Waiting times in theatre can be a source of friction – but is the delay due to mandatory anaesthetic faff around time (MAFAT), or AWOL surgeons? Elizabeth Travis, and orthopaedic house officer in New Zealand and colleagues, have been trying to create and evidence base to argue the toss, and she joins me now to discuss her study, Operating...

Michelle Sinclar, a GP in Hampshire who is concerned that GP premises aren't fit for purpose and limit her ability to provide fully rounded patient care. BMJ Voices is a collection of readers’ experiences of working in the NHS. For this, The BMJ is seeking short audio submissions from UK listeners. These submissions will be published on...

However well intentioned, working in detention centres amounts to complicity in torture, says David Berger, a district medical officer in emergency medicine at Broome Hospital in Australia. However, Steven Miles, chair in bioethics at the University of Minnesota thinks that they play an important role in telling the world about conditions in...

The same piece of evidence may reach you via a journalist, or via your doctor - but the way in which that evidence is communicated is changed by your relationship between that person. Julia Beluz from Vox and Victor Montori from the Mayo Clinic join us to discuss if it's possible to reconcile those competing points of view.

Andrew Elder, a professor at the University of Edinburgh talks about likelihood ratios in diagnostic testing, and how they’re helpful in thinking about how context changes the predictive value of a test. This is part of a wider discussion on the evidence behind clinical examination of the cardiovascular system...

Oversimplification and lack of evidence stigmatise people with mental illness and impede prevention efforts, says Simon Wessley, professor of psychiatry at King's College London, in an editorial published on thebmj.com. Read the full editorial: http://www.bmj.com/content/354/bmj.i4869

Middle East respiratory syndrome (MERS) is an acute viral respiratory tract infection caused by the novel betacoronavirus. Cases have been limited to the Arabian Peninsula and its surrounding countries, and to travellers from the Middle East or their contacts. The clinical spectrum of infection varies from no symptoms or mild respiratory...

The UK government published its report Childhood Obesity: a Plan for Action, in August 2016. A new analysis article takes them to task for the inadequacy of that response to a growing problem. Neena Modi is a professor of neonatal medicine, at Imperial College London, and president of the Royal College of Paediatrics and Child Health, and joins...

It’s been 10 years since electronic cigarettes hit the shelves in a big way - and since there controversy has reigned about their health effects - are they less unhealthy than smoking traditional tobacco cigarettes, and will they increase nicotine dependence? Its to that last point that new research, published on BMJ.com is looking into -...

Average body temperature is 37°C, right? That was the conclusion of Carl Wunderlich in his magnum opus, The Course of Temperature in Diseases - Wunderlich published that in 1868, following his extensive collection of body temperature readings - and 37°C stuck. But, it’s not as simple as that Philip Mackowiak, emeritus professor of medicine, and...

Acute respiratory distress syndrome was first described in 1967 and has become a defining condition in critical care. Around 40% of patients with ARDS will die, and survivors experience long term sequelae. No drug treatments exist for ARDS, however good supportive management reduces harm and improves outcome. In this podcast, John Laffey,...

Worldwide, the rate of type II diabetes is estimated to be around 1 in 11 people - about 9%. For the Pima people of Arizona, 38% of the adult population have the condition - but across the border in Mexico, the rate drops down to 7%. The difference between the groups is their life experience - one side displaced, the other on their traditional...

Mendelian randomisation - it’s a technique that uses the chance distribution of genes in a population, combined with big data sets, to investigate causative relationships. But there are a lot of questions we have in The BMJ about how the technique works - the association between genes and apparently non-biologically mediated behaviours, how much...

Healthy self confidence has an important role in surgery, but what came first - the surgeon or the ego? In this conversation, Christopher Myers, Yemeng Lu-Myers, and Amir Ghaferi join us to talk about the (very few) surgeons who behave badly in theatre, and why that behaviour has persisted, and can be detrimental. Read their full...

A new collection of articles published by The BMJ includes twelve country case studies, each an evaluation of multisectoral collaboration in action at scale on women’s, children’s, and adolescent’s health. Collectively these twelve studies inform an overarching synthesis and accompanying commentaries, drawing together lessons learned in...

Here's a taster for our new student podcast - Sharp Scratch. We're talking about the hidden curriculum, things you need to know to function as a doctor, but are rarely formally taught. This is a taster - if you enjoy, subscribe! https://podcasts.apple.com/gb/podcast/student-bmj-podcast/id331561304 Sharp Scratch episode 1: Surviving the night...

As Syria enters its ninth year of conflict, doctors are struggling to provide health care to a badly damaged country. While dealing with medicine shortages, mass casualties and everything that comes with working in a warzone, healthcare facilities and their staff are also facing an unprecedented number of targeted and often repeated attacks....

For the next few months Talk Evidence is going to focus on the new corona virus pandemic. There is an enormous amount of uncertainty about the disease, what the symptoms are, fatality rate, treatment options, things we shouldn't be doing. We're going to try to get away from the headlines and talk about what we need to know - to hopefully give...

Eve Van Cauter
Mar 1, 1992; 41:368-377
Original Article

Ralph A. DeFronzo
Apr 1, 2009; 58:773-795
Banting Lecture

G Xu
Dec 1, 1999; 48:2270-2276
Articles

Paul E Lacy
Jan 1, 1967; 16:35-39
Original Contribution

Norikazu Maeda
Sep 1, 2001; 50:2094-2099
Pathophysiology

ME Griffin
Jun 1, 1999; 48:1270-1274
Articles

Ralph A DeFronzo
Jun 1, 1988; 37:667-687
Lilly Lecture 1987

This study aims to model genetic, immunologic, metabolomics, and proteomic biomarkers for development of islet autoimmunity (IA) and progression to type 1 diabetes in a prospective high-risk cohort. We studied 67 children: 42 who developed IA (20 of 42 progressed to diabetes) and 25 control subjects matched for sex and age. Biomarkers were assessed at four time points: earliest available sample, just prior to IA, just after IA, and just prior to diabetes onset. Predictors of IA and progression to diabetes were identified across disparate sources using an integrative machine learning algorithm and optimization-based feature selection. Our integrative approach was predictive of IA (area under the receiver operating characteristic curve [AUC] 0.91) and progression to diabetes (AUC 0.92) based on standard cross-validation (CV). Among the strongest predictors of IA were change in serum ascorbate, 3-methyl-oxobutyrate, and the PTPN22 (rs2476601) polymorphism. Serum glucose, ADP fibrinogen, and mannose were among the strongest predictors of progression to diabetes. This proof-of-principle analysis is the first study to integrate large, diverse biomarker data sets into a limited number of features, highlighting differences in pathways leading to IA from those predicting progression to diabetes. Integrated models, if validated in independent populations, could provide novel clues concerning the pathways leading to IA and type 1 diabetes.

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.

Director of the Pan American Health Organization (PAHO), Dr Carissa F. Etienne, today called for accelerated and expanded testing for COVID-19 in countries of the Americas. “We need a clearer view of where the virus is circulating and how...

Jon Miller is having trouble believing that baseball legend Frank Robinson is gone. Robinson, 83, passed away Thursday morning.

Reds left-hander Alex Wood won his arbitration case over the club on Wednesday. Wood will earn $9.65 million on his one-year contract this season. Cincinnati had offered $8.7 million.

Even before the Reds underscored their determination to improve by making major offseason acquisitions for the club, first baseman Joey Votto was already working to improve his hitting and his overall game.

THE EDITOR, Madam: I arrived at the Constant Spring tax office at 6:05 a.m. on Monday, May 4 to renew my vehicle registration. At that hour, there were already 30 persons ahead of me. Persons related horror stories of spending up to five hours in...

THE EDITOR, Madam: THE JAMAICA Council for Persons with Disabilities (JCPD) – an agency of the Ministry of Labour...

Redlining a Holocaust is a rigorously researched oeuvre that establishes Dòwòti Désir as one of the most important figures in contemporary African thought. Redlining is an imaginative and monumental undertaking, a literary, visual, and oratorical...

Schwann cell–derived exosomes communicate with dorsal root ganglia (DRG) neurons. The current study investigated the therapeutic effect of exosomes derived from healthy Schwann cells (SC-Exos) on diabetic peripheral neuropathy (DPN). We found that intravenous administration of SC-Exos to type 2 diabetic db/db mice with peripheral neuropathy remarkably ameliorated DPN by improving sciatic nerve conduction velocity and increasing thermal and mechanical sensitivity. These functional improvements were associated with the augmentation of epidermal nerve fibers and remyelination of sciatic nerves. Quantitative RT-PCR and Western blot analysis of sciatic nerve tissues showed that SC-Exo treatment reversed diabetes-reduced mature form of miRNA (miR)-21, -27a, and -146a and diabetes-increased semaphorin 6A (SEMA6A); Ras homolog gene family, member A (RhoA); phosphatase and tensin homolog (PTEN); and nuclear factor-B (NF-B). In vitro data showed that SC-Exos promoted neurite outgrowth of diabetic DRG neurons and migration of Schwann cells challenged by high glucose. Collectively, these novel data provide evidence that SC-Exos have a therapeutic effect on DPN in mice and suggest that SC-Exo modulation of miRs contributes to this therapy.

Diabetic retinopathy (DR) is a widespread vision-threatening disease, and neuroretinal abnormality should be considered as an important problem. Brain-derived neurotrophic factor (BDNF) has recently been considered as a possible treatment to prevent DR-induced neuroretinal damage, but how BDNF is upregulated in DR remains unclear. We found an increase in hydrogen peroxide (H₂O₂) in the vitreous of patients with DR. We confirmed that human retinal endothelial cells secreted H₂O₂ by high glucose, and H₂O₂ reduced cell viability of MIO-M1, Müller glia cell line, PC12D, and the neuronal cell line and lowered BDNF expression in MIO-M1, whereas BDNF administration recovered PC12D cell viability. Streptozocin-induced diabetic rats showed reduced BDNF, which is mainly expressed in the Müller glia cell. Oral intake of eicosapentaenoic acid ethyl ester (EPA-E) ameliorated BDNF reduction and oscillatory potentials (OPs) in electroretinography (ERG) in DR. Mass spectrometry revealed an increase in several EPA metabolites in the eyes of EPA-E–fed rats. In particular, an EPA metabolite, 18-hydroxyeicosapentaenoic acid (18-HEPE), induced BDNF upregulation in Müller glia cells and recovery of OPs in ERG. Our results indicated diabetes-induced oxidative stress attenuates neuroretinal function, but oral EPA-E intake prevents retinal neurodegeneration via BDNF in Müller glia cells by increasing 18-HEPE in the early stages of DR.

Current therapeutic strategies for diabetic foot ulcer (DFU) have focused on developing topical healing agents, but few agents have controlled prospective data to support their effectiveness in promoting wound healing. We tested a stem cell mobilizing therapy for DFU using a combination of AMD3100 and low-dose FK506 (tacrolimus) (AF) in streptozocin-induced type 1 diabetic (T1DM) rats and type 2 diabetic Goto-Kakizaki (GK) rats that had developed peripheral artery disease and neuropathy. Here, we show that the time for healing back wounds in T1DM rats was reduced from 27 to 19 days, and the foot wound healing time was reduced from 25 to 20 days by treatment with AF (subcutaneously, every other day). Similarly, in GK rats treated with AF, the healing time on back wounds was reduced from 26 to 21 days. Further, this shortened healing time was accompanied by reduced scar and by regeneration of hair follicles. We found that AF therapy mobilized and recruited bone marrow–derived CD133⁺ and CD34⁺ endothelial progenitor cells and Ym1/2⁺ M2 macrophages into the wound sites, associated with enhanced capillary and hair follicle neogenesis. Moreover, AF therapy improved microcirculation in diabetic and neuropathic feet in GK rats. This study provides a novel systemic therapy for healing DFU.

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.

2 July 2014 , Volume 90, Number 4

Invitation Only Research Event

Event participants

Paula Hodges QC, Partner; Head, Global Arbitration Practice, Herbert Smith Freehills
Stéphane Brabant, Partner; Chairman, Africa Practice Group, Herbert Smith Freehills

Invitation Only Research Event

Invitation Only Research Event

Event participants

Dr Ashwini Swain, Fellow, CUTS Institute for Regulation and Competition
Glada Lahn, Senior Research Fellow, Energy, Environment and Resources, Chatham House
Dr Gareth Price, Senior Research Fellow, Asia Programme, Chatham House

We aimed to assess the value of ¹¹C-choline PET in patients with primary hyperparathyroidism and negative or discordant results on ^99mTc-sestamibi imaging and neck ultrasound. Methods: Eighty-seven such patients were assessed and subsequently underwent parathyroidectomy. PET/CT image data were analyzed semiquantitatively using SUV_max and SUV ratios (target to contralateral thyroid gland and carotid artery). A positive PET/CT result was defined as focal uptake significantly higher than regular thyroid tissue. Ectopic foci were also considered positive. Inconclusive PET/CT cases were defined as a lesion with uptake equal to normal thyroid tissue. If no prominent or ectopic uptake was detectable, the PET/CT result was considered negative. Results: When dichotomizing the ¹¹C-choline PET/CT imaging results by defining lesions with both positive and inconclusive uptake as positive, we found 84 of 92 lesions (91.3%) to have true-positive uptake whereas 8 lesions (8.7%) had false-positive uptake. One lesion showed false-negative uptake; the sensitivity was 98.8%. The corresponding positive predictive value for lesions was 91.3%. The mean SUV_max was 6.15 ± 4.92 in 72 lesions with positive uptake (70 patients) and 2.96 ± 2.32 in 20 lesions with inconclusive uptake (18 patients). Conclusion: These results in a large group of patients indicate that ¹¹C-choline PET/CT is a promising tool for parathyroid adenoma localization when ultrasound and ^99mTc-sestamibi imaging yield negative or discordant results.

Primary hyperparathyroidism (PHPT) is a common endocrine disorder, definitive treatment usually requiring surgical removal of the offending parathyroid glands. To perform focused surgical approaches, it is necessary to localize all hyperfunctioning glands. The aim of the study was to compare the efficiency of established conventional scintigraphic imaging modalities with emerging ¹⁸F-fluorocholine PET/CT imaging in preoperative localization of hyperfunctioning parathyroid glands in a larger series of PHPT patients. Methods: In total, 103 patients with PHPT were imaged preoperatively with ¹⁸F-fluorocholine PET/CT and conventional scintigraphic imaging methods, consisting of ^99mTc-sestamibi SPECT/CT, ^99mTc-sestamibi/pertechnetate subtraction imaging, and ^99mTc-sestamibi dual-phase imaging. The results of histologic analysis, as well as intact parathyroid hormone and serum calcium values obtained 1 d after surgery and on follow-up, served as the standard of truth for evaluation of imaging results. Results: Diagnostic performance of ¹⁸F-fluorocholine PET/CT surpassed conventional scintigraphic methods (separately or combined), with calculated sensitivity of 92% for PET/CT and 39%–56% for conventional imaging (65% for conventional methods combined) in the entire patient group. Subgroup analysis, differentiating single and multiple hyperfunctioning parathyroid glands, showed PET/CT to be most valuable in the group with multiple hyperfunctioning glands, with sensitivity of 88%, whereas conventional imaging was significantly inferior, with sensitivity of 22%–34% (44% combined). Conclusion: ¹⁸F-fluorocholine PET/CT is a diagnostic modality superior to conventional imaging methods in patients with PHPT, allowing for accurate preoperative localization.

M2 macrophages play an important role in tissue repair and regeneration. They have also been found to modulate β-cell replication in mouse models of pancreatic injury and disease. We previously reported that β-cell replication is strongly increased in a subgroup of human organ donors characterized by prolonged duration of stay in an intensive care unit (ICU) and increased number of leukocytes in the pancreatic tissue. In the present study we investigated the relationship between duration of stay in the ICU, M2 macrophages, vascularization, and pancreatic cell replication. Pancreatic organs from 50 donors without diabetes with different durations of stay in the ICU were analyzed by immunostaining and digital image analysis. The number of CD68⁺CD206⁺ M2 macrophages increased three- to sixfold from ≥6 days’ duration of stay in the ICU onwards. This was accompanied by a threefold increased vascular density and a four- to ninefold increase in pancreatic cells positive for the replication marker Ki67. A strong correlation was observed between the number of M2 macrophages and β-cell replication. These results show that a prolonged duration of stay in the ICU is associated with an increased M2 macrophage number, increased vascular density, and an overall increase in replication of all pancreatic cell types. Our data show evidence of marked levels of tissue repair in the human donor pancreas.

Caribbean Coffee Traders Limited, CCTL, is moving ahead with plans for a US$30-million bond placement, the proceeds from which it will likely use to expand the Starbucks chain it operates in three regional markets. The initial franchise agreement...