Background Whether convective modalities of dialysis, including hemofiltration (HF) and hemodiafiltration (HDF), improve cardiovascular outcomes and mortality is unclear. Study Design Systematic ...review and meta-analysis. Setting & Population Patients receiving HDF, HF, or standard hemodialysis (HD). Selection Criteria for Studies Randomized controlled trials. Intervention Convective modalities of dialysis (HDF and HF) versus standard HD. Outcomes The primary outcome was clinical cardiovascular outcomes. Secondary outcomes were all-cause mortality, episodes of symptomatic hypotension, dialysis adequacy, and β2 -microglobulin level. Relative risks (RRs) or weighted mean differences with 95% CIs for individual trials were pooled using random-effects models. Results The search yielded 16 trials including 3,220 patients. Therapies assessed were convective modalities (HDF or HF) compared with standard HD. Compared with HD, convective modalities did not significantly reduce the risk of cardiovascular events (RR, 0.85; 95% CI, 0.66-1.10) or all-cause mortality (RR, 0.83; 95% CI, 0.65-1.05). Convective modalities reduced symptomatic hypotension (RR, 0.49; 95% CI, 0.30-0.81) and improved serum β2 -microglobulin levels (−5.95 mg/L; 95% CI, −10.27 to −1.64), but had no impact on small-molecule clearance (weighted mean difference in Kt/V, 0.04; 95% CI, −0.04 to 0.12). There was a nonsignificant trend to a greater likelihood of receiving a kidney transplant for participants allocated to filtration therapies (RR, 1.19; 95% CI, 0.99-1.42). Limitations The trials were predominantly of suboptimal quality and underpowered, with imbalance in some prognostic variables at baseline. Intention-to-treat analysis was not used in some trials. Our analysis was limited to published outcomes. Conclusions The potential benefits of convective modalities over standard HD for cardiovascular outcomes and mortality remain unproved. Further high-quality randomized trials are needed to define the impact of these modalities on clinically important outcomes.
Purpose
Choice of renal replacement therapy (RRT) modality may affect renal recovery after acute kidney injury (AKI). We sought to compare the rate of dialysis dependence among severe AKI survivors ...according to the choice of initial renal replacement therapy (RRT) modality applied continuous (CRRT) or intermittent (IRRT).
Methods
Systematic searches of peer-reviewed publications in MEDLINE and EMBASE were performed (last update July 2012). All studies published after 2000 reporting dialysis dependence among survivors from severe AKI requiring RRT were included. Data on follow-up duration, sex, age, chronic kidney disease, illness severity score, vasopressors, and mechanical ventilation were extracted when available. Results were pooled using a random-effects model.
Results
We identified 23 studies: seven randomized controlled trials (RCTs) and 16 observational studies involving 472 and 3,499 survivors, respectively. Pooled analyses of RCTs showed no difference in the rate of dialysis dependence among survivors (relative risk, RR 1.15 95 % confidence interval (CI) 0.78–1.68,
I
2
= 0 %). However, pooled analyses of observational studies suggested a higher rate of dialysis dependence among survivors who initially received IRRT as compared with CRRT (RR 1.99 95 % CI 1.53–2.59,
I
2
= 42 %). These findings were consistent with adjusted analyses (performed in 7/16 studies), which found a higher rate of dialysis dependence in IRRT-treated patients odds ratio (OR) 2.2–25 (5 studies) or no difference (2 studies).
Conclusions
Among AKI survivors, initial treatment with IRRT might be associated with higher rates of dialysis dependence than CRRT. However, this finding largely relies on data from observational trials, potentially subject to allocation bias, hence further high-quality studies are necessary.
Mineral dust is an important component of the climate system, affecting the
radiation balance, cloud properties, biogeochemical cycles, regional
circulation and precipitation, as well as having ...negative effects on
aviation, solar energy generation and human health. Dust size and composition
has an impact on all these processes. However, changes in dust size
distribution and composition during transport, particularly for coarse
particles, are poorly understood and poorly represented in climate models.
Here we present new in situ airborne observations of dust in the Saharan Air
Layer (SAL) and the marine boundary layer (MBL) at the beginning of its
transatlantic transport pathway, from the AERosol
Properties – Dust (AER-D) fieldwork in August 2015,
within the peak season of North African dust export. This study focuses on
coarse-mode dust properties, including size distribution, mass loading,
shape, composition, refractive indices and optical properties. Size
distributions from 0.1 to 100 µm diameter (d) are presented, fully
incorporating the coarse and giant modes of dust. Within the MBL, mean
effective diameter (deff) and volume median diameter (VMD) were 4.6 and 6.0 µm respectively, giant particles with a mode at
20–30 µm were observed, and composition was dominated by quartz and
alumino-silicates at d > 1 µm. Within the SAL, particles
larger than 20 µm diameter were always present up to 5 km altitude, in
concentrations over 10−5 cm−3, constituting up to 40 % of
total dust mass. Mean deff and VMD were 4.0 and 5.5 µm
respectively. Larger particles were detected in the SAL than can be explained
by sedimentation theory alone. Coarse-mode composition was dominated by
quartz and alumino-silicates; the accumulation mode showed a strong
contribution from sulfate-rich and sea salt particles. In the SAL, measured
single scattering albedos (SSAs) at 550 nm representing d < 2.5 µm were
0.93 to 0.98 (mean 0.97). Optical properties calculated for the full
size distribution (0.1 < d < 100 µm) resulted in lower
SSAs of 0.91–0.98 (mean 0.95) and mass extinction coefficients of 0.27–0.35 m2 g−1 (mean 0.32 m2 g−1). Variability in SSA was mainly
controlled by variability in dust composition (principally iron) rather than
by variations in the size distribution, in contrast with previous observations
over the Sahara where size is the dominant influence. It is important that
models are able to capture the variability and evolution of both dust
composition and size distribution with transport in order to accurately
represent the impacts of dust on climate. These results provide a new SAL
dust dataset, fully representing coarse and giant particles, to aid model
validation and development.
Abstract
Background
Among critically ill patients with acute kidney injury (AKI), earlier initiation of renal replacement therapy (RRT) may mitigate fluid accumulation and confer better outcomes ...among individuals with greater fluid overload at randomization.
Methods
We conducted a pre-planned post hoc analysis of the STandard versus Accelerated initiation of Renal Replacement Therapy in Acute Kidney Injury (STARRT-AKI) trial. We evaluated the effect of accelerated RRT initiation on cumulative fluid balance over the course of 14 days following randomization using mixed models after censoring for death and ICU discharge. We assessed the modifying effect of baseline fluid balance on the impact of RRT initiation strategy on key clinical outcomes. Patients were categorized in quartiles of baseline fluid balance, and the effect of accelerated versus standard RRT initiation on clinical outcomes was assessed in each quartile using risk ratios (95% CI) for categorical variables and mean differences (95% CI) for continuous variables.
Results
Among 2927 patients in the modified intention-to-treat analysis, 2738 had available data on baseline fluid balance and 2716 (92.8%) had at least one day of fluid balance data following randomization. Over the subsequent 14 days, participants allocated to the accelerated strategy had a lower cumulative fluid balance compared to those in the standard strategy (4509 (− 728 to 11,698) versus 5646 (0 to 13,151) mL,
p
= 0.03). Accelerated RRT initiation did not confer greater 90-day survival in any of the baseline fluid balance quartiles (quartile 1: RR 1.11 (95% CI 0.92 to 1.34), quartile 2: RR 1.03 (0.87 to 1.21); quartile 3: RR 1.08 (95% CI 0.91 to 1.27) and quartile 4: RR 0.87 (95% CI 0.73 to 1.03),
p
value for trend 0.08).
Conclusions
Earlier RRT initiation in critically ill patients with AKI conferred a modest attenuation of cumulative fluid balance. Nonetheless, among patients with greater fluid accumulation at randomization, accelerated RRT initiation did not have an impact on all-cause mortality.
Trial registration
: ClinicalTrials.gov number,
https://clinicaltrials.gov/ct2/show/NCT02568722
, registered October 6, 2015.
Sudden unexpected death in epilepsy (SUDEP) is the most common cause of death in patients with refractory epilepsy. The pathophysiology of SUDEP is unknown. Postictal phenomena such as postconvulsive ...immobility (PI), postictal generalized electroencephalography (EEG) suppression (PGES), arousal deficits, cardiac arrhythmias, central apneas, and obstructive apneas due to laryngospasms have been suggested to contribute to SUDEP. We present, to our knowledge, the first case of a near‐SUDEP event in a patient undergoing intracranial, stereotactic EEG (sEEG) monitoring. This case spotlights potential mediators of SUDEP, most notably the striking PGES and postictal apnea. The nature of the sEEG investigation illustrates the extent of cortical and subcortical postictal EEG suppression and showcases a transient return of cerebral activity likely to be missed on scalp‐EEG recording. Critically, this case emphasizes the importance of continuous cardiorespiratory monitoring and underscores the importance of postictal arousal as a pathophysiological mechanism in SUDEP.
The relationship between increased hemodialysis hours and patient outcomes remains unclear. We randomized (1:1) 200 adult recipients of standard maintenance hemodialysis from in-center and home-based ...hemodialysis programs to extended weekly (≥24 hours) or standard (target 12-15 hours, maximum 18 hours) hemodialysis hours for 12 months. The primary outcome was change in quality of life from baseline assessed by the EuroQol 5 dimension instrument (3 level) (EQ-5D). Secondary outcomes included medication usage, clinical laboratory values, vascular access events, and change in left ventricular mass index. At 12 months, median weekly hemodialysis hours were 24.0 (interquartile range, 23.6-24.0) and 12.0 (interquartile range, 12.0-16.0) in the extended and standard groups, respectively. Change in EQ-5D score at study end did not differ between groups (mean difference, 0.04 95% confidence interval, -0.03 to 0.11;
=0.29). Extended hours were associated with lower phosphate and potassium levels and higher hemoglobin levels. Blood pressure (BP) did not differ between groups at study end. Extended hours were associated with fewer BP-lowering agents and phosphate-binding medications, but were not associated with erythropoietin dosing. In a substudy with 95 patients, we detected no difference between groups in left ventricular mass index (mean difference, -6.0 95% confidence interval, -14.8 to 2.7 g/m
;
=0.18). Five deaths occurred in the extended group and two in the standard group (
=0.44); two participants in each group withdrew consent. Similar numbers of patients experienced vascular access events in the two groups. Thus, extending weekly hemodialysis hours did not alter overall EQ-5D quality of life score, but was associated with improvement in some laboratory parameters and reductions in medication burden. (Clinicaltrials.gov identifier: NCT00649298).
The purpose of this study was to determine the benefit and risk associated with antiplatelet therapy in the chronic kidney disease (CKD) population.
Cardiovascular and possibly bleeding risks are ...elevated in patients with CKD. The balance of benefit and harm associated with antiplatelet therapy remains uncertain.
The HOT (Hypertension Optimal Treatment) study randomly assigned participants with diastolic hypertension to aspirin (75 mg) or placebo. Study treatment effects were calculated using univariate proportional hazards regression models stratified by baseline estimated glomerular filtration rate (eGFR) with trends tested by adding interaction terms. End points included major cardiovascular events, total mortality, and major bleeding.
The study included 18,597 participants treated for 3.8 years. Baseline eGFR was < 60 ml/min/1.73 m(2) in 3,619 participants. Major cardiovascular events were reduced by 9% (95% confidence interval CI: -9% to 24%), 15% (95% CI: -17% to 39%), and 66% (95% CI: 33% to 83%) for patients with baseline eGFR of ≥ 60, 45 to 59, and < 45 ml/min/1.73 m(2), respectively (p trend = 0.03). Total mortality was reduced by 0% (95% CI: -20% to 17%), 11% (95% CI: -31% to 40%), and 49% (95% CI: 6% to 73%), respectively (p trend = 0.04). Major bleeding events were nonsignificantly greater with lower eGFR (hazard ratio HR: 1.52 95% CI: 1.11 to 2.08, HR: 1.70 95% CI: 0.74 to 3.88, and HR: 2.81 95% CI: 0.92 to 8.84, respectively; p trend = 0.30). Among every 1,000 persons with eGFR < 45 ml/min/1.73 m(2) treated for 3.8 years, 76 major cardiovascular events and 54 all-cause deaths will be prevented while 27 excess major bleeds will occur.
Aspirin therapy produces greater absolute reduction in major cardiovascular events and mortality in hypertensive patients with CKD than with normal kidney function. An increased risk of major bleeding appears to be outweighed by the substantial benefits.
Characterisation of bioaerosols has important implications within environment and public health sectors. Recent developments in ultraviolet light-induced fluorescence (UV-LIF) detectors such as the ...Wideband Integrated Bioaerosol Spectrometer (WIBS) and the newly introduced Multiparameter Bioaerosol Spectrometer (MBS) have allowed for the real-time collection of fluorescence, size and morphology measurements for the purpose of discriminating between bacteria, fungal spores and pollen.This new generation of instruments has enabled ever larger data sets to be compiled with the aim of studying more complex environments. In real world data sets, particularly those from an urban environment, the population may be dominated by non-biological fluorescent interferents, bringing into question the accuracy of measurements of quantities such as concentrations. It is therefore imperative that we validate the performance of different algorithms which can be used for the task of classification.For unsupervised learning we tested hierarchical agglomerative clustering with various different linkages. For supervised learning, 11 methods were tested, including decision trees, ensemble methods (random forests, gradient boosting and AdaBoost), two implementations for support vector machines (libsvm and liblinear) and Gaussian methods (Gaussian naïve Bayesian, quadratic and linear discriminant analysis, the k-nearest neighbours algorithm and artificial neural networks).The methods were applied to two different data sets produced using the new MBS, which provides multichannel UV-LIF fluorescence signatures for single airborne biological particles. The first data set contained mixed PSLs and the second contained a variety of laboratory-generated aerosol.Clustering in general performs slightly worse than the supervised learning methods, correctly classifying, at best, only 67. 6 and 91. 1 % for the two data sets respectively. For supervised learning the gradient boosting algorithm was found to be the most effective, on average correctly classifying 82. 8 and 98. 27 % of the testing data, respectively, across the two data sets.A possible alternative to gradient boosting is neural networks. We do however note that this method requires much more user input than the other methods, and we suggest that further research should be conducted using this method, especially using parallelised hardware such as the GPU, which would allow for larger networks to be trained, which could possibly yield better results.We also saw that some methods, such as clustering, failed to utilise the additional shape information provided by the instrument, whilst for others, such as the decision trees, ensemble methods and neural networks, improved performance could be attained with the inclusion of such information.
Mitochondrial Regulation of the Hippocampal Firing Rate Set Point and Seizure Susceptibility
Styr B, Gonen N, Zarhin D, Ruggiero A, Atsmon R, Gazit N, Braun G, Frere S, Vertkin I, Shapira I, Harel M, ...Heim LR, Katsenelson M, Rechnitz O, Fadila S, Derdikman D, Rubinstein M, Geiger T, Ruppin E, Slutsky I. Neuron. 2019. pii: S0896-6273(19)30334-4. doi:10.1016/j.neuron.2019.03.045. Epub ahead of print PMID: 31047779.
Maintaining average activity within a set-point range constitutes a fundamental property of central neural circuits. However, whether and how activity set points are regulated remains unknown. Integrating genome-scale metabolic modeling and experimental study of neuronal homeostasis, we identified mitochondrial dihydroorotate dehydrogenase (DHODH) as a regulator of activity set points in hippocampal networks. The DHODH inhibitor teriflunomide stably suppressed mean firing rates via synaptic and intrinsic excitability mechanisms by modulating mitochondrial Ca2+ buffering and spare respiratory capacity. Bidirectional activity perturbations under DHODH blockade triggered firing rate compensation, while stabilizing firing to the lower level, indicating a change in the firing rate set point. In vivo, teriflunomide decreased CA3–CA1 synaptic transmission and CA1 mean firing rate and attenuated susceptibility to seizures, even in the intractable Dravet syndrome epilepsy model. Our results uncover mitochondria as a key regulator of activity set points, demonstrate the differential regulation of set points and compensatory mechanisms, and propose a new strategy to treat epilepsy.
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