Costs associated with febrile neutropenia in solid tumor and lymphoma patients - an observational study in Singapore.

BackgroundThe primary objective was to describe the total direct inpatient costs among solid tumor and lymphoma patients with chemotherapy-induced febrile neutropenia (FN) and the factors that were associated with higher direct cost. The secondary objective was to describe the out-of-pocket patient payments and the factors that were associated with higher out-of-pocket patient payments.MethodsThis was a single-center observational study conducted at the largest cancer center in Singapore. All of the adult cancer patients hospitalized due to FN from 2009 to 2012 were studied. The primary outcomes were the total hospital cost and the out-of-pocket patient payments (adjusted by government subsidy) per FN episode. Univariate analysis and multiple linear regression were conducted to identify the factors associated with higher FN costs.ResultsThree hundred and sixty seven adult cancer patients were documented with FN-related hospitalizations. The mean total hospital cost was US$4,193 (95$3,779-4,607) and the mean out-of-pocket patient payment was US$2,230 (95$1,976-2,484), per FN episode. The factors associated with a higher total hospital cost were longer length of stay, severe sepsis, and lymphoma as underlying cancer. The out-of-pocket patient payment was positively associated with longer length of stay, severe sepsis, lymphoma diagnosed as underlying cancer, the therapeutic use of granulocyte colony-stimulating factor (GCSF), the private ward class, and younger patients.ConclusionsThe total hospital cost and out-of-pocket patient payments of FN management in lymphoma cases were substantial compared with other solid tumors. Factors associated with a higher FN management cost may be useful for developing appropriate strategies to reduce the cost of FN for cancer patients

How Much Do Focal Infarcts Distort White Matter Lesions and Global Cerebral Atrophy Measures?

BACKGROUND: White matter lesions (WML) and brain atrophy are important biomarkers in stroke and dementia. Stroke lesions, either acute or old, symptomatic or silent, are common in older people. Such stroke lesions can have similar signals to WML and cerebrospinal fluid (CSF) on magnetic resonance (MR) images, and may be classified accidentally as WML or CSF by MR image processing algorithms, distorting WML and brain atrophy volume from the true volume. We evaluated the effect that acute or old stroke lesions at baseline, and new stroke lesions occurring during follow-up, could have on measurement of WML volume, cerebral atrophy and their longitudinal progression. METHODS: We used MR imaging data from patients who had originally presented with acute lacunar or minor cortical ischaemic stroke symptoms, recruited prospectively, who were scanned at baseline and about 3 years later. We measured WML and CSF volumes (ml) semi-automatically. We manually outlined the acute index stroke lesion (ISL), any old stroke lesions present at baseline, and new lesions appearing de novo during follow-up. We compared baseline and follow-up WML volume, cerebral atrophy and their longitudinal progression excluding and including the acute ISL, old and de novo stroke lesions. A non-parametric test (Wilcoxon's signed rank test) was used to compare the effects. RESULTS: Among 46 patients (mean age 72 years), 33 had an ISL visible on MR imaging (median volume 2.05 ml, IQR 0.88–8.88) and 7 of the 33 had old lacunes at baseline: WML volume was 8.54 ml (IQR 5.86–15.80) excluding versus 10.98 ml (IQR 6.91–24.86) including ISL (p < 0.001). At follow-up, median 39 months later (IQR 30–45), 3 patients had a de novo stroke lesion; total stroke lesion volume had decreased in 11 and increased in 22 patients: WML volume was 12.17 ml (IQR 8.54–19.86) excluding versus 14.79 ml (IQR 10.02–38.03) including total stroke lesions (p < 0.001). Including/excluding lacunes at baseline or follow-up also made small differences. Twenty-two of the 33 patients had tissue loss due to stroke lesions between baseline and follow-up, resulting in a net median brain tissue volume loss (i.e. atrophy) during follow-up of 24.49 ml (IQR 12.87–54.01) excluding versus 24.61 ml (IQR 15.54–54.04) including tissue loss due to stroke lesions (p < 0.001). Including stroke lesions in the WML volume added substantial noise, reduced statistical power, and thus increased sample size estimated for a clinical trial. CONCLUSIONS: Failure to exclude even small stroke lesions distorts WML volume, cerebral atrophy and their longitudinal progression measurements. This has important implications for design and sample size calculations for observational studies and randomised trials using WML volume, WML progression or brain atrophy as outcome measures. Improved methods of discriminating between stroke lesions and WML, and between tissue loss due to stroke lesions and true brain atrophy are required

A planetary system as the origin of structure in Fomalhaut's dust belt

The Sun and >15 percent of nearby stars are surrounded by dusty debris disks that must be collisionally replenished by asteroids and comets, as the dust would otherwise be depleted on <10 Myr timescales (ref. 1). Theoretical studies show that disk structure can be modified by the gravitational influence of planets (ref. 2-4), but the observational evidence is incomplete, at least in part because maps of the thermal infrared emission from disks have low linear resolution (35 AU in the best case; ref. 5). Optical images provide higher resolution, but the closest examples (AU Mic and Beta Pic) are edge-on (ref. 6,7), preventing the direct measurement of azimuthal and radial disk structure that is required for fitting theoretical models of planetary perturbations. Here we report the detection of optical light reflected from the dust grains orbiting Fomalhaut (HD 216956). The system is inclined 24 degrees away from edge-on, enabling the measurement of disk structure around its entire circumference, at a linear resolution of 0.5 AU. The dust is distributed in a belt 25 AU wide, with a very sharp inner edge at a radial distance of 133 AU, and we measure an offset of 15 AU between the belt's geometric centre and Fomalhaut. Taken together, the sharp inner edge and offset demonstrate the presence of planet-mass objects orbiting Fomalhaut.Comment: 8 pages, 3 figures, 1 tabl

PLK1 Interacts and Phosphorylates Axin That Is Essential for Proper Centrosome Formation

10.1371/journal.pone.0049184PLoS ONE711

Liver Progenitor Cell Line HepaRG Differentiated in a Bioartificial Liver Effectively Supplies Liver Support to Rats with Acute Liver Failure

A major roadblock to the application of bioartificial livers is the need for a human liver cell line that displays a high and broad level of hepatic functionality. The human bipotent liver progenitor cell line HepaRG is a promising candidate in this respect, for its potential to differentiate into hepatocytes and bile duct cells. Metabolism and synthesis of HepaRG monolayer cultures is relatively high and their drug metabolism can be enhanced upon treatment with 2% dimethyl sulfoxide (DMSO). However, their potential for bioartificial liver application has not been assessed so far. Therefore, HepaRG cells were cultured in the Academic Medical Center bioartificial liver (AMC-BAL) with and without DMSO and assessed for their hepatic functionality in vitro and in a rat model of acute liver failure. HepaRG-AMC-BALs cultured without DMSO eliminated ammonia and lactate, and produced apolipoprotein A-1 at rates comparable to freshly isolated hepatocytes. Cytochrome P450 3A4 transcript levels and activity were high with 88% and 37%, respectively, of the level of hepatocytes. DMSO treatment of HepaRG-AMC-BALs reduced the cell population and the abovementioned functions drastically. Therefore, solely HepaRG-AMC-BALs cultured without DMSO were tested for efficacy in rats with acute liver failure (n = 6). HepaRG-AMC-BAL treatment increased survival time of acute liver failure rats ∼50% compared to acellular-BAL treatment. Moreover, HepaRG-AMC-BAL treatment decreased the progression of hepatic encephalopathy, kidney failure, and ammonia accumulation. These results demonstrate that the HepaRG-AMC-BAL is a promising bioartificial liver for clinical application

Life-threatening hemobilia caused by hepatic pseudoaneurysm after T-tube choledochostomy: report of a case

<p>Abstract</p> <p>Background</p> <p>Hemobilia is a rare but lethal biliary tract complication. There are several causes of hemobilia which might be classified as traumatic or nontraumatic. Hemobilia caused by pseudoaneurysm might result from hepatobiliary surgery or percutaneous interventional hepatobiliary procedures. However, to our knowledge, there are no previous reports pertaining to hemobilia caused by hepatic pseudoaneurysm after T-tube choledochostomy.</p> <p>Case presentation</p> <p>A 65-year-old male was admitted to our hospital because of acute calculous cholecystitis and cholangitis. He underwent cholecystectomy, choledocholithotomy via a right upper quadrant laparotomy and a temporary T-tube choledochostomy was created. However, on the 19th day after operation, he suffered from sudden onset of hematemesis and massive fresh blood drainage from the T-tube choledochostomy. Imaging studies confirmed the diagnosis of pseudoaneurysm associated hemobilia. The probable association of T-tube choledochostomy with pseudoaneurysm and hemobilia is also demonstrated. He underwent emergent selective microcoils emobolization to occlude the feeding artery of the pseudoaneurysm.</p> <p>Conclusions</p> <p>Pseudoaneurysm associated hemobilia may occur after T-tube choledochostomy. This case also highlights the importance that hemobilia should be highly suspected in a patient presenting with jaundice, right upper quadrant abdominal pain and upper gastrointestinal bleeding after liver or biliary surgery.</p

Cyclin T1-Dependent Genes in Activated CD4+ T and Macrophage Cell Lines Appear Enriched in HIV-1 Co-Factors

HIV-1 is dependent upon cellular co-factors to mediate its replication cycle in CD4+ T cells and macrophages, the two major cell types infected by the virus in vivo. One critical co-factor is Cyclin T1, a subunit of a general RNA polymerase II elongation factor known as P-TEFb. Cyclin T1 is targeted directly by the viral Tat protein to activate proviral transcription. Cyclin T1 is up-regulated when resting CD4+ T cells are activated and during macrophage differentiation or activation, conditions that are also necessary for high levels of HIV-1 replication. Because Cyclin T1 is a subunit of a transcription factor, the up-regulation of Cyclin T1 in these cells results in the induction of cellular genes, some of which might be HIV-1 co-factors. Using shRNA depletions of Cyclin T1 and transcriptional profiling, we identified 54 cellular mRNAs that appear to be Cyclin T1-dependent for their induction in activated CD4+ T Jurkat T cells and during differentiation and activation of MM6 cells, a human monocytic cell line. The promoters for these Cyclin T1-dependent genes (CTDGs) are over-represented in two transcription factor binding sites, SREBP1 and ARP1. Notably, 10 of these CTDGs have been reported to be involved in HIV-1 replication, a significant over-representation of such genes when compared to randomly generated lists of 54 genes (p value<0.00021). The results of siRNA depletion and dominant-negative protein experiments with two CTDGs identified here, CDK11 and Casein kinase 1 gamma 1, suggest that these genes are involved either directly or indirectly in HIV-1 replication. It is likely that the 54 CTDGs identified here include novel HIV-1 co-factors. The presence of CTDGs in the protein space that was available for HIV-1 to sample during its evolution and acquisition of Tat function may provide an explanation for why CTDGs are enriched in viral co-factors

Severity of acute hepatitis and its outcome in patients with dengue fever in a tertiary care hospital Karachi, Pakistan (South Asia)

<p>Abstract</p> <p>Background</p> <p>Liver injury due to dengue viral infection is not uncommon. Acute liver injury is a severe complicating factor in dengue, predisposing to life-threatening hemorrhage, Disseminated Intravascular Coagulation (DIC) and encephalopathy. Therefore we sought to determine the frequency of hepatitis in dengue infection and to compare the outcome (length of stay, in hospital mortality, complications) between patients of Dengue who have mild/moderate (ALT 23-300 IU/L) v/s severe acute hepatitis (ALT > 300 IU/L).</p> <p>Methods</p> <p>A Cohort study of inpatients with dengue viral infection done at Aga Khan University Hospital Karachi. All patients (≥ 14 yrs age) admitted with diagnosis of Dengue Fever (DF), Dengue Hemorrhagic Fever (DHF) or Dengue Shock Syndrome (DSS) were included. Chi square test was used to compare categorical variables and fischer exact test where applicable. Survival analysis (Cox regression and log rank) for primary outcome was done. Student t test was used to compare continuous variables. A p value of less than or equal to 0.05 was taken as significant.</p> <p>Results</p> <p>Six hundred and ninety nine patients were enrolled, including 87% (605) patients with DF and 13% (94) patients with DHF or DSS. Liver functions tests showed median ALT of 88.50 IU/L; IQR 43.25-188 IU/L, median AST of 174 IU/L; IQR 87-371.5 IU/L and median T.Bil of 0.8 mg/dl; IQR 0.6-1.3 mg/dl. Seventy one percent (496) had mild to moderate hepatitis and 15% (103) had severe hepatitis. Mean length of stay (LOS) in patients with mild/moderate hepatitis was 3.63 days v.s 4.3 days in those with severe hepatitis (P value 0.002). Overall mortality was 33.3% (n = 6) in mild/moderate hepatitis vs 66.7% (n = 12) in severe hepatitis group (p value < 0.001). Cox regression analysis also showed significantly higher mortality in severe hepatitis group (H.R (4.91; 95% CI 1.74-13.87 and P value 0.003) and in DHF/DSS (5.43; CI 1.86-15.84 and P value 0.002). There was a significant difference for the complications like Bleeding (P value < 0.001), Acute Renal failure (ARF) (P value 0.002), Acalculus cholecystitis (P value 0.04) and encephalopathy (P value 0.02) in mild/moderate and Severe hepatitis groups respectively.</p> <p>Conclusion</p> <p>Severe hepatitis (SGPT>300IU) in Dengue is associated with prolonged LOS, mortality, bleeding and RF.</p

Fecal microbiota and bile acid interactions with systemic and adipose tissue metabolism in diet-induced weight loss of obese postmenopausal women

Microbiota and bile acids in the gastrointestinal tract profoundly alter systemic metabolic processes. In obese subjects, gradual weight loss ameliorates adipose tissue inflammation and related systemic changes. We assessed how rapid weight loss due to a very low calorie diet (VLCD) affects the fecal microbiome and fecal bile acid composition, and their interactions with the plasma metabolome and subcutaneous adipose tissue inflammation in obesity. We performed a prospective cohort study of VLCD-induced weight loss of 10% in ten grades 2-3 obese postmenopausal women in a metabolic unit. Baseline and post weight loss evaluation included fasting plasma analyzed by mass spectrometry, adipose tissue transcription by RNA sequencing, stool 16S rRNA sequencing for fecal microbiota, fecal bile acids by mass spectrometry, and urinary metabolic phenotyping by H-NMR spectroscopy. Outcome measures included mixed model correlations between changes in fecal microbiota and bile acid composition with changes in plasma metabolite and adipose tissue gene expression pathways. Alterations in the urinary metabolic phenotype following VLCD-induced weight loss were consistent with starvation ketosis, protein sparing, and disruptions to the functional status of the gut microbiota. We show that the core microbiome was preserved during VLCD-induced weight loss, but with changes in several groups of bacterial taxa with functional implications. UniFrac analysis showed overall parallel shifts in community structure, corresponding to reduced abundance of the genus Roseburia and increased Christensenellaceae;g__ (unknown genus). Imputed microbial functions showed changes in fat and carbohydrate metabolism. A significant fall in fecal total bile acid concentration and reduced deconjugation and 7-α-dihydroxylation were accompanied by significant changes in several bacterial taxa. Individual bile acids in feces correlated with amino acid, purine, and lipid metabolic pathways in plasma. Furthermore, several fecal bile acids and bacterial species correlated with altered gene expression pathways in adipose tissue. VLCD dietary intervention in obese women changed the composition of several fecal microbial populations while preserving the core fecal microbiome. Changes in individual microbial taxa and their functions correlated with variations in the plasma metabolome, fecal bile acid composition, and adipose tissue transcriptome

Inhibition of the inositol kinase Itpkb augments calcium signaling in lymphocytes and reveals a novel strategy to treat autoimmune disease

Emerging approaches to treat immune disorders target positive regulatory kinases downstream of antigen receptors with small molecule inhibitors. Here we provide evidence for an alternative approach in which inhibition of the negative regulatory inositol kinase Itpkb in mature T lymphocytes results in enhanced intracellular calcium levels following antigen receptor activation leading to T cell death. Using Itpkb conditional knockout mice and LMW Itpkb inhibitors these studies reveal that Itpkb through its product IP4 inhibits the Orai1/Stim1 calcium channel on lymphocytes. Pharmacological inhibition or genetic deletion of Itpkb results in elevated intracellular Ca2+ and induction of FasL and Bim resulting in T cell apoptosis. Deletion of Itpkb or treatment with Itpkb inhibitors blocks T-cell dependent antibody responses in vivo and prevents T cell driven arthritis in rats. These data identify Itpkb as an essential mediator of T cell activation and suggest Itpkb inhibition as a novel approach to treat autoimmune disease