Several scoring systems predict mortality in alcohol-associated hepatitis (AH), including the Maddrey discriminant function (mDF) and model for end-stage liver disease (MELD) score developed in the ...United States, Glasgow alcoholic hepatitis score in the United Kingdom, and age, bilirubin, international normalized ratio, and creatinine score in Spain. To date, no global studies have examined the utility of these scores, nor has the MELD-sodium been evaluated for outcome prediction in AH. In this study, we assessed the accuracy of different scores to predict short-term mortality in AH and investigated additional factors to improve mortality prediction.
Patients admitted to hospital with a definite or probable AH were recruited by 85 tertiary centers in 11 countries and across 3 continents. Baseline demographic and laboratory variables were obtained. The primary outcome was all-cause mortality at 28 and 90 days.
In total, 3,101 patients were eligible for inclusion. After exclusions (n = 520), 2,581 patients were enrolled (74.4% male, median age 48 years, interquartile range 40.9-55.0 years). The median MELD score was 23.5 (interquartile range 20.5-27.8). Mortality at 28 and 90 days was 20% and 30.9%, respectively. The area under the receiver operating characteristic curve for 28-day mortality ranged from 0.776 for MELD-sodium to 0.701 for mDF, and for 90-day mortality, it ranged from 0.773 for MELD to 0.709 for mDF. The area under the receiver operating characteristic curve for mDF to predict death was significantly lower than all other scores. Age added to MELD obtained only a small improvement of AUC.
These results suggest that the mDF score should no longer be used to assess AH's prognosis. The MELD score has the best performance in predicting short-term mortality.
A ternary composite of CNT/polypyrrole/hydrous MnO2 is prepared by in situ chemical method and its electrochemical performance is evaluated by using cyclic voltammetry (CV), impedance measurement and ...constant-current charge/discharge cycling techniques. For comparative purpose, binary composites such as CNT/hydrous MnO2 and polypyrrole/hydrous MnO2 are prepared and also investigated for their physical and electrochemical performances. The specific capacitance (SC) values of the ternary composite, CNT/hydrous MnO2 and polypyrrole/hydrous MnO2 binary composites estimated by CV technique in 1.0M Na2SO4 electrolyte are 281, 150 and 35Fg-1 at 20mVs-1 and 209, 75 and 7Fg-1 at 200mVs-1, respectively. The electrochemical stability of ternary composite electrode is investigated by switching the electrode back and forth for 10,000 times between 0.1 and 0.9V versus Ag/AgCl at 100mVs-1. The electrode exhibits good cycling stability, retaining up to 88% of its initial charge at 10,000th cycle. A full cell assembled with the ternary composite electrodes shows a SC value of 149Fg-1 at a current loading of 1.0mAcm-2 during initial cycling, which decreased drastically to a value of 35Fg-1 at 2000th cycle. Analytical techniques such as scanning electron microscopy (SEM), X-ray diffraction spectroscopy (XRD), Brunauer-Emmet-Teller (BET) surface area measurement and inductively coupled plasma-atomic emission spectrometry (ICP-AES) are also used to characterize the composite materials.
This prospective study was conducted with the Korean Cancer Study Group to evaluate the efficacy and safety of cetuximab combined with modified FOLFOX6 (mFOLFOX6) as first-line treatment in recurrent ...or metastatic gastric cancer and to identify potential predictive biomarkers. Patients received cetuximab 400 mg m(-2) at week 1 and 250 mg m(-2) weekly thereafter until disease progression. Oxaliplatin (100 mg m(-2)) and leucovorin (100 mg m(-2)) were administered as a 2-h infusion followed by a 46-h continuous infusion of 5-fluorouracil (2400 mg m(-2)) every 2 weeks for a maximum of 12 cycles. Biomarkers potentially associated with efficacy were analysed. Among 38 evaluable patients, confirmed response rate (RR) was 50.0% (95% CI 34.1-65.9). Median time-to-progression (TTP) was 5.5 months (95% CI 4.5-6.5) and overall survival (OS) 9.9 months. Eleven patients having tumour EGFR expression by immunohistochemistry with low serum EGF and TGF-alpha levels showed a 100% RR compared to 37.0% in the remaining 27 patients (P<0.001). Moreover, ligand level increased when disease progressed in seven out of eight patients with EGFR expression and low baseline ligand level. No patient exhibited EGFR amplification or K-ras mutations. Gastric cancer patients with EGFR expression and low ligand levels had better outcomes with cetuximab/mFOLFOX6 treatment.
The AMoRE collaboration is preparing for the AMoRE-II experiment that will probe neutrinoless double beta decay with 100 kg of
100
Mo isotope. The
100
Mo nuclide will be mainly in the form of lithium ...molybdate crystals that are instrumented with metallic magnetic calorimeters (MMC), which detect the phonon excitations produced by electrons from neutrinoless double beta decay in the crystals. The energy resolution at a
Q
-value = 3.034 MeV is around 10 keV within a temperature ranging between 10 and 20 mK. Increasing the crystal mass of individual detector modules will reduce the number of detector channels and allow a few practical advantages associated with crystal growing, detector preparation, and operation of the experiment. To this end, we carried out an experiment with a 6 cm (diameter (D)) × 6 cm (height (H)) cylindrical lithium molybdate crystal of 516 g mass, which is 73% more massive than the 5 cm (D) × 5 cm (H) crystals that are currently being used in the AMoRE-I setup. We found that the larger crystal detector shows good performance characteristics in terms of energy resolution, signal time constant and particle identification capability, which makes it a suitable option for the AMoRE-II experiment.
Autosomal recessive Stargardt disease (STGD1) is a macular dystrophy caused by mutations in the ABCA4 (ABCR) gene. The disease phenotype that is most recognized in STGD1 patients, and also in the ...Abca4-/- mouse (a disease model), is lipofuscin accumulation in retinal pigment epithelium. Here, we tested whether delivery of the normal (wt) human ABCA4 gene to the subretinal space of the Abca4 -/- mice via lentiviral vectors would correct the disease phenotype; that is, reduce accumulation of the lipofuscin pigment A2E. Equine infectious anemia virus (EIAV)-derived lentiviral vectors were constructed expressing either the human ABCA4 gene or the LacZ reporter gene under the control of the constitutive (CMV) or photoreceptor-specific (Rho) promoters. Abca4-/- mice were injected subretinally with 1 microl ( approximately 5.0 x 10(5) TU) of each EIAV vector in one eye at postnatal days 4 and 5. An injection of saline, an EIAV-null vector, or an uninjected contralateral eye served as a control. Mice were killed at various times after injection to determine photoreceptor (PR) transduction efficiency and A2E concentrations. EIAV-LacZ vectors transduced from 5 to 20% of the PRs in the injected area in mice. Most importantly, a single subretinal injection of EIAV-CMV-ABCA4 to Abca4-/- mouse eyes substantially reduced disease-associated A2E accumulation compared to untreated and mock-treated control eyes. Treated eyes of Abca4-/- mice accumulated 8-12 pmol per eye (s.d.=2.7) of A2E 1 year after treatment, amounts comparable to wt controls, whereas mock-treated or untreated eyes had 3-5 times more A2E (27-39 pmol per eye, s.d.=1.5; P=0.001-0.005). Although extrapolation to humans requires caution, the high transduction efficiency of both rod and cone photoreceptors and the statistically significant reduction of A2E accumulation in the mouse model of STGD1 suggest that lentiviral gene therapy is a potentially efficient tool for treating ABCA4-associated diseases.
Summary
Aim: Although depression and anxiety are the most common psychological problems among dialysis patients, little is known about the association between depression, anxiety and quality of life ...(QOL) in patients with predialysis chronic kidney disease (CKD). Therefore, we assessed the prevalence of depression and anxiety, and their association with QOL in patients with predialysis CKD.
Methods: Two hundred and eight predialysis patients (male 61.1%) with a mean age of 55.7 ± 13.7 years and an estimated glomerular filtration rate < 60 ml/min/1.73 m2 were enrolled. Depression and anxiety were assessed with the Hospital Anxiety and Depression Scale. Patients with anxiety and depression scores ≥ 8 were diagnosed with anxiety and depression disorders respectively. The WHOQOL‐BREF questionnaire was used to assess patient QOL.
Results: The prevalence of depression (47.1%) and anxiety (27.6%) did not differ across CKD stages. Depression correlated positively with age, employment, income, education, comorbidity index, haemoglobin level, albumin concentration and anxiety score, and negatively with all WHOQOL‐BREF domain scores. Anxiety correlated significantly with QOL, but not with socioeconomic factors. In a multiple regression analysis, haemoglobin level, anxiety and QOL were independent factors associated with depression. In a linear regression analysis, depression and anxiety independently correlated with QOL after we adjusted for age, alcohol use, employment, income, education, haemoglobin level and albumin concentration.
Conclusions: Patients with predialysis CKD have a high prevalence of depression and anxiety, which are associated with reduced QOL. Early detection of depression and anxiety and active interventions should be considered to improve the QOL of these patients.
On September 14, 2015, the Laser Interferometer Gravitational-Wave Observatory (LIGO) detected a gravitational-wave transient (GW150914); we characterize the properties of the source and its ...parameters. The data around the time of the event were analyzed coherently across the LIGO network using a suite of accurate waveform models that describe gravitational waves from a compact binary system in general relativity. GW150914 was produced by a nearly equal mass binary black hole of masses 36(+5/-4) solar mass and 29(+4/-4) solar mass; for each parameter we report the median value and the range of the 90% credible interval. The dimensionless spin magnitude of the more massive black hole is bound to be less than 0.7 (at 90% probability). The luminosity distance to the source is 410(+160/-180) Mpc, corresponding to a redshift 0.09(+0.03/−0.04) assuming standard cosmology. The source location is constrained to an annulus section of 610 sq deg, primarily in the southern hemisphere. The binary merges into a black hole of mass 62(+4/−4) solar mass and spin 0.67(+0.05/−0.07). This black hole is significantly more massive than any other inferred from electromagnetic observations in the stellar-mass regime.
Multiple myeloma (MM) is an incurable hematological malignancy that causes most patients to eventually relapse and die from their disease. The 20S proteasome inhibitor bortezomib has emerged as an ...effective drug for MM treatment; however, intrinsic and acquired resistance to bortezomib has already been observed in MM patients. We evaluated the involvement of mitochondria in resistance to bortezomib‐induced cell death in two different MM cell lines (bortezomib‐resistant KMS20 cells and bortezomib‐sensitive KMS28BM cells). Indices of mitochondrial function, including membrane potential, oxygen consumption rate and adenosine‐5′‐triphosphate and mitochondrial Ca2+ concentrations, were positively correlated with drug resistance of KMS cell lines. Mitochondrial genes including CYPD, SOD2 and MCU were differentially expressed in KMS cells. Thus, changes in the expression of these genes lead to changes in mitochondrial activity and in bortezomib susceptibility or resistance, and their combined effect contributes to differential sensitivity or resistance of MM cells to bortezomib. In support of this finding, coadministration of bortezomib and 2‐methoxyestradiol, a SOD inhibitor, rendered KMS20 cells sensitive to apoptosis. Our results provide new insight into therapeutic modalities for MM patients. Studying mitochondrial activity and specific mitochondrial gene expression in fresh MM specimens might help predict resistance to proapoptotic chemotherapies and inform clinical decision‐making.
What's new?
While proteasome inhibitor bortezomib is an effective drug for multiple myeloma (MM), therapy can cause both intrinsic and acquired resistance. Here the authors evaluated the involvement of mitochondria using bortezomib‐resistant and ‐sensitive MM cell lines. Indices of mitochondrial function, including membrane potential, oxygen consumption rate, and adenosine‐5'‐triphosphate and mitochondrial Ca2+ concentrations, were positively correlated with drug resistance. Mitochondrial genes such as CYPD, SOD2, and MCU were also differentially expressed, contributing to the differential mitochondrial activity and sensitivity to bortezomib. Studying mitochondrial activity and specific mitochondrial gene expression in MM specimens might help predict resistance to pro‐apoptotic chemotherapies and inform clinical decision‐making.
Fibrolamellar carcinoma (FLC) is a rare liver tumor driven by the DNAJ-PKAc fusion protein that affects healthy young patients. Little is known about the immune response to FLC, limiting rational ...design of immunotherapy. Multiplex immunohistochemistry and gene expression profiling were performed to characterize the FLC tumor immune microenvironment and adjacent non-tumor liver (NTL). Flow cytometry and T cell receptor (TCR) sequencing were performed to determine the phenotype of tumor-infiltrating immune cells and the extent of T cell clonal expansion. Fresh human FLC tumor slice cultures (TSCs) were treated with antibodies blocking programmed cell death protein-1 (PD-1) and interleukin-10 (IL-10), with results measured by cleaved caspase-3 immunohistochemistry. Immune cells were concentrated in fibrous stromal bands, rather than in the carcinoma cell compartment. In FLC, T cells demonstrated decreased activation and regulatory T cells in FLC had more frequent expression of PD-1 and CTLA-4 than in NTL. Furthermore, T cells had relatively low levels of clonal expansion despite high TCR conservation across individuals. Combination PD-1 and IL-10 blockade signficantly increased cell death in human FLC TSCs. Immunosuppresion in the FLC tumor microenvironment is characterized by T cell exclusion and exhaustion, which may be reversible with combination immunotherapy.
Leukocyte telomere length (LTL) is considered a biomarker of human aging and based on cross-sectional studies it shortens with age. However, longitudinal studies reported that many adults display LTL ...lengthening.
Using Southern blots, we compared cross-sectional rates of age-related LTL change across a ∼20 year age range with those based on longitudinal evaluations in three surveys (S1, S2, and S3) with three time intervals: S1-S2 (5.8 years), S2-S3 (6.6 years), and S1-S3 (12.4 years). Hierarchical linear modeling was used to explore LTL dynamics using LTL data from S1, S2, and S3.
Cross-sectionally, mean LTL shortenings were 24.6, 25.4, and 23.6 bp/y at S1, S2, and S3, respectively. Longitudinally, more variation was observed in the rate of LTL change during the shorter than longer follow-up periods. Furthermore, using simple differences in LTL, 14.4% and 10.7% of individuals displayed LTL lengthening during S1-S2 and S2-S3, respectively, but only 1.5% during S1-S3 (p < 0.001). The estimated mean rate of LTL shortening based on averaging empirical Bayes' estimates of LTL from a parsimonious hierarchical linear modeling model was 31 bp/y with a range from 23 to 47 bp/y with none of the participants showing LTL lengthening over the average 12.4 years of follow-up.
As aging displays a unidirectional progression, it is unlikely that LTL elongates with age. LTL elongation in longitudinal studies primarily reflects measurement errors of LTL in relation to the duration of follow-up periods.
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