Abstract Background Although epidemiological studies have reported positive associations between circulating urate levels and cardiometabolic diseases, causality remains uncertain. Objectives Through ...a Mendelian randomization approach, we assessed whether serum urate levels are causally relevant in type 2 diabetes mellitus (T2DM), coronary heart disease (CHD), ischemic stroke, and heart failure (HF). Methods This study investigated 28 single nucleotide polymorphisms known to regulate serum urate levels in association with various vascular and nonvascular risk factors to assess pleiotropy. To limit genetic confounding, 14 single nucleotide polymorphisms exclusively associated with serum urate levels were used in a genetic risk score to assess associations with the following cardiometabolic diseases (cases/controls): T2DM (26,488/83,964), CHD (54,501/68,275), ischemic stroke (14,779/67,312), and HF (4,526/18,400). As a positive control, this study also investigated our genetic instrument in 3,151 gout cases and 68,350 controls. Results Serum urate levels, increased by 1 SD due to the genetic score, were not associated with T2DM, CHD, ischemic stroke, or HF. These results were in contrast with previous prospective studies that did observe increased risks of these 4 cardiometabolic diseases for an equivalent increase in circulating urate levels. However, a 1 SD increase in serum urate levels due to the genetic score was associated with increased risk of gout (odds ratio: 5.84; 95% confidence interval: 4.56 to 7.49), which was directionally consistent with previous observations. Conclusions Evidence from this study does not support a causal role of circulating serum urate levels in T2DM, CHD, ischemic stroke, or HF. Decreasing serum urate levels may not translate into risk reductions for cardiometabolic conditions.
The human left and right atria have different susceptibilities to develop atrial fibrillation (AF). However, the molecular events related to structural and functional changes that enhance AF ...susceptibility are still poorly understood.
The purpose of this study was to characterize gene expression and genetic variation in human atria.
We studied the gene expression profiles and genetic variations in 53 left atrial and 52 right atrial tissue samples collected from the Myocardial Applied Genomics Network (MAGNet) repository. The tissues were collected from heart failure patients undergoing transplantation and from unused organ donor hearts with normal ventricular function. Gene expression was profiled using the Affymetrix GeneChip Human Genome U133A Array. Genetic variation was profiled using the Affymetrix Genome-Wide Human SNP Array 6.0.
We found that 109 genes were differentially expressed between left and right atrial tissues. A total of 187 and 259 significant cis-associations between transcript levels and genetic variants were identified in left and right atrial tissues, respectively. We also found that a single nucleotide polymorphism at a known AF locus, rs3740293, was associated with the expression of MYOZ1 in both left and right atrial tissues.
We found a distinct transcriptional profile between the right and left atrium and extensive cis-associations between atrial transcripts and common genetic variants. Our results implicate MYOZ1 as the causative gene at the chromosome 10q22 locus for AF.
Summary Background Human genome sequencing has transformed our understanding of genomic variation and its relevance to health and disease, and is now starting to enter clinical practice for the ...diagnosis of rare diseases. The question of whether and how some categories of genomic findings should be shared with individual research participants is currently a topic of international debate, and development of robust analytical workflows to identify and communicate clinically relevant variants is paramount. Methods The Deciphering Developmental Disorders (DDD) study has developed a UK-wide patient recruitment network involving over 180 clinicians across all 24 regional genetics services, and has performed genome-wide microarray and whole exome sequencing on children with undiagnosed developmental disorders and their parents. After data analysis, pertinent genomic variants were returned to individual research participants via their local clinical genetics team. Findings Around 80 000 genomic variants were identified from exome sequencing and microarray analysis in each individual, of which on average 400 were rare and predicted to be protein altering. By focusing only on de novo and segregating variants in known developmental disorder genes, we achieved a diagnostic yield of 27% among 1133 previously investigated yet undiagnosed children with developmental disorders, whilst minimising incidental findings. In families with developmentally normal parents, whole exome sequencing of the child and both parents resulted in a 10-fold reduction in the number of potential causal variants that needed clinical evaluation compared to sequencing only the child. Most diagnostic variants identified in known genes were novel and not present in current databases of known disease variation. Interpretation Implementation of a robust translational genomics workflow is achievable within a large-scale rare disease research study to allow feedback of potentially diagnostic findings to clinicians and research participants. Systematic recording of relevant clinical data, curation of a gene–phenotype knowledge base, and development of clinical decision support software are needed in addition to automated exclusion of almost all variants, which is crucial for scalable prioritisation and review of possible diagnostic variants. However, the resource requirements of development and maintenance of a clinical reporting system within a research setting are substantial. Funding Health Innovation Challenge Fund, a parallel funding partnership between the Wellcome Trust and the UK Department of Health.
The Society for Sarcopenia, Cachexia, and Wasting Disease convened an expert panel to develop nutritional recommendations for prevention and management of sarcopenia. Exercise (both resistance and ...aerobic) in combination with adequate protein and energy intake is the key component of the prevention and management of sarcopenia. Adequate protein supplementation alone only slows loss of muscle mass. Adequate protein intake (leucine-enriched balanced amino acids and possibly creatine) may enhance muscle strength. Low 25(OH) vitamin D levels require vitamin D replacement.
Previous coronary artery bypass grafting increases predicted operative risk for conventional valve replacement, according to the Society of Thoracic Surgeons risk algorithm. Additionally, the ...presence of coronary artery disease (CAD) has been demonstrated to increase procedural risk with conventional aortic valve replacement. Significant coexisting CAD requires preemptive percutaneous coronary intervention (PCI) in patients under consideration for transcatheter aortic valve implantation (TAVI). This study examined the impact of previous coronary artery bypass grafting or PCI on procedural outcomes and overall survival in patients having TAVI.
Two hundred and one high-risk patients were enrolled in two international feasibility studies from December 2005 to February 2008 for the treatment of aortic stenosis using TAVI. Thirty patients were excluded from analysis due to failure to successfully deploy the valve in the aortic annulus. Data were collected concurrently using an ad hoc database that included operative and long-term survival. Previous cardiovascular intervention prior to TAVI was used to identify the existence of concomitant CAD. Logistic regression along with Kaplan-Meier estimates were employed to establish the association between CAD and survival from TAVI.
Overall mortality after TAVI was significantly higher among the CAD group (35.7%) in contrast with the non-CAD patients (18.4%), p = 0.01. Logistic regression analysis found that patients who had CAD were 10.1 times more likely to die (95% confidence interval 2.1 to 174.8) within 30 days of the procedure than those who did not. Proportional hazards analysis established that the risk of dying at any point in time was 2.3 times higher among the patients with CAD (95% confidence interval 1.29 to 4.17). Kaplan-Meier survival curves demonstrate improved long-term survival among patients without CAD.
Coexisting coronary artery disease negatively impacts procedural outcomes and long-term survival in patients undergoing TAVI, and implies that risk assessment and anticipated outcomes might be inaccurate due to stratification as isolated aortic valve replacement rather than AVR+CABG. Comparison of procedural outcomes, based on operative approach without controlling for unequal distribution of CAD in the cohorts, are likely invalid.
We did a systematic review of reviews with evidence on the effectiveness of prevention, early intervention, harm reduction, and treatment of problem use in young people for tobacco, alcohol, and ...illicit drugs (eg, cannabis, opioids, amphetamines, or cocaine). Taxation, public consumption bans, advertising restrictions, and minimum legal age are effective measures to reduce alcohol and tobacco use, but are not available to target illicit drugs. Interpretation of the available evidence for school-based prevention is affected by methodological issues; interventions that incorporate skills training are more likely to be effective than information provision-which is ineffective. Social norms and brief interventions to reduce substance use in young people do not have strong evidence of effectiveness. Roadside drug testing and interventions to reduce injection-related harms have a moderate-to-large effect, but additional research with young people is needed. Scarce availability of research on interventions for problematic substance use in young people indicates the need to test interventions that are effective with adults in young people. Existing evidence is from high-income countries, with uncertain applicability in other countries and cultures and in subpopulations differing in sex, age, and risk status. Concerted efforts are needed to increase the evidence base on interventions that aim to reduce the high burden of substance use in young people.
During puberty, when young people are completing their education, transitioning into employment, and forming longer-term intimate relationships, a shift in emotional regulation and an increase in ...risky behaviour, including substance use, is seen. This Series paper considers the potential effects of alcohol, tobacco, and illicit drug use during this period on: social, psychological, and health outcomes in adolescence and young adulthood; role transitions, and later health and social outcomes of regular substance use initiated in adolescence; and the offspring of young people who use substances. We sourced consistent support for causal relations between substance use and outcomes and evidence of biological plausibility from different but complementary research designs. Many adverse health and social outcomes have been associated with different types of substance use. The major challenge lies in deciding which are causal. Furthermore, qualitatively different harms are associated with different substances, differences in life stage when these harms occur, and the quality of evidence for different substances and health outcomes varies substantially. The preponderance of evidence comes from a few high-income countries, thus whether the same social and health outcomes would occur in other countries and cultures is unclear. Nonetheless, the number of harms that are causally related to substance use in young people warrant high-quality research design interventions to prevent or ameliorate these harms.
Objective Risk algorithms were used to identify a high-risk population for transcatheter aortic valve implantation instead of standard aortic valve replacement in patients with aortic stenosis. We ...evaluated the efficacy of these methods for predicting outcomes in high-risk patients undergoing aortic valve replacement. Methods Data were collected on 638 patients identified as having isolated aortic valve replacement between January 1, 1998 and December 31, 2006, using The Society of Thoracic Surgeons (STS) database. Long-term survival was determined from the Social Security Death Index or family contact. Operative risk was calculated using the STS Predicted Risk of Mortality, the EuroSCORE logistic and additive algorithms, and the Ambler Risk Score. Patients at or above the 90th percentile of risk (8.38% for STS, 33.47% for logistic, 12% for additive, 14.3% for Ambler) were identified as high risk. We then compared actual with predicted mortality and each algorithm’s ability to identify patients with the worst long-term survival. Results Operative mortality was 24 of 638 (3.76%). An additional 121 (19.0%) patients died during the follow-up study period (mean 4.2 ± 2.7 years). Overall mortality was 145 of 638 (22.7%). Expected versus observed mortality for the high-risk group by algorithm was 13.3% versus 18.8% for STS, 50.9% versus 15.6% for logistic, 14.0% versus 11.9% for additive, and 19.0% versus 13.4% by Ambler. Long-term mortality, per high-risk group, was 64.1% in the STS Predicted Risk of Mortality, 45.3% in the logistic, 45.2% in the additive, and 40.2% in Ambler Risk Score. Logistic regression showed that the STS algorithm was the most sensitive in defining the patients most at risk for long-term mortality. Conclusion The STS Predicted Risk of Mortality most accurately predicted perioperative and long-term mortality for the highest risk patients having aortic valve replacement.
The Society of Thoracic Surgeons predictive algorithms can be used to help patients understand the risks in having a surgical procedure. However, elderly patients are frequently more concerned about ...the quality of their remaining life and whether they will return home. Currently, we have no predictors of which patients are likely to return to independent living after surgery. We followed patients discharged home or to an extended care facility to determine which patients were most likely to return home and be alive at one year.
This single-hospital, retrospective study followed 590 cardiac surgery patients (January 2008 to December 2009) for at least 1 year after discharge. Follow-up data were collected by contacting facilities, patients, and families, and Social Security Death Index searches.
At hospital discharge, 84.4% went home, 3.7% to rehab, 7.5% to skilled nursing facilities (SNF), and 4.4% to a long-term acute care facility (LTAC). Predictors for facility discharge include increasing age, female, dialysis, emergent status, procedures other than CAB, preoperative stroke, and moderate to severe tricuspid insufficiency. The most significant predictors of dying or still being in a facility at 1 year include being on dialysis, right heart failure, and having chronic lung disease. Considering perioperative complications, requiring prolonged ventilation decreases the odds of being home and alive at 1 year by 67%: one-year survival at home, 95.4%; rehabilitation, 63.6%; SNF, 52.3%; and LTAC, 30.8%.
Many patients discharged to extended care do not return to their previous lifestyle; only 30.8% of those requiring care in a LTAC facility are alive at home at 1 year.
In the past decade, minimally invasive approaches have been developed for aortic valve surgery. We reviewed our data to determine if the use of the PORT ACCESS technique has improved hospital ...morbidity and mortality.
Data were collected on 90 patients who had a replacement of their aortic valve using PORT ACCESS procedures (PORT ACCESS aortic valve replacement PAVR). This group was then matched 1:4 to a control group having aortic valve replacement surgery using a standard sternotomy approach.
The two groups had no statistically significant differences in preoperative risk factors. The perioperative and 30-day outcomes from the matched AVR and PAVR groups showed no mortalities in the PAVR group and 3.1% in the AVR group. Mean length of stay was shorter for PAVR patients (7.2 +/- 5.0 days; median 6 days) compared with the mean stay in the sternotomy group (8.5 +/- 9.5 days; median 6 days), PAVR patients also had statistically significant shorter intensive care unit stays, and time on ventilator. The number of patients needing ventilator support postoperatively was significantly lower in the PORT ACCESS group. Cross-clamp and perfusion times were longer in the PAVR group. No other morbidity was significantly different between groups, except for postoperative tamponade (higher in PAVR group).
In this analysis of matched patients, the patients having aortic valve replacement using PORT ACCESS procedures, spent a shorter time in the intensive care unit and had less need for postoperative ventilator usage (both number of patients using a ventilator and the mean time of use) in comparison with patients undergoing conventional sternotomy.
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