Erin R. Wallace

Subclinical Thyroid Dysfunction and Fracture Risk: A Meta-analysis

IMPORTANCE Associations between subclinical thyroid dysfunction and fractures are unclear and clinical trials are lacking. OBJECTIVE To assess the association of subclinical thyroid dysfunction with hip, nonspine, spine, or any fractures. DATA SOURCES AND STUDY SELECTION The databases of MEDLINE and EMBASE (inception to March 26, 2015) were searched without language restrictions for prospective cohort studies with thyroid function data and subsequent fractures. DATA EXTRACTION Individual participant data were obtained from 13 prospective cohorts in the United States, Europe, Australia, and Japan. Levels of thyroid function were defined as euthyroidism (thyroid-stimulating hormone [TSH], 0.45-4.49 mIU/L), subclinical hyperthyroidism (TSH <0.45 mIU/L), and subclinical hypothyroidism (TSH ≥4.50-19.99 mIU/L) with normal thyroxine concentrations. MAIN OUTCOME AND MEASURES The primary outcome was hip fracture. Any fractures, nonspine fractures, and clinical spine fractures were secondary outcomes. RESULTS Among 70,298 participants, 4092 (5.8%) had subclinical hypothyroidism and 2219 (3.2%) had subclinical hyperthyroidism. During 762,401 person-years of follow-up, hip fracture occurred in 2975 participants (4.6%; 12 studies), any fracture in 2528 participants (9.0%; 8 studies), nonspine fracture in 2018 participants (8.4%; 8 studies), and spine fracture in 296 participants (1.3%; 6 studies). In age- and sex-adjusted analyses, the hazard ratio (HR) for subclinical hyperthyroidism vs euthyroidism was 1.36 for hip fracture (95% CI, 1.13-1.64; 146 events in 2082 participants vs 2534 in 56,471); for any fracture, HR was 1.28 (95% CI, 1.06-1.53; 121 events in 888 participants vs 2203 in 25,901); for nonspine fracture, HR was 1.16 (95% CI, 0.95-1.41; 107 events in 946 participants vs 1745 in 21,722); and for spine fracture, HR was 1.51 (95% CI, 0.93-2.45; 17 events in 732 participants vs 255 in 20,328). Lower TSH was associated with higher fracture rates: for TSH of less than 0.10 mIU/L, HR was 1.61 for hip fracture (95% CI, 1.21-2.15; 47 events in 510 participants); for any fracture, HR was 1.98 (95% CI, 1.41-2.78; 44 events in 212 participants); for nonspine fracture, HR was 1.61 (95% CI, 0.96-2.71; 32 events in 185 participants); and for spine fracture, HR was 3.57 (95% CI, 1.88-6.78; 8 events in 162 participants). Risks were similar after adjustment for other fracture risk factors. Endogenous subclinical hyperthyroidism (excluding thyroid medication users) was associated with HRs of 1.52 (95% CI, 1.19-1.93) for hip fracture, 1.42 (95% CI, 1.16-1.74) for any fracture, and 1.74 (95% CI, 1.01-2.99) for spine fracture. No association was found between subclinical hypothyroidism and fracture risk. CONCLUSIONS AND RELEVANCE Subclinical hyperthyroidism was associated with an increased risk of hip and other fractures, particularly among those with TSH levels of less than 0.10 mIU/L and those with endogenous subclinical hyperthyroidism. Further study is needed to determine whether treating subclinical hyperthyroidism can prevent fractures.

Blood pressure variability and the risk of all-cause mortality, incident myocardial infarction, and incident stroke in the cardiovascular health study

BACKGROUND Recent reports have linked variability in visit-to-visit systolic blood pressure (SBP) to risk of mortality and stroke, independent of the effect of mean SBP level. This study aimed to evaluate whether variability in SBP is associated with all-cause mortality, incident myocardial infarction (MI), and incident stroke, independent of mean SBP or trends in SBP levels over time. METHODS The Cardiovascular Health Study is a longitudinal cohort study of vascular risk factors and disease in the elderly. Participants who attended their first 5 annual clinic visits and experienced no event before the 5th visit were eligible (n = 3,852). Primary analyses were restricted to participants not using antihypertensive medications throughout the first 5 clinic visits (n = 1,642). Intraindividual SBP variables were defined using each participants 5-visit blood pressure measures. Cox proportional hazards models estimated adjusted hazard ratios (HRs) per SD increase in intraindividual SBP variability, adjusted for intraindividual SBP mean and change over time. RESULTS Over a mean follow-up of 9.9 years, there were 844 deaths, 203 MIs, and 195 strokes. Intraindividual SBP variability was significantly associated with increased risk of mortality (HR = 1.13; 95% confidence interval (CI) = 1.05-1.21) and of incident MI (HR = 1.20; 95%CI = 1.06-1.36), independent of the effect from adjustment factors. Intraindividual SBP variability was not associated with risk of stroke (HR = 1.03; 95% CI = 0.89-1.21). CONCLUSIONS Long-term visit-to-visit SBP variability was independently associated with a higher risk of subsequent mortality and MI but not stroke. More research is needed to determine the relationship of BP variability with cardiovascular risk and the clinical implications.

Population-based study of risk factors for severe maternal morbidity.

BACKGROUND Severe maternal morbidity (SMM) is a serious health condition potentially resulting in death without immediate medical attention, including organ failure, obstetric shock and eclampsia. SMM affects 20000 US women every year; however, few population-based studies have examined SMM risk factors. METHODS We conducted a population-based case-control study linking birth certificate and hospital discharge data from Washington State (1987-2008), identifying 9485 women with an antepartum, intrapartum or postpartum SMM with ≥3-day hospitalisation or transfer from another facility and 41 112 random controls. Maternal age, race, smoking during pregnancy, parity, pre-existing medical condition, multiple birth, prior caesarean delivery, and body mass index were assessed as risk factors with logistic regression to estimate odds ratios (OR) and 95% confidence intervals [CI], adjusted for education and delivery payer source. RESULTS Older women (35-39: OR 1.65 [CI 1.52, 1.79]; 40+: OR 2.48 [CI 2.16, 2.81]), non-White women (Black: OR 1.82 [CI 1.64, 2.01]; American Indian: OR 1.52 [CI 1.32, 1.73]; Asian/Pacific Islander: OR 1.30 [CI 1.19, 1.41]; Hispanic: OR 1.17 [CI 1.07, 1.27]) and women at parity extremes (nulliparous: OR 1.83 [CI 1.72, 1.95]; parity 3+: OR 1.34 [CI 1.23, 1.45]) were at greater risk of SMM. Women with a pre-existing medical condition (OR 2.10 [CI 1.88, 2.33]), a multiple birth (OR 2.54 [CI 2.26, 2.82]) and a prior caesarean delivery (OR 2.08 [CI 1.93, 2.23]) were also at increased risk. CONCLUSION The risk factors identified are not modifiable at the individual level; therefore, provider and system-level factors may be the most appropriate target for preventing SMM.

Intellectual and Academic Functioning of School-Age Children With Single-Suture Craniosynostosis

OBJECTIVE: We compared the developmental status of school-age children with single-suture craniosynostosis (case group) and unaffected children (control group). Within the case group we compared the performance of children distinguished by location of suture fusion (sagittal, metopic, unicoronal, lambdoid). METHODS: We administered standardized tests of intelligence, reading, spelling, and math to 182 case participants and 183 control participants. This sample represented 70% of those tested during infancy before case participants had corrective surgery. RESULTS: After adjustment for demographics, case participants’ average scores were lower than those of control participants on all measures. The largest observed differences were in Full-Scale IQ and math computation, where case participants’ adjusted mean scores were 2.5 to 4 points lower than those of control participants (Ps ranged from .002 to .09). Adjusted mean case–control differences on other measures of achievement were modest, although case deficits became more pronounced after adjustment for participation in developmental interventions. Among case participants, 58% had no discernible learning problem (score <25th percentile on a standardized achievement test). Children with metopic, unicoronal, and lambdoid synostosis tended to score lower on most measures than did children with sagittal fusions (Ps ranged from <.001 to .82). CONCLUSIONS: The developmental delays observed among infants with single-suture craniosynostosis are partially evident at school age, as manifested by lower average scores than those of control participants on measures of IQ and math. However, case participants’ average scores were only slightly lower than those of control participants on reading and spelling measures, and the frequency of specific learning problems was comparable. Among case participants, those with unicoronal and lambdoid fusions appear to be the most neurodevelopmentally vulnerable.

Plasma Phospholipid Saturated Fatty Acids and Incident Atrial Fibrillation: The Cardiovascular Health Study

Background Prior studies suggest that circulating fatty acids may influence the risk of atrial fibrillation (AF), but little is known about the associations of circulating saturated fatty acids with risk of AF. Methods and Results The study population included 2899 participants from the Cardiovascular Health Study, a community‐based longitudinal cohort of adults aged 65 years or older in the United States who were free of prevalent coronary heart disease and AF in 1992. Cox regression was used to assess the association of all the long‐chain saturated fatty acids—palmitic acid (16:0), stearic acid (18:0), arachidic acid (20:0), behenic acid (22:0), and lignoceric acid (24:0)—with incident AF. During a median of 11.2 years of follow‐up, 707 cases of incident AF occurred. After adjustment for other AF risk factors, higher levels of circulating 16:0 were associated with a higher risk of AF (hazard ratio comparing highest and lowest quartiles: 1.48; 95% CI: 1.18, 1.86). In contrast, higher levels of circulating 18:0, 20:0, 22:0, and 24:0 were each associated with a lower risk of AF. The hazard ratios (95% CI) for AF in the top and bottom quartiles were 0.76 (95% CI: 0.61, 0.95) for 18:0; 0.78 (95% CI: 0.63, 0.97) for 20:0; 0.62 (95% CI: 0.50, 0.78) for 22:0; and 0.68 (95% CI: 0.55, 0.85) for 24:0. Conclusions Results from this prospective cohort study of older adults demonstrate divergent associations of circulating 16:0 versus longer‐chain saturated fatty acids with incident AF, highlighting the need to investigate both determinants of these levels and potential pathways of the observed differential risk.

Serum urate levels and the risk of hip fractures: data from the Cardiovascular Health Study

PURPOSE Uric acid inhibits vitamin D activation experimentally and higher serum urate levels are associated with higher parathyroid hormone levels in humans suggesting a link between uric acid and bone health. We hypothesized that hyperuricemia may increase the risk of fractures in older adults. METHODS 1963 men and 2729 women ≥65 years of age who participated in the Cardiovascular Health Study and had baseline serum urate levels were included in the study. The primary outcome was incident hip fracture, assessed prospectively through June, 2008 by inpatient and outpatient records. The analysis was stratified by sex a priori. RESULTS There was a U-shaped relationship between serum urate levels and hip fractures in men. Men in the lowest and the highest urate quartiles (<4.88 and ≥6.88 mg/dL respectively) had a significantly higher rate of fractures in unadjusted analysis. However, upon multivariate adjustment, only the HR for hip fracture in highest quartile versus the reference remained significant (HR 1.9; 95% C.I. 1.1, 3.1; p value 0.02). High serum urate levels were not associated with hip fractures in women. CONCLUSION In this large prospective cohort of community-dwelling older adults, increased serum urate levels were associated with an increased risk of hip fractures in men. Further studies are needed to confirm these findings and to understand the mechanisms that underlie them.

Clinical ScienceSerum urate levels and the risk of hip fractures: data from the Cardiovascular Health Study☆

PURPOSE Uric acid inhibits vitamin D activation experimentally and higher serum urate levels are associated with higher parathyroid hormone levels in humans suggesting a link between uric acid and bone health. We hypothesized that hyperuricemia may increase the risk of fractures in older adults. METHODS 1963 men and 2729 women ≥65 years of age who participated in the Cardiovascular Health Study and had baseline serum urate levels were included in the study. The primary outcome was incident hip fracture, assessed prospectively through June, 2008 by inpatient and outpatient records. The analysis was stratified by sex a priori. RESULTS There was a U-shaped relationship between serum urate levels and hip fractures in men. Men in the lowest and the highest urate quartiles (<4.88 and ≥6.88 mg/dL respectively) had a significantly higher rate of fractures in unadjusted analysis. However, upon multivariate adjustment, only the HR for hip fracture in highest quartile versus the reference remained significant (HR 1.9; 95% C.I. 1.1, 3.1; p value 0.02). High serum urate levels were not associated with hip fractures in women. CONCLUSION In this large prospective cohort of community-dwelling older adults, increased serum urate levels were associated with an increased risk of hip fractures in men. Further studies are needed to confirm these findings and to understand the mechanisms that underlie them.

Variation in resting heart rate over 4 years and the risks of myocardial infarction and death among older adults

Objective Resting heart rate (RHR) is an established predictor of myocardial infarction (MI) and mortality, but the relationship between variation in RHR over a period of several years and health outcomes is unclear. We evaluated the relationship between long-term variation in RHR and the risks of incident MI and mortality among older adults. Methods 1991 subjects without cardiovascular disease from the Cardiovascular Health Study were included. RHR was taken from resting ECGs at the first five annual study visits. RHR mean, trend and variation were estimated with linear regression. Subjects were followed for incident MI and death until December 2010. HRs for RHR mean, trend and variation are reported for differences of 10 bpm, 2 bpm/year and 2 bpm, respectively. Results 262 subjects had an incident MI event (13%) and 1326 died (67%) during 12 years of median follow-up. In primary analyses adjusted for cardiovascular risk factors, RHR mean (HR 1.12; 95% CI 1.05 to 1.20) and variation (HR 1.08; 95% CI 1.03 to 1.13) were associated with the risk of death while trend was not. None of the RHR variables were significantly associated with the risk of incident MI events; however, CIs were wide and the MI associations with RHR variables were not significantly different from the mortality associations. Adjusting for additional variables did not affect estimates, and there were no significant interactions with sex. Conclusions Variation in RHR over a period of several years represents a potential predictor of long-term mortality among older persons free of cardiovascular disease.

Language, learning, and memory in children with and without single-suture craniosynostosis

OBJECTIVE The language and memory functions of children with and without single-suture craniosynostosis (SSC) were compared at school age (mean 7.45 years, standard deviation [SD] 0.54 years). The children in this cohort were originally recruited in infancy and prior to cranial surgery for those with SSC. METHODS Individual evaluations of 179 school-aged children with SSC and 183 controls were conducted (70% of the original cohort) using standardized measures of language, learning, and memory. Parents participated in an interview about specialized education interventions and school progress. Parents and teachers completed questionnaires about language development. RESULTS Children with SSC (cases) obtained lower scores than controls on all measures. The adjusted differences in language, learning, and memory scores were modest, with SD ranging from 0.0 to -0.4 (p values ranged from 0.001 to 0.99). Censored normal regression was used to account for intervention services received prior to the school-age evaluation; this increased case-control differences (SD range 0.1 to -0.5, p value range 0.001 to 0.50). Mean scores for cases in each SSC diagnostic group were lower than those for controls, with the greatest differences observed among children with unilateral coronal craniosynostosis. CONCLUSIONS Children with SSC continue to show poorer performance than controls on language, learning, and memory tasks at early elementary school age, even when controlling for known confounders, although mean differences are small. Multidisciplinary care, including direct psychological assessment, for children with SSC should extend through school age with a specific focus on language and conceptual learning, as these are areas of potential risk. Future research is needed to investigate language, memory, and learning for this population during the middle to high school years.

Incident Atrial Fibrillation and Disability-Free Survival in the Cardiovascular Health Study

To assess the associations between incident atrial fibrillation (AF) and disability‐free survival and risk of disability.