Non-alcoholic fatty liver disease (NAFLD) is closely linked with obesity and the prevalence of NAFLD is about 17% to 33% in the Western world. There is a strong association of NAFLD with insulin ...resistance and, hence, insulin sensitisers have been tried. This systematic review examined the clinical effectiveness of insulin sensitisers in patients with NAFLD, to help decide whether or not a trial or trials of the insulin sensitisers was necessary and also to explore whether or not non-invasive alternatives to liver biopsy were available that could be used in a large trial of the insulin sensitisers.
To review the use of insulin sensitisers in the treatment of NAFLD.
A systematic review of the clinical effectiveness of metformin, rosiglitazone and pioglitazone was carried out, including reviews and randomised controlled trials (RCTs). Databases searched were MEDLINE, 1950 to June 2010; EMBASE, 1980 to June 2010; Science Citation Index Expanded, June 2010; Conference Proceedings Citation Index - Science June 2010; The Cochrane Library 2005-10. Abstracts were screened independently by two researchers. A narrative review of diagnostic methods was conducted.
Clinical effectiveness. We identified 15 RCTs (one available as abstract). Four papers explored efficacy of pioglitazone, one rosiglitazone, eight metformin; two compared metformin and rosiglitazone, although one used both metformin and rosiglitazone. The duration of most trials was between 6 and 12 months. Many trials had a small number of participants and the quality of the studies was mixed. Pioglitazone improved all parameters of liver histology. Metformin showed mixed results, with ultrasound changes in two studies showing some improvement in steatosis, whereas there were no changes in the other two. Metformin, however, showed no improvement in non-alcoholic steatohepatitis (NASH) stages. Metformin showed greater reduction in glycosylated haemoglobin (-0.23% to -1.2% vs -0.2% to -0.7%) and fasting plasma glucose (+0.05 to -3.19 mmol/l vs -0.17 to -1.11 mmol/l) compared with pioglitazone. Metformin led to weight reduction (-4.3 to -6.7 kg), whereas participants on pioglitazone gained weight (+2.5 to +4.7 kg). Alanine aminotransferase levels were reduced with both metformin and pioglitazone; however, the reduction in levels with pioglitazone was not different to that caused by vitamin E. Most studies suggested that metformin led to a significant reduction in insulin resistance. Diagnosis. Non-invasive methods of diagnosing NAFLD without liver biopsy, using combinations of clinical history, laboratory tests and ultrasound, have been explored, but so far liver biopsy is the only proven method of distinguishing simple steatosis from NASH. Transient elastography appears useful, but less so in obese individuals. Magnetic resonance spectroscopy shows promise, but is expensive and not readily available.
Mixed quality of trials, with lack of detail as to how some trials were conducted. Many trials had small numbers of patients.
The main need for drug trials is at the NASH stage. However, at present, any trial in the more advanced forms of NAFLD would have to use liver biopsy. The highest priority for research may, therefore, be in the diagnosis of NAFLD, and the differentiation between steatosis and NASH. The newer agents, the glucagon-like peptide-1 analogues such as liraglutide, may be more worthy of a trial.
The National Institute for Health Research Health Technology Assessment programme.
Aims/hypothesis Physical inactivity is implicated in unfavourable patterns of obesity and cardiometabolic risk in childhood. However, few studies have quantified these associations using objective ...physical activity measurements in children from different ethnic groups. We examined these associations in UK children of South Asian, black African-Caribbean and white European origin. Methods This was a cross-sectional study of 2,049 primary school children in three UK cities, who had standardised anthropometric measurements, provided fasting blood samples and wore activity monitors for up to 7 days. Data were analysed using multilevel linear regression and allowing for measurement error. Results Overall physical activity levels showed strong inverse graded associations with adiposity markers (particularly sum of skinfold thicknesses), fasting insulin, HOMA insulin resistance, triacylglycerol and C-reactive protein; for an increase of 100 counts of physical activity per min of registered time, levels of these factors were 12.2% (95% CI 10.2-14.1%), 10.2% (95% CI 7.5-12.8%), 10.2% (95% CI 7.5-12.8%), 5.8% (95% CI 4.0-7.5%) and 19.2% (95% CI 13.9-24.2%) lower, respectively. Similar increments in physical activity levels were associated with lower diastolic blood pressure (1.0 mmHg, 95% CI 0.6-1.5 mmHg) and LDL-cholesterol (0.04 mmol/l, 95% CI 0.01-0.07 mmol/l), and higher HDL-cholesterol (0.02 mmol/l, 95% CI 0.01-0.04 mmol/l). Moreover, associations were broadly similar in strength in all ethnic groups. All associations between physical activity and cardiometabolic risk factors were reduced (albeit variably) after adjustment for adiposity. Conclusions/interpretation Objectively measured physical activity correlates at least as well with obesity and cardiometabolic risk factors in South Asian and African-Caribbean children as in white European children, suggesting that efforts to increase activity levels in such groups would have equally beneficial effects.
GDF15, a hormone acting on the brainstem, has been implicated in the nausea and vomiting of pregnancy, including its most severe form, hyperemesis gravidarum (HG), but a full mechanistic ...understanding is lacking
. Here we report that fetal production of GDF15 and maternal sensitivity to it both contribute substantially to the risk of HG. We confirmed that higher GDF15 levels in maternal blood are associated with vomiting in pregnancy and HG. Using mass spectrometry to detect a naturally labelled GDF15 variant, we demonstrate that the vast majority of GDF15 in the maternal plasma is derived from the feto-placental unit. By studying carriers of rare and common genetic variants, we found that low levels of GDF15 in the non-pregnant state increase the risk of developing HG. Conversely, women with β-thalassaemia, a condition in which GDF15 levels are chronically high
, report very low levels of nausea and vomiting of pregnancy. In mice, the acute food intake response to a bolus of GDF15 is influenced bi-directionally by prior levels of circulating GDF15 in a manner suggesting that this system is susceptible to desensitization. Our findings support a putative causal role for fetally derived GDF15 in the nausea and vomiting of human pregnancy, with maternal sensitivity, at least partly determined by prepregnancy exposure to the hormone, being a major influence on its severity. They also suggest mechanism-based approaches to the treatment and prevention of HG.
Aims/hypothesis
The aim of this study was to examine the prevalence of and risk factors for diabetic retinopathy in people with newly diagnosed type 2 diabetes mellitus, using Scottish national data.
...Methods
We identified individuals diagnosed with type 2 diabetes mellitus in Scotland between January 2005 and May 2008 using data from the national diabetes database. We calculated the prevalence of retinopathy and ORs for risk factors associated with retinopathy at first screening.
Results
Of the 51,526 people with newly diagnosed type 2 diabetes mellitus identified, 91.4% had been screened by 31 December 2010. The median time to first screening was 315 days (interquartile range IQR 111–607 days), but by 2008 the median was 83 days (IQR 51–135 days). The prevalence at first screening of any retinopathy was 19.3%, and for referable retinopathy it was 1.9%. For individuals screened after a year the prevalence of any retinopathy was 20.5% and referable retinopathy was 2.3%. Any retinopathy at screening was associated with male sex (OR 1.19, 95% CI 1.14, 1.25), HbA
1c
(OR 1.07, 95% CI 1.06, 1.08 per 1% 11 mmol/mol increase), systolic BP (OR 1.06, 95% CI 1.05, 1.08 per 10 mmHg increase), time to screening (OR for screening >1 year post diagnosis = 1.12, 95% CI 1.07, 1.17) and obesity (OR 0.87, 95% CI 0.82, 0.93) in multivariate analysis.
Conclusions/interpretation
The prevalence of retinopathy at first screening is lower than in previous UK studies, consistent with earlier diagnosis of diabetes. Most newly diagnosed type 2 diabetic patients in Scotland are screened within an acceptable interval and the prevalence of referable disease is low, even in those with delayed screening.
Aims/hypothesis
The aim of our study was to identify subgroups of patients attending the Scottish Diabetic Retinopathy Screening (DRS) programme who might safely move from annual to two yearly ...retinopathy screening.
Methods
This was a retrospective cohort study of screening data from the DRS programme collected between 2005 and 2011 for people aged ≥12 years with type 1 or type 2 diabetes in Scotland. We used hidden Markov models to calculate the probabilities of transitions to referable diabetic retinopathy (referable background or proliferative retinopathy) or referable maculopathy.
Results
The study included 155,114 individuals with no referable diabetic retinopathy or maculopathy at their first DRS examination and with one or more further DRS examinations. There were 11,275 incident cases of referable diabetic eye disease (9,204 referable maculopathy, 2,071 referable background or proliferative retinopathy). The observed transitions to referable background or proliferative retinopathy were lower for people with no visible retinopathy vs mild background retinopathy at their prior examination (respectively, 1.2% vs 8.1% for type 1 diabetes and 0.6% vs 5.1% for type 2 diabetes). The lowest probability for transitioning to referable background or proliferative retinopathy was among people with two consecutive screens showing no visible retinopathy, where the probability was <0.3% for type 1 and <0.2% for type 2 diabetes at 2 years.
Conclusions/interpretation
Transition rates to referable diabetic eye disease were lowest among people with type 2 diabetes and two consecutive screens showing no visible retinopathy. If such people had been offered two yearly screening the DRS service would have needed to screen 40% fewer people in 2009.
Aims/hypothesis The aim of the study was to examine the association of existing diabetes (i.e. already diagnosed prior to pregnancy), gestational diabetes and glycosuria (both diagnosed and ...ascertained during pregnancy) with birthweight and future offspring BMI, waist circumference and fat mass (assessed by dual x-ray emission absorptiometry). Methods A prospective pregnancy/birth cohort study was performed using data from the Avon Longitudinal Study of Parents and Children. Results Among 10,591 mother-offspring pairs included in analyses with birth size, women with existing diabetes (n = 40), those diagnosed with gestational diabetes (n = 53) and those with at least two episodes of ++ glycosuria (n = 372) had greater mean birthweight and odds for macrosomia (birthweight > 4,000 g) than women with none of these. Adjusted odds ratios for macrosomia were 3.56 (95% CI 1.53-8.28), 5.50 (95% CI 1.18-10.30) and 1.58 (95% CI 1.18-2.12) for existing diabetes, gestational diabetes and glycosuria, respectively. Among 6,842 mother-offspring pairs with anthropometric measurements at age 9-11 years, maternal gestational diabetes and glycosuria (but not existing diabetes) were associated with increased offspring odds of general or central overweight/obesity. For gestational diabetes, these associations attenuated towards the null with adjustment for maternal prepregnancy BMI, but independent associations remained for glycosuria. The adjusted odds ratio for general overweight/obesity when comparing women with at least two episodes of ++ glycosuria with those with no evidence of diabetes or glycosuria was 1.35 (95% CI 1.00-1.82) and that for central obesity (top 10% waist circumference vs all others) was 1.31 (95% CI 1.00-1.72). Conclusions/interpretation These results provide some evidence for a long-term effect of maternal glycaemia in pregnancy on offspring obesity risk.
Abstract
Background
Coronavirus disease-19 (COVID-19) infection causes persistent health problems such as breathlessness, chest pain and fatigue, and therapies for the prevention and early treatment ...of post-COVID-19 syndromes are needed. Accordingly, we are investigating the effect of a resistance exercise intervention on exercise capacity and health status following COVID-19 infection.
Methods
A two-arm randomised, controlled clinical trial including 220 adults with a diagnosis of COVID-19 in the preceding 6 months. Participants will be classified according to clinical presentation: Group A, not hospitalised due to COVID but persisting symptoms for at least 4 weeks leading to medical review; Group B, discharged after an admission for COVID and with persistent symptoms for at least 4 weeks; or Group C, convalescing in hospital after an admission for COVID.
Participants will be randomised to usual care or usual care plus a personalised and pragmatic resistance exercise intervention for 12 weeks. The primary outcome is the incremental shuttle walks test (ISWT) 3 months after randomisation with secondary outcomes including spirometry, grip strength, short performance physical battery (SPPB), frailty status, contacts with healthcare professionals, hospitalisation and questionnaires assessing health-related quality of life, physical activity, fatigue and dyspnoea.
Discussion
Ethical approval has been granted by the National Health Service (NHS) West of Scotland Research Ethics Committee (REC) (reference: GN20CA537) and recruitment is ongoing. Trial findings will be disseminated through patient and public forums, scientific conferences and journals.
Trial registration
ClinicialTrials.gov
NCT04900961
. Prospectively registered on 25 May 2021
The genetic modifications through breeding of crop plants have long been used to improve the yield and quality. However, precise genome editing (GE) could be a very useful supplementary tool for ...improvement of crop plants by targeted genome modifications. Various GE techniques including ZFNs (zinc finger nucleases), TALENs (transcription activator-like effector nucleases), and most recently clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 (CRISPR-associated protein 9)-based approaches have been successfully employed for various crop plants including fruit trees. CRISPR/Cas9-based approaches hold great potential in GE due to their simplicity, competency, and versatility over other GE techniques. However, to the best of our knowledge no such genetic improvement has ever been developed in date palm-an important fruit crop in Oasis agriculture. The applications of CRISPR/Cas9 can be a challenging task in date palm GE due to its large and complex genome, high rate of heterozygosity and outcrossing,
regeneration and screening of mutants, high frequency of single-nucleotide polymorphism in the genome and ultimately genetic instability. In this review, we addressed the potential application of CRISPR/Cas9-based approaches in date palm GE to improve the sustainable date palm production. The availability of the date palm whole genome sequence has made it feasible to use CRISPR/Cas9 GE approach for genetic improvement in this species. Moreover, the future prospects of GE application in date palm are also addressed in this review.
Aims
To describe the association between socio‐economic status and mortality in a nation‐wide cohort of people with type 1 diabetes in Scotland and to compare patterns over time and with the general ...population.
Methods
A retrospective cohort study was performed using data for people with type 1 diabetes from a population‐based register linked to mortality records. Socio‐economic status was derived from quintiles of an area‐based measure: the Scottish Index of Multiple Deprivation. Sex‐specific directly age‐standardized mortality rates for each Scottish Index of Multiple Deprivation quintile and rate ratios comparing the most vs least deprived quintile were calculated for two time periods: 2006–2010 and 2011–2015. Data for the population without type 1 diabetes between 2011 and 2015 were available for comparison.
Results
Data for 3802 deaths among 33 547 people with type 1 diabetes were available. The age‐standardized mortality rate per 1000 person‐years decreased over time (from 2006–2010 to 2011–2015) for men and women with type 1 diabetes: 24.8 to 20.2 and 22.5 to 17.6, respectively. Mortality in populations with and without type 1 diabetes was generally higher for men than women and was inversely associated with socio‐economic status. Rate ratios for the most vs least deprived groups increased over time among people with type 1 diabetes (men: 2.49 to 2.81; women: 1.92 to 2.86) and were higher than among populations without type 1 diabetes in 2011–2015 (men: 2.06; women: 1.66).
Conclusions
Socio‐economic deprivation was associated with a steeper mortality gradient in people with type 1 diabetes than in the population without type 1 diabetes in Scotland. Age‐standardized mortality has decreased over time but socio‐economic inequalities may be increasing.
What's new?
The socio‐economic gradient in mortality within the general population and in type 2 diabetes is established. Scandinavian population‐based cohort studies of people with type 1 diabetes have reported an inverse association between socio‐economic status and mortality but there are no contemporary data for the UK.
This study found that socio‐economic deprivation was associated with higher mortality in people with type 1 diabetes in Scotland, that the effect of deprivation was larger than in the general population and that inequalities appear to be widening over time.
Effective interventions to reduce socio‐economic inequalities in outcomes of type 1 diabetes are required.
Summary
What is already known about this subject
In adults, associations between body mass index (BMI), waist‐to‐height ratio (WHtR) and cardiometabolic outcomes are similar.
In children and ...adolescents, results from cross‐sectional studies examining the associations between BMI z scores, WHtR and cardiometabolic outcomes are conflicting and there is a paucity of prospective data.
What this study adds
This is the first study to demonstrate the prospective association between WHtR in childhood and cardiometabolic outcomes in adolescent boys.
WHtR is a simple calculation that can be used to identify children and adolescents for cardiometabolic risk without the need for reference growth charts.
The WHtR cut‐point of ≥0.5 was highly specific in identifying cardiometabolic risk co‐occurrence but has poor sensitivity.
Objective
To examine the associations between body mass index (BMI) and waist‐to‐height ratio (WHtR) measured in childhood and adolescence and cardiometabolic risk factors in adolescence.
Methods
Secondary data analysis of the Avon Longitudinal Study of Parents and Children, a population based cohort. Data from 2858 adolescents aged 15.5 (standard deviation 0.4) years and 2710 of these participants as children aged 7–9 years were used in this analysis. Outcome measures were cardiometabolic risk factors, including triglycerides, low density lipoprotein cholesterol, high density lipoprotein cholesterol, insulin, glucose and blood pressure at 15 years of age.
Results
Both BMI and WHtR measured at ages 7–9 years and at age 15 years were associated with cardiometabolic risk factors in adolescents. A WHtR ≥0.5 at 7–9 years increased the odds by 4.6 95% confidence interval 2.6 to 8.1 for males and 1.6 0.7 to 3.9 for females of having three or more cardiometabolic risk factors in adolescence. Cross‐sectional analysis indicated that adolescents who had a WHtR ≥0.5, the odds ratio of having three or more cardiometabolic risk factors was 6.8 4.4 to 10.6 for males and 3.8 2.3 to 6.3 for females. The WHtR cut‐point was highly specific in identifying cardiometabolic risk co‐occurrence in male children and adolescents as well as female children (90 to 95%), but had poor sensitivity (17 to 53%). Similar associations were observed when BMI was used to define excess adiposity.
Conclusions
WHtR is a simple alternative to age and sex adjusted BMI for assessing cardiometabolic risk in adolescents.
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