This week the Trump administration has banned the sale of flavoured vapes in the USA. The reason for that is the sudden rash of cases of pulmonary disease, including deaths, linked to vaping. The mechanism by which vaping may be causing damage to the lungs is as yet unclear, and our understanding is hampered by the heterogeneous nature of the...

If you’re lucky enough to not be back at work, you might be feeling like you need to quickly refresh your medical knowledge - and this podcast the BMJ’s education editors take you on a whistlestop tour through the BMJ’s education articles of 2019. Tom Nolan (GP in London) is joined by Navjoyt Ladher (GP in London), Anita Jain (GP in India) and...

This edition of talk evidence was recorded before the big increase in covid-19 infections in the UK, and then delayed by some self isolation. We'll be back with more evidence on the pandemic very soon. As always Duncan Jarvies is joined by Helen Macdonald (resting GP and editor at The BMJ) and Carl Heneghan (active GP, director of Oxford...

In this week’s episode, we discuss bystander guilt, convergence, brain hacks and “how you can sneeze on someone’s brain from anywhere in the world”. How can GPs cope with the myriad worries around treating patients during the current pandemic, both on the frontline and in general practice? How do we recognise and break unhelpful anxious behaviour...

We are more than six weeks into the lockdown and if you were to gauge the mood of the nation, it would be one of fatigue. It started as an all-hands-on-deck emergency situation, but it now transpires that the current work situation for healthcare professionals is not going to change any time soon. This is a marathon rather than a sprint. So how...

Joachim Spranger
Mar 1, 2003; 52:812-817
Pathophysiology

Franz M Matschinsky
Feb 1, 1996; 45:223-241
Banting Lecture 1995

Samar I. Itani
Jul 1, 2002; 51:2005-2011
Rapid Publications

The cardiovascular benefits of fibrates have been shown to be heterogeneous and to depend on the presence of atherogenic dyslipidemia. We investigated whether genetic variability in the PPARA gene, coding for the pharmacological target of fibrates (PPAR-α), could be used to improve the selection of patients with type 2 diabetes who may derive cardiovascular benefit from addition of this treatment to statins. We identified a common variant at the PPARA locus (rs6008845, C/T) displaying a study-wide significant influence on the effect of fenofibrate on major cardiovascular events (MACE) among 3,065 self-reported white subjects treated with simvastatin and randomized to fenofibrate or placebo in the ACCORD-Lipid trial. T/T homozygotes (36% of participants) experienced a 51% MACE reduction in response to fenofibrate (hazard ratio 0.49; 95% CI 0.34–0.72), whereas no benefit was observed for other genotypes (P_interaction = 3.7 x 10^–4). The rs6008845-by-fenofibrate interaction on MACE was replicated in African Americans from ACCORD (N = 585, P = 0.02) and in external cohorts (ACCORD-BP, ORIGIN, and TRIUMPH, total N = 3059, P = 0.005). Remarkably, rs6008845 T/T homozygotes experienced a cardiovascular benefit from fibrate even in the absence of atherogenic dyslipidemia. Among these individuals, but not among carriers of other genotypes, fenofibrate treatment was associated with lower circulating levels of CCL11—a proinflammatory and atherogenic chemokine also known as eotaxin (P for rs6008845-by-fenofibrate interaction = 0.003). The GTEx data set revealed regulatory functions of rs6008845 on PPARA expression in many tissues. In summary, we have found a common PPARA regulatory variant that influences the cardiovascular effects of fenofibrate and that could be used to identify patients with type 2 diabetes who would derive benefit from fenofibrate treatment, in addition to those with atherogenic dyslipidemia.

PORT OF SPAIN, Trinidad, CMC – Prime Minister Dr Keith Rowley Saturday dismissed as a “dishonest last gasp and gamble of a dangerously delusional woman” a statement by Opposition Leader Kamla Persad Bissessar calling for him...

Frank Robinson, a trailblazing figure who was Major League Baseball's first African-American manager and one of its greatest players during a career that spanned 21 seasons, died Thursday after a prolonged illness. He was 83.

Though some Reds fans were disappointed that Billy Hamilton wasn't brought back this season, it didn't take long for Cincinnati to find another dynamic player who also brings flash and unpredictability. That would be outfielder Yasiel Puig.

Utility player and Rule 5 selection Connor Joe has been working with the catchers since Reds Spring Training opened. What makes that a little more interesting is that Joe has never caught a game professionally.

THE EDITOR, Madam: On May 5, 2020, at about 8:40 a.m., I went completely berserk, telling two staff members of the Bank of Nova Scotia from the Liguanea branch some proper Jamaica vernaculars, long like the Holland Bamboo. I was astonished by my...

We continue the positive reinforcement of humane spirit and action when humanity, as a collective, is grappling with an unprecedented calamity. “We shall overcome” is the mantra, and going by the ­indomitable strength we possess, we ­definitely...

We continue our journey highlighting the journey of Peace Corps volunteers (PCV). In this third and final instalment, the underlying and broad message is that volunteerism is a combination of one’s personal choices, external influences, and a keen...

Incretin hormone dysregulation contributes to reduced insulin secretion and hyperglycemia in patients with type 2 diabetes mellitus (T2DM). Resistance to glucose-dependent insulinotropic polypeptide (GIP) action may occur through desensitization or downregulation of β-cell GIP receptors (GIP-R). Studies in rodents and cell lines show GIP-R expression can be regulated through peroxisome proliferator–activated receptor (PPAR) response elements (PPREs). Whether this occurs in humans is unknown. To test this, we conducted a randomized, double-blind, placebo-controlled trial of pioglitazone therapy on GIP-mediated insulin secretion and adipocyte GIP-R expression in subjects with well-controlled T2DM. Insulin sensitivity improved, but the insulinotropic effect of infused GIP was unchanged following 12 weeks of pioglitazone treatment. In parallel, we observed increased GIP-R mRNA expression in subcutaneous abdominal adipocytes from subjects treated with pioglitazone. Treatment of cultured human adipocytes with troglitazone increased PPAR binding to GIP-R PPREs. These results show PPAR agonists regulate GIP-R expression through PPREs in human adipocytes, but suggest this mechanism is not important for regulation of the insulinotropic effect of GIP in subjects with T2DM. Because GIP has antilipolytic and lipogenic effects in adipocytes, the increased GIP-R expression may mediate accretion of fat in patients with T2DM treated with PPAR agonists.

Reduced storage of dietary fatty acids (DFAs) in abdominal adipose tissues with enhanced cardiac partitioning has been shown in subjects with type 2 diabetes (T2D) and prediabetes. We measured DFA metabolism and organ partitioning using positron emission tomography with oral and intravenous long-chain fatty acid and glucose tracers during a standard liquid meal in 12 obese subjects with T2D before and 8–12 days after bariatric surgery (sleeve gastrectomy or sleeve gastrectomy and biliopancreatic diversion with duodenal switch). Bariatric surgery reduced cardiac DFA uptake from a median (standard uptake value [SUV]) 1.75 (interquartile range 1.39–2.57) before to 1.09 (1.04–1.53) after surgery (P = 0.01) and systemic DFA spillover from 56.7 mmol before to 24.7 mmol over 6 h after meal intake after surgery (P = 0.01), with a significant increase in intra-abdominal adipose tissue DFA uptake from 0.15 (0.04–0.31] before to 0.49 (0.20–0.59) SUV after surgery (P = 0.008). Hepatic insulin resistance was significantly reduced in close association with increased DFA storage in intra-abdominal adipose tissues (r = –0.79, P = 0.05) and reduced DFA spillover (r = 0.76, P = 0.01). We conclude that bariatric surgery in subjects with T2D rapidly reduces cardiac DFA partitioning and hepatic insulin resistance at least in part through increased intra-abdominal DFA storage and reduced spillover.

Diabetic retinopathy is the most common microvascular complication of diabetes, and in the advanced diabetic retinopathy appear vitreal fibrovascular membranes that consist of a variety of cells, including vascular endothelial cells (ECs). New therapeutic approaches for this diabetic complication are urgently needed. Here, we report that in cultured human retinal microvascular ECs, high glucose induced expression of p110, which was also expressed in ECs of fibrovascular membranes from patients with diabetes. This catalytic subunit of a receptor-regulated PI3K isoform is known to be highly enriched in leukocytes. Using genetic and pharmacological approaches, we show that p110 activity in cultured ECs controls Akt activation, cell proliferation, migration, and tube formation induced by vascular endothelial growth factor, basic fibroblast growth factor, and epidermal growth factor. Using a mouse model of oxygen-induced retinopathy, p110 inactivation was found to attenuate pathological retinal angiogenesis. p110 inhibitors have been approved for use in human B-cell malignancies. Our data suggest that antagonizing p110 constitutes a previously unappreciated therapeutic opportunity for diabetic retinopathy.

Type 2 diabetes accounts for 90% of the population with diabetes, and these patients are generally obese and hyperlipidemic. In addition to hyperglycemia, hyperlipidemia is also closely related with diabetic retinopathy. The aim was to investigate retinopathy in a model closely mimicking the normal progression and metabolic features of the population with type 2 diabetes and elucidate the molecular mechanism. Retinopathy was evaluated in rats fed a 45% kcal as fat diet for 8 weeks before administering streptozotocin, 30 mg/kg body weight (T2D), and compared with age- and duration-matched type 1 diabetic rats (T1D) (60 mg/kg streptozotocin). The role of epigenetic modifications in mitochondrial damage was evaluated in retinal microvasculature. T2D rats were obese and severely hyperlipidemic, with impaired glucose and insulin tolerance compared with age-matched T1D rats. While at 4 months of diabetes, T1D rats had no detectable retinopathy, T2D rats had significant retinopathy, their mitochondrial copy numbers were lower, and mtDNA and Rac1 promoter DNA methylation was exacerbated. At 6 months, retinopathy was comparable in T2D and T1D rats, suggesting that obesity exaggerates hyperglycemia-induced epigenetic modifications, accelerating mitochondrial damage and diabetic retinopathy. Thus, maintenance of good lifestyle and BMI could be beneficial in regulating epigenetic modifications and preventing/retarding retinopathy in patients with diabetes.

Members Event

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Professor Dieter Helm CBE, Professor of Energy Policy, University of Oxford

Chair: David Shukman, Science Editor, BBC News

5 December 2017

Lower-income countries are in many ways more ‘circular’ than their developed-economy counterparts – the question is how to turn this into a development opportunity.

Most Major League teams still use a five-man starting rotation, but it takes a lot more pitchers than that to make it through a 162-game season. It certainly helps to have a potent one-two punch at the top of the rotation.

After seeing improved communication between pitchers and catchers last year, the "campfire" drill was put back on the D-backs' schedule and took place Friday at Salt River Fields.

The mothballing of Britain’s Nightingale hospitals, some of which have yet to treat a single covid-19 patient, has raised questions about whether resources to fight the pandemic were...

The present study examined the predictive values of amyloid PET, ¹⁸F-FDG PET, and nonimaging predictors (alone and in combination) for development of Alzheimer dementia (AD) in a large population of patients with mild cognitive impairment (MCI). Methods: The study included 319 patients with MCI from the Alzheimer Disease Neuroimaging Initiative database. In a derivation dataset (n = 159), the following Cox proportional-hazards models were constructed, each adjusted for age and sex: amyloid PET using ¹⁸F-florbetapir (pattern expression score of an amyloid-β AD conversion–related pattern, constructed by principle-components analysis); ¹⁸F-FDG PET (pattern expression score of a previously defined ¹⁸F-FDG–based AD conversion–related pattern, constructed by principle-components analysis); nonimaging (functional activities questionnaire, apolipoprotein E, and mini-mental state examination score); ¹⁸F-FDG PET + amyloid PET; amyloid PET + nonimaging; ¹⁸F-FDG PET + nonimaging; and amyloid PET + ¹⁸F-FDG PET + nonimaging. In a second step, the results of Cox regressions were applied to a validation dataset (n = 160) to stratify subjects according to the predicted conversion risk. Results: On the basis of the independent validation dataset, the ¹⁸F-FDG PET model yielded a significantly higher predictive value than the amyloid PET model. However, both were inferior to the nonimaging model and were significantly improved by the addition of nonimaging variables. The best prediction accuracy was reached by combining ¹⁸F-FDG PET, amyloid PET, and nonimaging variables. The combined model yielded 5-y free-of-conversion rates of 100%, 64%, and 24% for the low-, medium- and high-risk groups, respectively. Conclusion: ¹⁸F-FDG PET, amyloid PET, and nonimaging variables represent complementary predictors of conversion from MCI to AD. Especially in combination, they enable an accurate stratification of patients according to their conversion risks, which is of great interest for patient care and clinical trials.

Fibroblast activation protein (FAP), which promotes tumor growth and progression, is overexpressed in cancer-associated fibroblasts of many human epithelial cancers. Because of its low expression in normal organs, FAP is an excellent target for theranostics. In this study, we used radionuclides with relatively long half-lives, ⁶⁴Cu (half-life, 12.7 h) and ²²⁵Ac (half-life, 10 d), to label FAP inhibitors (FAPIs) in mice with human pancreatic cancer xenografts. Methods: Male nude mice (body weight, 22.5 ± 1.2 g) were subcutaneously injected with human pancreatic cancer cells (PANC-1, n = 12; MIA PaCa-2, n = 8). Tumor xenograft mice were investigated after the intravenous injection of ⁶⁴Cu-FAPI-04 (7.21 ± 0.46 MBq) by dynamic and delayed PET scans (2.5 h after injection). Static scans 1 h after the injection of ⁶⁸Ga-FAPI-04 (3.6 ± 1.4 MBq) were also acquired for comparisons using the same cohort of mice (n = 8). Immunohistochemical staining was performed to confirm FAP expression in tumor xenografts using an FAP-α-antibody. For radioligand therapy, ²²⁵Ac-FAPI-04 (34 kBq) was injected into PANC-1 xenograft mice (n = 6). Tumor size was monitored and compared with that of control mice (n = 6). Results: Dynamic imaging of ⁶⁴Cu-FAPI-04 showed rapid clearance through the kidneys and slow washout from tumors. Delayed PET imaging of ⁶⁴Cu-FAPI-04 showed mild uptake in tumors and relatively high uptake in the liver and intestine. Accumulation levels in the tumor or normal organs were significantly higher for ⁶⁴Cu-FAPI-04 than for ⁶⁸Ga-FAPI-04, except in the heart, and excretion in the urine was higher for ⁶⁸Ga-FAPI-04 than for ⁶⁴Cu-FAPI-04. Immunohistochemical staining revealed abundant FAP expression in the stroma of xenografts. ²²⁵Ac-FAPI-04 injection showed significant tumor growth suppression in the PANC-1 xenograft mice, compared with the control mice, without a significant change in body weight. Conclusion: This proof-of-concept study showed that ⁶⁴Cu-FAPI-04 and ²²⁵Ac-FAPI-04 could be used in theranostics for the treatment of FAP-expressing pancreatic cancer. α-therapy targeting FAP in the cancer stroma is effective and will contribute to the development of a new treatment strategy.

β-Cell antigen recognition by autoreactive T cells is essential in type 1 diabetes (T1D) pathogenesis. Recently, insulin hybrid peptides (HIPs) were identified as strong agonists for CD4 diabetogenic T cells. Here, using BDC2.5 transgenic and NOD mice, we investigated T-cell recognition of the HIP2.5 epitope, which is a fusion of insulin C-peptide and chromogranin A (ChgA) fragments, and compared it with the WE14 and ChgA_29–42 epitopes. We measured in situ two-dimensional affinity on individual live T cells from thymus, spleen, pancreatic lymph nodes, and islets before and after diabetes. Although preselection BDC2.5 thymocytes possess higher affinity than splenic BDC2.5 T cells for all three epitopes, peripheral splenic T cells maintained high affinity only to the HIP2.5 epitope. In polyclonal NOD mice, a high frequency (~40%) of HIP2.5-specific islet T cells were identified at both prediabetic and diabetic stages comprising two distinct high- and low-affinity populations that differed in affinity by 100-fold. This high frequency of high- and low-affinity HIP2.5 T cells in the islets potentially represents a major risk factor in diabetes pathogenesis.

THE ACQUISITION of Epping resulted in Total Jamaica controlling nearly a third of the retail gasolene market, but that’s not enough to lessen competition, the Fair Trading Commission, FTC, has found. “The acquisition is unlikely to have either the...

SUPREME VENTURES Limited, SVL, has locked down its Acropolis gaming lounge since March 18, when the Government mandated the closure of all lounges and bars. Sports wagering has fallen precipitously, concomitant with the suspension of sporting...

Members Event

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Helen Thompson, Professor of Political Economy, University of Cambridge; Host, Talking Politics
Chairs: Hans Kundnani, Senior Research Fellow, Europe Programme, Chatham House
Laura Cram, Professor of European Politics, University of Edinburgh. Co-Editor, Government and Opposition: An International Journal of Comparative Politics
 

Members Event

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Abigail Watson, Research Manager, Oxford Research Group
Dr Jamie Gaskarth, Reader in Foreign Policy and International Relations, University of Birmingham; Author, Secrets and Spies: UK Intelligence Accountability After Iraq and Snowden
Jo Hare, Ethics Counsellor
Dr Claudia Hillebrand, Senior Lecturer in International Relations, Cardiff University
Chair: Professor Sir David Omand GCB, Visiting Professor, King's College London; Security and Intelligence Coordinator, Cabinet Office, UK (2002-05); Director, GCHQ (1996-97)

Even as the 1.8 million number swirls in the discussion of how many DREAMers would be placed on a path to citizenship, proposals debated in the Senate in February 2018 would have resulted in the legalization of smaller numbers, as this commentary explains. It offers estimates of potential beneficiaries of several Senate proposals, including one backed by the White House, and analysis of key criteria.

The Trump administration took sweeping action in 2018 to slow legal immigration, make life harder for some immigrants already in the United States, rebuff would-be asylum seekers, and reduce refugee resettlement. Shaping a narrative of crisis at the border, the administration significantly changed the U.S. asylum system, deployed troops and tear gas, and separated families—yet Central American migrants continued to arrive.

Approximately 11,500 unaccompanied children were apprehended at the U.S.-Mexico border in May, putting this year on track to exceed 2014's surge. As the U.S. government struggles to care for these child migrants, with public outrage mounting over reports of unsafe, filthy conditions in initial Border Patrol custody, the failure of the executive branch and Congress to plan for increased shelter and care demands are increasingly apparent, as this article explores.

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.

For generations, migrants have emigrated from Senegal, particularly from in and around the Senegal River Valley. With France a key destination, French policy changes have had significant impact on Senegalese migrants and the hometown associations through which they support development in Senegal. This article explores how these policy shifts influence development and quality of life in the Senegal River Valley.

In the Philippines, a pervasive culture of migration has led millions to seek opportunities abroad, particularly since an economic downturn in the 1970s. The government has long embraced exporting labor as official economic policy, but over time, the focus has shifted: first to protecting workers overseas and much more recently to linking migration and development. This article explores the evolution of Filipino migration policy and trends.

This policy brief explores the relationship between environmental change and migration to Europe in light of recent scholarship challenging the notion that environmental change triggers mass migration. It presents an overview of European policy response in this area and summarizes the spectrum of proposed solutions.

Nearly 4 million South Sudanese have been driven from their homes by violence or food insecurity since late 2013, roughly half seeking refuge in neighboring countries. Drought and conflict have converged in the young country to fuel one of the world's most severe humanitarian emergencies. This article examines refugee flows from South Sudan, underlying drivers, and regional and international responses to the crisis.

While skilled migration brings widely acknowledged economic benefits for destination countries and migrants, its impact on countries of origin has been the subject of more debate. Despite a growing consensus that origin countries can benefit from emigration and the circulation of skills, enabling this potential to be fully exploited remains a challenge. This report examines initiatives that develop skills and human capital.

For a growing population of migrants deported from Mexico and the United States to Central America, the conditions upon return typically are worse than when they left, setting up a revolving-door cycle of migration, deportation, and remigration. This report provides a detailed profile of reception and reintegration services offered in El Salvador, Guatemala, and Honduras to deported migrants, examining their challenges and opportunities for improvement. 

Forty-two governors, Republican and Democrat alike, have affirmed their consent for continued refugee resettlement, bypassing an invitation from the Trump administration to stop accepting refugees. These actions, which reportedly surprised the White House, suggest there may be limits to the Trump immigration agenda when it comes to refugees, as this Policy Beat explores.

OBJECTIVE

To evaluate and compare the efficacy of long-term use of low-dose aspirin for the prevention of dementia in men and women.