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Aims The optimal timing of an invasive strategy (IS) in non-ST-elevation acute coronary syndrome (NSTE-ACS) is controversial. Recent randomized controlled trials (RCTs) and long-term follow-up data have yet to be included in a contemporary meta-analysis. Methods and results A systematic review of RCTs that compared an early IS vs. delayed IS for NSTE-ACS was conducted by searching MEDLINE, Embase, and Cochrane Central Register of Controlled Trials. A meta-analysis was performed by pooling relative risks (RRs) using a random-effects model. The primary outcome was all-cause mortality. Secondary outcomes included myocardial infarction (MI), recurrent ischaemia, admission for heart failure (HF), repeat re-vascularization, major bleeding, stroke, and length of hospital stay. This study was registered with PROSPERO (CRD42021246131). Seventeen RCTs with outcome data from 10 209 patients were included. No significant differences in risk for all-cause mortality [RR: 0.90, 95% confidence interval (CI): 0.78–1.04], MI (RR: 0.86, 95% CI: 0.63–1.16), admission for HF (RR: 0.66, 95% CI: 0.43–1.03), repeat re-vascularization (RR: 1.04, 95% CI: 0.88–1.23), major bleeding (RR: 0.86, 95% CI: 0.68–1.09), or stroke (RR: 0.95, 95% CI: 0.59–1.54) were observed. Recurrent ischaemia (RR: 0.57, 95% CI: 0.40–0.81) and length of stay (median difference: −22 h, 95% CI: −36.7 to −7.5 h) were reduced with an early IS. Conclusion In all-comers with NSTE-ACS, an early IS does not reduce all-cause mortality, MI, admission for HF, repeat re-vascularization, or increase major bleeding or stroke when compared with a delayed IS. Risk of recurrent ischaemia and length of stay are significantly reduced with an early IS.

The use of the lambda-mu-sigma (LMS) method for estimating centiles and producing reference ranges has received much interest in clinical practice, especially for assessing growth in childhood. However, this method may not be directly applicable where measures are based on a score calculated from question response categories that is bounded within finite intervals, for example, in psychometrics. In such cases, the main assumption of normality of the conditional distribution of the transformed response measurement is violated due to the presence of ceiling (and floor) effects, leading to biased fitted centiles when derived using the common LMS method. This paper describes the methodology for constructing reference intervals when the response variable is bounded and explores different distribution families for the centile estimation, using a score derived from a parent-completed assessment of cognitive and language development in 24 month-old children. Results indicated that the z-scores, and thus the extracted centiles, improved when kurtosis was also modeled and that the ceiling effect was addressed with the use of the inflated binomial distribution. Therefore, the selection of the appropriate distribution when constructing centile curves is crucial.

Vascular tone is regulated by the relative contractile state of vascular smooth muscle cells (VSMCs). Several integrins directly modulate VSMC contraction by regulating calcium influx through L-type voltage-gated CaSVEP1 and integrin binding were confirmed by immunoprecipitation and cell binding assays. Human induced pluripotent stem cell-derived VSMCs were used in in vitro [CaWe confirmed the ligation of SVEP1 to integrin α9β1 and additionally found SVEP1 to directly bind to integrin α4β1. Inhibition of SVEP1, integrin α4β1 or α9β1 significantly enhanced [CaOur studies reveal a novel role for SVEP1 and the integrins α4β1 and α9β1 in reducing VSMC contractility. This could provide an explanation for the genetic associations with blood pressure risk at the SVEP1 and ITGA9 loci.

ObjectiveTo investigate percutaneous coronary intervention (PCI) practice in an international cohort of patients with spontaneous coronary artery dissection (SCAD). To explore factors associated with complications and study angiographic and longer term outcomes.MethodsSCAD patients (n=215, 94% female) who underwent PCI from three national cohort studies were investigated and compared with a matched cohort of conservatively managed SCAD patients (n=221).ResultsSCAD-PCI patients were high risk at presentation with only 8.8% undergoing PCI outside the context of ST-elevation myocardial infarction/cardiac arrest, thrombolysis in myocardial infarction (TIMI) 0/1 flow or proximal dissections. PCI complications occurred in 38.6% (83/215), with 13.0% (28/215) serious complications. PCI-related complications were associated with more extensive dissections (multiple vs single American Heart Association coronary segments, OR 1.9 (95% CI: 1.06–3.39),p=0.030), more proximal dissections (proximal diameter per mm, OR 2.25 (1.38–3.67), p=0.001) and dissections with no contrast penetration of the false lumen (Yip-Saw 2 versus 1, OR 2.89 (1.12–7.43), p=0.028). SCAD-PCI involved long lengths of stent (median 46mm, IQR: 29–61mm). Despite these risks, SCAD-PCI led to angiographic improvements in those with reduced TIMI flow in 84.3% (118/140). Worsening TIMI flow was only seen in 7.0% (15/215) of SCAD-PCI patients. Post-PCI major adverse cardiovascular and cerebrovascular events (MACCE) and left ventricular function outcomes were favourable.ConclusionWhile a conservative approach to revascularisation is favoured, SCAD cases with higher risk presentations may require PCI. SCAD-PCI is associated with longer stent lengths and a higher risk of complications but leads to overall improvements in coronary flow and good medium-term outcomes in patients.

n/a Funding Agencies|British Heart Foundation [PG/13/96/30608]; National Institute for Health and Care Research rare disease translational collaboration; Leicester National Institute for Health and Care Research Biomedical Research Center; Beat SCAD

BackgroundTelomere length is associated with risk of several age–related diseases and cancers. The extent to which telomere length may be modifiable through lifestyle and behaviour and whether this has any clinical consequences is unknown.MethodsIn up to 422,797 participants in UK Biobank, we investigated associations of leucocyte telomere length (LTL) with 117 potentially modifiable traits, as well as two indices of healthy behaviours incorporating smoking, physical activity, diet, maintenance of a healthy body weight and alcohol intake. Associations were interpreted as age–related change in LTL by dividing the trait beta coefficients with the age–coefficient. We used Mendelian Randomisation (MR) to test causality of the observed associations of educational attainment and smoking behaviour with LTL. We investigated whether the associations of LTL with 22 diseases were modified by the number of healthy behaviours and the extent to which the associations of more healthy behaviours with greater life expectancy and lower risk of coronary artery disease (CAD) may be mediated through LTL.Results71 traits showed significant associations with LTL but most were modest, equivalent to ConclusionsSeveral potentially modifiable traits and healthy behaviours have a quantifiable association with LTL, at least some of which are likely to be causal. However, these effects are not of a sufficient magnitude to substantially alter the association between LTL and various diseases or life expectancy.

Funder: Health Data Research UK EU/EFPIA Innovative Medicines Initiative Joint Undertaking BigData@Heart (11607)., Funder: Health Data Research UK, Telomeres, the end fragments of chromosomes, play key roles in cellular proliferation and senescence. Here we characterize the genetic architecture of naturally occurring variation in leukocyte telomere length (LTL) and identify causal links between LTL and biomedical phenotypes in 472,174 well-characterized UK Biobank participants. We identified 197 independent sentinel variants associated with LTL at 138 genomic loci (108 new). Genetically determined differences in LTL were associated with multiple biological traits, ranging from height to bone marrow function, as well as several diseases spanning neoplastic, vascular and inflammatory pathologies. Finally, we estimated that, at the age of 40 years, people with an LTL >1 s.d. shorter than the population mean had a 2.5-year-lower life expectancy compared with the group with ≥1 s.d. longer LDL. Overall, we furnish new insights into the genetic regulation of LTL, reveal wide-ranging influences of LTL on physiological traits, diseases and longevity, and provide a powerful resource available to the global research community.

Objectives This study aimed to investigate associations between persisting amblyopia into adulthood and its “real-life” impacts and inform the current debate about the value of childhood vision screening programs. Methods Associations between persisting amblyopia and diverse socioeconomic, health, and well-being outcomes were investigated in multivariable-adjusted (sex, age, ethnicity, deprivation) regression models, with 126 400 participants (aged 40-70 years) of the UK Biobank with complete ophthalmic data. Analysis by age group (cohort 1, 60-70 years; cohort 2, 50-59 years; cohort 3, 40-49 years) assessed temporal trends. Results Of 3395 (3%) participants with confirmed amblyopia, overall 77% (2627) had persisting amblyopia, declining from 78% in cohort 1 to 73% in cohort 3. The odds of persisting amblyopia were 5.91 (5.24-6.66) and 2.49 (2.21-2.81) times greater in cohort 1 and cohort 2, respectively, than cohort 3. The odds were also higher for more socioeconomically deprived groups and for any “other than white” ethnicity. Reduced participation in sport, adverse general and mental health, and well-being were all independently associated with persisting amblyopia, with the strongest associations in the youngest cohorts. Associations with lower educational attainment and economic outcomes were only evident in the oldest cohort. Conclusions There has been a decline in the overall frequency of persisting amblyopia since the introduction of universal child vision screening in the United Kingdom. Nevertheless, most adults treated for amblyopia in childhood have persisting vision deficits. There was no evidence that persisting amblyopia has vision-mediated effects on educational, employment-related, or economic outcomes. The observed adverse outcomes were largely those not directly mediated by vision. Patients undergoing treatment should be counseled about long-term outcomes.

BackgroundRefractive error is an increasing global public health concern that requires robust and reliable research to identify modifiable risk factors and provide accurate estimates of population burden. We investigated the impact of reclassification of individuals when using different threshold values of spherical equivalent (SE) to define myopia, on estimates of frequency, distribution and associations with risk factors, to inform current international initiatives to standardise definitions.MethodsA random sample of 1985 individuals from the 1958 British birth cohort, at age 44, had autorefraction and self-reported on educational attainment and social class.Refraction status assigned in three different models using SE: (A) moderate to high myopia −3 diopters (D) or more extreme (≤−3.00D), (B) hypermetropia +1.00D or more extreme (≥+1.00D) and (C) mild myopia using three different thresholds: −1.00D, −0.75D or −0.50D, hence reciprocal changes in definition of emmetropia.ResultsFrequency estimates and associations with risk factors altered significantly as the threshold value for myopia moved towards SE 0.0D: prevalence of mild myopia increased from 28% to 47%, the association with highest educational attainment attenuated and with higher social class strengthened, with changes in risk ratios of approximately 20%.ConclusionEven small changes in the threshold definition of myopia (±0.25D) can significantly affect the conclusions of epidemiological studies, creating both false-positive and false-negative associations for specific risk factors. An international classification for refractive error, empirically evidenced and cognisant of the question(s) being addressed and the population(s) being studied, is needed to serve better translational research, practice and policy.

Background Muscle wasting in the critically ill is up to 2% per day and delays patient recovery and rehabilitation. It is linked to inflammation, organ failure and severity of illness. The aims of this study were to understand the relationship between muscle depth loss, and nutritional and inflammatory markers during prolonged critical illness. Secondly, to identify when during critical illness catabolism might decrease, such that targeted nutritional strategies may logically be initiated. Methods This study was conducted in adult intensive care units in two large teaching hospitals. Patients anticipated to be ventilated for >48 hours were included. Serum C-reactive protein (mg/L), urinary urea (mmol/24h), 3-methylhistidine (μmol/24h) and nitrogen balance (g/24h) were measured on days 1, 3, 7 and 14 of the study. Muscle depth (cm) on ultrasound were measured on the same days over the bicep (bicep and brachialis muscle), forearm (flexor compartment of muscle) and thigh (rectus femoris and vastus intermedius). Results Seventy-eight critically ill patients were included with mean age of 59 years (SD: 16) and median Intensive care unit (ICU) length of stay of 10 days (IQR: 6–16). Starting muscle depth, 8.5cm (SD: 3.2) to end muscle depth, 6.8cm (SD: 2.2) were on average significantly different over 14 days, with mean difference -1.67cm (95%CI: -2.3 to -1cm), p

Background: The Parent Report of Children's Abilities–Revised (PARCA-R) can be used to identify preterm born children at risk for developmental delay at age 24 months. However, standardised scores for assessing all children in the general population and quantifying development relative to the norm are unavailable, thus limiting the use of the questionnaire. We aimed to develop scores that are standardised by age and sex for the PARCA-R to assess children's cognitive and language development at age 24–27 months. Methods: Anonymised data from PARCA-R questionnaires completed by parents of 2 year-old children in three previous studies were obtained to form a standardisation sample (n=6402) representative of the UK general population. Anonymised data were obtained from three further studies to assess the external validity (n=709) and clinical validity (n=1456) of the standardised scores. The L(lamda)M(mu)S(sigma) method was used to develop age- and sex-specific standardised scores for three scales (nonverbal cognitive development; language development; total Parent Report Composite (PRC)) for children in four 1-month age bands spanning 23·5 to 27·5 months of age. Findings: We included 6402 children (mean age 25 months and 1 day [range 23 months and 16 days to 27 months and 15 days]) in the standardisation sample and 709 (mean age 24 months and 19 days [23 months and 16 days to 27 months and 15 days]) to test the external validity and 1456 (mean age 24 months and 8·5 days [23 months and 16 days to 27 months and 15 days]) to test the clinical validity of the standardised scores. For all PARCA-R scales, mean standardised scores approximated 100 (SD 15) in both sexes and all age groups. These scores were independent of socioeconomic status. Standardised scores were close to 100 (15) in the external validation sample, showing the validity of the scores. Standardised scores for the total PRC scale for children born very preterm ( Interpretation: The PARCA-R provides a norm-referenced, standardised assessment of cognitive and language development at 24-27 months of age. The questionnaire is available non-commercially with translations currently available in 14 languages, thus providing clinicians and researchers with a cost-effective tool for assessing development and identifying children with delay.

Background Critically ill patients lose up to 2% of muscle mass per day. We assessed the feasibility of administering a leucine-enriched essential amino acid (L-EAA) supplement to mechanically ventilated trauma patients with the aim of assessing the effect on skeletal muscle mass and function. Methods A randomised feasibility study was performed over six months in intensive care (ICU). Patients received 5 g L-EAA five times per day in addition to standard feed (L-EAA group) or standard feed only (control group) for up to 14 days. C-reactive protein, albumin, IL-6, IL-10, urinary 3-MH, nitrogen balance, protein turnover ([1-13C] leucine infusion), muscle depth change (ultrasound), functional change (Katz and Barthel indices) and muscle strength Medical Research Council (MRC) sum score to assess ICU Acquired Weakness were measured sequentially. Results Eight patients (9.5% of screened patients) were recruited over six months. L-EAA doses were provided on 91/124 (73%) occasions. Inflammatory and urinary marker data were collected; serial muscle depth measurements were lacking due to short length of stay. Protein turnover studies were performed on five occasions. MRC sum score could not be performed as patients were not able to respond to the screening questions. The Katz and Barthel indices did not change. L-EAA delivery was achievable, but meaningful functional and muscle mass outcome measures require careful consideration in the design of a future randomised controlled trial. Conclusion L-EAA was practical to provide, but we found significant barriers to recruitment and measurement of the chosen outcomes which would need to be addressed in the design of a future, large randomised controlled trial. Trial registration ISRCTN Registry, ISRCTN79066838. Registered on 25 July 2012.

ObjectivesChildren born preterm are at higher risk for special educational needs and poor academic attainment compared with term-born peers, yet education professionals receive limited training and have poor knowledge of preterm birth. We have developed an interactive e-learning resource and evaluated its efficacy in improving teachers’ knowledge of preterm birth and their confidence in supporting the learning of children born preterm.SettingEight primary, infant or junior schools in England.Participants61 teachers of children aged 4–11 years, of which 55 (90%) were female.InterventionInteractive e-learning resource designed to improve education professionals’ knowledge of long-term outcomes following preterm birth and strategies that can be used to support children’s learning (www.pretermbirth.info). In a repeated measures design, participants were given up to 30 days access to the e-learning resource, before and after which they completed the Preterm Birth Knowledge Scale (PB-KS; scores 0–33; higher scores indicate greater knowledge) to assess knowledge of outcomes of prematurity. Four Likert scale items were used to assess confidence in supporting children’s learning and 10 items were used to evaluate the utility of the resource. PB-KS scores and responses on confidence item were compared pre-resource and post-resource use.ResultsPB-KS scores significantly increased after accessing the e-learning resource (median (95% CI): pre-resource 13 (11 to 14); post-resource 29 (28 to 30)), equating to a 2.6 SD increase in PB-KS scores. Teachers’ confidence in supporting children born preterm was also significantly improved after using the resource. The utility of the resource was evaluated positively by participants with 97% reporting that they would recommend its use to others.ConclusionsThe e-learning resource substantially improved teachers’ knowledge of preterm birth and their confidence in supporting preterm children in the classroom. Use of this resource may represent a key advance in improving educational outcomes for children born preterm.

To evaluate the prevalence of sexual activity and contraception methods used by Greek adolescents. To assess the effect of various factors in the decision making on sexual activity.A cross-sectional study design was applied. SETTING-PARTICIPANTS: The population (N = 1538) consisted of a random sample, stratified according to locality and population density, of 20 public junior high and high schools located in the urban district of Athens, Greece.Anonymous self-completed questionnaires were used to assess sexual practices, contraception methods, and factors affecting sexual activity choices.Spearman association calculations and chi-square were used, while regression analysis models were also applied.We examined the sexual practices among Greek adolescents, and indicated the psychosocial factors that may influence adolescents' sexual behavior.16% of the adolescents have had sexual intercourse, while the boy/girl ratio was 3/1 (P0.05). Mean age of sexual debut was 14 +/- 1.5 years. An additional 20% have had any other sexual experience at a mean age 13.5 +/- 1.5 years. Although sexually active adolescents generally use condoms (90.6%), only 32% use them properly (at every and throughout sexual contact). At least half of them do not have adequate protection (no method used or unreliable methods applied), while 8.2% of the girls have used emergency contraception. Adolescents with unstable home environment (divorce, recent death, not living with mother) or sexually experienced peers, as well as those that seek sexual education from siblings or friends have higher possibilities of being sexually active.Greek adolescents can be sexually active at a young age and they need sexual education on safe sex practices.

Importance Despite the existing country-specific strategies tackling social inequalities in visual health in adults, little is known about trends in visual function in childhood and its association with social position. Objective To investigate the distribution of childhood visual function in the United Kingdom and associations with early-life social position between 1961 and 1986, a period of significant social change. Design, Setting, and Participants Longitudinal cohort study using harmonized data sets from the British 1946, 1958, and 1970 national birth cohorts. In total, 14 283 cohort members with complete data on visual acuity at age 15 or 16 years, measured in 1961, 1974, and 1986, respectively, for each cohort, and social position were assessed. Main Outcomes and Measures Using habitual distance visual acuity (with correction if prescribed), participants were assigned to a visual function category ranging from bilateral normal to visual impairment/severe visual impairment/blindness ( International Statistical Classification of Diseases, Tenth Revision, Clinical Modification ). Distribution of visual function over time and associations with social position (risk ratios [RRs] and 95% confidence intervals) were analyzed. Results Complete data were available for 3152 participants (aged 15 years; 53% boys [n = 1660]) in the 1946 Medical Research Council National Survey of Health and Development, 6683 participants (aged 16 years; 51% boys [n = 3420]) in the 1958 National Child Development Study, and 4448 participants (aged 16 years; 48% boys [n = 2156]) in the 1970 British Birth Cohort Study. The proportion of children with bilateral normal vision decreased by 1.3% (95% CI, −5.1% to 2.7%) in 1974 and 1.7% (95% CI, −5.9% to 2.7%) in 1986. The risk of overall impaired vision increased by 1.20 times (95% CI, 1.01-1.43) and the risk of visual impairment/severe visual impairment/blindness by 1.75 times (95% CI, 1.03-2.98) during this period. Girls were consistently at increased risk of all vision impairment categories. Higher social position at birth and in childhood was associated with reduced risk of visual impairment/severe visual impairment/blindness (RR, 0.58; 95% CI, 0.20-1.68) and unilateral impairment (RR, 0.89; 95% CI, 0.72-1.11), respectively. Conclusions and Relevance Our study provides evidence of temporal decline in childhood visual function between 1961 and 1986. Despite the limited power of the analysis owing to the small sample size of those with impaired vision, we found an emergence of a contribution of sociodemographic status to the cohort effect that may be the antecedent of the current picture of childhood blindness. Equally, early-life social position may also have contributed to the current social patterning in visual function in older adults in the United Kingdom. These findings highlight the potential value of targeting children in national ophthalmic public policies tackling inequalities.

The aim of the study was to determine mean food availability based on the data of national Household Budget Surveys (HBS) provided for the years 1999 and 2004, and also to identify the trends in dietary patterns of the Croatian population according to the Data Food Networking (DAFNE) procedure.The Croatian National Statistics Bureau conducted the first HBS survey in 1999 on the sample of 2937 households and the second in 2004 on 2847 households, respectively. Those two raw data sets together with the data on relevant socio-demographic characteristics: household locality, number of household members, education and occupation of the household head were sent to the DAFNE coordinating centre in Athens. A post-harmonisation of the raw data was performed according to DAFNE procedure. Further, data were statistically analysed and integrated into the DAFNE databank (DafneSoft).Average daily food availability per person/day for both surveyed years seems to be satisfying. However, a dietary pattern showed discrepancies between proposed dietary guidelines and consumption of some food items. In comparison with proposed daily intake of 400 grams or more of fruits and vegetables, an average availability is lower and accounts 343 grams in 1999 and 314 grams in 2004. Availability of fish and seafood is low (23-27 g) but in the same time daily availability of meat and meat products is high (181-186 g), especially regarding red meat. During the five year period a decreasing trend is evident for availability of most food items, including lipids and sugar products. The availability has increased only for nuts, fruit and vegetable juices. The differences in availability of certain food groups are evident amongst some socio-economic categories of households. In urban households the availability of milk products, fish, vegetables, fruit and fruit juices is higher than in rural households, as it is in households with higher educated in comparison to low educated household heads. The highest food availability is registered in households with one person. However, there is a general trend that the food quantities are lowering in households with a growing number of persons.The data of HBS harmonised and statistically analysed according to DAFNE methodology offers the possibility to monitor and compare dietary habits and trends in food availability on national level as well as across European countries. If the HBS data are properly expanded and exploited they could become valuable tool for planning national food and nutrition policy, development of national dietary guidelines, promotion of healthy eating, planning and implementation of public health interventions, and for many other positive features.

Objective: To evaluate time trends in the availability of soft drinks, to identify food choices associated with their consumption and to assess the relationship between socio-economic status and daily soft drink availability in a wide range of European countries. Design: Data on food and beverage availability collected through the national household budget surveys and harmonized in the DAFNE (Data Food Networking) project were used. Averages and variability of soft drink availability were estimated and tests for time trends were performed. The daily availability of food groups which appear to be correlated with that of soft drinks was further estimated. Multivariate logistic and linear regression models were applied to evaluate the association between socio-economic status and the acquisition of soft drinks. Setting: Twenty-four European countries. Subjects: Nationally representative samples of households. Results: The availability of soft drinks is steadily and significantly increasing. Households in West and North Europe reported higher daily availability of soft drinks in comparison to other European regions. Soft drinks were also found to be correlated with lower availability of plant foods and milk and higher availability of meat and sugar products. Lower socio-economic status was associated with more frequent and higher availability of soft drinks in the household. Conclusions: Data collected in national samples of twenty-four European countries showed disparities in soft drink availability among socio-economic strata and European regions. The correlation of soft drinks with unfavourable dietary choices has public health implications, particularly among children and adolescents., DAFNE