Evidence suggests that maintenance of vancomycin trough concentrations at between 15 and 20 mg/liter, as currently recommended, is frequently unnecessary to achieve the daily area under the ...concentration-time curve (AUC
) target of ≥400 mg · h/liter. Many patients with trough concentrations in this range have AUC
values in excess of the therapeutic threshold and within the exposure range associated with nephrotoxicity. On the basis of this, the Detroit Medical Center switched from trough concentration-guided dosing to AUC-guided dosing to minimize potentially unnecessary vancomycin exposure. The primary objective of this analysis was to assess the impact of this intervention on vancomycin-associated nephrotoxicity in a single-center, retrospective quasi-experiment of hospitalized adult patients receiving intravenous vancomycin from 2014 to 2015. The primary analysis compared the incidence of nephrotoxicity between patients monitored by assessment of the AUC
and those monitored by assessment of the trough concentration. Multivariable logistic and Cox proportional hazards regression examined the independent association between the monitoring strategy and nephrotoxicity. Secondary analysis compared vancomycin exposures (total daily dose, AUC, and trough concentrations) between monitoring strategies. Overall, 1,280 patients were included in the analysis. After adjusting for severity of illness, comorbidity, duration of vancomycin therapy, and concomitant receipt of nephrotoxins, AUC-guided dosing was independently associated with lower nephrotoxicity by both logistic regression (odds ratio, 0.52; 95% confidence interval CI, 0.34 to 0.80;
= 0.003) and Cox proportional hazards regression (hazard ratio, 0.53; 95% CI, 0.35 to 0.78;
= 0.002). AUC-guided dosing was associated with lower total daily vancomycin doses, AUC values, and trough concentrations. Vancomycin AUC-guided dosing was associated with reduced nephrotoxicity, which appeared to be a result of reduced vancomycin exposure.
Global resources of heavy Rare Earth Elements (REE) are dominantly sourced from Chinese regolith-hosted ion-adsorption deposits in which the REE are inferred to be weakly adsorbed onto clay minerals. ...Similar deposits elsewhere might provide alternative supply for these high-tech metals, but the adsorption mechanisms remain unclear and the adsorbed state of REE to clays has never been demonstrated in situ. This study compares the mineralogy and speciation of REE in economic weathering profiles from China to prospective regoliths developed on peralkaline rocks from Madagascar. We use synchrotron X-ray absorption spectroscopy to study the distribution and local bonding environment of Y and Nd, as proxies for heavy and light REE, in the deposits. Our results show that REE are truly adsorbed as easily leachable 8- to 9-coordinated outer-sphere hydrated complexes, dominantly onto kaolinite. Hence, at the atomic level, the Malagasy clays are genuine mineralogical analogues to those currently exploited in China.
Repopulation of the injured heart with new, functional cardiomyocytes remains a daunting challenge for cardiac regenerative medicine. An ideal therapeutic approach would involve an effective method ...at achieving direct conversion of injured areas to functional tissue in situ.
The aim of this study was to develop a strategy that identified and evaluated the potential of specific micro (mi)RNAs capable of inducing reprogramming of cardiac fibroblasts directly to cardiomyocytes in vitro and in vivo.
Using a combinatorial strategy, we identified a combination of miRNAs 1, 133, 208, and 499 capable of inducing direct cellular reprogramming of fibroblasts to cardiomyocyte-like cells in vitro. Detailed studies of the reprogrammed cells demonstrated that a single transient transfection of the miRNAs can direct a switch in cell fate as documented by expression of mature cardiomyocyte markers, sarcomeric organization, and exhibition of spontaneous calcium flux characteristic of a cardiomyocyte-like phenotype. Interestingly, we also found that miRNA-mediated reprogramming was enhanced 10-fold on JAK inhibitor I treatment. Importantly, administration of miRNAs into ischemic mouse myocardium resulted in evidence of direct conversion of cardiac fibroblasts to cardiomyocytes in situ. Genetic tracing analysis using Fsp1Cre-traced fibroblasts from both cardiac and noncardiac cell sources strongly suggests that induced cells are most likely of fibroblastic origin.
The findings from this study provide proof-of-concept that miRNAs have the capability of directly converting fibroblasts to a cardiomyocyte-like phenotype in vitro. Also of significance is that this is the first report of direct cardiac reprogramming in vivo. Our approach may have broad and important implications for therapeutic tissue regeneration in general.
Evidence supports vancomycin therapeutic-drug monitoring by area under the concentration-time curve (AUC), but data to establish an AUC upper limit are limited and published nephrotoxicity thresholds ...range widely. The objective of this analysis was to examine the association between initial vancomycin AUC and nephrotoxicity. This was a multicenter, retrospective cohort study of adult patients receiving intravenous vancomycin from 2014 to 2015. Nephrotoxicity was defined as a serum creatinine increase of 0.5 mg/liter and 50% from baseline on consecutive measurements. Vancomycin exposure profile during the initial 48 h of therapy was estimated using maximum
probability Bayesian estimation. Vancomycin AUC and minimum-concentration (
) thresholds most strongly associated with nephrotoxicity were identified via classification and regression tree (CART) analysis. Predictive performances of CART-derived and other candidate AUC thresholds was assessed through positive and negative predictive value and receiver operating characteristic curves. Poisson regression was used to quantify the association between exposure thresholds and nephrotoxicity while adjusting for confounders. Among 323 patients included, nephrotoxicity was significantly higher in patients with AUCs from 0 to 48 h (AUC
) of ≥1,218 mg · h/liter, AUC
of ≥677 mg · h/liter, AUC
of ≥683 mg · h/liter, and day 1
(
) of ≥18.8 mg/liter. Vancomycin exposure in excess of these thresholds was associated with a 3- to 4-fold-increased risk of nephrotoxicity in Poisson regression. The predictive performance of AUC for nephrotoxicity was maximized at daily AUC values between 600 and 800 mg · h/liter. Although these data support an AUC range for vancomycin-associated nephrotoxity rather than a single threshold, available evidence suggests that a daily AUC limit of 700 mg · h/liter is reasonable.
Penttinen syndrome is a distinctive disorder characterized by a prematurely aged appearance with lipoatrophy, epidermal and dermal atrophy along with hypertrophic lesions that resemble scars, thin ...hair, proptosis, underdeveloped cheekbones, and marked acro-osteolysis. All individuals have been simplex cases. Exome sequencing of an affected individual identified a de novo c.1994T>C p.Val665Ala variant in PDGFRB, which encodes the platelet-derived growth factor receptor β. Three additional unrelated individuals with this condition were shown to have the identical variant in PDGFRB. Distinct mutations in PDGFRB have been shown to cause infantile myofibromatosis, idiopathic basal ganglia calcification, and an overgrowth disorder with dysmorphic facies and psychosis, none of which overlaps with the clinical findings in Penttinen syndrome. We evaluated the functional consequence of this causative variant on the PDGFRB signaling pathway by transfecting mutant and wild-type cDNA into HeLa cells, and transfection showed ligand-independent constitutive signaling through STAT3 and PLCγ. Penttinen syndrome is a clinically distinct genetic condition caused by a PDGFRB gain-of-function mutation that is associated with a specific and unusual perturbation of receptor function.
Several families have been reported with autosomal-dominant frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS), genetically linked to chromosome 9p21. Here, we report an expansion ...of a noncoding GGGGCC hexanucleotide repeat in the gene C9ORF72 that is strongly associated with disease in a large FTD/ALS kindred, previously reported to be conclusively linked to chromosome 9p. This same repeat expansion was identified in the majority of our families with a combined FTD/ALS phenotype and TDP-43-based pathology. Analysis of extended clinical series found the C9ORF72 repeat expansion to be the most common genetic abnormality in both familial FTD (11.7%) and familial ALS (23.5%). The repeat expansion leads to the loss of one alternatively spliced C9ORF72 transcript and to formation of nuclear RNA foci, suggesting multiple disease mechanisms. Our findings indicate that repeat expansion in C9ORF72 is a major cause of both FTD and ALS.
► Noncoding repeat expansion in C9ORF72 causes FTD and ALS linked to chromosome 9p ► C9ORF72 repeat expansion forms nuclear RNA foci in brain and spinal cord ► Repeat expansion results in loss of one alternatively spliced C9ORF72 transcript ► Repeat expansion in C9ORF72 is a major cause of both FTD and ALS
Summary Background Hexanucleotide repeat expansions in chromosome 9 open reading frame 72 ( C9ORF72 ) are the most common known genetic cause of frontotemporal dementia (FTD) and motor neuron disease ...(MND). We assessed whether expansion size is associated with disease severity or phenotype. Methods We did a cross-sectional Southern blot characterisation study (Xpansize-72) in a cohort of individuals with FTD, MND, both these diseases, or no clinical phenotype. All participants had GGGGCC repeat expansions in C9ORF72 , and high quality DNA was available from one or more of the frontal cortex, cerebellum, or blood. We used Southern blotting techniques and densitometry to estimate the repeat size of the most abundant expansion species. We compared repeat sizes between different tissues using Wilcoxon rank sum and Wilcoxon signed rank tests, and between disease subgroups using Kruskal-Wallis rank sum tests. We assessed the association of repeat size with age at onset and age at collection using a Spearman's test of correlation, and assessed the association between repeat size and survival after disease onset using Cox proportional hazards regression models. Findings We included 84 individuals with C9ORF72 expansions: 35 had FTD, 16 had FTD and MND, 30 had MND, and three had no clinical phenotype. We focused our analysis on three major tissue subgroups: frontal cortex (available from 41 patients 21 with FTD, 11 with FTD and MND, and nine with MND), cerebellum (40 patients 20 with FTD, 12 with FTD and MND, and eight with MND), and blood (47 patients 15 with FTD, nine with FTD and MND, and 23 with MND and three carriers who had no clinical phenotype). Repeat lengths in the cerebellum were smaller (median 12·3 kb about 1667 repeat units, IQR 11·1–14·3) than those in the frontal cortex (33·8 kb about 5250 repeat units, 23·5–44·9; p<0·0001) and those in blood (18·6 kb about 2717 repeat units, 13·9–28·1; p=0·0002). Within these tissues, we detected no difference in repeat length between disease subgroups (cerebellum p=0·96, frontal cortex p=0·27, blood p=0·10). In the frontal cortex of patients with FTD, repeat length correlated with age at onset ( r =0·63; p=0·003) and age at sample collection ( r =0·58; p=0·006); we did not detect such a correlation in samples from the cerebellum or blood. When assessing cerebellum samples from the overall cohort, survival after disease onset was 4·8 years (IQR 3·0–7·4) in the group with expansions greater than 1467 repeat units (the 25th percentile of repeat lengths) versus 7·4 years (6·3–10·9) in the group with smaller expansions (HR 3·27, 95% CI 1·34–7·95; p=0·009). Interpretation We detected substantial variation in repeat sizes between samples from the cerebellum, frontal cortex, and blood, and longer repeat sizes in the cerebellum seem to be associated with a survival disadvantage. Our findings indicate that expansion size does affect disease severity, which—if replicated in other cohorts—could be relevant for genetic counselling. Funding The ALS Therapy Alliance, the National Institute of Neurological Disorders and Stroke, the National Institute on Aging, the Arizona Department of Health Services, the Arizona Biomedical Research Commission, and the Michael J Fox Foundation for Parkinson's Research.
The sources of dissolved inorganic carbon (DIC) used to produce scleractinian coral skeletons are not understood. Yet this knowledge is essential for understanding coral biomineralization and ...assessing the potential impacts of ocean acidification on coral reefs. Here we use skeletal boron geochemistry to reconstruct the DIC chemistry of the fluid used for coral calcification. We show that corals concentrate DIC at the calcification site substantially above seawater values and that bicarbonate contributes a significant amount of the DIC pool used to build the skeleton. Corals actively increase the pH of the calcification fluid, decreasing the proportion of DIC present as CO2 and creating a diffusion gradient favouring the transport of molecular CO2 from the overlying coral tissue into the calcification site. Coupling the increases in calcification fluid pH and DIC yields high calcification fluid CO3(2-) and induces high aragonite saturation states, favourable to the precipitation of the skeleton.
Abstract We aimed to identify new candidate genes potentially involved in early-onset Alzheimer's disease (EOAD). Exome sequencing was conducted on 45 EOAD patients with either a family history of ...Alzheimer's disease (AD, <65 years) or an extremely early age at the onset (≤55 years) followed by multiple variant filtering according to different modes of inheritance. We identified 29 candidate genes potentially involved in EOAD, of which the gene TYROBP , previously implicated in AD, was selected for genetic and functional follow-up. Using 3 patient cohorts, we observed rare coding TYROBP variants in 9 out of 1110 EOAD patients, whereas no such variants were detected in 1826 controls ( p = 0.0001), suggesting that at least some rare TYROBP variants might contribute to EOAD risk. Overexpression of the p.D50_L51ins14 TYROBP mutant led to a profound reduction of TREM2 expression, a well-established risk factor for AD. This is the first study supporting a role for genetic variation in TYROBP in EOAD, with in vitro support for a functional effect of the p.D50_L51ins14 TYROBP mutation on TREM2 expression.
Understanding how rising seawater
p
CO
2
and temperatures impact coral aragonite accretion is essential for predicting the future of reef ecosystems. Here, we report 2 long-term (10–11 month) studies ...assessing the effects of temperature (25 and 28 °C) and both high and low seawater
p
CO
2
(180–750 μatm) on the calcification, photosynthesis and respiration of individual massive
Porites
spp. genotypes. Calcification rates were highly variable between genotypes, but high seawater
p
CO
2
reduced calcification significantly in 4 of 7 genotypes cultured at 25 °C but in only 1 of 4 genotypes cultured at 28 °C. Increasing seawater temperature enhanced calcification in almost all corals, but the magnitude of this effect was seawater
p
CO
2
dependent. The 3 °C temperature increase enhanced calcification rate on average by 3% at 180 μatm, by 35% at 260 μatm and by > 300% at 750 μatm. The rate increase at high seawater
p
CO
2
exceeds that observed in inorganic aragonites. Responses of gross/net photosynthesis and respiration to temperature and seawater
p
CO
2
varied between genotypes, but rates of all these processes were reduced at the higher seawater temperature. Increases in seawater temperature, below the thermal stress threshold, may mitigate against ocean acidification in this coral genus, but this moderation is not mediated by an increase in net photosynthesis. The response of coral calcification to temperature cannot be explained by symbiont productivity or by thermodynamic and kinetic influences on aragonite formation.
PDF
