Prior sepsis studies evaluating antibiotic timing have shown mixed results.
To evaluate the association between antibiotic timing and mortality among patients with sepsis receiving antibiotics within ...6 hours of emergency department registration.
Retrospective study of 35,000 randomly selected inpatients with sepsis treated at 21 emergency departments between 2010 and 2013 in Northern California. The primary exposure was antibiotics given within 6 hours of emergency department registration. The primary outcome was adjusted in-hospital mortality. We used detailed physiologic data to quantify severity of illness within 1 hour of registration and logistic regression to estimate the odds of hospital mortality based on antibiotic timing and patient factors.
The median time to antibiotic administration was 2.1 hours (interquartile range, 1.4-3.1 h). The adjusted odds ratio for hospital mortality based on each hour of delay in antibiotics after registration was 1.09 (95% confidence interval CI, 1.05-1.13) for each elapsed hour between registration and antibiotic administration. The increase in absolute mortality associated with an hour's delay in antibiotic administration was 0.3% (95% CI, 0.01-0.6%; P = 0.04) for sepsis, 0.4% (95% CI, 0.1-0.8%; P = 0.02) for severe sepsis, and 1.8% (95% CI, 0.8-3.0%; P = 0.001) for shock.
In a large, contemporary, and multicenter sample of patients with sepsis in the emergency department, hourly delays in antibiotic administration were associated with increased odds of hospital mortality even among patients who received antibiotics within 6 hours. The odds increased within each sepsis severity strata, and the increased odds of mortality were greatest in septic shock.
E-cadherin and p120 catenin (p120) are essential for epithelial homeostasis, but can also exert pro-tumorigenic activities. Here, we resolve this apparent paradox by identifying two spatially and ...functionally distinct junctional complexes in non-transformed polarized epithelial cells: one growth suppressing at the apical zonula adherens (ZA), defined by the p120 partner PLEKHA7 and a non-nuclear subset of the core microprocessor components DROSHA and DGCR8, and one growth promoting at basolateral areas of cell-cell contact containing tyrosine-phosphorylated p120 and active Src. Recruitment of DROSHA and DGCR8 to the ZA is PLEKHA7 dependent. The PLEKHA7-microprocessor complex co-precipitates with primary microRNAs (pri-miRNAs) and possesses pri-miRNA processing activity. PLEKHA7 regulates the levels of select miRNAs, in particular processing of miR-30b, to suppress expression of cell transforming markers promoted by the basolateral complex, including SNAI1, MYC and CCND1. Our work identifies a mechanism through which adhesion complexes regulate cellular behaviour and reveals their surprising association with the microprocessor.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SBMB, UILJ, UKNU, UL, UM, UPUK
Evidence supporting the effectiveness of care management programs for complex patients has been inconclusive. However, past reviews have not focused on complexity primarily defined by multimorbidity ...and healthcare utilization. We conducted a systematic review of care management interventions targeting the following three patient groups: adults with two or more chronic medical conditions, adults with at least one chronic medical condition and concurrent depression, and adults identified based solely on high past or predicted healthcare utilization.
Eligible studies were identified from PubMed, published between 06/01/2005 and 05/31/2015, and reported findings from a randomized intervention that tested a comprehensive, care management intervention. Identified interventions were grouped based on the three "complex" categories of interest (described above). Two investigators extracted data using a structured abstraction form and assessed RCT quality.
We screened 989 article titles for eligibility from which 847 were excluded. After reviewing the remaining 142 abstracts, 83 articles were excluded. We reviewed the full-text of 59 full-text articles and identified 15 unique RCTs for the final analysis. Of these 15 studies, two focused on patients with two or more chronic medical conditions, seven on patients with at least one chronic medical condition and depression, and six on patients with high past or predicted healthcare utilization. Measured outcomes included utilization, chronic disease measures, and patient-reported outcomes. The seven studies targeting patients with at least one chronic medical condition and depression demonstrated significant improvement in depression symptoms (ranging from 9.2 to 48.7% improvement). Of the six studies that focused on high utilizers, two showed small reductions in utilization. The quality of the research methodology in most of the studies (12/15) was rated fair or poor.
Interventions were more likely to be successful when patients were selected based on having at least one chronic medical condition and concurrent depression, and when patient-reported outcomes were assessed. Future research should focus on the role of mental health in complex care management, finding better methods for identifying patients who would benefit most from care management, and determining which intervention components are needed for which patients.
Celotno besedilo
Dostopno za:
CEKLJ, DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Ageing is a major risk factor for many neurological pathologies, but its mechanisms remain unclear. Unlike other tissues, the parenchyma of the central nervous system (CNS) lacks lymphatic ...vasculature and waste products are removed partly through a paravascular route. (Re)discovery and characterization of meningeal lymphatic vessels has prompted an assessment of their role in waste clearance from the CNS. Here we show that meningeal lymphatic vessels drain macromolecules from the CNS (cerebrospinal and interstitial fluids) into the cervical lymph nodes in mice. Impairment of meningeal lymphatic function slows paravascular influx of macromolecules into the brain and efflux of macromolecules from the interstitial fluid, and induces cognitive impairment in mice. Treatment of aged mice with vascular endothelial growth factor C enhances meningeal lymphatic drainage of macromolecules from the cerebrospinal fluid, improving brain perfusion and learning and memory performance. Disruption of meningeal lymphatic vessels in transgenic mouse models of Alzheimer's disease promotes amyloid-β deposition in the meninges, which resembles human meningeal pathology, and aggravates parenchymal amyloid-β accumulation. Meningeal lymphatic dysfunction may be an aggravating factor in Alzheimer's disease pathology and in age-associated cognitive decline. Thus, augmentation of meningeal lymphatic function might be a promising therapeutic target for preventing or delaying age-associated neurological diseases.
Background and objectives
Decisional regret is common in bereaved parents. We aimed to identify factors associated with and to explain patterns of parental decisional regret.
Methods
We used a ...convergent mixed‐methods design including quantitative items and free‐text responses from a survey of parents 6–24 months from their child's death from cancer. Parents expressed whether they had regrets about decisions during the end of their child's life (Yes/No/I don't know) and elaborated with free text. Results of qualitative content analysis of free‐text responses guided development and interpretation of quantitative multinomial models.
Results
Parents (N = 123 surveys, N = 84 free text) primarily identified as White (84%), mothers (63%), and primary caregivers (69%) for their children. Forty‐seven (38%) parents reported decisional regret, 61 (49%) indicated no regret, and 15 (12%) were unsure. Mothers (relative risk RR: 10.3, 95%CI: 1.3, 81.3, p = .03) and parents who perceived greater suffering at the end of their child's life (RR = 3.8, 95%CI: 1.2, 11.7, p = .02) were at increased risk of regret; qualitative evaluation revealed elements of self‐blame and difficulty reconciling treatment choices with the ultimate outcome. Preparation for symptoms was associated with decreased risk of regret (RR = 0.1, 95%CI: 0, .3, p < .01) with qualitative reflections focused on balanced teamwork that alerted parents for what to expect and how to make meaningful final memories.
Conclusions
Though decisional regret is common among cancer‐bereaved parents, mothers and those who perceive more suffering in their children may be at particular risk. Close collaboration between families and clinicians to prepare for symptoms and proactively attend to and minimize suffering may help alleviate decisional regret.
An industrial process for the selective activation of methane under mild conditions would be highly valuable for controlling emissions to the environment and for utilizing vast new sources of natural ...gas. The only selective catalysts for methane activation and conversion to methanol under mild conditions are methane monooxygenases (MMOs) found in methanotrophic bacteria; however, these enzymes are not amenable to standard enzyme immobilization approaches. Using particulate methane monooxygenase (pMMO), we create a biocatalytic polymer material that converts methane to methanol. We demonstrate embedding the material within a silicone lattice to create mechanically robust, gas-permeable membranes, and direct printing of micron-scale structures with controlled geometry. Remarkably, the enzymes retain up to 100% activity in the polymer construct. The printed enzyme-embedded polymer motif is highly flexible for future development and should be useful in a wide range of applications, especially those involving gas-liquid reactions.
In a randomized trial, 798 patients with varicose veins were assigned to undergo laser ablation, foam sclerotherapy, or surgery. At 5 years, disease-specific quality of life was better after laser ...ablation or surgery than after foam sclerotherapy, and cost-effectiveness analysis favored laser ablation.
The microbiome is an important and increasingly-studied mediator of organismal metabolism, although how the microbiome affects metabolism remains incompletely understood. Many investigators use ...antibiotics to experimentally perturb the microbiome. However, antibiotics have poorly understood yet profound off-target effects on behavior and diet, including food and water aversion, that can confound experiments and limit their applicability. We thus sought to determine the relative influence of microbiome modulation and off-target antibiotic effects on the behavior and metabolic activity of mice.
Mice treated with oral antibiotics via drinking water exhibited significant weight loss in fat, liver, and muscle tissue. These mice also exhibited a reduction in water and food consumption, with marked variability across antibiotic regimens. While administration of bitter-tasting but antimicrobially-inert compounds caused a similar reduction in water consumption, this did not cause tissue weight loss or reduced food consumption. Mice administered intraperitoneal antibiotics (bypassing the gastrointestinal tract) exhibited reduced tissue weights and oral intake, comparable to the effects of oral antibiotics. Antibiotic-treated germ-free mice did not have reduced tissue weights, providing further evidence that direct microbiome modulation (rather than behavioral effects) mediates these metabolic changes.
While oral antibiotics cause profound effects on food and water consumption, antibiotic effects on organismal metabolism are primarily mediated by microbiome modulation. We demonstrate that tissue-specific weight loss following antibiotic administration is due primarily to microbiome effects rather than food and water aversion, and identify antibiotic regimens that effectively modulate gut microbiota while minimizing off-target behavioral effects.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Although adult vertebrates sense changes in head position by using two classes of accelerometer, at larval stages zebrafish lack functional semicircular canals and rely exclusively on their otolithic ...organs to transduce vestibular information.
Despite this limitation, we find that larval zebrafish perform an effective vestibulo-ocular reflex (VOR) that serves to stabilize gaze in response to pitch and roll tilts. By using single-cell electroporations and targeted laser ablations, we identified a specific class of central vestibular neurons, located in the tangential nucleus, that are essential for the utricle-dependent VOR. Tangential nucleus neurons project contralaterally to extraocular motoneurons and in addition to multiple sites within the reticulospinal complex.
We propose that tangential neurons function as a broadband inertial accelerometer, processing utricular acceleration signals to control the activity of extraocular and postural neurons, thus completing a fundamental three-neuron circuit responsible for gaze stabilization.
► The utricle and its associated circuitry drive a broadband vestibular-ocular reflex ► Linear summation of bilateral utricular signals mediates compensatory eye rotations ► Central vestibular neurons in the tangential nucleus are necessary for the VOR ► Visual and vestibular signals interact to enhance gaze stabilization
Critical to the success of three-dimensional (3D) printing of living materials with high performance is the development of new ink materials and 3D geometries that favor long-term cell functionality. ...Here we report the use of freeze-dried live cells as the solid filler to enable a new living material system for direct ink writing of catalytically active microorganisms with tunable densities and various self-supporting porous 3D geometries. Baker’s yeast was used as an exemplary live whole-cell biocatalyst, and the printed structures displayed high resolution, large scale, high catalytic activity and long-term viability. An unprecedented high cell loading was achieved, and cell inks showed unique thixotropic behavior. In the presence of glucose, printed bioscaffolds exhibited increased ethanol production compared to bulk counterparts due largely to improved mass transfer through engineered porous structures. The new living materials developed in this work could serve as a versatile platform for process intensification of an array of bioconversion processes utilizing diverse microbial biocatalysts for production of high-value products or bioremediation applications.
PDF
