Allopurinol is a urate-lowering therapy used to treat patients with gout. Previous studies have shown that allopurinol has positive effects on several cardiovascular parameters. The ALL-HEART study ...aimed to determine whether allopurinol therapy improves major cardiovascular outcomes in patients with ischaemic heart disease.
ALL-HEART was a multicentre, prospective, randomised, open-label, blinded-endpoint trial done in 18 regional centres in England and Scotland, with patients recruited from 424 primary care practices. Eligible patients were aged 60 years or older, with ischaemic heart disease but no history of gout. Participants were randomly assigned (1:1), using a central web-based randomisation system accessed via a web-based application or an interactive voice response system, to receive oral allopurinol up-titrated to a dose of 600 mg daily (300 mg daily in participants with moderate renal impairment at baseline) or to continue usual care. The primary outcome was the composite cardiovascular endpoint of non-fatal myocardial infarction, non-fatal stroke, or cardiovascular death. The hazard ratio (allopurinol vs usual care) in a Cox proportional hazards model was assessed for superiority in a modified intention-to-treat analysis (excluding randomly assigned patients later found to have met one of the exclusion criteria). The safety analysis population included all patients in the modified intention-to-treat usual care group and those who took at least one dose of randomised medication in the allopurinol group. This study is registered with the EU Clinical Trials Register, EudraCT 2013-003559-39, and ISRCTN, ISRCTN32017426.
Between Feb 7, 2014, and Oct 2, 2017, 5937 participants were enrolled and then randomly assigned to receive allopurinol or usual care. After exclusion of 216 patients after randomisation, 5721 participants (mean age 72·0 years SD 6·8, 4321 75·5% males, and 5676 99·2% white) were included in the modified intention-to-treat population, with 2853 in the allopurinol group and 2868 in the usual care group. Mean follow-up time in the study was 4·8 years (1·5). There was no evidence of a difference between the randomised treatment groups in the rates of the primary endpoint. 314 (11·0%) participants in the allopurinol group (2·47 events per 100 patient-years) and 325 (11·3%) in the usual care group (2·37 events per 100 patient-years) had a primary endpoint (hazard ratio HR 1·04 95% CI 0·89–1·21, p=0·65). 288 (10·1%) participants in the allopurinol group and 303 (10·6%) participants in the usual care group died from any cause (HR 1·02 95% CI 0·87–1·20, p=0·77).
In this large, randomised clinical trial in patients aged 60 years or older with ischaemic heart disease but no history of gout, there was no difference in the primary outcome of non-fatal myocardial infarction, non-fatal stroke, or cardiovascular death between participants randomised to allopurinol therapy and those randomised to usual care.
UK National Institute for Health and Care Research.
This study investigated associations between measures of adiposity from age 36 and spine shape at 60-64 years. Thoracolumbar spine shape was characterised using statistical shape modelling on lateral ...dual-energy x-ray absorptiometry images of the spine from 1529 participants of the MRC National Survey of Health and Development, acquired at age 60-64. Associations of spine shape modes with: 1) contemporaneous measures of total and central adiposity (body mass index (BMI), waist circumference (WC)) and body composition (android:gynoid fat mass ratio and lean and fat mass indices, calculated as whole body (excluding the head) lean or fat mass (kg) divided by height2 (m)2); 2) changes in total and central adiposity between age 36 and 60-64 and 3) age at onset of overweight, were tested using linear regression models. Four modes described 79% of the total variance in spine shape. In men, greater lean mass index was associated with a larger lordosis whereas greater fat mass index was associated with straighter spines. Greater current BMI was associated with a more uneven curvature in men and with larger anterior-posterior (a-p) vertebral diameters in both sexes. Greater WC and fat mass index were also associated with a-p diameter in both sexes. There was no clear evidence that gains in BMI and WC during earlier stages of adulthood were associated with spine shape but younger onset of overweight was associated with a more uneven spine and greater a-p diameter. In conclusion, sagittal spine shapes had different associations with total and central adiposity; earlier onset of overweight and prior measures of WC were particularly important.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Abstract
Objectives
Responsive biomarkers are needed to assess the progression of OA and their lack has hampered previous clinical trials. Statistical shape modelling (SSM) from radiographic images ...identifies those at greatest risk of fast-progression or joint replacement, but its sensitivity to change has not previously been measured. This study evaluates the responsiveness of SSM in knee OA in a 12-month observational study.
Methods
A total of 109 people were recruited who had undergone knee radiographs in the previous 12 months, and were grouped based on severity of radiographic OA (Kellgren–Lawrence grading). An SSM was built from three dual-energy X-ray absorptiometry scans at 6-month intervals. Change-over-time and OA were assessed using generalized estimating equations, standardized response means (SRM) and reliable change indices
Results
Mode 1 showed typical features of radiographic OA and had a strong link with Kellgren–Lawrence grading but did not change significantly during the study. Mode 3 showed asymmetrical changes consistent with medial cartilage loss, osteophytes and joint malalignment, and was responsive to change, with a 12-month SRM of 0.63. The greatest change was observed in the moderate radiographic OA group (SRM 0.92) compared with the controls (SRM 0.21), and the reliable change index identified 14% of this group whose progression was clinically significant.
Conclusion
Shape changes linked the progression of osteophytosis with increasing malalignment within the joint. Modelling of the whole joint enabled quantification of change beyond the point where bone-to-bone contact has been made. The knee SSM is, therefore, a responsive biomarker for radiographic change in knees over 12 months.
Allopurinol is a xanthine oxidase inhibitor that lowers serum uric acid and is used to prevent acute gout flares in patients with gout. Observational and small interventional studies have suggested ...beneficial cardiovascular effects of allopurinol.
To determine whether allopurinol improves major cardiovascular outcomes in patients with ischaemic heart disease.
Prospective, randomised, open-label, blinded endpoint multicentre clinical trial.
Four hundred and twenty-four UK primary care practices.
Aged 60 years and over with ischaemic heart disease but no gout.
Participants were randomised (1 : 1) using a central web-based randomisation system to receive allopurinol up to 600 mg daily that was added to usual care or to continue usual care.
The primary outcome was the composite of non-fatal myocardial infarction, non-fatal stroke or cardiovascular death. Secondary outcomes were non-fatal myocardial infarction, non-fatal stroke, cardiovascular death, all-cause mortality, hospitalisation for heart failure, hospitalisation for acute coronary syndrome, coronary revascularisation, hospitalisation for acute coronary syndrome or coronary revascularisation, all cardiovascular hospitalisations, quality of life and cost-effectiveness. The hazard ratio (allopurinol vs. usual care) in a Cox proportional hazards model was assessed for superiority in a modified intention-to-treat analysis.
From 7 February 2014 to 2 October 2017, 5937 participants were enrolled and randomised to the allopurinol arm (
= 2979) or the usual care arm (
= 2958). A total of 5721 randomised participants (2853 allopurinol; 2868 usual care) were included in the modified intention-to-treat analysis population (mean age 72.0 years; 75.5% male). There was no difference between the allopurinol and usual care arms in the primary endpoint, 314 (11.0%) participants in the allopurinol arm (2.47 events per 100 patient-years) and 325 (11.3%) in the usual care arm (2.37 events per 100 patient-years), hazard ratio 1.04 (95% confidence interval 0.89 to 1.21);
= 0.65. Two hundred and eighty-eight (10.1%) participants in the allopurinol arm and 303 (10.6%) participants in the usual care arm died, hazard ratio 1.02 (95% confidence interval 0.87 to 1.20);
= 0.77. The pre-specified health economic analysis plan was to perform a 'within trial' cost-utility analysis if there was no statistically significant difference in the primary endpoint, so NHS costs and quality-adjusted life-years were estimated over a 5-year period. The difference in costs between treatment arms was +£115 higher for allopurinol (95% confidence interval £17 to £210) with no difference in quality-adjusted life-years (95% confidence interval -0.061 to +0.060). We conclude that there is no evidence that allopurinol used in line with the study protocol is cost-effective.
The results may not be generalisable to younger populations, other ethnic groups or patients with more acute ischaemic heart disease. One thousand six hundred and thirty-seven participants (57.4%) in the allopurinol arm withdrew from randomised treatment, but an on-treatment analysis gave similar results to the main analysis.
The ALL-HEART study showed that treatment with allopurinol 600 mg daily did not improve cardiovascular outcomes compared to usual care in patients with ischaemic heart disease. We conclude that allopurinol should not be recommended for the secondary prevention of cardiovascular events in patients with ischaemic heart disease but no gout.
The effects of allopurinol on cardiovascular outcomes in patients with ischaemic heart disease and co-existing hyperuricaemia or clinical gout could be explored in future studies.
This trial is registered as EU Clinical Trials Register (EudraCT 2013-003559-39) and ISRCTN (ISRCTN 32017426).
This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 11/36/41) and is published in full in
; Vol. 28, No. 18. See the NIHR Funding and Awards website for further award information.
Spine shape changes dramatically in early life, influenced by attainment of developmental milestones such as independent walking. Whether these associations persist across life is unknown. Therefore, ...we investigated associations between developmental milestones and spine shape, as determined using statistical shape models (SSMs) of lumbar spine from dual‐energy X‐ray absorptiometry scans in 1327 individuals (688 female) at 60 to 64 years in the MRC National Survey of Health and Development. Lumbar lordosis angle (L4 inferior endplate to T12 superior endplate) was measured using the two‐line Cobb method. In analyses adjusted for sex, height, lean and fat mass, socioeconomic position, and birthweight, later walking age was associated with greater lordosis described by SSM1 (regression coefficient, 0.023; 95% CI, 0.000‐0.047; P = .05) and direct angle measurement. Modest associations between walking age and less variation in anterior‐posterior vertebral size caudally (SSM6) were also observed (0.021; 95% CI, −0.002 to 0.044; P = .07). Sex interactions showed that later walking was associated with larger relative vertebral anterior‐posterior dimensions in men (SSM3; −0.043; 95% CI, −0.075 to 0.01; P = .01) but not women (0.018; 95% CI, −0.0007 to 0.043; P = .17). Similar associations were observed between age at independent standing and SSMs but there was little evidence of association between sitting age and spine shape. Unadjusted associations between walking age and SSMs 1 and 6 remained similar after adjustment for potential confounders and mediators. This suggests that these associations may be explained by altered mechanical loading of the spine during childhood growth, although other factors could contribute. Early life motor development, particularly walking, may have a lasting effect on the features of spine morphology with clinical significance.
Objective
To examine relationships between known osteoarthritis (OA) susceptibility loci and hip shape in a population‐based cohort of perimenopausal women in order to investigate whether hip shape ...contributes to OA development.
Methods
Hip shape was measured, using statistical shape modeling, on dual x‐ray absorptiometry scans of the hip from mothers in the Avon Longitudinal Study of Parents and Children (ALSPAC). The proximal femur and superior acetabulum were outlined, and independent hip shape modes were generated. In a subregional model, points were restricted to the acetabulum and superior femoral head. Associations between 11 OA‐related single‐nucleotide polymorphisms, identified by literature search, and shape modes were analyzed in a multivariate canonical correlation analysis.
Results
A total of 3,111 women (mean age 48 years) had genetic and hip shape data. The KLHDC5/PTHLH rs10492367 OA risk allele was associated with a wider upper femur in the whole shape model (P = 1 × 10−5). The DOT1L rs12982744 OA risk allele was associated with reduced superior joint space in the subregional shape model (P = 2 × 10−3). The COL11A1 rs4907986 OA risk allele was associated with lateral displacement of the femoral head relative to the acetabulum in the subregional shape model (P = 5 × 10−4). Regional association plots identified an additional COL11A1 locus in moderate linkage disequilibrium with rs4907986, which was more strongly associated with hip shape (rs10047217; P = 3 × 10−6). Colocalization analysis indicated sharing of genetic signals for hip shape and hip OA for the KLHDC5/PTHLH and COL11A1 loci.
Conclusion
Hip OA susceptibility loci were associated with shape in this study, suggesting that these loci (and potentially yet‐to‐be‐identified hip OA loci) could contribute to hip OA in later life via perturbing biologic pathways that mediate morphology development.
The anatomical shape of bones and joints is important for their proper function but quantifying this, and detecting pathological variations, is difficult to do. Numerical descriptions would also ...enable correlations between joint shapes to be explored. Statistical shape modelling (SSM) is a method of image analysis employing pattern recognition statistics to describe and quantify such shapes from images; it uses principal components analysis to generate modes of variation describing each image in terms of a set of numerical scores after removing global size variation. We used SSM to quantify the shapes of the hip and the lumbar spine in dual‐energy x‐ray absorptiometry (DXA) images from 1511 individuals in the MRC National Survey of Health and Development at ages 60–64 years. We compared shapes of both joints in men and women and hypothesised that hip and spine shape would be strongly correlated. We also investigated associations with height, weight, body mass index (BMI) and local (hip or lumber spine) bone mineral density. In the hip, all except one of the first 10 modes differed between men and women. Men had a wider femoral neck, smaller neck‐shaft angle, increased presence of osteophytes and a loss of the femoral head/neck curvature compared with women. Women presented with a flattening of the femoral head and greater acetabular coverage of the femoral head. Greater weight was associated with a shorter, wider femoral neck and larger greater and lesser trochanters. Taller height was accompanied by a flattening of the curve between superior head and neck and a larger lesser trochanter. Four of the first eight modes describing lumbar spine shape differed between men and women. Women tended to have a more lordotic spine than men with relatively smaller but caudally increasing anterior‐posterior (a‐p) vertebral diameters. Men were more likely to have a straighter spine with larger vertebral a‐p diameters relative to vertebral height than women, increasing cranially. A weak correlation was found between body weight and a‐p vertebral diameter. No correlations were found between shape modes and height in men, whereas in women there was a weak positive correlation between height and evenness of spinal curvature. Linear relationships between hip and spine shapes were weak and inconsistent in both sexes, thereby offering little support for our hypothesis.
In conclusion, men and women entering their seventh decade have small but statistically significant differences in the shapes of their hips and their spines. Associations with height, weight, BMI and BMD are small and correspond to subtle variations whose anatomical significance is not yet clear. Correlations between hip and spine shapes are small.
This collection of essays seeks to challenge the notion of the supremacy of the brain as the key organ of the Enlightenment, by focusing on the workings of the bowels and viscera that so obsessed ...writers and thinkers during the long eighteenth-century. These inner organs and the digestive process acted as counterpoints to politeness and other modes of refined sociability, drawing attention to the deeper workings of the self. Moving beyond recent studies of luxury and conspicuous consumption, where dysfunctional bowels have been represented as a symptom of excess, this book seeks to explore other manifestations of the visceral and to explain how the bowels played a crucial part in eighteenth-century emotions and perceptions of the self. The collection offers an interdisciplinary and cross-cultural perspective on entrails and digestion by addressing urban history, visual studies, literature, medical history, religious history, and material culture in England, France, and Germany.
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