SEARCH for Diabetes in Youth (SEARCH) was initiated in 2000 as a multicenter study to address major gaps in the understanding of childhood diabetes in the United States. An active registry of youth ...diagnosed with diabetes at age <20 years since 2002 assessed prevalence, annual incidence, and trends by age, race/ethnicity, sex, and diabetes type. An observational cohort nested within the population‐based registry was established to assess the natural history and risk factors for acute and chronic diabetes‐related complications, as well as the quality of care and quality of life of children and adolescents with diabetes from diagnosis into young adulthood. SEARCH findings have contributed to a better understanding of the complex and heterogeneous nature of youth‐onset diabetes. Continued surveillance of the burden and risk of type 1 and type 2 diabetes is important to track and monitor incidence and prevalence within the population. SEARCH reported evidence of early diabetes complications highlighting that continuing the long‐term follow‐up of youth with diabetes is necessary to further our understanding of its natural history and to develop the most appropriate approaches to primary, secondary, and tertiary prevention of diabetes and its complications. This review summarizes two decades of research and suggests avenues for further work.
We provide a summary of the design and methods used, and an overview of major findings since the inception of the SEARCH for Diabetes in Youth Study in 2000. These include a summary of the risk, burden, and prognosis of diabetes diagnosed under the age of 20 years, with an emphasis on the disparities that were identified over these years. We also summarize morbidity and mortality information; patterns of, and barriers to, care of diabetes in youth; behavioral and social correlates; issues related to sustainable surveillance; and what the increase in young adults with diabetes who become parents implies.
Clinical biomarkers for brain metastases remain elusive. Increased availability of genomic profiling has brought discovery of these biomarkers to the forefront of research interests.
In this single ...institution retrospective series, 130 patients presenting with brain metastasis secondary to Non-Small Cell Lung Cancer (NSCLC) underwent comprehensive genomic profiling conducted using next generation circulating tumor deoxyribonucleic acid (DNA) (Guardant Health, Redwood City, CA). A total of 77 genetic mutation identified and correlated with nine clinical outcomes using appropriate statistical tests (general linear models, Mantel-Haenzel Chi Square test, and Cox proportional hazard regression models). For each outcome, a genetic signature composite score was created by summing the total genes wherein genes predictive of a clinically unfavorable outcome assigned a positive score, and genes with favorable clinical outcome assigned negative score.
Seventy-two genes appeared in at least one gene signature including: 14 genes had only unfavorable associations, 36 genes had only favorable associations, and 22 genes had mixed effects. Statistically significant associated signatures were found for the clinical endpoints of brain metastasis velocity, time to distant brain failure, lowest radiosurgery dose, extent of extracranial metastatic disease, concurrent diagnosis of brain metastasis and NSCLC, number of brain metastases at diagnosis as well as distant brain failure. Some genes were solely associated with multiple favorable or unfavorable outcomes.
Genetic signatures were derived that showed strong associations with different clinical outcomes in NSCLC brain metastases patients. While these data remain to be validated, they may have prognostic and/or therapeutic impact in the future.
Using Liquid biopsy in NSCLC brain metastases patients, the genetic signatures identified in this series are associated with multiple clinical outcomes particularly these ones that lead to early or more numerous metastases. These findings can be reverse-translated in laboratory studies to determine if they are part of the genetic pathway leading to brain metastasis formation.
Cancers related to tobacco use and African-American ancestry are under-characterized by genomics. This gap in precision oncology research represents a major challenge in the health disparities in the ...United States.
The Precision Oncology trial at the Wake Forest Baptist Comprehensive Cancer Center enrolled 431 cancer patients from March 2015 to May 2016. The composition of these patients consists of a high representation of tobacco-related cancers (e.g., lung, colorectal, and bladder) and African-American ancestry (13.5%). Tumors were sequenced to identify mutations to gain insight into genetic alterations associated with smoking and/or African-American ancestry.
Tobacco-related cancers exhibit a high mutational load. These tumors are characterized by high-frequency mutations in
, DNA damage repair genes (
and
and chromatin remodeling genes (the lysine methyltransferases
or
, and
or
. These tobacco-related cancers also exhibit augmented tumor heterogeneities. Smoking related genetic mutations were validated by The Cancer Genome Atlas dataset that includes 2,821 cases with known smoking status. The Wake Forest and The Cancer Genome Atlas cohorts (431 and 7,991 cases, respectively) revealed a significantly increased mutation rate in the
gene in the African-American subgroup studied. Both cohorts also revealed 5 genes (e.g.
) significantly amplified in the African-American population.
These results provide strong evidence that tobacco is a major cause of genomic instability and heterogeneity in cancer.
mutations and key oncogene amplifications emerge as key factors contributing to cancer outcome disparities among different racial/ethnic groups.
Objective To evaluate the effects of smoking on early markers of cardiovascular disease (arterial stiffness) in adolescents with and without type 1 diabetes (T1D) in the SEARCH Cardiovascular Disease ...Study. Study design Participants included 606 youth (18.9 ± 3.3 years, 83% non-Hispanic white; 50% male). Six groups were defined: (1) smokers with T1D (n = 80); (2) former smokers with T1D (n = 88); (3) nonsmokers with T1D (n = 232); (4) smokers without T1D (n = 40); (5) former smokers without T1D former (n = 51); and (6) nonsmokers without T1D (n = 115). Arterial stiffness measurements included pulse wave velocity (PWV), augmentation index, and brachial distensibility. Multivariate linear regression was used to assess the independent and joint effects of T1D and smoking on arterial stiffness. Results Nearly 20% of both youth with and without T1D and T1D were smokers. In youth without T1D, smokers had higher trunk and arm PWV. After adjustment for potential confounders, T1D, but not smoking, was an independent predictor of PWV ( P < .05). Moreover, smoking status did not modify the association between T1D and increased arterial stiffness. Conclusions We found a high prevalence of smoking among youth with and without T1D; however, smoking status was not independently associated with increased arterial stiffness in youth with T1D.
Atherosclerotic renal artery stenosis is a problem with no consensus on diagnosis or therapy. The consequences of renal ischemia are neuroendocrine activation, hypertension, and renal insufficiency ...that can potentially result in acceleration of atherosclerosis, further renal dysfunction, myocardial infarction, heart failure, stroke, and death. Whether revascularization improves clinical outcomes when compared with optimum medical therapy is unknown.
CORAL is a randomized clinical trial contrasting optimum medical therapy alone to stenting with optimum medical therapy on a composite cardiovascular and renal end point: cardiovascular or renal death, myocardial infarction, hospitalization for congestive heart failure, stroke, doubling of serum creatinine, and need for renal replacement therapy. The secondary end points evaluate the effectiveness of revascularization in important subgroups of patients and with respect to all-cause mortality, kidney function, renal artery patency, microvascular renal function, and blood pressure control. We will also correlate stenosis severity with longitudinal renal function and determine the value of stenting from the perspectives of quality of life and cost-effectiveness. The primary entry criteria are (1) an atherosclerotic renal stenosis of ≥60% with a 20 mm Hg systolic pressure gradient or ≥80% with no gradient necessary and (2) systolic hypertension of ≥155 mm Hg on ≥2 antihypertensive medications. Randomization will occur in 1080 subjects. The study has 90% power to detect a 28% reduction in primary end point hazard rate.
CORAL represents a unique opportunity to determine the incremental value of stent revascularization, in addition to optimal medical therapy, for the treatment of atherosclerotic renal artery stenosis.
The investigators used NHANES data for 2005 to 2010 to extrapolate the effects of the new 2013 cholesterol treatment guidelines across the United States. They estimate that the new guidelines would ...increase the number of adults eligible for statin therapy by 12.8 million.
Until recently, the guidelines of the Third Adult Treatment Panel (ATP III) of the National Cholesterol Education Program were the recommended guidelines to aid in the treatment of hyperlipidemia in the United States.
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The ATP-III guidelines identified patients with established cardiovascular disease or diabetes and low-density lipoprotein (LDL) cholesterol levels of 100 mg per deciliter (2.59 mmol per liter) or higher as candidates for statin therapy. In addition, the ATP-III guidelines recommended the use of statin therapy for primary prevention in patients on the basis of a combined assessment of LDL cholesterol level and the 10-year risk of coronary . . .
The registry-based randomized trial may make less expensive, more efficient clinical studies possible. But before the new study design can be widely used, questions about the quality of the ...underlying data sets must be addressed.
The randomized trial is one of the most powerful tools clinical researchers possess, a tool that enables them to evaluate the effectiveness of new (or established) therapies while accounting for the effects of unmeasured confounders and selection bias by indication. Randomized trials, especially huge megatrials, have transformed medical practice. Thanks to randomized trials, we no longer, for example, treat acute myocardial infarction with lidocaine and nitrates. Instead we use rapid revascularization, anticoagulants, and antiplatelet agents, and during long-term follow-up we routinely prescribe statins, beta-blockers, and angiotensin-converting–enzyme inhibitors. But the reputation of randomized trials has suffered of late,
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owing to reasonable . . .
Many young adults with moderate hyperlipidemia do not meet statin treatment criteria under the new American Heart Association/American College of Cardiology cholesterol guidelines because they focus ...on 10-year cardiovascular risk. We evaluated the association between years of exposure to hypercholesterolemia in early adulthood and future coronary heart disease (CHD) risk.
We examined Framingham Offspring Cohort data to identify adults without incident cardiovascular disease to 55 years of age (n=1478), and explored the association between duration of moderate hyperlipidemia (non-high-density lipoprotein cholesterol ≥ 160 mg/dL) in early adulthood and subsequent CHD. At median 15-year follow-up, CHD rates were significantly elevated among adults with prolonged hyperlipidemia exposure by 55 years of age: 4.4% for those with no exposure, 8.1% for those with 1 to 10 years of exposure, and 16.5% for those with 11 to 20 years of exposure (P<0.001); this association persisted after adjustment for other cardiac risk factors including non-high-density lipoprotein cholesterol at 55 years of age (hazard ratio, 1.39; 95% confidence interval, 1.05-1.85 per decade of hyperlipidemia). Overall, 85% of young adults with prolonged hyperlipidemia would not have been recommended for statin therapy at 40 years of age under current national guidelines. However, among those not considered statin therapy candidates at 55 years of age, there remained a significant association between cumulative exposure to hyperlipidemia in young adulthood and subsequent CHD risk (adjusted hazard ratio, 1.67; 95% confidence interval, 1.06-2.64).
Cumulative exposure to hyperlipidemia in young adulthood increases the subsequent risk of CHD in a dose-dependent fashion. Adults with prolonged exposure to even moderate elevations in non-high-density lipoprotein cholesterol have elevated risk for future CHD and may benefit from more aggressive primary prevention.
In this trial, 947 patients with renal-artery stenosis were assigned to renal-artery stenting or medical therapy. At a median of 43 months, there was no significant between-group difference in the ...rate of a composite end point of adverse cardiovascular and renal events.
Renal-artery stenosis, which is present in 1 to 5% of people with hypertension,
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often occurs in combination with peripheral arterial or coronary artery disease.
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Results of community-based screening suggest that the prevalence among persons older than 65 years of age may be as high as 7%.
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Renal-artery stenosis may result in hypertension, ischemic nephropathy, and multiple long-term complications.
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Uncontrolled studies performed in the 1990s suggested that renal-artery angioplasty or stenting resulted in significant reductions in systolic blood pressure
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and in the stabilization of chronic kidney disease.
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Subsequently, there were rapid increases in the rate of renal-artery . . .
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