Improved clinical investigation and evaluation of high-risk medical devices: the rationale and objectives of CORE-MD (Coordinating Research and Evidence for Medical Devices).

In the European Union (EU) the delivery of health services is a national responsibility but there are concerted actions between member states to protect public health. Approval of pharmaceutical products is the responsibility of the European Medicines Agency, whereas authorizing the placing on the market of medical devices is decentralized to independent 'conformity assessment' organizations called notified bodies. The first legal basis for an EU system of evaluating medical devices and approving their market access was the medical device directives, from the 1990s. Uncertainties about clinical evidence requirements, among other reasons, led to the EU Medical Device Regulation (2017/745) that has applied since May 2021. It provides general principles for clinical investigations but few methodological details-which challenges responsible authorities to set appropriate balances between regulation and innovation, pre- and post-market studies, and clinical trials and real-world evidence. Scientific experts should advise on methods and standards for assessing and approving new high-risk devices, and safety, efficacy, and transparency of evidence should be paramount. The European Commission recently awarded a Horizon 2020 grant to a consortium led by the European Society of Cardiology and the European Federation of National Associations of Orthopaedics and Traumatology, that will review methodologies of clinical investigations, advise on study designs, and develop recommendations for aggregating clinical data from registries and other real-world sources. The CORE-MD project (Coordinating Research and Evidence for Medical Devices) will run until March 2024; here we describe how it may contribute to the development of regulatory science in Europe.

Prevalence of subclinical cardiac abnormalities in patients with metal-on-metal hip replacements.

BACKGROUND: Metal-on-metal (MOM) hip prostheses have a higher failure rate than conventional prostheses and leaching of cobalt and chromium has been linked to cardiomyopathy. We screened MOM subjects to evaluate if cobalt and chromium are related to subclinical cardiac dysfunction. METHODS: A single centre, non-randomised, observational study using echocardiography in 95 patients who had undergone MOM hip prostheses, and 15 age matched controls with non-MOM hip replacement. Serial plasma cobalt and chromium levels were recorded, and data compared by tertiles of cobalt exposure. RESULTS: Indexed left ventricular (LV) end-diastolic and end-systolic volumes (EDVi and ESVi) increased with tertile of cobalt (omnibus p = 0.003 for EDVi and ESVi), as did indexed left atrial (LA) volumes (p = 0.003). MOM subjects had 25% larger EDVi than controls, 32% larger ESVi (40 ml vs. 32 ml, and 15 ml vs. 11 ml, p = 0.003 for both) and 28% larger indexed LA (23 ml vs. 18 ml, p = 0.002). There were no differences in LV systolic or diastolic function, including ejection fraction, tissue velocity and mitral E/e'. Estimated glomerular filtration rate was 18% lower in the highest tertile compared with the lowest (p = 0.01) and correlated inversely with LA volume (r = -0.36, p < 0.001) and LV EDV (r = -0.24, p = 0.02). CONCLUSIONS: No correlations between sensitive measures of systolic or diastolic cardiac function or serum cobalt/chromium levels were observed in this study. However, there was a relationship between increasing left ventricular and left atrial volumes and declining renal function with high cobalt levels which requires further evaluation in MOM patients.

Central arterial stiffness and diastolic dysfunction are associated with insulin resistance and abdominal obesity in young women but polycystic ovary syndrome does not confer additional risk.

STUDY QUESTION: Are arterial stiffness, carotid intima-media thickness and diastolic dysfunction increased in young women with polycystic ovary syndrome (PCOS) independently of the effects of obesity? SUMMARY ANSWER: Insulin resistance and central obesity are associated with subclinical cardiovascular dysfunction in young women, but a diagnosis of PCOS does not appear to confer additional risk at this age. WHAT IS KNOWN ALREADY: Some studies have shown that young women with PCOS may have increased measures of cardiovascular risk, including arterial stiffness, carotid intima-media thickness and myocardial dysfunction. However, it is difficult to establish how much of this risk is due to PCOS per se and how much is due to obesity and insulin resistance, which are common in PCOS and themselves associated with greater vascular risk. STUDY DESIGN, SIZE, DURATION: This cross-sectional study comprised 84 women with PCOS and 95 healthy volunteers, aged 16-45 years. PARTICIPANTS/MATERIALS, SETTING, METHODS: The study was conducted in a university hospital. Subjects underwent a comprehensive assessment of body composition (including computed tomography (CT) assessment of visceral fat; VF), measurements of arterial stiffness (aortic pulse wave velocity; aPWV), common carotid intima-media thickness (ccIMT), diastolic function (longitudinal tissue velocity; e':a') and endocrinological measures. A sample size of 80 in each group gave 80% power for detecting a difference of 0.45 m/s in aPWV or a difference of 0.25 in e':a'. MAIN RESULTS AND THE ROLE OF CHANCE: After adjustment for age and body mass index (BMI), PCOS subjects had a greater insulin response (insulin area under the curve-IAUC) following glucose challenge (adjusted difference [AD] 35 900 pmol min/l, P < 0.001) and higher testosterone (AD 0.57 nmol/l, P < 0.001) and high molecular weight adiponectin than controls (AD 3.01 µg/ml, P = 0.02), but no significant differences in aPWV (AD -0.13 m/s, P = 0.33), ccIMT (AD -0.01 mm, P = 0.13), or e':a' (AD -0.01, P = 0.86) were observed. After adjustment for age, height and central pulse pressure, e':a' and aPWV were associated with logVF and IAUC. ccIMT was not related to logVF. The relationships between e':a' or aPWV and insulin resistance were only partly attenuated by adjusting for logVF. There was no significant relationship between aPWV or e':a' and either testosterone or adiponectin. LIMITATIONS, REASONS FOR CAUTION: The study recruited young women meeting the Rotterdam criteria for PCOS diagnosis; hence our findings may not be generalizable to older patients or those meeting other definitions of the syndrome. Biochemical hyperandrogenism was based solely on measurement of total testosterone. Cases and controls were not matched in advance for age and BMI, although the influence of these variables on the cardiovascular outcome measures was adjusted for. WIDER IMPLICATIONS OF THE FINDINGS: This study shows that central arterial stiffness and diastolic dysfunction are not increased in young women with PCOS, whereas they are associated with both insulin resistance and central obesity. Obesity thus represents the greatest modifiable risk factor for cardiovascular disease in young women with PCOS and lifestyle measures which target weight reduction are critical. STUDY FUNDING/COMPETING INTERESTS: This study received no specific grant support from any funding body. The authors have no conflicts of interest to declare.

PTPN2 but not PTPN22 is associated with Crohn's disease in a New Zealand population.

Recent genome-wide association studies have provided evidence for the involvement of the genes PTPN2 and PTPN22 in the pathogenesis of Crohn's disease (CD). We investigated whether genetic variants in these genes were associated with CD in a New Zealand population. Single-nucleotide polymorphisms (SNPs) rs2542151 (PTPN2) and rs2476601 (PTPN22) were genotyped in 315 CD cases and 481 controls. In this sample, we were able to confirm an association between CD and PTPN2 (genotypic P = 0.019 and allelic P = 0.011), and phenotypic analysis showed an association of this SNP with late age at first diagnosis, inflammatory and penetrating CD behaviour, requirement of bowel resection and being a smoker at diagnosis. There was no evidence for an association with PTPN22.

Arterial wave intensity and ventricular-arterial coupling by vascular ultrasound: rationale and methods for the automated analysis of forwards and backwards running waves.

Wave intensity (WI) in the circulation is estimated noninvasively as the product of instantaneous changes in pressure and velocity. We recorded diameter as a surrogate for pressure, and velocity in the right common carotid artery using an Aloka SSD-5500 ultrasound scanner. We developed automated software, applying the water hammer equation to obtain local wave speed from the slope of a pressure/velocity loop during early systole to separate net WI into individual forwards and backwards-running waves. A quality index was developed to test for noisy data. The timing, duration, peak amplitude and net energy of separated WI components were measured in healthy subjects with a wide age range. Age and arterial stiffness were independent predictors of local wave speed, whereas backwards-travelling waves correlated more strongly with ventricular systolic function than with age-related changes in arterial stiffness. Separated WI offers detailed insight into ventricular-arterial interactions that may be useful for assessing the relative contributions of ventricular and vascular function to wave travel.

Medical treatment of Marfan syndrome: a time for change.

It is accepted practice to prescribe beta-blockers in order to retard aortic dilatation and prevent aortic dissection and rupture in patients with Marfan syndrome. A critical review of the published pharmacological studies shows this practice to be based on limited evidence. The data from small clinical and experimental studies with surrogate end points suggest greater potential benefit from alternative drug regimens, and a recent experimental study showed that losartan may interrupt the mechanism of disease as well as deal with its functional consequences. It is now essential to perform large, collaborative, randomised controlled trials with clinical end points of new treatments in Marfan syndrome.

Report on the European Association of Echocardiography accreditations in echocardiography: December 2003-September 2006.

AIMS: The European Association of Echocardiography (EAE) launched its Accreditation scheme in echocardiography in December 2003. Currently there are accreditations in Adult Transthoracic Echocardiography and Transesophageal Echocardiography and an Accreditation in Echocardiography for Congenital Disease will be launched in December 2006. METHODS AND RESULTS: Over the past 3years 350 applicants have undertaken the written exams and 157 applicants have completed the process and achieved accreditation. This report summarises the accreditation process, the details of the numbers of applicants and their progress through the Accreditation scheme. This report also provides data about the performance of the written exam, its reliability and the effectiveness of the questions and data about the reproducibility of the log book marking system. CONCLUSION: Taken together this report provides evidence that the EAE Accreditation schemes have been effective in establishing a standard for echocardiographic practice and an accreditation that is effectively organised, reliable, robust and successful.

Acute effects of caffeine and tobacco on arterial function and wave travel.

BACKGROUND: Caffeine and tobacco consumption are risk factors for heart failure, but their effects remain controversial. It has been hypothesized that they cause alterations in arterial stiffness and arterial wave travel which may increase ventricular loading. In this study the authors examined the influence of these widely used stimulants on wave intensity and arterial stiffness parameters using carotid wave intensity analysis. MATERIALS AND METHODS: A new Doppler-based ultrasound method was used to measure the acute effects of caffeine and tobacco on wave intensity in the right common carotid artery. The measurements enabled changes in arterial stiffness parameters to be recorded. RESULTS: In 17 subjects compared with 10 controls, caffeine increased blood pressure, early systolic wave intensity and wave speed, but late-systolic wave intensity and mid-systolic reflections were unchanged. In 11 smokers studied before and after smoking one cigarette, blood pressure and arterial stiffness increased but wave intensity was unchanged. No changes were observed in the controls. CONCLUSIONS: Increased wave intensity during ejection after caffeine suggested sympathomimetic effects on the left ventricular function. Increased wave speed in the common carotid artery implied augmented central loading after caffeine, but the absence of measurable changes in local arterial stiffness in the carotid artery suggested more complex and regional effects. Cigarette smoking acutely increased local arterial stiffness in the common carotid artery. These changes can be detected using wave intensity analysis.

The future of cardiovascular imaging and non-invasive diagnosis: a joint statement from the European Association of Echocardiography, the Working Groups on Cardiovascular Magnetic Resonance, Computers in Cardiology, and Nuclear Cardiology, of the European Society of Cardiology, the European Association of Nuclear Medicine, and the Association for European Paediatric Cardiology.

Advances in medical imaging now make it possible to investigate any patient with cardiovascular disease using multiple methods which vary widely in their technical requirements, benefits, limitations, and costs. The appropriate use of alternative tests requires their integration into joint clinical diagnostic services where experts in all methods collaborate. This statement summarises the principles that should guide developments in cardiovascular diagnostic services.

Subclinical hypothyroidism, arterial stiffness, and myocardial reserve.

CONTEXT: Subclinical hypothyroidism (SCH) is associated with increased risk of cardiac disease; its impact on arterial function is less clear. OBJECTIVE: The objective of the study was the assessment of arterial and cardiac function. DESIGN: The study was a 6-month controlled observational study using pulse wave analysis and tissue Doppler dobutamine stress echocardiography. SETTING: The study was conducted at a thyroid clinic. PATIENTS: Nineteen female SCH patients with raised TSH, normal free T(4), and no cardiovascular disease [aged 49.2 +/- 3.8 yr; body mass index (BMI) 29.9 +/- 6.7 kg/m(2)] were recruited from the thyroid clinic, and 10 female controls (aged 50.2 +/- 3.4 yr; BMI 29.7 +/- 7.2 kg/m(2)) also participated in the study. INTERVENTIONS: Incremental doses of l-thyroxine were used. MAIN OUTCOME MEASURES: Indices of vascular stiffness and left ventricular echocardiographic function were measured. RESULTS: Baseline augmentation gradient was elevated in SCH, compared with controls [10.3 +/- 5.1 (sd) mm Hg vs. 8.0 +/- 4.2, P < 0.05]; when euthyroid (mean T(4) dose 114 mug/d), it fell to 8.8 +/- 5.3 mm Hg (P < 0.05). Heart rate-corrected augmentation index was 26.7 +/- 9.9 vs. 18.8 +/- 9.9% (P < 0.02), falling to 19.7 +/- 9.6% (P < 0.001) after treatment. Time of travel of the reflected wave was 139.3 +/- 11.7 msec, compared with 141.5 +/- 8.8 msec in controls (P < 0.05), increasing to 144.9 +/- 11.9 msec (P < 0.05). There were no differences in resting global, regional left ventricular function, or regional myocardial velocities during maximal dobutamine stress between SCH patients and controls, or in treated patients, compared with baseline. CONCLUSIONS: Arterial stiffness was increased in SCH and improved with l-thyroxine, which may be beneficial, whereas myocardial functional reserve was similar to controls and remained unaltered after treatment.

Increased risk of lymphoma among inflammatory bowel disease patients treated with azathioprine and 6-mercaptopurine.

BACKGROUND: Inflammatory bowel disease (IBD) is commonly treated with immunomodulators such as azathioprine and 6-mercaptopurine (6-MP). Studies examining lymphoma risk in IBD patients treated with these medications have been underpowered and have yielded conflicting conclusions. AIMS: The purpose of this meta-analysis was to provide a more precise estimate of the relative risk of lymphoma among IBD patients treated with azathioprine or 6-MP. METHODS: Studies were included if they were English language, full article, cohort studies specifically designed to evaluate cancer as an adverse outcome of treatment with azathioprine or 6-MP. Pooled standardised incidence ratios were calculated to estimate the relative risk of lymphoma associated with therapy. Heterogeneity was assessed using Poisson regression. Sensitivity analyses examined the influence of individual studies on risk estimate and heterogeneity statistics. RESULTS: Six studies were identified that met our inclusion criteria. When the data were combined across all studies, the pooled relative risk was 4.18 (95% confidence interval 2.07-7.51; 11 observed cases, 2.63 expected). Sensitivity analysis showed that exclusion of any one study had a relatively small effect on the pooled relative risk estimate (range 3.49-5.21) but excluding either the study with the highest or lowest estimated relative risk eliminated the statistically significant heterogeneity. CONCLUSIONS: Our data suggest an approximate fourfold increased risk of lymphoma in IBD patients treated with azathioprine/6-MP. The increased risk of lymphoma could be a result of the medications, the severity of the underlying disease, or a combination of the two.

Strain rate imaging after dynamic stress provides objective evidence of persistent regional myocardial dysfunction in ischaemic myocardium: regional stunning identified?

OBJECTIVE: To investigate whether persistent ischaemic dysfunction of the myocardium after dynamic stress can be diagnosed from changes in ultrasonic strain rate and strain. DESIGN: Prospective observational study, with age matched controls. SETTING: University hospital. PATIENTS AND METHODS: 26 patients (23 men, mean (SD) age 58.9 (8.1) years) with coronary artery disease but no infarction and 12 controls (9 men, aged 56.1 (8.8) years) with normal coronary arteriography and negative exercise test underwent treadmill exercise (Bruce protocol). Tissue Doppler echocardiography was performed at baseline, at peak exercise, and at intervals up to one hour. Systolic and diastolic velocity, strain, and strain rate were recorded in the basal anterior segment of 16 patients with proximal left anterior descending coronary artery disease. RESULTS: Patients developed ischaemia, since they experienced angina, exercised for less time, and reached a lower workload than the control group, and had ST segment depression (-2.4 mm). Myocardial systolic velocity immediately after exercise increased by 31% and strain rate fell by 25% compared with increases of 92% and 62%, respectively, in the control group (p < 0.05). During recovery, myocardial systolic velocity and strain rate normalised quickly, whereas systolic strain remained depressed at 30 and 60 minutes after exercise, by 21% and 23%, respectively, compared with baseline (p < 0.05 versus controls). Myocardial diastolic velocities and strain rate normalised but early diastolic strain remained depressed by 32% compared with controls for 60 minutes (p < 0.05). Strain during atrial contraction was abnormal for 30 minutes. CONCLUSIONS: Myocardial strain shows regional post-ischaemic dysfunction in systole and diastole and may become a useful diagnostic tool in patients presenting with chest pain with a normal ECG.

Genome-wide RNAi identifies p53-dependent and -independent regulators of germ cell apoptosis in C. elegans.

We used genome-wide RNA interference (RNAi) to identify genes that affect apoptosis in the C. elegans germ line. RNAi-mediated knockdown of 21 genes caused a moderate to strong increase in germ cell death. Genetic epistasis studies with these RNAi candidates showed that a large subset (16/21) requires p53 to activate germ cell apoptosis. Apoptosis following knockdown of the genes in the p53-dependent class also depended on a functional DNA damage response pathway, suggesting that these genes might function in DNA repair or to maintain genome integrity. As apoptotic pathways are conserved, orthologues of the worm germline apoptosis genes presented here could be involved in the maintenance of genomic stability, p53 activation, and fertility in mammals.

Prevalence and clinical significance of incidental paraprosthetic valvar regurgitation: a prospective study using transoesophageal echocardiography.

OBJECTIVE: To assess the prevalence, mechanisms, and significance of paraprosthetic regurgitation detected incidentally by transoesophageal echocardiography (TOE) in patients after heart valve replacement. DESIGN: Prospective observational study. SETTING: Tertiary referral centre. PATIENTS: 360 consecutive patients (mean (SD) age 65.8(9.5) years, 193 women) undergoing elective first ever valve replacement. METHODS: Postoperative and follow up TOE, and tests for haemolysis and anaemia. RESULTS: There were 243 aortic, 90 mitral, and 27 double valve replacements, using 316 mechanical and 44 tissue valves, giving 270 aortic and 117 mitral valves. One patient with severe paraprosthetic mitral regurgitation underwent immediate reoperation and was excluded from subsequent analyses. Paraprosthetic jets were detected around 16 (6%) of the aortic and 38 (32%) of the mitral valves (p < 0.05) at the postoperative study. Follow up TOE was available for 151 aortic and 67 mitral valves, 0.9 (0.5) years after operation. Paraprosthetic jets were present in 15 (10%) of the aortic and 10 (15%) of the mitral valves (NS). Two thirds of the aortic and a fifth of the mitral jets were new. Paraprosthetic jets were more common in aortic valves in a supra-annular (12 of 88, 14%) than in an intra-annular position (4 or 182, 2%; p < 0.005) and in mitral valves inserted with continuous (36 of 88, 41%) rather than interrupted sutures (2 of 28, 7%; p < 0.001). Lactate dehydrogenase concentration was higher in patients with paraprosthetic jets than in those without (752 (236) v 654 (208) IU/l, p < 0.001). Haemoglobin and haptoglobin concentrations were not different. CONCLUSIONS: Small paraprosthetic leaks are common, are related to surgical factors, are not associated with increased subclinical haemolysis, and are benign during the first year after heart valve replacement.