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,...

Winter pressures on NHS services have kicked in a little bit earlier than usual. So here to discuss that, and also the issue of how local NHS leaders can support staff in times of extreme pressure. Discussing that with Rebecca Coombes, The BMJ’s head of news and views, are Matthew Inada-Kim, a consultant in acute and general medicine at...

Trial MVA85A - monkey trials for a booster vaccine for BCG, developed by researchers at Oxford University, is the subject of an investigation published on bmj.com. Experts warn that today’s investigation is just one example of “a systematic failure” afflicting preclinical research and call for urgent action “to make animal research more fit for...

A study published by The BMJ today reports a possible association between intake of highly processed (“ultra-processed”) food in the diet and cancer. Ultra-processed foods include packaged baked goods and snacks, fizzy drinks, sugary cereals, ready meals and reconstituted meat products - often containing high levels of sugar, fat, and salt, but...

That’s Jo Shapiro is a surgeon and manager in Brigham and Women’s hospital, she’s also director of the Center for Professionalism and Peer Support, and has written an editorial for The BMJ on tackling unprofessional behaviour. In this discussion, she and I talked about what she thinks (beyond the illegal) are the most damaging behaviours seen...

Patients who are depressed and prescribed antidepressants may report weight gain, but there has been limited research into the association between the two. However new observational research published on bmj.com aims to identify that association. Rafael Gafoor, a psychiatrist and researcher at Kings College London, and one of the authors of that...

Brits have a reputation as Europe’s boozers - and for good reason, with alcohol consumption higher than much of the rest of the continent. That reputation is extended to our young people too - but is it still deserved? Joanna Inchley, senior research fellow at the University of St Andrews, explains new research on decreasing drinking -...

Helen Macdonald and Carl Heneghan are back again talking about what's happened in the world of evidence this month. They start by talking about shoulders - what does the evidence say about treating subacromial pain, and why the potential for a subgroup effect shouldn't change our views about stop surgery (for now, more research needed). (16.00)...

An “author pays” publishing model is the only fair way to make biomedical research findings accessible to all, say David Sanders, professor of gastroenterology at Sheffield University, but James Ashton and worries that it can lead to bias in the evidence base towards commercially driven results - as those are the researchers who can pay for open...

Nicole Stott is an engineer, aquanaut and one of the 220 astronauts to have lived and worked on the International Space Station. In a confined space, under huge pressure, with no way out, it's important that teams maintain healthy dynamics, and individuals can manage their stress adequately, and in this podcast Nicole explains a little about...

Fertility awareness based methods of contraception are increasingly being used for pregnancy prevention. In the US, the proportion of contraceptive users who choose such methods has grown from 1% in 2008 to approximately 3% in 2014.  Relative to other methods of pregnancy prevention, however, substantial misinformation exists around fertility...

We know that exercise is good for you - the WHO recommends at least 150 minutes of moderate intensity or 75 minutes of vigorous intensity aerobic physical activity each week. That recommendation is built on evidence that relied on self reporting that may underestimate the amount of lower intensity exercise those people were doing, and at the...

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...

Talk Evidence is back, with your monthly take on the world of EBM with Duncan Jarvies and GPs Carl Heneghan (also director for the Centre of Evidence Based Medicine at the University of Oxford) and Helen Macdonald (also The BMJ's UK research Editor). This month Carl talks about evidence that restricting your diet might improve health at a...

In many countries (including the UK and Australia) it is still common practice for hospital doctors to write letters to patients’ general practitioners (GPs) following outpatient consultations, and for patients to receive copies of these letters. However, Hugh Rayner, consultant nephrologist, and Peter Rees, former Chair of the Academy of...

Reports from Italy, and more recently from the U.S. show the strain the healthcare system is under during this pandemic. We know that staff will step up in an emergency, but this isn’t a fire or a bombing, this is going to last for months. So how can organisations be proactive in supporting staff, and how can leaders try to mitigate the...

Markus Tiedge
Nov 1, 1997; 46:1733-1742
Original Article

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

G Perseghin
Aug 1, 1999; 48:1600-1606
Articles

The Diabetes Control and Complications Trial Research Group
Aug 1, 1995; 44:968-983
Original Article

JW Baynes
Jan 1, 1999; 48:1-9
Articles

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

U.K. Prospective Diabetes Study Group
Nov 1, 1995; 44:1249-1258
Perspectives in Diabetes

John W Baynes
Apr 1, 1991; 40:405-412
Perspectives in Diabetes

Night shift work, behavioral rhythms, and the common MTNR1B risk single nucleotide polymorphism (SNP), rs10830963, associate with type 2 diabetes; however, whether they exert joint effects to exacerbate type 2 diabetes risk is unknown. Among employed participants of European ancestry in the UK Biobank (N = 189,488), we aimed to test the cross-sectional independent associations and joint interaction effects of these risk factors on odds of type 2 diabetes (n = 5,042 cases) and HbA_1c levels (n = 175,156). Current shift work, definite morning or evening preference, and MTNR1B rs10830963 risk allele associated with type 2 diabetes and HbA_1c levels. The effect of rs10830963 was not modified by shift work schedules. While marginal evidence of interaction between self-reported morningness-eveningness preference and rs10830963 on risk of type 2 diabetes was seen, this interaction did not persist when analysis was expanded to include all participants regardless of employment status and when accelerometer-derived sleep midpoint was used as an objective measure of morningness-eveningness preference. Our findings suggest that MTNR1B risk allele carriers who carry out shift work or have more extreme morningness-eveningness preference may not have enhanced risk of type 2 diabetes.

An application earlier this year by Mahoe Gaming Enterprises Limited (MGEL) has not benefited from any preferential treatment by the Betting, Gaming and Lotteries Commission (BGLC). That was the finding of ex-commissioner of the Integrity...

No sooner than the Government’s announced its intention to restart the economy, private sector groups are advocating for longer working hours to fast-track recovery during the COVID-19 pandemic. In a collaborative move, the Jamaica Manufacturers...

During some Reds pitchers fielding practice, or PFP drills, on Friday, Amir Garrett was playing first base. Alex Wood was at shortstop and Brandon Finnegan was flashing some skills all over the infield.

THE EDITOR, Madam: I am an educator at the secondary level. I teach at a school that is located in the western part of Jamaica. I am writing this letter with a high level of distress. The Ministry of Education is asking for too much at this point...

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

THE EDITOR, Madam: With most things grinding to a halt worldwide, this pandemic has proven to be as much of an economic crisis as it is a health one. Many sectors have changed their day-to-day operations, with some allowing for greater flexibility...

At the outset, author Ivy Slater shares the existential crisis that spurred her to change careers. Slater’s psychosocial experience after the passing of her father and the stagnation she experienced at her printing business proved exhaustively...

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.

Insulin-mediated microvascular recruitment (IMVR) regulates delivery of insulin and glucose to insulin-sensitive tissues. We have previously proposed that perivascular adipose tissue (PVAT) controls vascular function through outside-to-inside communication and through vessel-to-vessel, or "vasocrine," signaling. However, direct experimental evidence supporting a role of local PVAT in regulating IMVR and insulin sensitivity in vivo is lacking. Here, we studied muscles with and without PVAT in mice using combined contrast-enhanced ultrasonography and intravital microscopy to measure IMVR and gracilis artery diameter at baseline and during the hyperinsulinemic-euglycemic clamp. We show, using microsurgical removal of PVAT from the muscle microcirculation, that local PVAT depots regulate insulin-stimulated muscle perfusion and glucose uptake in vivo. We discovered direct microvascular connections between PVAT and the distal muscle microcirculation, or adipomuscular arterioles, the removal of which abolished IMVR. Local removal of intramuscular PVAT altered protein clusters in the connected muscle, including upregulation of a cluster featuring Hsp90ab1 and Hsp70 and downregulation of a cluster of mitochondrial protein components of complexes III, IV, and V. These data highlight the importance of PVAT in vascular and metabolic physiology and are likely relevant for obesity and diabetes.

Invitation Only Research Event

Invitation Only Research Event

Invitation Only Research Event

Jake Lamb's education at first base hit another checkpoint during Monday's initial full-squad workout when he went through bunt drills for the first time.

A rise in mortality is a price worth paying to restart the US economy, President Trump has said, as many states flout advice from scientists and reopen beaches, cinemas, or hair salons while new...

Inflammation contributes to ventricular remodeling after myocardial ischemia, but its role in nonischemic heart failure is poorly understood. Local tissue inflammation is difficult to assess serially during pathogenesis. Although ¹⁸F-FDG accumulates in inflammatory leukocytes and thus may identify inflammation in the myocardial microenvironment, it remains unclear whether this imaging technique can isolate diffuse leukocytes in pressure-overload heart failure. We aimed to evaluate whether inflammation with ¹⁸F-FDG can be serially imaged in the early stages of pressure-overload–induced heart failure and to compare the time course with functional impairment assessed by cardiac MRI. Methods: C57Bl6/N mice underwent transverse aortic constriction (TAC) (n = 22), sham surgery (n = 12), or coronary ligation as an inflammation-positive control (n = 5). MRI assessed ventricular geometry and contractile function at 2 and 8 d after TAC. Immunostaining identified the extent of inflammatory leukocyte infiltration early in pressure overload. ¹⁸F-FDG PET scans were acquired at 3 and 7 d after TAC, under ketamine-xylazine anesthesia to suppress cardiomyocyte glucose uptake. Results: Pressure overload evoked rapid left ventricular dilation compared with sham (end-systolic volume, day 2: 40.6 ± 10.2 μL vs. 23.8 ± 1.7 μL, P < 0.001). Contractile function was similarly impaired (ejection fraction, day 2: 40.9% ± 9.7% vs. 59.2% ± 4.4%, P < 0.001). The severity of contractile impairment was proportional to histology-defined myocardial macrophage density on day 8 (r = –0.669, P = 0.010). PET imaging identified significantly higher left ventricular ¹⁸F-FDG accumulation in TAC mice than in sham mice on day 3 (10.5 ± 4.1 percentage injected dose [%ID]/g vs. 3.8 ± 0.9 %ID/g, P < 0.001) and on day 7 (7.8 ± 3.7 %ID/g vs. 3.0 ± 0.8 %ID/g, P = 0.006), though the efficiency of cardiomyocyte suppression was variable among TAC mice. The ¹⁸F-FDG signal correlated with ejection fraction (r = –0.75, P = 0.01) and ventricular volume (r = 0.75, P < 0.01). Western immunoblotting demonstrated a 60% elevation of myocardial glucose transporter 4 expression in the left ventricle at 8 d after TAC, indicating altered glucose metabolism. Conclusion: TAC induces rapid changes in left ventricular geometry and contractile function, with a parallel modest infiltration of inflammatory macrophages. Metabolic remodeling overshadows inflammatory leukocyte signal using ¹⁸F-FDG PET imaging. More selective inflammatory tracers are requisite to identify the diffuse local inflammation in pressure overload.

In glioma patients, differentiation between tumor progression (TP) and treatment-related changes (TRCs) remains challenging. Difficulties in classifying imaging alterations may result in a delay or an unnecessary discontinuation of treatment. PET using O-(2-¹⁸F-fluoroethyl)-l-tyrosine (¹⁸F-FET) has been shown to be a useful tool for detecting TP and TRCs. Methods: We retrospectively evaluated 127 consecutive patients with World Health Organization grade II–IV glioma who underwent ¹⁸F-FET PET imaging to distinguish between TP and TRCs. ¹⁸F-FET PET findings were verified by neuropathology (40 patients) or clinicoradiologic follow-up (87 patients). Maximum tumor-to-brain ratios (TBR_max) of ¹⁸F-FET uptake and the slope of the time–activity curves (20–50 min after injection) were determined. The diagnostic accuracy of ¹⁸F-FET PET parameters was evaluated by receiver-operating-characteristic analysis and ² testing. The prognostic value of ¹⁸F-FET PET was estimated using the Kaplan–Meier method. Results: TP was diagnosed in 94 patients (74%) and TRCs in 33 (26%). For differentiating TP from TRCs, receiver-operating-characteristic analysis yielded an optimal ¹⁸F-FET TBR_max cutoff of 1.95 (sensitivity, 70%; specificity, 71%; accuracy, 70%; area under the curve, 0.75 ± 0.05). The highest accuracy was achieved by a combination of TBR_max and slope (sensitivity, 86%; specificity, 67%; accuracy, 81%). However, accuracy was poorer when tumors harbored isocitrate dehydrogenase (IDH) mutations (91% in IDH-wild-type tumors, 67% in IDH-mutant tumors, P < 0.001). ¹⁸F-FET PET results correlated with overall survival (P < 0.001). Conclusion: In our neurooncology department, the diagnostic performance of ¹⁸F-FET PET was convincing but slightly inferior to that of previous reports.

Posttreatment high-grade gliomas are usually monitored with contrast-enhanced MRI, but its diagnostic accuracy is limited as it cannot adequately distinguish between true tumor progression and treatment-related changes. According to recent Response Assessment in Neuro-Oncology recommendations, PET overcomes this limitation. However, it is currently unknown which tracer yields the best results. Therefore, a systematic review and metaanalysis were performed to compare the diagnostic accuracy of the different PET tracers in differentiating tumor progression from treatment-related changes in high-grade glioma patients. Methods: PubMed, Web of Science, and Embase were searched systematically. Study selection, data extraction, and quality assessment were performed independently by 2 authors. Metaanalysis was performed using a bivariate random-effects model when at least 5 studies were included. Results: The systematic review included 39 studies (11 tracers). ¹⁸F-FDG (12 studies, 171 lesions) showed a pooled sensitivity and specificity of 84% (95% confidence interval, 72%–92%) and 84% (95% confidence interval, 69%–93%), respectively. O-(2-¹⁸F-fluoroethyl)-l-tyrosine (¹⁸F-FET) (7 studies, 172 lesions) demonstrated a sensitivity of 90% (95% confidence interval, 81%–95%) and specificity of 85% (95% confidence interval, 71%–93%). For S-¹¹C-methyl)-l-methionine (¹¹C-MET) (8 studies, 151 lesions), sensitivity was 93% (95% confidence interval, 80%–98%) and specificity was 82% (95% confidence interval, 68%–91%). The numbers of included studies for the other tracers were too low to combine, but sensitivity and specificity ranged between 93%–100% and 0%–100%, respectively, for ¹⁸F-FLT; 85%–100% and 72%–100%, respectively, for 3,4-dihydroxy-6-¹⁸F-fluoro-l-phenylalanine (¹⁸F-FDOPA); and 100% and 70%–88%, respectively, for ¹¹C-choline. Conclusion: ¹⁸F-FET and ¹¹C-MET, both amino-acid tracers, showed a comparably higher sensitivity than ¹⁸F-FDG in the differentiation between tumor progression and treatment-related changes in high-grade glioma patients. The evidence for other tracers is limited; thus, ¹⁸F-FET and ¹¹C-MET are preferred when available. Our results support the incorporation of amino-acid PET tracers for the treatment evaluation of high-grade gliomas.

The University of Iowa recently completed a 4-y expedition into the uncharted waters of the Food and Drug Administration (FDA) new-drug application (NDA) process that ultimately resulted in approval of ⁶⁸Ga-DOTATOC in August 2019. The journey was enlightening, revealing a highly structured, arcane, but rigorous regulatory approval process. The FDA proved to be an efficient, reasonable, and communicative regulatory body that achieved balance between support of the initiative and its mission-bound, process-bound duty to ensure that the application met the expected safety and efficacy standards of the agency. With several clinically valuable PET radiopharmaceuticals without intellectual property residing in regulatory limbo, without industry champions to bring them to marketing approval, there may be justification for a more concerted effort from the molecular imaging community into generating better understanding, support, and perhaps even infrastructure for the academic NDA. As a first step, this article briefly describes the start-to-finish story for ⁶⁸Ga-DOTATOC, including a description of the clinical trials, a broad overview of the structured content of the NDA document, and the distilled experiences associated with the ⁶⁸Ga-DOTATOC NDA process. It is anticipated that with sustained free sharing of information relating to the FDA drug registration process, it will prove less daunting and more efficient in future academically sponsored NDA filings for PET imaging agents.

The signal peptide of preproinsulin is a major source for HLA class I autoantigen epitopes implicated in CD8 T cell (CTL)–mediated β-cell destruction in type 1 diabetes (T1D). Among them, the 10-mer epitope located at the C-terminal end of the signal peptide was found to be the most prevalent in patients with recent-onset T1D. While the combined action of signal peptide peptidase and endoplasmic reticulum (ER) aminopeptidase 1 (ERAP1) is required for processing of the signal peptide, the mechanisms controlling signal peptide trimming and the contribution of the T1D inflammatory milieu on these mechanisms are unknown. Here, we show in human β-cells that ER stress regulates ERAP1 gene expression at posttranscriptional level via the IRE1α/miR-17-5p axis and demonstrate that inhibition of the IRE1α activity impairs processing of preproinsulin signal peptide antigen and its recognition by specific autoreactive CTLs during inflammation. These results underscore the impact of ER stress in the increased visibility of β-cells to the immune system and position the IRE1α/miR-17 pathway as a central component in β-cell destruction processes and as a potential target for the treatment of autoimmune T1D.

Branson Centre goes digital The Caribbean branch of Branson Centre of Entrepreneurship has shifted fully to online delivery of its services. This includes online training and support in three business development areas: finance, strategic...

FOUR MORE applicants are vying to provide mobile payment services in various formats, including one applicant seeking to use phone credit as a cash equivalent, but successful applicants will fall under a new framework the regulator calls its “...