Background. Randomized trials support use of procalcitonin (PCT)-based algorithms to decrease duration of antibiotics for critically ill patients with sepsis. However, current use of PCT and ...associated outcomes in real-world clinical settings is unclear. We sought to determine PCT use in critically ill patients with sepsis in the United States and to examine associations between PCT use and clinical outcomes. Methods. This was a retrospective cohort study of approximately 20% of patients with sepsis hospitalized in US intensive care units. Hierarchical regression models were used to determine associations of PCT use with outcomes (antibiotic-days, incidence of Clostridium difficile infection, and in-hospital mortality). Sensitivity analyses were conducted to assess robustness of findings to different methods used to address unmeasured confounding (eg, instrumental variable, difference-in-differences analyses). Results. Among 20 750 critically ill patients with sepsis in 107 hospitals with PCT available, 3769 (18%) patients had PCT levels checked; 1119 (29.7%) had serial PCT measurements. PCT use was associated with increased antibiotic-days (adjusted relative risk, 1.1; 95% confidence interval CI, 1.15–1.18) and incidence of C. difficile (adjusted odds ratio, 1.42; 95% CI, 1.09–1.85) without a change in mortality (adjusted hazard ratio, 1.05; 95% CI, 0.93–1.19). Analysis of PCT use by instrumental variable and difference-in-difference analyses showed similar lack of antibiotic or outcome improvements associated with PCT use. Conclusions. PCT use was not associated with improved antibiotic use or other clinical outcomes in real-world settings. Programs to improve implementation of PCT-based strategies are warranted prior to widespread adoption.
Over the past 2 decades, the use of intravenous ketamine infusions as a treatment for chronic pain has increased dramatically, with wide variation in patient selection, dosing, and monitoring. This ...has led to a chorus of calls from various sources for the development of consensus guidelines.
In November 2016, the charge for developing consensus guidelines was approved by the boards of directors of the American Society of Regional Anesthesia and Pain Medicine and, shortly thereafter, the American Academy of Pain Medicine. In late 2017, the completed document was sent to the American Society of Anesthesiologists' Committees on Pain Medicine and Standards and Practice Parameters, after which additional modifications were made. Panel members were selected by the committee chair and both boards of directors based on their expertise in evaluating clinical trials, past research experience, and clinical experience in developing protocols and treating patients with ketamine. Questions were developed and refined by the committee, and the groups responsible for addressing each question consisted of modules composed of 3 to 5 panel members in addition to the committee chair. Once a preliminary consensus was achieved, sections were sent to the entire panel, and further revisions were made. In addition to consensus guidelines, a comprehensive narrative review was performed, which formed part of the basis for guidelines.
Guidelines were prepared for the following areas: indications; contraindications; whether there was evidence for a dose-response relationship, or a minimum or therapeutic dose range; whether oral ketamine or another N-methyl-D-aspartate receptor antagonist was a reasonable treatment option as a follow-up to infusions; preinfusion testing requirements; settings and personnel necessary to administer and monitor treatment; the use of preemptive and rescue medications to address adverse effects; and what constitutes a positive treatment response. The group was able to reach consensus on all questions.
Evidence supports the use of ketamine for chronic pain, but the level of evidence varies by condition and dose range. Most studies evaluating the efficacy of ketamine were small and uncontrolled and were either unblinded or ineffectively blinded. Adverse effects were few and the rate of serious adverse effects was similar to placebo in most studies, with higher dosages and more frequent infusions associated with greater risks. Larger studies, evaluating a wider variety of conditions, are needed to better quantify efficacy, improve patient selection, refine the therapeutic dose range, determine the effectiveness of nonintravenous ketamine alternatives, and develop a greater understanding of the long-term risks of repeated treatments.
•Annual lake phosphorus dynamic explained mostly by recycling and sedimentation•Mass balance unable to fully reproduce lake phosphorus cycling•Process-guided machine learning outperforms neural ...network or process alone•Missing long-term trend in lake phosphorus likely due to changes in loading
Phosphorus (P) loading to lakes is degrading the quality and usability of water globally. Accurate predictions of lake P dynamics are needed to understand whole-ecosystem P budgets, as well as the consequences of changing lake P concentrations for water quality. However, complex biophysical processes within lakes, along with limited observational data, challenge our capacity to reproduce short-term lake dynamics needed for water quality predictions, as well as long-term dynamics needed to understand broad scale controls over lake P. Here we use an emerging paradigm in modeling, process-guided machine learning (PGML), to produce a phosphorus budget for Lake Mendota (Wisconsin, USA) and to accurately predict epilimnetic phosphorus over a time range of days to decades. In our implementation of PGML, which we term a Process-Guided Recurrent Neural Network (PGRNN), we combine a process-based model for lake P with a recurrent neural network, and then constrain the predictions with ecological principles. We test independently the process-based model, the recurrent neural network, and the PGRNN to evaluate the overall approach. The process-based model accounted for most of the observed pattern in lake P; however it missed the long-term trend in lake P and had the worst performance in predicting winter and summer P in surface waters. The root mean square error (RMSE) for the process-based model, the recurrent neural network, and the PGRNN was 33.0 μg P L−1, 22.7 μg P L−1, and 20.7 μg P L−1, respectively. All models performed better during summer, with RMSE values for the three models (same order) equal to 14.3 μg P L−1, 10.9 μg P L−1, and 10.7 μg P L−1. Although the PGRNN had only marginally better RMSE during summer, it had lower bias and reproduced long-term decreases in lake P missed by the other two models. For all seasons and all years, the recurrent neural network had better predictions than process alone, with root mean square error (RMSE) of 23.8 μg P L−1 and 28.0 μg P L−1, respectively. The output of PGRNN indicated that new processes related to water temperature, thermal stratification, and long term changes in external loads are needed to improve the process model. By using ecological knowledge, as well as the information content of complex data, PGML shows promise as a technique for accurate prediction in messy, real-world ecological dynamics, while providing valuable information that can improve our understanding of process.
Abstract Purpose Poor hazard anticipation skills are a risk factor associated with high motor vehicle crash rates of young drivers. A number of programs have been developed to improve these skills. ...The purpose of this review was to assess the empirical literature on hazard anticipation training for young drivers. Methods Studies were included if they (1) included an assessment of hazard anticipation training outcomes; (2) were published between January 1, 1980 and December 31, 2013 in an English language peer-reviewed journal or conference proceeding; and (3) included at least one group that uniquely comprised a cohort of participants aged <21 years. Nineteen studies met inclusion criteria. Results Studies used a variety of training methods including interactive computer programs, videos, simulation, commentary driving, or a combination of approaches. Training effects were predominantly measured through computer-based testing and driving simulation with eye tracking. Four studies included an on-road evaluation. Most studies evaluated short-term outcomes (immediate or few days). In all studies, young drivers showed improvement in selected hazard anticipation outcomes but none investigated crash effects. Conclusions Although there is promise in existing programs, future research should include long-term follow-up, evaluate crash outcomes, and assess the optimal timing of hazard anticipation training taking into account the age and experience level of young drivers.
Disparities in patient selection for advanced therapeutics in health care have been identified in multiple studies, but it is unclear if disparities exist in patient selection for extracorporeal ...membrane oxygenation (ECMO), a rapidly expanding critical care resource.
To determine if disparities exist in patient selection for ECMO based on sex, primary insurance, and median income of the patient's neighborhood.
In a retrospective cohort study using the Nationwide Readmissions Database 2016-2019, we identified patients treated with mechanical ventilation (MV) and/or ECMO with billing codes. Patient sex, insurance, and income level for patients receiving ECMO were compared with the patients treated with MV only, and hierarchical logistic regression with the hospital as a random intercept was used to determine odds of receiving ECMO based on patient demographics.
We identified 2,170,752 MV hospitalizations with 18,725 cases of ECMO. Among patients treated with ECMO, 36.1% were female compared with 44.5% of patients treated with> MV only (adjusted odds ratio aOR for ECMO, 0.73; 95% confidence interval CI, 0.70-0.75). Of patients treated with ECMO, 38.1% had private insurance compared with 17.4% of patients treated with MV only. Patients with Medicaid were less likely to receive ECMO than patients with private insurance (aOR, 0.55; 95% CI, 0.52-0.57). Patients treated with ECMO were more likely to live in the highest-income neighborhoods compared with patients treated with MV only (25.1% vs. 17.3%). Patients living in the lowest-income neighborhoods were less likely to receive ECMO than those living in the highest-income neighborhoods (aOR, 0.63; 95% CI, 0.60-0.67).
Significant disparities exist in patient selection for ECMO. Female patients, patients with Medicaid, and patients living in the lowest-income neighborhoods are less likely to be treated with ECMO. Despite possible unmeasured confounding, these findings were robust to multiple sensitivity analyses. On the basis of previous work describing disparities in other areas of health care, we speculate that limited access in some neighborhoods, restrictive/biased interhospital transfer practices, differences in patient preferences, and implicit provider bias may contribute to the observed differences. Future studies with more granular data are needed to identify and modify drivers of observed disparities.
Reactive microglia are observed with aging and in Lewy body disorders, including within the olfactory bulb of men with Parkinson's disease. However, the functional impact of microglia in these ...disorders is still debated. Resetting these reactive cells by a brief dietary pulse of the colony-stimulating factor 1 receptor (CSF1R) inhibitor PLX5622 may hold therapeutic potential against Lewy-related pathologies. To our knowledge, withdrawal of PLX5622 after short-term exposure has not been tested in the preformed α-synuclein fibril (PFF) model, including in aged mice of both sexes. Compared to aged female mice, we report that aged males on the control diet showed higher numbers of phosphorylated α-synuclein+ inclusions in the limbic rhinencephalon after PFFs were injected in the posterior olfactory bulb. However, aged females displayed larger inclusion sizes compared to males. Short-term (14-day) dietary exposure to PLX5622 followed by control chow reduced inclusion numbers and levels of insoluble α-synuclein in aged males—but not females—and unexpectedly raised inclusion sizes in both sexes. Transient delivery of PLX5622 also improved spatial reference memory in PFF-infused aged mice, as evidenced by an increase in novel arm entries in a Y-maze. Superior memory was positively correlated with inclusion sizes but negatively correlated with inclusion numbers. Although we caution that PLX5622 delivery must be tested further in models of α-synucleinopathy, our data suggest that larger-sized—but fewer—α-synucleinopathic structures are associated with better neurological outcomes in PFF-infused aged mice.
•We leveraged a mouse model of preformed fibril-seeded, limbic alpha-synucleinopathy.•Aged female mice had fewer but larger-sized inclusions than aged males.•Transient PLX5622 reduced inclusion counts and insoluble α-synuclein in aged males.•Transient PLX5622 raised inclusion sizes and improved spatial reference memory.•Superior memory was linked to larger-sized but fewer inclusions.
Targeted cancer therapies have produced substantial clinical responses, but most tumors develop resistance to these drugs. Here, we describe a pharmacogenomic platform that facilitates rapid ...discovery of drug combinations that can overcome resistance. We established cell culture models derived from biopsy samples of lung cancer patients whose disease had progressed while on treatment with epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors and then subjected these cells to genetic analyses and a pharmacological screen. Multiple effective drug combinations were identified. For example, the combination of ALK and MAPK kinase (MEK) inhibitors was active in an ALK-positive resistant tumor that had developed a MAP2K1 activating mutation, and the combination of EGFR and fibroblast growth factor receptor (FGFR) inhibitors was active in an EGFR mutant resistant cancer with a mutation in FGFR3. Combined ALK and SRC (pp60c-src) inhibition was effective in several ALK-driven patient-derived models, a result not predicted by genetic analysis alone. With further refinements, this strategy could help direct therapeutic choices for individual patients.
Childhood and adolescence require adequate amount of micronutrients for normal growth and development. The primary objective of study was to assess the prevalence of deficiencies of Vitamins (Vitamin ...A, 25 Hydroxy Vitamin D, Vitamin B12 and Folate) and minerals (Calcium, Zinc, Selenium and Iron), among urban school going children aged 6-11 and 12-16 years in ten cities of India. Secondary objective was to find the association between micronutrient deficiencies with sociodemographic and anthropometric indicators.
A multi-center cross-sectional study was conducted across India. Participants in the age groups of 6 to 11 years (group 1) and 12 to 16 years (group 2) were selected from randomly chosen schools from each center. Data on socio economic status, anthropometric measures was collected. Blood samples were collected for biochemical analysis of micronutrients. Point estimates and 95% confidence intervals was used to assess the prevalence of deficiencies. Associations were observed using chi square, student t test and ANOVA test.
From April 2019 to February 2020, 2428 participants (1235 in group 1 and 1193 group 2) were recruited from 60 schools across ten cites. The prevalence of calcium and iron deficiency was 59.9% and 49.4% respectively. 25 Hydroxy Vitamin D deficiency was seen in 39.7% and vitamin B12 in 33.4% of subjects. Folate, Selenium and Zinc were deficient in 22.2%, 10.4% and 6.8% of subjects respectively. Vitamin A deficiency least (1.6%). Anemia was prevalent in 17.6% subjects and was more common among females.
One or more micronutrient deficiencies are found in almost one half of school going children in urban area. Hence efforts must be made to combat these on priority.
CTRI/2019/02/017783.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Ammonium dinitramide (ADN) based liquid monopropellants have been identified as environmentally benign substitutes for hydrazine monopropellant. However, new catalysts are to be developed for making ...ADN monopropellants cold-start capable. In the present study, performance of Co and Ba doped CuCr2O4 nanocatalysts prepared by hydrothermal method was evaluated on the decomposition of aqueous ADN solution and ADN liquid monopropellant (LMP103X). The catalysts were characterized by PXRD (Powder X-ray Diffraction), FTIR (Fourier Transform Infrared spectroscopy), SEM (Scanning Electron Microscopy), TEM (Transmission Electron Microscopy), EDS (Energy Dispersive X-ray Spectroscopy), and XPS (X-ray Photoelectron Spectroscopy). The nanosize was confirmed by SEM and TEM, while the nanoflake morphology was confirmed by the SEM analysis. Further, we obtained the elemental composition from the EDS analysis. We investigated the catalytic activity of the catalysts by thermogravimetric (TG) analysis and the developed catalysts lowered the decomposition temperature of ADN monopropellant by about 55 °C. The XPS analysis confirmed the presence of metal ions with different chemical states. Apparently, increase in the surface area of the catalysts and the mixed active sites as well as the development of oxygen vacancy on the catalyst surface introduced by metal doping are influencing the decomposition temperature of ADN samples.
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Mitochondrial Ca2+ uniporter (MCU)-mediated Ca2+ uptake promotes the buildup of reducing equivalents that fuel oxidative phosphorylation for cellular metabolism. Although MCU modulates mitochondrial ...bioenergetics, its function in energy homeostasis in vivo remains elusive. Here we demonstrate that deletion of the Mcu gene in mouse liver (MCUΔhep) and in Danio rerio by CRISPR/Cas9 inhibits mitochondrial Ca2+ (mCa2+) uptake, delays cytosolic Ca2+ (cCa2+) clearance, reduces oxidative phosphorylation, and leads to increased lipid accumulation. Elevated hepatic lipids in MCUΔhep were a direct result of extramitochondrial Ca2+-dependent protein phosphatase-4 (PP4) activity, which dephosphorylates AMPK. Loss of AMPK recapitulates hepatic lipid accumulation without changes in MCU-mediated Ca2+ uptake. Furthermore, reconstitution of active AMPK, or PP4 knockdown, enhances lipid clearance in MCUΔhep hepatocytes. Conversely, gain-of-function MCU promotes rapid mCa2+ uptake, decreases PP4 levels, and reduces hepatic lipid accumulation. Thus, our work uncovers an MCU/PP4/AMPK molecular cascade that links Ca2+ dynamics to hepatic lipid metabolism.
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•Mitochondrial Ca2+ powers FAO-dependent hepatocyte mitochondrial respiration•Hepatic MCU deletion promotes lipid accumulation and lowers ketone bodies•Blockade of mCa2+ buffering enhances AMPK dephosphorylation through PP4•Restoration of AMPK activity in MCUΔhep model improves lipid clearance
Hepatic mitochondrial Ca2+ shapes bioenergetics and lipid homeostasis. Tomar et al. demonstrate that MCU-mediated cCa2+ buffering serves as a crucial step in controlling hepatic fuel metabolism through an MCU/PP4/AMPK molecular cascade. Identification of these molecular signaling events aids in understanding how perturbation of mitochondrial ion homeostasis may contribute to the etiology of metabolic disorders.
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