A Novel Predictive Model for Hospital Survival in Patients who are Critically Ill with Dialysis-Dependent AKI: A Retrospective Single-Center Exploratory Study.

Background: Mortality of patients who are critically ill with AKI initiated on RRT is very high. Identifying modifiable and unmodifiable clinical variables at dialysis start that are associated with hospital survival can help, not only in prognostication, but also in clinical triaging. Methods: A retrospective observational study was conducted on patients with AKI-D who were initiated on RRT in the medical and surgical intensive care units (ICUs) of a high-acuity academic medical center from January 2010 through December 2015. We excluded patients with suspected poisoning, ESKD, stage 5 CKD not on dialysis, or patients with AKI-D initiated on RRT outside of the ICU setting. The primary outcome was in-hospital mortality. Results: Of the 416 patients who were critically ill with AKI-D admitted to the medical (38%), surgical (41%), and cardiac (21%) ICUs, with nearly 75% on artificial organ support, the mean age 62.1±14.8 years, mean SOFA score was 11.8±4.3, dialysis was initiated using continuous RRT in 261 (63%) and intermittent hemodialysis in 155 (37%) patients. Incidence of survival to hospital discharge was 48%. Using multivariable logistic regression with stepwise backward elimination, a prognostic model was created that included the variables age, CKD, COPD, admission, and within 24 hours of the start SOFA score, refractory hyperkalemia and uremic encephalopathy as dialysis indications, BUN >100 mg/dl, serum creatinine, serum lactate, serum albumin, CRRT as initial modality, severe volume overload, and abdominal surgery. The model exhibited good calibration (goodness of fit test, P=0.83) and excellent discrimination (optimism-corrected C statistic 0.93). Conclusions: In this single-center, diverse, critically ill AKI-D population, a novel prognostic model that combined widely used ICU scores, clinical and biochemical data at dialysis start, and dialysis indication and modality, robustly predicted short-term survival. External validation is needed to prove the generalizability of the study findings.

Automated Addressable Microfluidic Device for Minimally Disruptive Manipulation of Cells and Fluids within Living Cultures.

Cell culturing experiments are ubiquitous to the study of biology, development of new medical treatments, and the biomanufacturing industry. However, there are still major technological barriers limiting the advancement of knowledge and ballooning the experimental costs associated with these systems. For example, currently, it is difficult to perform nondisruptive monitoring and control of the cells in the cultured samples. This often necessitates the use of sacrificial assays and results in product inconsistency. To resolve these bottlenecks, we present a prototype "addressable" microfluidic technology capable of spatiotemporal fluid and cell manipulations within living cultures. As a proof-of-concept, we demonstrate its ability to perform additive manufacturing by seeding cells in spatial patterns (including co-culturing multiple cell types) and subtractive manufacturing by removing surface adherent cells via the focused flow of trypsin. Additionally, we show that the device can sample fluids and perform cell "biopsies" (which can be subsequently sent for ex situ analysis), from any location within its culture chamber. Finally, the on-chip plumbing is completely automated using external electronics. This opens the possibility of performing long-term computer-driven experiments, where the cell behavior is modulated in response to the minimally disruptive observations (e.g., fluid sampling and cell biopsies) throughout the entire duration of the cultures. A limitation of the presented α prototype is that it is only two-dimensional (2D). However, technology serves as a foundation for ultimately extending the concept to three-dimensional (3D). Another limitation of the device is that it is currently made from poly(dimethylsiloxane) (PDMS), while more work needs to be done to manufacture from a material that degrades away or allow the cells to lay down the tissue matrix. Unfortunately, the existing biodegradable materials are typically not strong enough for the fabrication of microfluidic valves. Hence, new ones need to be developed before this technology can become mainstream. Yet, it is the hope of the authors that this will be achieved soon, and the microfluidic plumbing technology will eventually be scaled up to 3D, to overcome the limitations of the conventional cell culturing platforms.

Evaluation of Quality of Pharmacoeconomic Studies in Asia-Pacific Region and Identification of Influencing Variables.

OBJECTIVES: To assess the quality of pharmacoeconomic studies and identify different variables influencing the quality of these studies conducted in the Asia-Pacific (APAC) region. METHODS: A systematic literature search was performed with PubMed and Cochrane using different combinations of terms for cost-effectiveness, cost-utility, and cost-minimization analyses. The Quality of Health Economic Studies (QHES) instrument was used for quality assessment of included studies. Logistic regression was performed to determine the association of factors with high-quality studies (QHES score ≥75). RESULTS: Of 262 retrieved studies, 128 met the inclusion criteria. The mean QHES score was 67.4 ± 1.35. The distribution of studies in each quality quartile was as follows: high (n = 59 [46.09%]), fair (n = 50 [39.06%]), and poor (n = 19 [14.83%]). Most of the high-quality studies (n = 80 [62.5%]) were conducted in Japan and Australia. Only 11 high-quality studies (18.64%) were published in specialty journals and 4 (6.78%) in Asian journals. Primary authors who had advanced training in health economics were associated with a higher number of high-quality studies (n = 51 [86.44%]). Training of primary authors was significantly associated with high-quality studies (odds ratio 7.1; 95% confidence interval 2.9-19.23). Impact factor of journal, per-capita expenditure on health care, and out-of-pocket expense on health did not have a significant association with high-quality scores. CONCLUSIONS: High-quality pharmacoeconomic research is confined to a few countries of the APAC; it can be improved by advance training of authors in public health or health economics. Also, a greater interest of various stakeholders in funding the research and the introduction of specialty journals in the APAC are warranted.

Molecular Inclusion Complexes of ß-Cyclodextrin Derivatives Enhance Aqueous Solubility and Cellular Internalization of Paclitaxel: Preformulation and In vitro Assessments.

Drugs with low aqueous solubility and permeability possess substantial challenges in designing effective and safe formulations. Synergistic solubility and permeability enhancement in a simple formulation can increase bioavailability and efficacy of such drugs. To overcome limitations of the clinical formulation of Taxol®, Paclitaxel (PTX) was reformulated with various ß-cyclodextrin (CD) derivatives suitable for parenteral administration. Results indicated that ß-CDs can efficiently form complexes with PTX at lower molar ratios, enhance aqueous solubility up to 500 times and improved cellular internalization of PTX. All ß-CD derivatives were found to be safe as excipient since none showed detectable signs of cyto-genotoxicity. As a result, the CD-PTX complexes significantly increased the cytotoxicity of the drug. The study concluded that CD-PTX formulations could substitute the current intravenous infusion of PTX obviating the use of non-inert excipient Cremophor EL.

An overview of visceral leishmaniasis elimination program in India: a picture imperfect.

Visceral leishmaniasis (VL) has been one of the most neglected tropical diseases in India. Concurrent and correct data on the burden of VL is vital to plan, allocate trained resources and to monitor the progress of the elimination program. More emphasis on integrated vector management can help in combating the disease spread. Effective surveillance, active and accurate diagnosis using rK39 strip test and use of an affordable, safe and efficient treatment option like liposomal amphotericin B remain the key components of VL control. Sustained advocacy, information, education and communication are needed in all the endemic areas. In this paper, we review the effectiveness of the strategies adopted in VL elimination in India.

Targeted nanomedicine for suppression of CD44 and simultaneous cell death induction in ovarian cancer: an optimal delivery of siRNA and anticancer drug.

PURPOSE: The proposed project is aimed at enhancing the efficiency of epithelial ovarian cancer treatment and reducing adverse side effects of chemotherapy using nanotechnology. Overexpression of the CD44 membrane receptor results in tumor initiation, growth, cancer stem cells' specific behavior, development of drug resistance, and metastases. We hypothesize that a developed cancer-targeted delivery system that combines CD44 siRNA with paclitaxel would successfully deliver its payload inside cancer cells, effectively induce cell death, and prevent metastases. EXPERIMENTAL DESIGN: We synthesized, characterized, and tested a nanoscale-based drug delivery system (DDS) containing a modified polypropylenimine (PPI) dendrimer as a carrier; anticancer drug paclitaxel as a cell death inducer; a synthetic analog of luteinizing hormone-releasing hormone (LHRH) peptide as a tumor-targeting moiety; and siRNA targeted to CD44 mRNA. The proposed DDS was tested in vitro and in vivo using metastatic ovarian cancer cells isolated from patients with malignant ascites. RESULTS: We found that in contrast with cells isolated from primary tumors, CD44 was highly overexpressed in metastatic cancer cells. Treatment with the proposed tumor-targeted nanoscale-based nucleic acid and DDS led to the suppression of CD44 mRNA and protein, efficient induction of cell death, effective tumor shrinkage, and prevention of adverse side effects on healthy organs. CONCLUSION: We show a high therapeutic potential for combinatorial treatment of ovarian carcinoma with a novel DDS that effectively transports siRNA targeting to CD44 mRNA simultaneously with cytotoxic agents. Clin Cancer Res; 19(22); 6193-204. ©2013 AACR.

Genotoxicity of different nanocarriers: possible modifications for the delivery of nucleic acids.

The prevention of cyto- and genotoxicity of nanocarriers is an important task in nanomedicine. In the present investigation, we, at the first time using similar experimental conditions, compared genotoxicity of nanocarriers with different composition, architecture, size, molecular weight and charge. Poly(ethylene glycol) polymers, neutral and cationic liposomes, micelles, poly(amindo amine) and poly(propyleneimine) dendrimers, quantum dots, mesoporous silica, and supermagnetic iron oxide (SPIO) nanoparticles were studied. All nanoparticles were used in non-cytotoxic concentrations. However, even in these concentrations, positively charged cationic liposomes, dendrimers, and SPIO nanoparticles induced genotoxicity leading to the significant formation of micronuclei in cells. Negatively charged and neutral nanocarriers were not genotoxic. A strong positive correlation was found between the number of formed micronuclei and the positive charge of nanocarriers. We proposed modifications of both types of dendrimers and SPIO nanoparticles that substantially decreased their genotoxicity and allowed for an efficient intracellular delivery of nucleic acids.