number 4)

Winners and losers

Growing inequality is analogous to global warming. Its effects are diffuse and long-term, and there is always something more pressing to deal with. The question is how much more unequal world income distribution can become before the resulting political instabilities and flows of migrants reach the point of directly harming the well being of the citizens of the rich world and the stability of their states. Before that point is reached we should mobilize our governments, the multilateral organizations, and international NGO's to establish as an overarching priority a more equal world income distribution-and not just, as now, fewer people in poverty. (Au)

Of rich and poor

In polite policymaking circles, inequality is like the subject that dares not speak its name. In recent years, egalitarianism has lost much of whatever political appeal it ever had, in the rich industrialized countries, in the developing world, (especially) in the ex-communist economies of the former Soviet Union and Central and Eastern Europe, and certainly in communist-run China. Governments and development institutions such as the World Bank and the IMF express their concerns about poverty, and frame policies intended to reduce it, but do not seem to regard inequality, as such, as worthy of much attention. The Economist, it must be admitted, has also subscribed to that point of view.