The Model for End-Stage Liver Disease (MELD) uses bilirubin, the international normalized ratio for prothrombin time, and creatinine to estimate the risk of death in patients waiting for liver ...transplantation. This analysis of about 14,000 registrants on the waiting list showed that the addition of the serum sodium concentration to the MELD score improves prognostic accuracy and may reduce mortality among patients on the waiting list who have low MELD scores and serum sodium levels.
This analysis of registrants on the waiting list for liver transplantation showed that the addition of the serum sodium concentration to the Model for End-Stage Liver Disease (MELD) score improves prognostic accuracy and may reduce mortality among patients on the waiting list who have low MELD scores and serum sodium levels.
The allocation of grafts for liver transplantation from deceased donors in the United States is based on medical urgency, which is estimated according to the Model for End-Stage Liver Disease (MELD) score. The MELD score is based on the results of three readily available, objective, and reproducible laboratory tests: the total serum bilirubin concentration, the international normalized ratio (INR) for the prothrombin time, and the serum creatinine concentration.
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In the United States, the MELD score has been used in determining priorities for organ allocation in liver transplantation since 2002.
In addition to the MELD score, the serum sodium concentration . . .
Congenital heart disease (CHD) is the leading cause of mortality from birth defects. Here, exome sequencing of a single cohort of 2,871 CHD probands, including 2,645 parent-offspring trios, ...implicated rare inherited mutations in 1.8%, including a recessive founder mutation in GDF1 accounting for ∼5% of severe CHD in Ashkenazim, recessive genotypes in MYH6 accounting for ∼11% of Shone complex, and dominant FLT4 mutations accounting for 2.3% of Tetralogy of Fallot. De novo mutations (DNMs) accounted for 8% of cases, including ∼3% of isolated CHD patients and ∼28% with both neurodevelopmental and extra-cardiac congenital anomalies. Seven genes surpassed thresholds for genome-wide significance, and 12 genes not previously implicated in CHD had >70% probability of being disease related. DNMs in ∼440 genes were inferred to contribute to CHD. Striking overlap between genes with damaging DNMs in probands with CHD and autism was also found.
KRAS mutant pancreatic ductal adenocarcinoma (PDAC) is characterized by a desmoplastic response that promotes hypovascularity, immunosuppression, and resistance to chemo- and immunotherapies. We show ...that a combination of MEK and CDK4/6 inhibitors that target KRAS-directed oncogenic signaling can suppress PDAC proliferation through induction of retinoblastoma (RB) protein-mediated senescence. In preclinical mouse models of PDAC, this senescence-inducing therapy produces a senescence-associated secretory phenotype (SASP) that includes pro-angiogenic factors that promote tumor vascularization, which in turn enhances drug delivery and efficacy of cytotoxic gemcitabine chemotherapy. In addition, SASP-mediated endothelial cell activation stimulates the accumulation of CD8+ T cells into otherwise immunologically “cold” tumors, sensitizing tumors to PD-1 checkpoint blockade. Therefore, in PDAC models, therapy-induced senescence can establish emergent susceptibilities to otherwise ineffective chemo- and immunotherapies through SASP-dependent effects on the tumor vasculature and immune system.
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•Therapy-induced senescence in PDAC triggers SASP-dependent vascular remodeling•SASP-mediated vascularization facilitates chemotherapy uptake and efficacy•SASP-mediated endothelial activation drives T cell infiltration into PDAC lesions•Senescence-inducing treatment potentiates PD-1 blockade in PDAC models
In mouse models of KRAS mutant pancreatic ductal adenocarcinoma, tumor cell senescence following MEK and CDK4/6 inhibition promotes vascular remodeling through induction of a pro-angiogenic senescence-associated secretory phenotype, leading to enhanced drug delivery and T cell infiltration that sensitizes these tumors to chemotherapy and immune checkpoint blockade.
There is massive variation in intron numbers across eukaryotic genomes, yet the major drivers of intron content during evolution remain elusive. Rapid intron loss and gain in some lineages contrast ...with long-term evolutionary stasis in others. Episodic intron gain could be explained by recently discovered specialized transposons called Introners, but so far Introners are only known from a handful of species. Here, we performed a systematic search across 3,325 eukaryotic genomes and identified 27,563 Introner-derived introns in 175 genomes (5.2%). Species with Introners span remarkable phylogenetic diversity, from animals to basal protists, representing lineages whose last common ancestor dates to over 1.7 billion years ago. Aquatic organisms were 6.5 times more likely to contain Introners than terrestrial organisms. Introners exhibit mechanistic diversity but most are consistent with DNA transposition, indicating that Introners have evolved convergently hundreds of times from nonautonomous transposable elements. Transposable elements and aquatic taxa are associated with high rates of horizontal gene transfer, suggesting that this combination of factors may explain the punctuated and biased diversity of species containing Introners. More generally, our data suggest that Introners may explain the episodic nature of intron gain across the eukaryotic tree of life. These results illuminate the major source of ongoing intron creation in eukaryotic genomes.
We have grown an antimicrobial polymer directly on the surfaces of glass and paper using atom transfer radical polymerization (ATRP). The method described here results in potentially permanent ...nonleaching antibacterial surfaces without the need to chemically graft the antimicrobial material to the substratum. The tertiary amine 2-(dimethylamino)ethyl methacrylate was polymerized directly onto Whatman #1 filter paper or glass slides via atom transfer radical polymerization. Following the polymerization, the tertiary amino groups were quaternized using an alkyl halide to produce a large concentration of quaternary ammonium groups on the polymer-modified surfaces. Incubating the modified materials with either Escherichia coli or Bacillus subtilis demonstrated that the modified surfaces had substantial antimicrobial capacity. The permanence of the antimicrobial activity was demonstrated through repeated use of a modified glass without significant loss of activity. Quaternary amines are believed to cause cell death by disrupting cell membranes allowing release of the intracellular contents. Atomic force microscopic imaging of cells on modified glass surfaces supports this hypothesis.
Diabetes-related foot infections occur in approximately 40% of diabetes-related foot ulcers and cause significant morbidity. Clinicians should consider patient risk factors (e.g., presence of foot ...ulcers greater than 2 cm, uncontrolled diabetes mellitus, poor vascular perfusion, comorbid illness) when evaluating for a foot infection or osteomyelitis. Indicators of infection include erythema, induration, tenderness, warmth, and drainage. Superficial wound cultures should be avoided because of the high rate of contaminants. Deep cultures obtained through aseptic procedures (e.g., incision and drainage, debridement, bone culture) help guide treatment. Plain radiography is used for initial imaging if osteomyelitis is suspected; however, magnetic resonance imaging or computed tomography may help if radiography is inconclusive, the extent of infection is unknown, or if the infection orientation needs to be determined to help in surgical planning. Staphylococcus aureus and Streptococcus agalactiae are the most commonly isolated pathogens, although polymicrobial infections are common. Antibiotic therapy should cover commonly isolated organisms and reflect local resistance patterns, patient preference, and the severity of the foot infection. Mild and some moderate infections may be treated with oral antibiotics. Severe infections require intravenous antibiotics. Treatment duration is typically one to two weeks and is longer for slowly resolving infections or osteomyelitis. Severe or persistent infections may require surgery and specialized team-based wound care. Although widely recommended, there is little evidence on the effectiveness of primary prevention strategies. Systematic assessment, counseling, and comorbidity management are hallmarks of effective secondary prevention for diabetes-related foot infections.
Thrombotic microangiopathy-induced thrombocytopenia-associated multiple organ failure and hyperinflammatory macrophage activation syndrome are important causes of late pediatric sepsis mortality that ...are often missed or have delayed diagnosis. The National Institutes of General Medical Science sepsis research working group recommendations call for application of new research approaches in extant clinical data sets to improve efficiency of early trials of new sepsis therapies. Our objective is to apply machine learning approaches to derive computable 24-h sepsis phenotypes to facilitate personalized enrollment in early anti-inflammatory trials targeting these conditions.
We applied consensus, k-means clustering analysis to our extant PHENOtyping sepsis-induced Multiple organ failure Study (PHENOMS) dataset of 404 children. 24-hour computable phenotypes are derived using 25 available bedside variables including C-reactive protein and ferritin.
Four computable phenotypes (PedSep-A, B, C, and D) are derived. Compared to all other phenotypes, PedSep-A patients (n = 135; 2% mortality) were younger and previously healthy, with the lowest C-reactive protein and ferritin levels, the highest lymphocyte and platelet counts, highest heart rate, and lowest creatinine (p < 0.05); PedSep-B patients (n = 102; 12% mortality) were most likely to be intubated and had the lowest Glasgow Coma Scale Score (p < 0.05); PedSep-C patients (n = 110; mortality 10%) had the highest temperature and Glasgow Coma Scale Score, least pulmonary failure, and lowest lymphocyte counts (p < 0.05); and PedSep-D patients (n = 56, 34% mortality) had the highest creatinine and number of organ failures, including renal, hepatic, and hematologic organ failure, with the lowest platelet counts (p < 0.05). PedSep-D had the highest likelihood of developing thrombocytopenia-associated multiple organ failure (Adj OR 47.51 95% CI 18.83-136.83, p < 0.0001) and macrophage activation syndrome (Adj OR 38.63 95% CI 13.26-137.75, p < 0.0001).
Four computable phenotypes are derived, with PedSep-D being optimal for enrollment in early personalized anti-inflammatory trials targeting thrombocytopenia-associated multiple organ failure and macrophage activation syndrome in pediatric sepsis. A computer tool for identification of individual patient membership ( www.pedsepsis.pitt.edu ) is provided. Reproducibility will be assessed at completion of two ongoing pediatric sepsis studies.
Instrument-assisted soft tissue mobilization (IASTM) is a popular myofascial treatment utilized by health care professionals. Currently, there is a lack of research on the effects of a light pressure ...IASTM treatment on the forearm region. The purpose of this study was to explore the effects of a light pressure IASTM technique at different application rates on grip strength and muscle stiffness. This study was considered exploratory with the goal of establishing methodology for future controlled studies.
Observational pretest and posttest clinical study.
Twenty-six healthy adults underwent one light pressure IASTM treatment to their dominant forearm muscles. Participants were allocated to 2 groups of 13 based upon treatment rate: 60 beats per minute and 120 beats per minute. Participants were tested pretreatment and posttreatment for grip strength and tissue stiffness via diagnostic ultrasound. One-way analyses of covariance were used to assess group differences posttreatment for grip strength and tissue stiffness.
Statistically significant posttreatment changes for grip strength and tissue stiffness were not found. Despite the nonstatistical significance, there were small decreases in grip strength and tissue stiffness. Faster (120 beats/min) IASTM application may have produced clinically meaningful decreases in grip strength along with a small decrease in tissue stiffness.
This report helps to establish methodology for future controlled studies on this topic. Sports medicine professionals should consider these results as exploratory and interpret them with caution. Future research is needed to confirm these findings and begin to postulate possible neurophysiological mechanisms.
The size and complexity of chemical kinetic models used to simulate combustion of hydrocarbon fuels continue to increase with our improved understanding of the underlying physical mechanisms, along ...with the improved ability to utilize such models as the result of increased computational power and efficiency. As mechanisms grow beyond thousands of species and tens of thousands of reactions, it becomes increasingly difficult to manually check for errors and physical inconsistencies. We present several automated methods to check for such issues in the specification of chemical reaction models. First, we demonstrate how discontinuities in thermodynamic data can cause simulation difficulties manifested as long wall-clock times and convergence failures. To correct this type of problem, we describe an automated method for refitting thermodynamic parameters. We also outline several methods to check the timescales of reaction rate coefficients to ensure physical consistency. All the methods are made available through a web-based tool (https://combustiontools.llnl.gov) intended to aid mechanism developers and users to improve the accuracy and performance of fuel models used by the combustion community.
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