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,...

Dyspareunia is a common but poorly understood problem affecting around 7.5% of sexually active women. It is an important and neglected area of female health, associated with substantial morbidity and distress. Women may be seen by several clinicians before a diagnosis is reached, There are also specialist psychosexual clinics, where men and women...

This week saw the latest Preventing Overdiagnosis conference - this time in Copenhagen. The conference is a is a forum where researchers and practitioners can present examples of overdiagnosis - and we heard about the various ways which disease definitions are being subtly widened, and diagnostic thresholds lowered. In this podcast we talk to...

The concept of overdiagnosis is pretty hard to get - especially if you’ve been educated in a paradigm where medicine has the answers, and it’s only every a positive intervention in someone’s life - the journey to understanding the flip side - that sometimes medicine can harm often takes what Stacey Carter director of Research for Social Change at...

We want clinical trials to be thorough - but Vinay Prasad, assistant professor of medicine at Oregon Health Science University, argues that the problem of overdiagnosis may be as prevalent, in the way we measure disease in our research, as our practice. In this podcast he joins us to discuss the problem, and why he thinks what qualifies as...

What can we learn from the shameful story of vaginal mesh? That thousands of women have been irreversibly harmed; that implants were approved on the flimsiest of evidence; that surgeons weren’t adequately trained and patients weren’t properly informed; that the dash for mesh, fuelled by its manufacturers, stopped the development of alternatives;...

You’ll have read in a clinical trial “Most patients had an acceptable adverse-event profile.” Or that a drug “has a manageable and mostly reversible safety profile.” And that “the tolerability was good overall.” In this podcast, Bishal Gyawali (@oncology_bg) joins us to describe what events those terms were actually describing in cancer drug...

In this EBM round-up, Carl Heneghan, Helen Macdonald and Duncan Jarvies are back to give you an update Dual vs single therapy for prevention of TIA or minor stroke - how does the advice that dual work better translate in the UK? Carl explains why Japan can teach us to get active and, how GPs can use that information to "drop a decade" in...

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...

This week we saw the release of the much awaited Yellowhammer documents from the government, documents which outline some of the risks involved with Britain’s sudden departure from the EU. The documents themselves outline that there are risks to the supply of medicines - but do not set out the detail of how those risks have been mitigated, and...

The BMJ in partnership with The Harvard Global Health Institute has launched a collection of articles exploring how to achieve effective universal health coverage (UHC). The collection highlights the importance of quality in UHC, potential finance models, how best to incentivise stakeholders, and some of the barriers to true UHC. One of those...

This week, Dr Arnav Agarwal joins Ray to share the perspective and experiences of a young, recently graduated doctor working in a busy, metropolitan hospital. Despite the long shifts and demanding environment, Arnav makes time and space to reflect on work, life and mortality through his thought-provoking poetry and volunteer work.

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 Helen talks about the messy business of colon cancer screening - which modality is...

Shane Rea
Nov 1, 1997; 46:1667-1677
Perspectives in Diabetes

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

Charles M. Alexander
May 1, 2003; 52:1210-1214
Complications

National Diabetes Data Group
Dec 1, 1979; 28:1039-1057
Articles

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.

Long-term hyperglycemia in patients with diabetes leads to human serum albumin (HSA) glycation, which may impair HSA function as a transport protein and affect the therapeutic efficacy of anticoagulants in patients with diabetes. In this study, a novel mass spectrometry approach was developed to reveal the differences in the profiles of HSA glycation sites between patients with diabetes and healthy subjects. K199 was the glycation site most significantly changed in patients with diabetes, contributing to different interactions of glycated HSA and normal HSA with two types of anticoagulant drugs, heparin and warfarin. An in vitro experiment showed that the binding affinity to warfarin became stronger when HSA was glycated, while HSA binding to heparin was not significantly influenced by glycation. A pharmacokinetic study showed a decreased level of free warfarin in the plasma of diabetic rats. A preliminary retrospective clinical study also revealed that there was a statistically significant difference in the anticoagulant efficacy between patients with diabetes and patients without diabetes who had been treated with warfarin. Our work suggests that larger studies are needed to provide additional specific guidance for patients with diabetes when they are administered anticoagulant drugs or drugs for treating other chronic diseases.

It was not the landing the Jamaicans who arrived at Kingston’s Norman Manley International Airport on Wednesday evening would want again. The 43 Jamaican ship workers of the Marella Discovery 2 were among the 115 people aboard the TUI charter flight that touched down amid the Kingston breeze and evening sunset.

The wet weather last Saturday (May 2) could not dampen the spirits of award-winning gospel artiste and ordained evangelist Kevin Downswell as he ventured into the St Catherine community of Central Village, where he spent some of his formative years...

PORT OF SPAIN, Trinidad, CMC – The Trinidad-based Caribbean Public Health Agency (CARPHA) is urging people in the region to remember that despite the coronavirus (COVID-19) pandemic, they must be mindful that other public health threats still...

Unlike recent Reds Spring Trainings, much of the drama about who would comprise the rotation was already removed on the first day of camp. That's when manager David Bell revealed the starting five would likely be -- in no particular order -- Sonny Gray, Tanner Roark, Alex Wood, Luis Castillo and Anthony DeSclafani.

Upon the passing of his physical on Tuesday, the Reds signed infielder/outfielder Derek Dietrich to a Minor League contract with an invitation to big league camp for Spring Training.

THE EDITOR, Madam: COVID-19 can be made to be the blame bearer for every ill, unless careful disaggregation is done to separate what is truly attributable to both its real scope and the understandable ripple effects of the virus. The quality of...

THE EDITOR, Madam: TO THE Jamaican Government: there are no trade laws that say you have to buy poison – foreign chicken, beef, produce and other agricultural staples are poisonous. They are chock-full of hormones, antibiotics, fillers, excess...

The COVID-19 pandemic around the world has taken the world by storm, touching the lives of every human being on Earth. The global nature of the crisis has united us as human beings and tragedy and deaths in any country by COVID-19 worry us all....

As the global battle against the deadly COVID-19 disease wages on, with each country’s government, healthcare industry, and general public playing its part in defeating this new and relatively unknown enemy, two seemingly unlikely foot soldiers...

The engaging storyline and realness of the characters in Barbara Jenkins’ De Rightest Place makes it a book you breeze through in a matter of days. Set mainly in and around a bar called De Rightest Place, in the environs of a working-class...

The BMP2/4 antagonist and novel adipokine Gremlin 1 is highly expressed in human adipose cells and increased in hypertrophic obesity. As a secreted antagonist, it inhibits the effect of BMP2/4 on adipose precursor cell commitment/differentiation. We examined mRNA levels of Gremlin 1 in key target tissues for insulin and also measured tissue and serum levels in several carefully phenotyped human cohorts. Gremlin 1 expression was high in adipose tissue, higher in visceral than in subcutaneous tissue, increased in obesity, and further increased in type 2 diabetes (T2D). A similar high expression was seen in liver biopsies, but expression was considerably lower in skeletal muscles. Serum levels were increased in obesity but most prominently in T2D. Transcriptional activation in both adipose tissue and liver as well as serum levels were strongly associated with markers of insulin resistance in vivo (euglycemic clamps and HOMA of insulin resistance), and the presence of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH). We also found Gremlin 1 to antagonize insulin signaling and action in human primary adipocytes, skeletal muscle, and liver cells. Thus, Gremlin 1 is a novel secreted insulin antagonist and biomarker as well as a potential therapeutic target in obesity and its complications T2D and NAFLD/NASH.

Excessive fructose consumption is closely linked to the pathogenesis of metabolic disease. Carbohydrate response element-binding protein (ChREBP) is a transcription factor essential for fructose tolerance in mice. However, the functional significance of liver ChREBP in fructose metabolism remains unclear. Here, we show that liver ChREBP protects mice against fructose-induced hepatotoxicity by regulating liver glycogen metabolism and ATP homeostasis. Liver-specific ablation of ChREBP did not compromise fructose tolerance, but rather caused severe transaminitis and hepatomegaly with massive glycogen overload in mice fed a high-fructose diet, while no obvious inflammation, cell death, or fibrosis was detected in the liver. In addition, liver ATP contents were significantly decreased by ChREBP deficiency in the fed state, which was rendered more pronounced by fructose feeding. Mechanistically, liver contents of glucose-6-phosphate (G6P), an allosteric activator of glycogen synthase, were markedly increased in the absence of liver ChREBP, while fasting-induced glycogen breakdown was not compromised. Furthermore, hepatic overexpression of LPK, a ChREBP target gene in glycolysis, could effectively rescue glycogen overload and ATP reduction, as well as mitigate fructose-induced hepatotoxicity in ChREBP-deficient mice. Taken together, our findings establish a critical role of liver ChREBP in coping with hepatic fructose stress and protecting from hepatotoxicity by regulating LPK.

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.

Clinical studies have suggested that changes in peripheral nerve microcirculation may contribute to nerve damage in diabetic polyneuropathy (DN). High-sensitivity troponin T (hsTNT) assays have been recently shown to provide predictive values for both cardiac and peripheral microangiopathy in type 2 diabetes (T2D). This study investigated the association of sciatic nerve structural damage in 3 Tesla (3T) magnetic resonance neurography (MRN) with hsTNT and N-terminal pro-brain natriuretic peptide serum levels in patients with T2D. MRN at 3T was performed in 51 patients with T2D (23 without DN, 28 with DN) and 10 control subjects without diabetes. The sciatic nerve’s fractional anisotropy (FA), a marker of structural nerve integrity, was correlated with clinical, electrophysiological, and serological data. In patients with T2D, hsTNT showed a negative correlation with the sciatic nerve’s FA (r = –0.52, P < 0.001), with a closer correlation in DN patients (r = –0.66, P < 0.001). hsTNT further correlated positively with the neuropathy disability score (r = 0.39, P = 0.005). Negative correlations were found with sural nerve conduction velocities (NCVs) (r = –0.65, P < 0.001) and tibial NCVs (r = –0.44, P = 0.002) and amplitudes (r = –0.53, P < 0.001). This study is the first to show that hsTNT is a potential indicator for structural nerve damage in T2D. Our results indirectly support the hypothesis that microangiopathy contributes to structural nerve damage in T2D.

21 July 2014

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

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

Invitation Only Research Event

2 September 2015

This paper explores the potential of using public procurement policy to promote the uptake of sustainable food products in order to reduce imports of agricultural products associated with deforestation.

28 January 2016

Private-sector commitments and government policies, a loss of support for biofuels, and health concerns over the consumption of palm oil and beef, are factors that may help to restrict the further expansion of agricultural land into forest areas.

Invitation Only Research Event

15 November 2016

The Arizona Diamondbacks agreed to terms on a contract extension with manager Torey Lovullo on Tuesday.

The Arizona Diamondbacks agreed to terms with catcher Caleb Joseph on a one-year contract. To make room for Joseph on the roster, the D-backs placed right-hander Taijuan Walker on the 60-day injured list. The D-backs' 40-man roster remains at 40.

Agencies have criticised the lack of action to protect the health needs of sex workers during the pandemic, with the English Collective of Prostitutes (ECP) warning of a “ticking time bomb of health...

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.

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.