Dina Appleby

Fibroblast growth factor 23 is elevated before parathyroid hormone and phosphate in chronic kidney disease

Fibroblast growth factor 23 (FGF23) regulates phosphorus metabolism and is a strong predictor of mortality in dialysis patients. FGF23 is thought to be an early biomarker of disordered phosphorus metabolism in the initial stages of chronic kidney disease (CKD). We measured FGF23 in baseline samples from 3879 patients in the Chronic Renal Insufficiency Cohort study, which is a diverse cohort of patients with CKD stage 2-4. Mean serum phosphate and median parathyroid hormone (PTH) levels were in the normal range, but median FGF23 was markedly greater than in healthy populations, and increased significantly with decreasing estimated glomerular filtration rate (eGFR). High levels of FGF23, defined as being above 100 RU/ml, were more common than secondary hyperparathyroidism and hyperphosphatemia in all strata of eGFR. The threshold of eGFR at which the slope of FGF23 increased was significantly higher than the corresponding threshold for PTH based on non-overlapping 95% confidence intervals. Thus, increased FGF23 is a common manifestation of CKD that develops earlier than increased phosphate or PTH. Hence, FGF23 measurements may be a sensitive early biomarker of disordered phosphorus metabolism in patients with CKD and normal serum phosphate levels.

Long-term Acute Care Hospital Utilization After Critical Illness

CONTEXT Long-term acute care hospitals have emerged as a novel approach for the care of patients recovering from severe acute illness, but the extent and increases in their activity at the national level are unknown. OBJECTIVE To examine temporal trends in long-term acute care hospital utilization after an episode of critical illness among fee-for-service Medicare beneficiaries aged 65 years or older. DESIGN, SETTING, AND PATIENTS Retrospective cohort study using the Medicare Provider Analysis and Review files from 1997 to 2006. We included all Medicare hospitalizations involving admission to an intensive care unit of an acute care, nonfederal hospital within the continental United States. MAIN OUTCOME MEASURES Overall long-term acute care utilization, associated costs, and survival following transfer. RESULTS The number of long-term acute care hospitals in the United States increased at a mean rate of 8.8% per year, from 192 in 1997 to 408 in 2006. During that time, the annual number of long-term acute care admissions after critical illness increased from 13,732 to 40,353, with annual costs increasing from

Treatment of localized periodontal disease in pregnancy does not reduce the occurrence of preterm birth: results from the Periodontal Infections and Prematurity Study (PIPS)

484 million to

Alterations in metabolic pathways and networks in Alzheimer's disease

1.325 billion. The age-standardized population incidence of long-term acute care utilization after critical illness increased from 38.1 per 100,000 in 1997 to 99.7 per 100,000 in 2006, with greater use among male individuals and black individuals in all periods. Over time, transferred patients had higher numbers of comorbidities (5.0 in 1997-2000 vs 5.8 in 2004-2006, P < .001) and were more likely to receive mechanical ventilation at the long-term acute care hospital (16.4% in 1997-2000 vs 29.8% in 2004-2006, P < .001). One-year mortality after long-term acute care hospital admission was high throughout the study period: 50.7% in 1997-2000 and 52.2% in 2004-2006. CONCLUSIONS Long-term acute care hospital utilization after critical illness is common and increasing. Survival among Medicare beneficiaries transferred to long-term acute care after critical illness is poor.

Evidence of a gene-environment interaction that predisposes to spontaneous preterm birth: a role for asymptomatic bacterial vaginosis and DNA variants in genes that control the inflammatory response

OBJECTIVE The purpose of this study was to test whether treating periodontal disease (PD) in pregnancy will reduce the incidence of spontaneous preterm delivery (SPTD) at < or = 35 weeks of gestation. STUDY DESIGN A multicenter, randomized clinical trial was performed. Subjects with PD were randomized to scaling and root planing (active) or tooth polishing (control). The primary outcome was the occurrence of SPTD at <35 weeks of gestation. RESULTS We screened 3563 subjects for PD; the prevalence of PD was 50%. Seven hundred fifty-seven subjects were assigned randomly; 378 subjects were assigned to the active group, and 379 subjects were assigned to the placebo group. Active treatment did not reduce the risk of SPTD at <35 weeks of gestation (relative risk, 1.19; 95% confidence interval [CI], 0.62-2.28) or composite neonatal morbidity (relative risk, 1.30; 95% CI, 0.83-2.04). There was a suggestion of an increase in the risk of indicated SPTD at <35 weeks of gestation in those subjects who received active treatment (relative risk, 3.01; 95% CI, 0.95-4.24). CONCLUSION Treating periodontal disease does not reduce the incidence of SPTD.

Utility of dilation and curettage in the diagnosis of pregnancy of unknown location

The pathogenic mechanisms of Alzheimer’s disease (AD) remain largely unknown and clinical trials have not demonstrated significant benefit. Biochemical characterization of AD and its prodromal phase may provide new diagnostic and therapeutic insights. We used targeted metabolomics platform to profile cerebrospinal fluid (CSF) from AD (n=40), mild cognitive impairment (MCI, n=36) and control (n=38) subjects; univariate and multivariate analyses to define between-group differences; and partial least square-discriminant analysis models to classify diagnostic groups using CSF metabolomic profiles. A partial correlation network was built to link metabolic markers, protein markers and disease severity. AD subjects had elevated methionine (MET), 5-hydroxyindoleacetic acid (5-HIAA), vanillylmandelic acid, xanthosine and glutathione versus controls. MCI subjects had elevated 5-HIAA, MET, hypoxanthine and other metabolites versus controls. Metabolite ratios revealed changes within tryptophan, MET and purine pathways. Initial pathway analyses identified steps in several pathways that appear altered in AD and MCI. A partial correlation network showed total tau most directly related to norepinephrine and purine pathways; amyloid-β (Ab42) was related directly to an unidentified metabolite and indirectly to 5-HIAA and MET. These findings indicate that MCI and AD are associated with an overlapping pattern of perturbations in tryptophan, tyrosine, MET and purine pathways, and suggest that profound biochemical alterations are linked to abnormal Ab42 and tau metabolism. Metabolomics provides powerful tools to map interlinked biochemical pathway perturbations and study AD as a disease of network failure.

Comparative survey of the topographical distribution of signature molecular lesions in major neurodegenerative diseases

OBJECTIVE We determined whether an environmental exposure to bacterial vaginosis (BV) modified genetic susceptibilities for spontaneous preterm delivery within genes that regulate the inflammatory response. STUDY DESIGN Maternal DNA samples and vaginal smears for Gram staining were collected from 743 women (68 preterm births). We used a 1536-single nucleotide polymorphism (SNP) custom chip to study associations between genotype distributions and preterm birth. RESULTS For 8 SNPs in 3 genes (protein kinase C alpha, fms-like tyrosine kinase 1, and interleukin 6), the odds ratios for preterm birth ranged from 1.9-4.0 among women with susceptible genotypes who were BV positive. The odds ratios for preterm birth were 2.0-5.0 times greater among women who were BV positive than among women who were BV negative. The significance of these differences was demonstrated by logistic regression analyses for genotype/BV interaction. CONCLUSION These results demonstrate that the risk of preterm delivery that is associated with tag SNPs in genes that regulate the inflammatory response is modified by an environmental exposure such as bacterial vaginosis.

Heart rate variability is a predictor of mortality in chronic kidney disease: a report from the CRIC Study.

OBJECTIVE We sought to determine utility of uterine evacuation for diagnosis of nonviable pregnancy of unknown location (PUL). STUDY DESIGN We conducted a cohort study to assess the prevalence of ectopic pregnancy (EP), overall, and stratified by presenting signs and symptoms in women with a nonviable PUL. RESULTS Of the 173 women, 66 (38%) had miscarriage (spontaneous abortion [SAB]) and 107 (62%) had EP. When initial human chorionic gonadotropin (hCG) was <2000 mIU/mL, the odds of an EP were greater (odds ratio, 4.32; 95% confidence interval, 2.04-9.12). Demographic factors, obstetric history, and clinical presentation were not useful in distinguishing between EP and SAB. Pre-evacuation hCG increase had strong trend association with EP (odds ratio, 2.14; 95% confidence interval, 0.98-4.68). A >30% fall in postcurettage hCG was suggestive, but was not a diagnostic indicator of SAB. CONCLUSION Uterine evacuation is a useful diagnostic aid for women with nonviable PUL. Nondiagnostic ultrasound findings and absolute and serial hCG values are associated with, but do not accurately predict final diagnosis.

Comparing metabolomic and pathologic biomarkers alone and in combination for discriminating Alzheimer’s disease from normal cognitive aging

An understanding of the anatomic distributions of major neurodegenerative disease lesions is important to appreciate the differential clinical profiles of these disorders and to serve as neuropathological standards for emerging molecular neuroimaging methods. To address these issues, here we present a comparative survey of the topographical distribution of the defining molecular neuropathological lesions among 10 neurodegenerative diseases from a large and uniformly assessed brain collection. Ratings of pathological severity in 16 brain regions from 671 cases with diverse neurodegenerative diseases are summarized and analyzed. These include: 1) amyloid‐β and tau lesions in Alzheimers disease; 2) tau lesions in three other tauopathies including Picks disease, progressive supranuclear palsy and corticobasal degeneration; 3) α‐synuclein inclusion ratings in four synucleinopathies including Parkinsons disease, Parkinsons disease with dementia, dementia with Lewy bodies, and multiple system atrophy; and 4) TDP‐43 lesions in two TDP‐43 proteinopathies, including frontotemporal lobar degeneration associated with TDP‐43 and amyotrophic lateral sclerosis. The data presented graphically and topographically confirm and extend previous pathological anatomic descriptions and statistical comparisons highlight the lesion distributions that either overlap or distinguish the diseases in each molecular disease category. J. Comp. Neurol. 521:4339–4355, 2013.

Clinical Factors Affecting the Accuracy of Ultrasonography in Symptomatic First-Trimester Pregnancy

Background/Aims: Low heart rate variability (HRV) is a risk factor for adverse outcomes in the general population. We aimed to determine the factors associated with HRV and evaluate the association between low HRV and clinical outcomes in patients with chronic kidney disease (CKD). Methods: A 10-second electrocardiogram was obtained at baseline in the Chronic Renal Insufficiency Cohort (CRIC) Study. HRV was measured by the standard deviation of all R-R intervals (SDNN) and the root mean square of successive differences between R-R intervals (RMSSD). Results: In 3,245 CRIC participants with available baseline SDNN and RMSSD, lower HRV was associated with older age, lack of exercise, heart failure, elevated phosphorus and hemoglobin A1c, and low estimated glomerular filtration rate. After a median follow-up of 4.2 years, in fully adjusted models, lower HRV was not associated with renal [SDNN: hazard rate, HR = 0.96 (95% confidence interval, CI 0.88-1.05); RMSSD: HR = 0.97 (95% CI 0.88-1.07)] or cardiovascular outcomes [SDNN: HR = 1.02 (95% CI 0.92-1.13); RMSSD: HR = 1.00 (95% CI 0.90-1.10)]. There was a nonlinear relationship between RMSSD and all-cause mortality with increased risk with both low and high RMSSD (p = 0.04). Conclusions: In a large cohort of patients with CKD, multiple risk factors for renal and cardiovascular diseases were associated with lower HRV. Lower HRV was not associated with increased risk for renal or cardiovascular outcomes, but both low and high RMSSD were associated with increased risk for all-cause mortality. In conclusion, HRV measured by RMSSD may be a novel and independent risk factor for mortality in CKD patients.