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The heme-regulatory motifs of heme oxygenase-2 contribute to the transfer of heme to the catalytic site for degradation [Protein Structure and Folding]

Heme-regulatory motifs (HRMs) are present in many proteins that are involved in diverse biological functions. The C-terminal tail region of human heme oxygenase-2 (HO2) contains two HRMs whose cysteine residues form a disulfide bond; when reduced, these cysteines are available to bind Fe3+-heme. Heme binding to the HRMs occurs independently of the HO2 catalytic active site in the core of the protein, where heme binds with high affinity and is degraded to biliverdin. Here, we describe the reversible, protein-mediated transfer of heme between the HRMs and the HO2 core. Using hydrogen-deuterium exchange (HDX)-MS to monitor the dynamics of HO2 with and without Fe3+-heme bound to the HRMs and to the core, we detected conformational changes in the catalytic core only in one state of the catalytic cycle—when Fe3+-heme is bound to the HRMs and the core is in the apo state. These conformational changes were consistent with transfer of heme between binding sites. Indeed, we observed that HRM-bound Fe3+-heme is transferred to the apo-core either upon independent expression of the core and of a construct spanning the HRM-containing tail or after a single turnover of heme at the core. Moreover, we observed transfer of heme from the core to the HRMs and equilibration of heme between the core and HRMs. We therefore propose an Fe3+-heme transfer model in which HRM-bound heme is readily transferred to the catalytic site for degradation to facilitate turnover but can also equilibrate between the sites to maintain heme homeostasis.




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A Variation on the Theme: SGLT2 Inhibition and Glucagon Secretion in Human Islets

David J. Hodson
May 1, 2020; 69:864-866
Commentaries




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Chemoprevention of colorectal cancer in individuals with previous colorectal neoplasia: systematic review and network meta-analysis




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Mathematical Reviews at JMM 2020 in Denver

Mathematical Reviews will be at the JMM in Denver, January 13-18, 2020. The Joint Mathematical Meetings is the largest gathering of mathematicians in the world.  There are lots of great activities:  invited lectures, special sessions, editorial meetings, exhibits, and the chance to … Continue reading




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Mathematics and epidemiology

Mathematics is a useful tool in studying the growth of infections in a population, such as what occurs in epidemics.  A simple model is given by a first-order differential equation, the logistic equation, $frac{dx}{dy}=eta x(1-x)$ which is discussed in almost any … Continue reading



  • Mathematics in the news

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Democrats Have Set Themselves Up to Fail in November's Election

21 February 2020

Dr Lindsay Newman

Senior Research Fellow, US and the Americas Programme
Debates and caucuses are proving that the party took the wrong lesson from the midterms. They're now applying that lesson to 2020 with potentially disastrous results.

2020-02-21-DemDebate.jpg

2020 Democratic presidential candidates at the debate in Las Vegas on 19 February. Photo: Getty Images.

The Democratic Party’s struggle for its future policy direction is evident this election season. The primary results in Iowa and New Hampshire, narrow first- and second-place finishes for Senator Bernie Sanders (a progressive) and former South Bend mayor Pete Buttigieg (a moderate), were just two indicators. During Wednesday night’s debate in Las Vegas, the split became even more obvious.

The six candidates onstage clashed on ideology (socialism and capitalism, progressivism and centrism) as well as policy (healthcare, climate change, fossil fuels, criminal justice, China). Buttigieg made plain the stakes for Democrats, saying, 'We’ve got to wake up as a party.'

If a Democratic candidate is elected to be the United States’ 46th president on 3 November, it will be despite this unresolved intra-party struggle.

One lesson the Democratic Party has taken from the 2018 midterm elections is that running candidates across the ideological spectrum is a winning formula.

It is easy to see how they came to this conclusion following the 2016 presidential and 2018 Congressional election experiences. In 2016, the favoured candidate status of former secretary of state Hillary Clinton deterred other aspirants from entering the Democratic primary ahead of a general election she went on to lose to Republican Donald Trump. In 2018, progressive and moderate centrist candidates, both first-timers and incumbents, ran and Democrats retook leadership in the House of Representatives with a 235-seat majority.

But what if this conclusion was noise and not the signal?

The Democratic National Committee (DNC) set the rules for the 2020 election based on the theory that by allowing an inclusive field (more than two dozen candidates entered the presidential race) the campaign processes, including debates, caucuses and primaries, would ultimately identify the most robust, representative candidate to go up against Donald Trump. Perhaps, and somewhat ironically, the 2016 Republican primary process, which involved a wide field culled by Trump’s unexpected success, informed the DNC’s reforms. And while very nice as a hypothesis of Bayesian updating, what has unfolded instead is a scattershot four-way — at times even five-way — race.

In the midst of this party divide, whoever ends up being the Democratic nominee will likely not represent the views of some meaningful proportion of the Democratic base. While healthcare remains the top issue across the Democratic electorate, there are those (candidates and voters) who want a single-payer option for all without a private insurance option and those who want to expand healthcare access while maintaining private insurers. Likewise, on foreign policy, there are those who link US trade policy with protecting American workers and who would therefore continue to use tariffs as a key trade policy, as well as those critical of Trump’s reliance on tariffs.

Compare that with the current state of the Republican Party. Trump’s approval with Republicans is in the high 80s, sometimes even low 90s, and after all but one Republican senator voted to acquit him in the Senate impeachment trial, the party is undeniably Trump’s. A sure sign is the historic turnout for Trump in his essentially uncontested Iowa and New Hampshire primaries.

Their own divisions pose a number of risks, then, for Democrats heading into November’s general election. The first one relates to vulnerabilities arising out of the primary process itself. If the fractures emerging from Iowa and New Hampshire persist, the likelihood of a quick wrap-up of the Democratic primary by April reduces, and the possibility of a contested Democratic convention in July increases (even if from a low base). While exciting television and Twitter fodder, a lengthy primary positions Democrats to go into the fall facing questions of party disunity behind the eventual nominee.

Although complicated to demonstrate empirically, some work has been done to understand whether the protracted 2016 Democratic primary and Sanders’ slow support for Democratic nominee Clinton in 2016 played a part in her defeat and Trump’s electoral success. A delayed general election campaign for the eventual Democratic nominee in 2020 almost certainly advantages President Trump’s money machine, which reportedly has more than twice as much on hand as then-president Barack Obama had going into his 2012 re-election. Further, unlike 2016, which was an open-seat election for the presidency, in 2020 Trump will have a demonstrated incumbent advantage.

The Democratic Party’s succession battle also raises risks around general election turnout. If Sanders is the party’s nominee, Biden or Buttigieg’s constituency may not come out to vote for him. More worrisome for Democrats, if Sanders is the party’s nominee then centrist voters, including those representing the finance industry, may peel off and vote for Trump, who has overseen economic expansion and record unemployment rates following the 2017 tax overhaul and various deregulations.

Alternatively, if Biden, Buttigieg or former mayor Michael Bloomberg become the nominee, Sanders’ many loyal supporters are likely to feel their policy priorities are not represented. And if those voters stay home because the Democratic nominee is not promising a political revolution, evidence suggests that depressed turnout levels may favour Republicans.

A third political peril relates to the business of legislating after the election. If despite the potential pitfalls a Democratic candidate manoeuvres and manages to build a winning coalition on 3 November, they will face the reality of legislative politics, which over the last 10 years have been defined by policy gridlock. Obama managed to get Obamacare through both Democratic-majority congressional chambers, but presided over divided chambers for the remainder of his term. Similarly, Trump’s major legislative accomplishment — the 2017 tax overhaul — was a result of Republican control in both the House of Representatives and the Senate.

A Democratic president will have to make progress on his or her agenda given not only the typical Republican-Democrat divide in Congress, but also facing potential raw divisions within the Democratic Party itself. In such a scenario, a Democratic administration may be tempted to take an expansive view of the president’s authority as we have seen under Trump, including relying on executive actions (tariffs and sanctions) on foreign policy.

The Democratic National Convention in Milwaukee, Wisconsin, beginning 13 July, and the party platform crafted over those four days present an essential opportunity to resolve the party’s divisions before November. If left unchecked, the party might find that its ex ante strategy for the 2020 Democratic primary ends in Trump’s re-election.

This article was originally published in the Independent.




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We are leaving them behind

  Never mind steel, We are creating new materials, Carbon nano-tubes, poly-ceramics, Twirl a ball above your head, we are Building elevators into space, Stringing massage parlours around the earth, We are engineering ourselves, Computer worlds and, Selling real estate, we Are leaving the old people, Behind, Stained curtains and they are, Walking into forests, […]




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Chemical leak at LG plant in India kills 11, about 1,000 injured

HYDERABAD, India (AP) — A gas leak at a chemical factory owned by a South Korean company in southern India early Thursday left at least 11 people dead and about 1,000 struggling to breathe. The chemical styrene, used to make plastic and...




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Patient spotlight - Doing it for themselves

In our accompanying roundtable discussion,we hear views from a group of patients and clinicians based largely in the UK on the actions required  to advance  progress towards providing patient centred care. To extend the conversation we talked to members of the BMJ's international patient advisory panel and other patient advocates - and what...




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Late effects of anticancer chemotherapy: It's hard to trust your body, after it's betrayed you

Lily was diagnosed at 14 years old with stage four Hodgkin's lymphoma and received six rounds of chemotherapy and two weeks of radiotherapy. She survived but now lives with the long term effects of that therapy - and joins us to discuss how it has impacted her quality of life. We're also joined by Saif Ahmad and Thankamma Ajithkumar, oncologists...




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How to stop generic drug price hikes (or at least reduce them)

Ravi Gupta, is a resident in internal medicine at Johns Hopkins in Baltimore - and as he said has seen the influence of sudden price hikes on his patients - between 2010 and 2015 more than 300 drugs in the U.S. have seen sudden increases of over %100. Ravi and his co-authors have suggested, and tested the feasibility of, a possible answer to...




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Biochem for kids

Each time you order a test for a child, do you think the population that makes up the baseline against which the results are measured? It turns out that that historically those reference intervals have been based on adults - but children, especially neonates and adolescents, are undergoing physiological changes that mean those reference intervals...




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Appropriate Use Criteria for Imaging Evaluation of Biochemical Recurrence of Prostate Cancer After Definitive Primary Treatment




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Prospective Evaluation of 18F-DCFPyL PET/CT in Biochemically Recurrent Prostate Cancer in an Academic Center: A Focus on Disease Localization and Changes in Management

18F-DCFPyL (2-(3-{1-carboxy-5-[(6-18F-fluoropyridine-3-carbonyl)-amino]-pentyl}-ureido)-pentanedioic acid) is a promising PET radiopharmaceutical targeting prostate-specific membrane antigen (PSMA). We present our experience with this single-academic-center prospective study evaluating the positivity rate of 18F-DCFPyL PET/CT in patients with biochemical recurrence (BCR) of prostate cancer (PC). Methods: We prospectively enrolled 72 men (52–91 y old; mean ± SD, 71.5 ± 7.2) with BCR after primary definitive treatment with prostatectomy (n = 42) or radiotherapy (n = 30). The presence of lesions compatible with PC was evaluated by 2 independent readers. Fifty-nine patients had scans concurrent with at least one other conventional scan: bone scanning (24), CT (21), MR (20), 18F-fluciclovine PET/CT (18), or 18F-NaF PET (14). Findings from 18F-DCFPyL PET/CT were compared with those from other modalities. Impact on patient management based on 18F-DCFPyL PET/CT was recorded from clinical chart review. Results: 18F-DCFPyL PET/CT had an overall positivity rate of 85%, which increased with higher prostate-specific antigen (PSA) levels (ng/mL): 50% (PSA < 0.5), 69% (0.5 ≤ PSA < 1), 100% (1 ≤ PSA < 2), 91% (2 ≤ PSA < 5), and 96% (PSA ≥ 5). 18F-DCFPyL PET detected more lesions than conventional imaging. For anatomic imaging, 20 of 41 (49%) CT or MRI scans had findings congruent with 18F-DCFPyL, whereas 18F-DCFPyL PET was positive in 17 of 41 (41%) cases with negative CT or MRI findings. For bone imaging, 26 of 38 (68%) bone or 18F-NaF PET scans were congruent with 18F-DCFPyL PET, whereas 18F-DCFPyL PET localized bone lesions in 8 of 38 (21%) patients with negative results on bone or 18F-NaF PET scans. In 8 of 18 (44%) patients, 18F-fluciclovine PET had located the same lesions as did 18F-DCFPyL PET, whereas 5 of 18 (28%) patients with negative 18F-fluciclovine findings had positive 18F-DCFPyL PET findings and 1 of 18 (6%) patients with negative 18F-DCFPyL findings had uptake in the prostate bed on 18F-fluciclovine PET. In the remaining 4 of 18 (22%) patients, 18F-DCFPyL and 18F-fluciclovine scans showed different lesions. Lastly, 43 of 72 (60%) patients had treatment changes after 18F-DCFPyL PET and, most noticeably, 17 of these patients (24% total) had lesion localization only on 18F-DCFPyL PET, despite negative results on conventional imaging. Conclusion: 18F-DCFPyL PET/CT is a promising diagnostic tool in the work-up of biochemically recurrent PC, given the high positivity rate as compared with Food and Drug Administration–approved currently available imaging modalities and its impact on clinical management in 60% of patients.




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Head-to-Head Comparison of 68Ga-PSMA-11 with 18F-PSMA-1007 PET/CT in Staging Prostate Cancer Using Histopathology and Immunohistochemical Analysis as a Reference Standard

18F-PSMA-1007 is a novel prostate-specific membrane antigen (PSMA)–based radiopharmaceutical for imaging prostate cancer (PCa). The aim of this study was to compare the diagnostic accuracy of 18F-PSMA-1007 with 68Ga-PSMA-11 PET/CT in the same patients presenting with newly diagnosed intermediate- or high-risk PCa. Methods: Sixteen patients with intermediate- or high-risk PCa underwent 18F-PSMA-1007 and 68Ga-PSMA-11 PET/CT within 15 d. PET findings were compared between the 2 radiotracers and with reference-standard pathologic specimens obtained from radical prostatectomy. The Cohen -coefficient was used to assess the concordance between 18F-PSMA-1007 and 68Ga-PSMA-11 for detection of intraprostatic lesions. The McNemar test was used to assess agreement between intraprostatic PET/CT findings and histopathologic findings. Sensitivity, specificity, positive predictive value, and negative predictive value were reported for each radiotracer. SUVmax was measured for all lesions, and tumor-to-background activity was calculated. Areas under receiver-operating-characteristic curves were calculated for discriminating diseased from nondiseased prostate segments, and optimal SUV cutoffs were calculated using the Youden index for each radiotracer. Results: PSMA-avid lesions in the prostate were identified in all 16 patients with an almost perfect concordance between the 2 tracers ( ranged from 0.871 to 1). Aside from the dominant intraprostatic lesion, similarly detected by both radiotracers, a second less intense positive focus was detected in 4 patients only with 18F-PSMA-1007. Three of these secondary foci were confirmed as Gleason grade 3 lesions, whereas the fourth was shown on pathologic examination to represent chronic prostatitis. Conclusion: This pilot study showed that both 18F-PSMA-1007 and 68Ga-PSMA-11 identify all dominant prostatic lesions in patients with intermediate- or high-risk PCa at staging. 18F-PSMA-1007, however, may detect additional low-grade lesions of limited clinical relevance.




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To Advance Trade and Climate Goals, ‘Global Britain’ Must Link Them

19 March 2020

Carolyn Deere Birkbeck

Associate Fellow, Global Economy and Finance Programme, and Hoffmann Centre for Sustainable Resource Economy

Dr Emily Jones

Associate Professor, Blavatnik School of Government

Dr Thomas Hale

Associate Professor, Blavatnik School of Government
COVID-19 is a sharp reminder of why trade policy matters. As the UK works to forge new trade deals, it must align its trade policy agenda with its climate ambition.

2020-03-19-Boris-Johnson-COP26.jpg

Boris Johnson at the launch of the UK-hosted COP26 UN Climate Summit at the Science Museum, London on February 4, 2020. Photo by Jeremy Selwyn - WPA Pool/Getty Images.

COVID-19 is a sharp reminder of why trade and climate policy matters. How can governments maintain access to critical goods and services, and ensure global supply chains function in times of crisis?

The timing of many trade negotiations is now increasingly uncertain, as are the UK’s plans to host COP26 in November. Policy work continues, however, and the EU has released its draft negotiating text for the new UK-EU trade deal, which includes a sub-chapter specifically devoted to climate. 

This is a timely reminder both of the pressing need for the UK to integrate its trade and climate policymaking and to use the current crisis-induced breathing space in international negotiations - however limited - to catch up on both strategy and priorities on this critical policy intersection.

The UK government has moved fast to reset its external trade relations post-Brexit. In the past month it formally launched bilateral negotiations with the EU and took up a seat at the World Trade Organization (WTO) as an independent member. Until the COVID-19 crisis hit, negotiations were also poised to start with the US.

The UK is also in the climate spotlight as host of COP26, the most important international climate negotiation since Paris in 2015, which presents a vital opportunity for the government to show leadership by aligning its trade agenda with its climate and sustainability commitments in bold new ways.

Not just an empty aspiration

This would send a signal that ‘Global Britain’ is not just an empty aspiration, but a concrete commitment to lead.

Not only is concerted action on the climate crisis a central priority for UK citizens, a growing and increasingly vocal group of UK businesses committed to decarbonization are calling on the government to secure a more transparent and predictable international market place that supports climate action by business.

With COP26, the UK has a unique responsibility to push governments to ratchet up ambition in the national contributions to climate action – and to promote coherence between climate ambition and wider economic policymaking, including on trade. If Britain really wants to lead, here are some concrete actions it should take.

At the national level, the UK can pioneer new ways to put environmental sustainability – and climate action in particular - at the heart of its trade agenda. Achieving the government’s ambitious Clean Growth Strategy - which seeks to make the UK the global leader in a range of industries including electric cars and offshore wind – should be a central objective of UK trade policy.

The UK should re-orient trade policy frameworks to incentivize the shift toward a more circular and net zero global economy. And all elements of UK trade policy could be assessed against environmental objectives - for example, their contribution to phasing out fossil fuels, helping to reverse overexploitation of natural resources, and support for sustainable agriculture and biodiversity.

In its bilateral and regional trade negotiations, the UK can and should advance its environment, climate and trade goals in tandem, and implementation of the Paris Agreement must be a core objective of the UK trade strategy.

A core issue for the UK is how to ensure that efforts to decarbonise the economy are not undercut by imports from high-carbon producers. Here, a ‘border carbon adjustment (BCA)’ - effectively a tax on the climate pollution of imports - would support UK climate goals. The EU draft negotiating text released yesterday put the issue of BCAs front and centre, making crystal clear that the intersection of climate, environment and trade policy goals will be a central issue for UK-EU trade negotiations.

Even with the United States, a trade deal can and should still be seized as a way to incentivize the shift toward a net zero and more circular economy. At the multilateral level, as a new independent WTO member, the UK has an opportunity to help build a forward-looking climate and trade agenda.

The UK could help foster dialogue, research and action on a cluster of ‘climate and trade’ issues that warrant more focused attention at the WTO. These include the design of carbon pricing policies at the border that are transparent, fair and support a just transition; proposals for a climate waiver for WTO rules; and identification of ways multilateral trade cooperation could promote a zero carbon and more circular global economy.  

To help nudge multilateral discussion along, the UK could also ask to join a critical ‘path finder’ effort by six governments, led by New Zealand, to pursue an agreement on climate change, trade and sustainability (ACCTS). This group aims to find ways forward on three central trade and climate issues: removing fossil fuel subsidies, climate-related labelling, and promoting trade in climate-friendly goods and services.

At present, the complex challenges at the intersection of climate, trade and development policy are too often used to defer or side-step issues deemed ‘too hard’ or ‘too sensitive’ to tackle. The UK could help here by working to ensure multilateral climate and trade initiatives share adjustment burdens, recognise the historical responsibility of developed countries, and do not unfairly disadvantage developing countries - especially the least developed.

Many developing countries are keen to promote climate-friendly exports as part of wider export diversification strategies  and want to reap greater returns from greener global value chains. Further, small island states and least-developed countries – many of which are Commonwealth members – that are especially vulnerable to the impacts of climate change and natural disasters, need support to adapt in the face of trade shocks and to build climate-resilient, trade-related infrastructure and export sectors.

As an immediate next step, the UK should actively support the growing number of WTO members in favour of a WTO Ministerial Statement on environmental sustainability and trade. It should work with its key trading partners in the Commonwealth and beyond to ensure the agenda is inclusive, supports achievement of the UN Sustainable Development Goals (SDGs) and helps developing countries benefit from a more environmentally sustainable global economy.

As the UK prepares to host COP26, negotiates deals with the EU and US, and prepares for its first WTO Ministerial meeting as an independent member, it must show it can lead the way nationally, bilaterally, and multilaterally. And to ensure the government acts, greater engagement from the UK’s business, civil society and research sectors is critical – we need all hands on deck to forge and promote concrete proposals for aligning UK trade policy with the climate ambition our world needs.




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To Advance Trade and Climate Goals, ‘Global Britain’ Must Link Them

19 March 2020

Carolyn Deere Birkbeck

Associate Fellow, Global Economy and Finance Programme, and Hoffmann Centre for Sustainable Resource Economy

Dr Emily Jones

Associate Professor, Blavatnik School of Government

Dr Thomas Hale

Associate Professor, Blavatnik School of Government
COVID-19 is a sharp reminder of why trade policy matters. As the UK works to forge new trade deals, it must align its trade policy agenda with its climate ambition.

2020-03-19-Boris-Johnson-COP26.jpg

Boris Johnson at the launch of the UK-hosted COP26 UN Climate Summit at the Science Museum, London on February 4, 2020. Photo by Jeremy Selwyn - WPA Pool/Getty Images.

COVID-19 is a sharp reminder of why trade and climate policy matters. How can governments maintain access to critical goods and services, and ensure global supply chains function in times of crisis?

The timing of many trade negotiations is now increasingly uncertain, as are the UK’s plans to host COP26 in November. Policy work continues, however, and the EU has released its draft negotiating text for the new UK-EU trade deal, which includes a sub-chapter specifically devoted to climate. 

This is a timely reminder both of the pressing need for the UK to integrate its trade and climate policymaking and to use the current crisis-induced breathing space in international negotiations - however limited - to catch up on both strategy and priorities on this critical policy intersection.

The UK government has moved fast to reset its external trade relations post-Brexit. In the past month it formally launched bilateral negotiations with the EU and took up a seat at the World Trade Organization (WTO) as an independent member. Until the COVID-19 crisis hit, negotiations were also poised to start with the US.

The UK is also in the climate spotlight as host of COP26, the most important international climate negotiation since Paris in 2015, which presents a vital opportunity for the government to show leadership by aligning its trade agenda with its climate and sustainability commitments in bold new ways.

Not just an empty aspiration

This would send a signal that ‘Global Britain’ is not just an empty aspiration, but a concrete commitment to lead.

Not only is concerted action on the climate crisis a central priority for UK citizens, a growing and increasingly vocal group of UK businesses committed to decarbonization are calling on the government to secure a more transparent and predictable international market place that supports climate action by business.

With COP26, the UK has a unique responsibility to push governments to ratchet up ambition in the national contributions to climate action – and to promote coherence between climate ambition and wider economic policymaking, including on trade. If Britain really wants to lead, here are some concrete actions it should take.

At the national level, the UK can pioneer new ways to put environmental sustainability – and climate action in particular - at the heart of its trade agenda. Achieving the government’s ambitious Clean Growth Strategy - which seeks to make the UK the global leader in a range of industries including electric cars and offshore wind – should be a central objective of UK trade policy.

The UK should re-orient trade policy frameworks to incentivize the shift toward a more circular and net zero global economy. And all elements of UK trade policy could be assessed against environmental objectives - for example, their contribution to phasing out fossil fuels, helping to reverse overexploitation of natural resources, and support for sustainable agriculture and biodiversity.

In its bilateral and regional trade negotiations, the UK can and should advance its environment, climate and trade goals in tandem, and implementation of the Paris Agreement must be a core objective of the UK trade strategy.

A core issue for the UK is how to ensure that efforts to decarbonise the economy are not undercut by imports from high-carbon producers. Here, a ‘border carbon adjustment (BCA)’ - effectively a tax on the climate pollution of imports - would support UK climate goals. The EU draft negotiating text released yesterday put the issue of BCAs front and centre, making crystal clear that the intersection of climate, environment and trade policy goals will be a central issue for UK-EU trade negotiations.

Even with the United States, a trade deal can and should still be seized as a way to incentivize the shift toward a net zero and more circular economy. At the multilateral level, as a new independent WTO member, the UK has an opportunity to help build a forward-looking climate and trade agenda.

The UK could help foster dialogue, research and action on a cluster of ‘climate and trade’ issues that warrant more focused attention at the WTO. These include the design of carbon pricing policies at the border that are transparent, fair and support a just transition; proposals for a climate waiver for WTO rules; and identification of ways multilateral trade cooperation could promote a zero carbon and more circular global economy.  

To help nudge multilateral discussion along, the UK could also ask to join a critical ‘path finder’ effort by six governments, led by New Zealand, to pursue an agreement on climate change, trade and sustainability (ACCTS). This group aims to find ways forward on three central trade and climate issues: removing fossil fuel subsidies, climate-related labelling, and promoting trade in climate-friendly goods and services.

At present, the complex challenges at the intersection of climate, trade and development policy are too often used to defer or side-step issues deemed ‘too hard’ or ‘too sensitive’ to tackle. The UK could help here by working to ensure multilateral climate and trade initiatives share adjustment burdens, recognise the historical responsibility of developed countries, and do not unfairly disadvantage developing countries - especially the least developed.

Many developing countries are keen to promote climate-friendly exports as part of wider export diversification strategies  and want to reap greater returns from greener global value chains. Further, small island states and least-developed countries – many of which are Commonwealth members – that are especially vulnerable to the impacts of climate change and natural disasters, need support to adapt in the face of trade shocks and to build climate-resilient, trade-related infrastructure and export sectors.

As an immediate next step, the UK should actively support the growing number of WTO members in favour of a WTO Ministerial Statement on environmental sustainability and trade. It should work with its key trading partners in the Commonwealth and beyond to ensure the agenda is inclusive, supports achievement of the UN Sustainable Development Goals (SDGs) and helps developing countries benefit from a more environmentally sustainable global economy.

As the UK prepares to host COP26, negotiates deals with the EU and US, and prepares for its first WTO Ministerial meeting as an independent member, it must show it can lead the way nationally, bilaterally, and multilaterally. And to ensure the government acts, greater engagement from the UK’s business, civil society and research sectors is critical – we need all hands on deck to forge and promote concrete proposals for aligning UK trade policy with the climate ambition our world needs.




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“Us” or “Them”? How Policies, Public Opinion, and Political Rhetoric Affect Immigrants’ Sense of Belonging

Citizenship and integration policies are often thought of as markers for whether a country is welcoming to immigrants. Yet research suggests that public opinion and political rhetoric play a bigger role in immigrants' sense of belonging. This article explores how boundaries between "us" and "them" are drawn through popular conceptions of nationhood and political rhetoric, and their impact on immigrants' belonging.




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Online learning in the time of Coronavirus: Tips for students and the instructors who support them

Abbe Herzig, AMS Director of Education In the midst of the upheaval due to the Coronavirus, students and faculty are transitioning to new virtual classrooms. Many of us haven’t chosen to learn or teach, but here we are, making the … Continue reading




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Dietary Nonheme, Heme, and Total Iron Intake and the Risk of Diabetes in Adults: Results From the China Health and Nutrition Survey

OBJECTIVE

Excessive iron intake has been linked to diabetes risk. However, the evidence is inconsistent. This study examined the association between dietary heme and nonheme iron intake and diabetes risk in the Chinese population.

RESEARCH DESIGN AND METHODS

We included 17,026 adults (8,346 men and 8,680 women) who were part of the China Health and Nutrition Survey (1991–2015) prospective cohort. Dietary intake was measured by three consecutive 24-h dietary recalls combined with a household food inventory. Diabetes cases were identified through a questionnaire. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% CIs.

RESULTS

A total of 547 men and 577 women developed diabetes during 202,138 person-years of follow-up. For men, the adjusted HRs (95% CIs) for quintiles of nonheme iron intake were 1.00, 0.77 (0.58–1.02), 0.72 (0.54–0.97), 0.63 (0.46–0.85), and 0.87 (0.64–1.19) (P-nonlinearity = 0.0015). The corresponding HRs (95% CIs) for women were 1.00, 0.63 (0.48–0.84), 0.57 (0.43–0.76), 0.58 (0.43–0.77), and 0.67 (0.49–0.91) (P-nonlinearity < 0.0001). The dose-response curves for the association between nonheme iron and total iron intake and diabetes followed a reverse J shape in men and an L shape in women. No significant associations were observed between heme iron intake and diabetes risk.

CONCLUSIONS

Total iron and nonheme iron intake was associated with diabetes risk, following a reverse J-shaped curve in men and an L-shaped curve in women. Sufficient intake of nonheme or total iron might be protective against diabetes, while excessive iron intake might increase the risk of diabetes among men.




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A Mathematical Model for the Determination of Total Area Under Glucose Tolerance and Other Metabolic Curves

Mary M Tai
Feb 1, 1994; 17:152-154
Short Report




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Gas leak at India chemical plant kills 8, sickens hundreds

At least eight people died and hundreds were hospitalized after toxic gas leaked from a chemical factory in southern India early Thursday, officials said.




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Journal of Public Health Dentistry study finds association between man-made chemical, childhood caries

Circulating levels of perfluorodecanoic acid, a type of perfluoroalkyl acid, may be associated with dental caries in children, according to a study published in the fall 2019 issue of the Journal of Public Health Dentistry.




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3M granted injunction against New Jersey company in N95 price-gouging scheme

A federal judge on May 4 granted 3M, the maker of N95 masks, an injunction against a New Jersey-based company accused of using 3M’s trademarks and deliberately inflating the price of the face masks.




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The Effects of Intensive Glycemic Control on Clinical Outcomes Among Patients With Type 2 Diabetes With Different Levels of Cardiovascular Risk and Hemoglobin A1c in the ADVANCE Trial

OBJECTIVE

To study whether the effects of intensive glycemic control on major vascular outcomes (a composite of major macrovascular and major microvascular events), all-cause mortality, and severe hypoglycemia events differ among participants with different levels of 10-year risk of atherosclerotic cardiovascular disease (ASCVD) and hemoglobin A1c (HbA1c) at baseline.

RESEARCH DESIGN AND METHODS

We studied the effects of more intensive glycemic control in 11,071 patients with type 2 diabetes (T2D), without missing values, in the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) trial, using Cox models.

RESULTS

During 5 years’ follow-up, intensive glycemic control reduced major vascular events (hazard ratio [HR] 0.90 [95% CI 0.83–0.98]), with the major driver being a reduction in the development of macroalbuminuria. There was no evidence of differences in the effect, regardless of baseline ASCVD risk or HbA1c level (P for interaction = 0.29 and 0.94, respectively). Similarly, the beneficial effects of intensive glycemic control on all-cause mortality were not significantly different across baseline ASCVD risk (P = 0.15) or HbA1c levels (P = 0.87). The risks of severe hypoglycemic events were higher in the intensive glycemic control group compared with the standard glycemic control group (HR 1.85 [1.41–2.42]), with no significant heterogeneity across subgroups defined by ASCVD risk or HbA1c at baseline (P = 0.09 and 0.18, respectively).

CONCLUSIONS

The major benefits for patients with T2D in ADVANCE did not substantially differ across levels of baseline ASCVD risk and HbA1c.




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microRNA-21/PDCD4 Proapoptotic Signaling From Circulating CD34+ Cells to Vascular Endothelial Cells: A Potential Contributor to Adverse Cardiovascular Outcomes in Patients With Critical Limb Ischemia

OBJECTIVE

In patients with type 2 diabetes (T2D) and critical limb ischemia (CLI), migration of circulating CD34+ cells predicted cardiovascular mortality at 18 months after revascularization. This study aimed to provide long-term validation and mechanistic understanding of the biomarker.

RESEARCH DESIGN AND METHODS

The association between CD34+ cell migration and cardiovascular mortality was reassessed at 6 years after revascularization. In a new series of T2D-CLI and control subjects, immuno-sorted bone marrow CD34+ cells were profiled for miRNA expression and assessed for apoptosis and angiogenesis activity. The differentially regulated miRNA-21 and its proapoptotic target, PDCD4, were titrated to verify their contribution in transferring damaging signals from CD34+ cells to endothelial cells.

RESULTS

Multivariable regression analysis confirmed that CD34+ cell migration forecasts long-term cardiovascular mortality. CD34+ cells from T2D-CLI patients were more apoptotic and less proangiogenic than control subjects and featured miRNA-21 downregulation, modulation of several long noncoding RNAs acting as miRNA-21 sponges, and upregulation of the miRNA-21 proapoptotic target PDCD4. Silencing miR-21 in control subject CD34+ cells phenocopied the T2D-CLI cell behavior. In coculture, T2D-CLI CD34+ cells imprinted naïve endothelial cells, increasing apoptosis, reducing network formation, and modulating the TUG1 sponge/miRNA-21/PDCD4 axis. Silencing PDCD4 or scavenging reactive oxygen species protected endothelial cells from the negative influence of T2D-CLI CD34+ cells.

CONCLUSIONS

Migration of CD34+ cells predicts long-term cardiovascular mortality in T2D-CLI patients. An altered paracrine signaling conveys antiangiogenic and proapoptotic features from CD34+ cells to the endothelium. This damaging interaction may increase the risk for life-threatening complications.




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[ Politics ] Open Question : Why do people in Chicago kill themselves for nothing?




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Are We Judging Actions, Or the People Behind Them?

Like lunar and solar eclipses, there are some Washington phenomena that are so common they ought to have distinct names. Here is one: A public figure comes to be hated by large numbers of people. But the person cannot be prosecuted or punished, perhaps because his behavior did not involve a crime so...




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Mathematics at 2019 SACNAS

Below I share some details about SACNAS and some of the mathematical events that happened at this year’s SACNAS National Conference.  I hope that this may also serve as an invitation/motivation for anyone interested in diversity and mathematics to participate … Continue reading





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As European policymakers take stock of seasonal worker programmes, MPI Europe brief outlines principles to improve these schemes for all parties

Findings will be discussed during 25 February MPI Europe – SVR webinar




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As Millions Are Pushed from Jobs amid Pandemic, the Loss of Employer Health Coverage &amp; Limited Access to Public Coverage for Many Immigrants Hold Major Implications for Them – and U.S. Overall

WASHINGTON – As more than 33 million U.S. workers have lost their jobs since March amid the pandemic-induced economic crisis, immigrants are among the most vulnerable: They are more likely than the U.S. born to be laid off and to live in communities with high COVID-19 infection rates, and less likely to have health insurance coverage and access to a doctor or other usual source of health care.




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Myocardial Ischemic Burden and Differences in Prognosis Among Patients With and Without Diabetes: Results From the Multicenter International REFINE SPECT Registry

OBJECTIVE

Prevalence and prognostic impact of cardiovascular disease differ between patients with or without diabetes. We aimed to explore differences in the prevalence and prognosis of myocardial ischemia by automated quantification of total perfusion deficit (TPD) among patients with and without diabetes.

RESEARCH DESIGN AND METHODS

Of 20,418 individuals who underwent single-photon emission computed tomography myocardial perfusion imaging, 2,951 patients with diabetes were matched to 2,951 patients without diabetes based on risk factors using propensity score. TPD was categorized as TPD = 0%, 0% < TPD < 1%, 1% ≤ TPD < 5%, 5% ≤ TPD ≤ 10%, and TPD >10%. Major adverse cardiovascular events (MACE) were defined as a composite of all-cause mortality, myocardial infarction, unstable angina, or late revascularization.

RESULTS

MACE risk was increased in patients with diabetes compared with patients without diabetes at each level of TPD above 0 (P < 0.001 for interaction). In patients with TPD >10%, patients with diabetes had greater than twice the MACE risk compared with patients without diabetes (annualized MACE rate 9.4 [95% CI 6.7–11.6] and 3.9 [95% CI 2.8–5.6], respectively, P < 0.001). Patients with diabetes with even very minimal TPD (0% < TPD < 1%) experienced a higher risk for MACE than those with 0% TPD (hazard ratio 2.05 [95% CI 1.21–3.47], P = 0.007). Patients with diabetes with a TPD of 0.5% had a similar MACE risk as patients without diabetes with a TPD of 8%.

CONCLUSIONS

For every level of TPD >0%, even a very minimal deficit of 0% < TPD < 1%, the MACE risk was higher in the patients with diabetes compared with patients without diabetes. Patients with diabetes with minimal ischemia had comparable MACE risk as patients without diabetes with significant ischemia.




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Glycated Hemoglobin, Prediabetes, and the Links to Cardiovascular Disease: Data From UK Biobank

OBJECTIVE

HbA1c levels are increasingly measured in screening for diabetes; we investigated whether HbA1c may simultaneously improve cardiovascular disease (CVD) risk assessment, using QRISK3, American College of Cardiology/American Heart Association (ACC/AHA), and Systematic COronary Risk Evaluation (SCORE) scoring systems.

RESEARCH DESIGN AND METHODS

UK Biobank participants without baseline CVD or known diabetes (n = 357,833) were included. Associations of HbA1c with CVD was assessed using Cox models adjusting for classical risk factors. Predictive utility was determined by the C-index and net reclassification index (NRI). A separate analysis was conducted in 16,596 participants with known baseline diabetes.

RESULTS

Incident fatal or nonfatal CVD, as defined in the QRISK3 prediction model, occurred in 12,877 participants over 8.9 years. Of participants, 3.3% (n = 11,665) had prediabetes (42.0–47.9 mmol/mol [6.0–6.4%]) and 0.7% (n = 2,573) had undiagnosed diabetes (≥48.0 mmol/mol [≥6.5%]). In unadjusted models, compared with the reference group (<42.0 mmol/mol [<6.0%]), those with prediabetes and undiagnosed diabetes were at higher CVD risk: hazard ratio (HR) 1.83 (95% CI 1.69–1.97) and 2.26 (95% CI 1.96–2.60), respectively. After adjustment for classical risk factors, these attenuated to HR 1.11 (95% CI 1.03–1.20) and 1.20 (1.04–1.38), respectively. Adding HbA1c to the QRISK3 CVD risk prediction model (C-index 0.7392) yielded a small improvement in discrimination (C-index increase of 0.0004 [95% CI 0.0001–0.0007]). The NRI showed no improvement. Results were similar for models based on the ACC/AHA and SCORE risk models.

CONCLUSIONS

The near twofold higher unadjusted risk for CVD in people with prediabetes is driven mainly by abnormal levels of conventional CVD risk factors. While HbA1c adds minimally to cardiovascular risk prediction, those with prediabetes should have their conventional cardiovascular risk factors appropriately measured and managed.




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Case Study: Potential Pitfalls of Using Hemoglobin A1c as the Sole Measure of Glycemic Control

Huy A. Tran
Jul 1, 2004; 22:141-143
Case Studies




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Mathematical Metaphors


Theories in all areas of science tell us something about the world. They are images, or models, or representations of reality. Theories tell stories about the world and are often associated with stories about their discovery. Like the story (probably apocryphal) that Newton invented the theory of gravity after an apple fell on his head. Or the story (probably true) that Kekule discovered the cyclical structure of benzene after day-dreaming of a snake seizing its tail. Theories are metaphors that explain reality.

A theory is scientific if it is precise, quantitative, and amenable to being tested. A scientific theory is mathematical. Scientific theories are mathematical metaphors.

A metaphor uses a word or phrase to define or extend or focus the meaning of another word or phrase. For example, "The river of time" is a metaphor. We all know that rivers flow inevitably from high to low ground. The metaphor focuses the concept of time on its inevitable uni-directionality. Metaphors make sense because we understand what they mean. We all know that rivers are wet, but we understand that the metaphor does not mean to imply that time drips, because we understand the words and their context. But on the other hand, a metaphor - in the hands of a creative and imaginative person - might mean something unexpected, and we need to think carefully about what the metaphor does, or might, mean. Mathematical metaphors - scientific models - also focus attention in one direction rather than another, which gives them explanatory and predictive power. Mathematical metaphors can also be interpreted in different and surprising ways.

Some mathematical models are very accurate metaphors. For instance, when Galileo dropped a heavy object from the leaning tower of Pisa, the distance it fell increased in proportion to the square of the elapsed time. Mathematical equations sometimes represent reality quite accurately, but we understand the representation only when the meanings of the mathematical terms are given in words. The meaning of the equation tells us what aspect of reality the model focuses on. Many things happened when Galileo released the object - it rotated, air swirled, friction developed - while the equation focuses on one particular aspect: distance versus time. Likewise, the quadratic equation that relates distance to time can also be used to relate energy to the speed of light, or to relate population growth rate to population size. In Galileo's case the metaphor relates to freely falling objects.

Other models are only approximations. For example, a particular theory describes the build up of mechanical stress around a crack, causing damage in the material. While cracks often have rough or ragged shapes, this important and useful theory assumes the crack is smooth and elliptical. This mathematical metaphor is useful because it focuses the analysis on the radius of curvature of the crack that is critical in determining the concentration of stress.

Not all scientific models are approximations. Some models measure something. For example, in statistical mechanics, the temperature of a material is proportional to the average kinetic energy of the molecules in the material. The temperature, in degrees centigrade, is a global measure of random molecular motion. In economics, the gross domestic product is a measure of the degree of economic activity in the country.

Other models are not approximations or measures of anything, but rather graphical portrayals of a relationship. Consider, for example, the competition among three restaurants: Joe's Easy Diner, McDonald's, and Maxim's de Paris. All three restaurants compete with each other: if you're hungry, you've got to choose. Joe's and McDonald's are close competitors because they both specialize in hamburgers but also have other dishes. They both compete with Maxim's, a really swank and expensive boutique restaurant, but the competition is more remote. To model the competition we might draw a line representing "competition", with each restaurant as a dot on the line. Joe's and McDonald's are close together and far from Maxim's. This line is a mathematical metaphor, representing the proximity (and hence strength) of competition between the three restaurants. The distances between the dots are precise, but what the metaphor means, in terms of the real-world competition between Joe, McDonald, and Maxim, is not so clear. Why a line rather than a plane to refine the "axes" of competition (price and location for instance)? Or maybe a hill to reflect difficulty of access (Joe's is at one location in South Africa, Maxim's has restaurants in Paris, Peking, Tokyo and Shanghai, and McDonald's is just about everywhere). A metaphor emphasizes some aspects while ignoring others. Different mathematical metaphors of the same phenomenon can support very different interpretations or insights.

The scientist who constructs a mathematical metaphor - a model or theory - chooses to focus on some aspects of the phenomenon rather than others, and chooses to represent those aspects with one image rather than another. Scientific theories are fascinating and extraordinarily useful, but they are, after all, only metaphors.




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A history of Indigenous languages -- and how to revitalize them | Lindsay Morcom

Indigenous languages across North America are under threat of extinction due to the colonial legacy of cultural erasure, says linguist Lindsay Morcom. Highlighting grassroots strategies developed by the Anishinaabe people of Canada to revive their language and community, Morcom makes a passionate case for enacting policies that could protect Indigenous heritage for generations to come.




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Alabama School Board Members Weigh In on Plan to Replace Them

State Board of Education members weighed in today about a proposal to eliminate their elected positions and replace the board with an appointed commission.




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Employment contracts : getting them right for your clients... and for your own business! / presented by Kaz Eaton, Flinders Chambers.




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Family Court consent orders and enforcement applications : a “how to” guide for presenting them in an acceptable form / presented by Verity Brown, Registrar FCA.




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A survey of the orange-bellied parrot Neophema chrysogaster in Tasmania, Victoria & South Australia : a report prepared for World Wildlife Fund (Australia) / P. B. Brown & R. I. Wilson.




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National recovery plan for the Orange-bellied parrot (Neophema chrysogaster).




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Health Complaints – Who handles them? Are lawyers involved?.




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Offensive words in wills : putting them in and taking them out / paper presented by Christopher Parker, Treloar & Treloar.




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Navigating the Lifetime Support Scheme Rules - Slides - R Singh and R Weckert.




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Fentanyl, Inc. : how rogue chemists are creating the deadliest wave of the opioid epidemic / Ben Westhoff.

Designer drugs -- Fentanyl.




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D.C. Charters Aren't Pushing Kids Out. But They're Not Always Welcoming Them In, Either

The District of Columbia's charters aren't always "backfilling" seats, and there's little financial incentive for them to do so.




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Des maladies foetales qui peuvent faire obstacle à l'accouchement : thèse ... / par Alphonse Herrgott.

Paris : O. Doin, 1878.




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Des ruptures utérines pendant le travail de l'accouchement, considérées surtout au point de vue des symptômes et du traitement / par le Dr Jacques Jolly.

Paris : Delahaye, 1873.




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Descriptive Biochemie : mit besonderer Berücksichtigung der chemischen Arbeitsmethoden / von Sigmund Fränkel.

Wiesbaden : J.F. Bergmann, 1907.