Thyroid Dysfunction and Cardiovascular Events in Patients With Dysglycemia.

OBJECTIVES: Subclinical thyroid disease is the most common form of thyroid dysfunction and may be associated with adverse cardiovascular outcomes in people at high risk for cardiovascular events. Our objective in this study was to assess the association of thyroid function and thyroid hormone replacement with cardiovascular outcomes in high-risk individuals with dysglycemia and additional cardiovascular risk factors. METHODS: The relationship between baseline thyrotropin (TSH) level and incidence of the composite outcome of nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death; an expanded composite of this outcome plus revascularization or hospitalization for heart failure; and mortality was assessed in 8,401 ORIGIN trial participants with a baseline measurement of TSH. The hazard of each outcome according to either baseline levothyroxine use or TSH-defined hyperthyroidism, euthyroidism, subclinical hypothyroidism, and overt hypothyroidism was estimated before and after adjustment for baseline demographic and clinical characteristics and treatment allocation. RESULTS: Of all participants, 91.5% were euthyroid, 0.8% were hyperthyroid, 5.5% had subclinical hypothyroidism, and 2.2% had overt hypothyroidism. Subclinical hypothyroidism predicted both the expanded cardiovascular outcome (hazard ratio [HR]=1.24, 95% confidence interval [CI] 1.06 to 1.46) and mortality (HR=1.37, 95% CI 1.12 to 1.67), whereas levothyroxine use predicted fewer deaths (HR=0.72, 95% CI 0.56 to 0.94). CONCLUSION: Subclinical hypothyroidism predicts future cardiovascular events and mortality in people with dysglycemia and other cardiovascular risk factors.

Robust odor identification in novel olfactory environments in mice.

Relevant odors signaling food, mates, or predators can be masked by unpredictable mixtures of less relevant background odors. Here, we developed a mouse behavioral paradigm to test the role played by the novelty of the background odors. During the task, mice identified target odors in previously learned background odors and were challenged by catch trials with novel background odors, a task similar to visual CAPTCHA. Female wild-type (WT) mice could accurately identify known targets in novel background odors. WT mice performance was higher than linear classifiers and the nearest neighbor classifier trained using olfactory bulb glomerular activation patterns. Performance was more consistent with an odor deconvolution method. We also used our task to investigate the performance of female Cntnap2-/- mice, which show some autism-like behaviors. Cntnap2-/- mice had glomerular activation patterns similar to WT mice and matched WT mice target detection for known background odors. However, Cntnap2-/- mice performance fell almost to chance levels in the presence of novel backgrounds. Our findings suggest that mice use a robust algorithm for detecting odors in novel environments and this computation is impaired in Cntnap2-/- mice.

Nailfold capillaroscopy and deep learning in diabetes.

OBJECTIVE: To determine whether nailfold capillary images, acquired using video capillaroscopy, can provide diagnostic information about diabetes and its complications. RESEARCH DESIGN AND METHODS: Nailfold video capillaroscopy was performed in 120 adult patients with and without type 1 or type 2 diabetes, and with and without cardiovascular disease. Nailfold images were analyzed using convolutional neural networks, a deep learning technique. Cross-validation was used to develop and test the ability of models to predict five5 prespecified states (diabetes, high glycosylated hemoglobin, cardiovascular event, retinopathy, albuminuria, and hypertension). The performance of each model for a particular state was assessed by estimating areas under the receiver operating characteristics curves (AUROC) and precision recall curves (AUPR). RESULTS: A total of 5236 nailfold images were acquired from 120 participants (mean 44 images per participant) and were all available for analysis. Models were able to accurately identify the presence of diabetes, with AUROC 0.84 (95% confidence interval [CI] 0.76, 0.91) and AUPR 0.84 (95% CI 0.78, 0.93), respectively. Models were also able to predict a history of cardiovascular events in patients with diabetes, with AUROC 0.65 (95% CI 0.51, 0.78) and AUPR 0.72 (95% CI 0.62, 0.88) respectively. CONCLUSIONS: This proof-of-concept study demonstrates the potential of machine learning for identifying people with microvascular capillary changes from diabetes based on nailfold images, and for possibly identifying those most likely to have diabetes-related complications.

Are U-shaped relationships between risk factors and outcomes artifactual?

BACKGROUND: The objective of this study was to evaluate whether the observed nadir in a U- or J-shaped relationship between a particular risk factor and a future health outcome is a function of the distribution of the risk factor in the sample being analyzed. METHODS: Data from the ORIGIN trial were used to assess the relationship between three risk factors (weight, systolic blood pressure, and serum insulin) and the hazard of a major cardiovascular event comprising a nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. Three spline curves were generated for each risk factor. The first was based on all available data, the second for a subgroup with a higher mean risk factor level, and the third for a subgroup with a lower mean risk factor level. Nadir levels of the risk factor (i.e., risk factor levels predicting the lowest hazard) were then identified for each spline curve. RESULTS: When compared to the nadir values based on all available data, nadir values for all three risk factors were higher for the subgroups with higher mean levels and lower for those with lower mean levels. CONCLUSIONS: The distribution of a risk factor in the population is an important determinant of its nadir value. Populations with high or low values may have high and low nadirs, respectively. Identification of a nadir for a modifiable risk factor from epidemiologic relationships may therefore arise from this distribution bias and is therefore unrelated to therapeutic targets.

Age Demographics of Subjects Enrolled in Global, Interventional Phase 3 Melanoma Clinical Trials.

BACKGROUND: Melanoma is a skin cancer with a rising worldwide incidence of just over 280,000 individuals with the greatest burden of illness in European, New Zealander, and Australian populations. Patients are diagnosed with melanoma with the mean and median ages being 65 and 59 years old, respectively. Phase 3 trials not only provide a wide representation of the target population but also study the efficacy for a certain intervention. OBJECTIVE: The objective of this literature review is to analyze patient demographics of phase 3 trials for melanoma and identify if there is a true disparity between the clinical trial age demographics and the natural epidemiological age demographics. DATA SOURCES: The authors conducted a search on clinicaltrials.gov, a publicly available resource that lists clinical trials and their data. The reported mean and median ages for each trial were extracted after determining if each trial meets our inclusion criteria. Weighted mean and median ages were calculated using an online calculator. Data from 35 trials were evaluated with 30 trials reporting a weighted mean age of 55.85 years and 5 trials reporting a weighted median age of 55.14 years. CONCLUSION: Based on the results, melanoma clinical trials enroll patients who are younger than the epidemiological mean and median ages. Due to this underrepresentation of the elderly patients with melanoma, clinical trials may provide limited application for the use of their results.

A Dive Into Oliceridine and Its Novel Mechanism of Action.

The current state of the opioid epidemic has revealed the need of utilizing proper pain management, especially in the postoperative setting where there is overuse of potent analgesics. However, the adequate treatment of pain is necessary to reduce mortality and cost of burden while increasing recovery and improving quality of life. Treatment of pain can be difficult to standardize as the guidelines from the American Pain Society discuss the importance of tailoring treatment options based on a patient's sensitivities and risk factors. An effective fast-acting analgesic with adequate potency and few adverse events is the key to alleviating acute pain. Oliceridine (Olinvyk®, Trevena Inc., Chesterbrook, USA) is a novel G protein-biased µ-opioid receptor agonist designed to decrease opioid-related adverse events (ORAEs) compared to conventional opioids. This article discusses oliceridine's novel mechanism of action and current place in therapy. After a literature search on clinicaltrials.gov, three clinical trials were analyzed to understand the safety and efficacy of oliceridine. These trials demonstrated a comparable efficacy to morphine with a decreased risk for serious adverse events. However, further studies need to be conducted to evaluate the true safety impact of oliceridine compared to conventional opioids.

Cardiovascular Outcomes Trials of Glucose-Lowering Drugs or Strategies in Type 2 Diabetes.

As recently as 20 years ago there were no randomized controlled trials of potentially cardiovascular protective therapies in people with type 2 diabetes. The ongoing cardiovascular trials bring needed evidence. Both primary and subsidiary analyses have transformed diabetes from a largely eminence based specialty to one that is firmly evidence based. These studies have provided evidence supporting glucose-lowering drugs for patients with cardiovascular risk factors. Randomized controlled trials such as those described here will continue to challenge assumptions and create new approaches and paradigms that can be pursued to reduce and hopefully eliminate serious cardiovascular and other consequences of diabetes.

Low Use of Oral Anticoagulant Prescribing for Secondary Stroke Prevention: Results From the Ontario Stroke Registry.

BACKGROUND: Oral anticoagulation reduces the risk of stroke in atrial fibrillation but is often underused. OBJECTIVES: To identify factors associated with oral anticoagulant prescribing and adherence after stroke or transient ischemic attack (TIA). RESEARCH DESIGN: Retrospective cohort study using linked Ontario Stroke Registry and prescription claims data. SUBJECTS: Consecutive patients with atrial fibrillation and ischemic stroke/TIA admitted to 11 stroke centers in Ontario, Canada between 2003 and 2011. MEASURES: We used modified Poisson regression models to determine predictors of anticoagulant prescribing and multiple logistic regression to determine predictors of 1-year adherence. RESULTS: Of the 5781 patients in the study cohort, 4235 (73%) were prescribed oral anticoagulants at discharge. Older patients were less likely to receive anticoagulation [adjusted relative risk (aRR) for each additional year=0.997; 95% confidence interval (CI), 0.995-0.998], as were those with TIA compared with ischemic stroke (aRR=0.904; 95% CI, 0.865-0.945), prior gastrointestinal bleed (aRR=0.778; 95% CI, 0.693-0.873), dementia (aRR=0.912; 95% CI, 0.856-0.973), and those from a long-term care facility (aRR=0.810; 95% CI, 0.737-0.891). After limiting the sample to those without obvious contraindications to anticoagulation, age, dementia, and long-term care residence continued to be associated with lower prescription of oral anticoagulants. One-year adherence to therapy was similar across most patient groups. CONCLUSIONS: Age, dementia, and long-term care residence are predictors of lower oral anticoagulant use for secondary stroke prevention and represent key target areas for quality improvement initiatives.

Erythropoietin and glucose homeostasis in women at varying degrees of future diabetic risk.

AIMS/BACKGROUND: Recently, there has been considerable interest in the potential anti-diabetic effects of erythropoietin in animal models. It is not known, however, whether endogenous erythropoietin is associated with glucose regulation in humans. METHODS: We evaluated the longitudinal relationship between endogenous erythropoietin at 3-months postpartum and glucose homeostasis at 12-months postpartum in a cohort of 229 women with varying degrees of glucose intolerance in their recent pregnancy, a model of the early natural history of pre-diabetes/diabetes. The women reflected the full spectrum of glucose tolerance in pregnancy from normal (n=63) to mildly abnormal (n=65) to gestational impaired glucose tolerance (n=46) to gestational diabetes (n=55), and hence a broad range of future diabetic risk. RESULTS: At 3-months postpartum, there was no difference in serum erythropoietin between these 4 groups (p=0.22). After covariate adjustment, erythropoietin was not associated with beta-cell function, insulin sensitivity, or glycemia at either 3- or 12-months postpartum. On multiple linear regression analyses, however, erythropoietin at 3-months emerged as an independent predictor of both systolic (beta=0.51326, p=0.003) and diastolic blood pressure (beta=0.3321, p=0.01) at 12-months. CONCLUSION: Endogenous erythropoietin is not associated with glucose homeostasis early in the natural history of metabolic disease, but may be relevant to vascular health.

Management of a large periapical lesion using Biodentine(™) as retrograde restoration with eighteen months evident follow up.

Injury to anterior teeth is a common event. It requires a treatment approach that assures the complete biologic healing and functional restoration of the tooth or teeth involved. A cystic lesion, which is unable to heal nonsurgically, heals well with surgical intervention and use of mineral trioxide aggregate (MTA) as retrograde filling has been reported in literature. Another material with largely improved handling properties; Biodentine(™) (Septodont, St. Maurdes Fossés, France) was introduced in 2011. It is a calcium silicate based material and manufacturers claim that it can be used for crown and root dentin repair treatment, repair of perforations or resorptions, apexification, and root end fillings. This article presents a case report of surgical management of a large cystic lesion using Biodentine(™) as retrograde filling material which has not been reported in literature so far. Eighteen months radiographic follow-up exhibited completely healed cystic lesion.

Combination of blepharospasm and apraxia of eyelid opening: a condition resistant to treatment.

Blepharospasm is seen in many cases of Parkinsonism including progressive supranuclear palsy. These patients usually respond well to botulinum toxin, however some patients subsequently fail to respond to even higher doses of botulinum toxin after an initial good response. They should not be considered failure of treatment with botulinum toxin, as a significant number of these patients have underlying apraxia of eyelid opening in addition to blepharospasm, which may be the cause of failure to respond to botulinum toxin. Combination of eyelid crutches or myomectomy with botulinum toxin is more effective in these patients as compared to an individual treatment modality. In this report, we present two patients with progressive supranuclear palsy who failed to respond to botulinum toxin because they had underlying apraxia of lid opening. Partial myomectomy in one patient and eyelid crutches in the other in combination with botulinum toxin lead to a much better response to botulinum toxin.

Evaluation of care management for the uninsured.

BACKGROUND: In 2008, Kern Medical Center established a Care Management Program (CMP) for low-income adults identified as frequent users of hospital services. Frequent users are defined as having 4 or more emergency department (ED) visits or admissions, 3 or more admissions, or 2 or more admissions and 1 ED visit within 1 year. The CMP helps patients access primary care and medical and social resources. OBJECTIVE: To determine whether the CMP reduces ED visits and hospitalizations among frequent users. METHOD: Between August 2007 and January 2010, a retrospective analysis was conducted using Kern Medical Center encounter data. ED visits and inpatient visits were compared pre- and postenrollment for care managed patients (n = 98). The analysis included a comparison group (n = 160) of frequent users matched on the basis of race and age. Multivariate analyses were performed to evaluate the difference in utilization between groups, and to adjust for potential group differences. RESULTS: There was a reduction in the median number of ED visits per year from 6.0 ± 5.0 (median ± interquartile range) pre-enrollment to 1.7 ± 3.3 [corrected] postenrollment (P < 0.0001). The difference in inpatient admissions pre- and postenrollment was 0.0 ± 1.0 (P < 0.0001). After adjusting for multiple factors, multivariate analysis demonstrated that care managed patients had a 32% lower risk of visiting the ED than the comparison group (P < 0.0001). There was no difference in inpatient admissions between groups. CONCLUSIONS: CMP that helps patients navigate the health care system and access social and medical resources show significant promise in reducing ED utilization.

Strain differences in the impact of dietary restriction on fetal growth and pregnancy in mice.

The association between suboptimal intrauterine environment and developmental origins of adult health and disease is variable, suggesting that genotype may contribute to eventual outcome. The objective of this study was to characterize maternal and fetal responses to maternal dietary restriction during pregnancy in 2 phylogenetically distant strains of mice. Pregnant A/J (n=35) and C57BL/6J (B6) (n=36) mice underwent either a 30% dietary restriction (DR) from day 6.5 until day 17.5 of gestation or were fed ad libitum. Seven mothers from each strain and diet were randomly selected for dissection on day 18.5 to assess fetal body and organ weights and maternal endocrine status through the collection of serum to measure progesterone, corticosterone, cortisol, and estradiol levels. The remaining mice were allowed to deliver spontaneously to assess gestational effects. Both strains showed similar responses to maternal DR during pregnancy in terms of reductions in maternal weight gain during pregnancy, reductions in fetal body weight, increased pup death within 24 hours of birth, and decreased placental 11beta-HSD2 protein expression. The impact of maternal DR was greater in B6 mice than A/J when assessing reductions in fetal kidney weight, embryo-placenta ratio, increases in placental weight, fetal brain-liver ratio, and maternal corticosterone and cortisol levels. Moreover, preterm delivery was significantly increased in DR B6 mice compared to DR A/J mice. The observed strain variations in response to dietary restriction may offer a unique opportunity to investigate gene-environment interactions associated with developmental origins of adult health and disease.