Fibroblast growth factor 23 (FGF23) regulates phosphorus metabolism and is a strong predictor of mortality in dialysis patients. FGF23 has been proposed as an early biomarker of disordered phosphorus metabolism in earlier stages of chronic kidney disease (CKD), but data from large, well-characterized CKD cohorts are lacking. We measured FGF23 in baseline samples from 3,879 participants in the Chronic Renal Insufficiency Cohort study, a nationally representative, diverse CKD cohort with mean (± sd) estimated glomerular filtration rate (eGFR) of 42.8 ± 13.5 ml/min/1.73m2. Serum phosphate (3.7 ± 0.7 mg/dl) and parathyroid hormone (PTH; median 54, interquartile range [IQR] 35 – 89 pg/ml) levels were in the normal range, but FGF23 (median 145, IQR 96 – 239 RU/ml) was markedly greater than in healthy populations and increased significantly with decreasing eGFR. FGF23 excess, defined as ≥ 100 RU/ml, was more common than secondary hyperparathyroidism (≥ 65 pg/ml) and hyperphosphatemia (≥ 4.6 mg/dl) in all strata of eGFR, and the eGFR threshold at which the slope of FGF23 increased (57.8; 95%CI: 55.4 – 60.8 ml/min/1.73m2) was higher than the corresponding threshold for PTH (46.9; 95%CI: 45.5 – 51.4 ml/min/1.73m2). Thus, increased FGF23 is a common manifestation of CKD that develops earlier than increases in phosphate or PTH. These findings provide additional support for use of FGF23 as a sensitive early screening test to identify disordered phosphorus metabolism in CKD patients with normal serum phosphate levels.

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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 growth of their activity at the national level is 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 ≥ 65 years of age. 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, non-federal 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 $484 million to $1.325 billion. The age-standardized population incidence of long-term acute care utilization after critical illness increased from 38.1/100,000 in 1997 to 99.7/100,000 in 2006, with greater use among male individuals and black individuals in all time periods. Over time, transferred patients had higher numbers of comorbidities (5.0 in 1997–2000 versus 5.8 in 2004–2006, p<0.001), and were more likely to receive mechanical ventilation at the long-term acute care hospital (16.4% in 1997–2000 versus 29.8% in 2004–2006, p<0.001). 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.

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.

LODDS showed a clear prognostic superiority over both pN and rN schemes. It could serve as an important reference for the tumour node metastasis (TNM) node classification.

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.

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 ten neurodegenerative diseases from a large and uniformly assessed brain collection. Ratings of pathological severity in sixteen brain regions from 671 cases with diverse neurodegenerative diseases were summarized and analyzed. These included: a) amyloid-β and tau lesions in Alzheimer’s disease, b) tau lesions in three other tauopathies including Pick’s disease, progressive supranuclear palsy and corticobasal degeneration, c) α-synuclein inclusion ratings in four synucleinopathies including Parkinson’s disease, Parkinson’s disease with dementia, dementia with Lewy bodies and multiple system atrophy, and d) 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.

Seven to thirteen percent of women are either prescribed or taking (depending on the study) an antidepressant during pregnancy [1]. Although generally low risk, antidepressants have been associated with postnatal adaptation syndrome [2]. Because antidepressants freely cross into the intrauterine environment, it is our aim to summarize the current findings on placental transfer of antidepressants. The antidepressants reviewed are limited to those that are commonly prescribed to the pregnant patient suffering from depression or anxiety. The biological mechanisms regulating placental transport are both complex and multi-determined. Placental anatomy and pharmacokinetics are reviewed along with the latest advances in the understanding of active cellular molecular transport and placental metabolism. In addition, we consider how non-placental and fetal factors contribute to the distribution of drugs across the placenta. The data on placental passage of antidepressants is discussed in the context of the three commonly used research methodologies: animal models, ex vivo perfusion models, and in vivo models. The goal of this review is to inform clinical decision-making by improving understanding of how placental and pharmacokinetic factors relate to the data on antidepressant drug transfer and postnatal adaptation syndrome (PNAS). Incorporating maternal and fetal genetics will be the next step in assisting clinicians to make more informed choices regarding which antidepressants are the least likely to have extensive fetal exposure.