Patient and Disease-Specific Induced Pluripotent Stem Cells for Discovery of Personalized Cardiovascular Drugs and Therapeutics.

Human induced pluripotent stem cells (iPSCs) have emerged as an effective platform for regenerative therapy, disease modeling, and drug discovery. iPSCs allow for the production of limitless supply of patient-specific somatic cells that enable advancement in cardiovascular precision medicine. Over the past decade, researchers have developed protocols to differentiate iPSCs to multiple cardiovascular lineages, as well as to enhance the maturity and functionality of these cells. Despite significant advances, drug therapy and discovery for cardiovascular disease have lagged behind other fields such as oncology. We speculate that this paucity of drug discovery is due to a previous lack of efficient, reproducible, and translational model systems. Notably, existing drug discovery and testing platforms rely on animal studies and clinical trials, but investigations in animal models have inherent limitations due to interspecies differences. Moreover, clinical trials are inherently flawed by assuming that all individuals with a disease will respond identically to a therapy, ignoring the genetic and epigenomic variations that define our individuality. With ever-improving differentiation and phenotyping methods, patient-specific iPSC-derived cardiovascular cells allow unprecedented opportunities to discover new drug targets and screen compounds for cardiovascular disease. Imbued with the genetic information of an individual, iPSCs will vastly improve our ability to test drugs efficiently, as well as tailor and titrate drug therapy for each patient

Internet Predictions

More than a dozen leading experts give their opinions on where the Internet is headed and where it will be in the next decade in terms of technology, policy, and applications. They cover topics ranging from the Internet of Things to climate change to the digital storage of the future. A summary of the articles is available in the Web extras section

Glutathione S-transferase activity influences busulfan pharmacokinetics in patients with beta thalassemia major undergoing bone marrow transplantation

Busulfan, at a dose of 16 mg/kg, is widely used in combination with cyclophosphamide as a conditioning regimen for patients undergoing bone marrow transplantation. Wide interindividual variation in busulfan kinetics and rapid clearance of the drug have been reported, especially in children. Some of the factors contributing to interpatient variability have been identified. They include circadian rhythms, age, disease, drug interaction, changes in hepatic function, and busulfan bioavailability. In this study, we demonstrate that hepatic glutathione S-transferase (GST) activity correlates negatively with busulfan maximum and minimum concentrations (Pearson's correlation r = -0.74 and -0.77, respectively) and positively with busulfan clearance (Pearson's correlation r = 0.728) in children with thalassemia major in the age range of 2 to 15 years. We also found that plasma alpha GST levels were 5 to 10 times higher in patients with thalassemia than in normal controls and age-matched leukemic patients, either reflecting extensive liver damage, elevated expression of the enzyme, or both in thalassemic patients. Plasma alpha GST concentrations showed a similar correlation with busulfan kinetic parameters to that observed for hepatic GST. The status of hepatic GST activity accounts, at least in part, for the observed interindividual variation in busulfan kinetics, while the observed association with plasma alpha GST is difficult to explain at present

A Novel and Automated Approach to Classify Radiation Induced Lung Tissue Damage on CT Scans

Radiation-induced lung damage (RILD) is a common side effect of radiotherapy (RT). The ability to automatically segment, classify, and quantify different types of lung parenchymal change is essential to uncover underlying patterns of RILD and their evolution over time. A RILD dedicated tissue classification system was developed to describe lung parenchymal tissue changes on a voxel-wise level. The classification system was automated for segmentation of five lung tissue classes on computed tomography (CT) scans that described incrementally increasing tissue density, ranging from normal lung (Class 1) to consolidation (Class 5). For ground truth data generation, we employed a two-stage data annotation approach, akin to active learning. Manual segmentation was used to train a stage one auto-segmentation method. These results were manually refined and used to train the stage two auto-segmentation algorithm. The stage two auto-segmentation algorithm was an ensemble of six 2D Unets using different loss functions and numbers of input channels. The development dataset used in this study consisted of 40 cases, each with a pre-radiotherapy, 3-, 6-, 12-, and 24-month follow-up CT scans (n = 200 CT scans). The method was assessed on a hold-out test dataset of 6 cases (n = 30 CT scans). The global Dice score coefficients (DSC) achieved for each tissue class were: Class (1) 99% and 98%, Class (2) 71% and 44%, Class (3) 56% and 26%, Class (4) 79% and 47%, and Class (5) 96% and 92%, for development and test subsets, respectively. The lowest values for the test subsets were caused by imaging artefacts or reflected subgroups that occurred infrequently and with smaller overall parenchymal volumes. We performed qualitative evaluation on the test dataset presenting manual and auto-segmentation to a blinded independent radiologist to rate them as 'acceptable', 'minor disagreement' or 'major disagreement'. The auto-segmentation ratings were similar to the manual segmentation, both having approximately 90% of cases rated as acceptable. The proposed framework for auto-segmentation of different lung tissue classes produces acceptable results in the majority of cases and has the potential to facilitate future large studies of RILD

Cost-effectiveness of hydroxyurea for sickle cell anemia in a low-income African setting: a model-based evaluation of two dosing regimens

Background and Objective: The disease burden of sickle cell anemia (SCA) in sub-Saharan African (SSA) countries is substantial, with many children dying without an established diagnosis or proper treatment. The global burden of SCA is increasing each year, making therapeutic intervention a high priority. Hydroxyurea is the only disease-modifying therapy with proven feasibility and efcacy suitable for SSA; however, no one has quantifed the health economic implications of its use. Therefore, from the perspective of the health care provider, we estimated the incremental cost-efectiveness of hydroxyurea as a fxed-dose regimen or maximum tolerated dose (MTD) regimen, versus SCA care without hydroxyurea. Methods: We estimated the cost of providing outpatient treatment at a pediatric sickle cell clinic in Kampala, Uganda. These estimates were used in a discrete-event simulation model to project mean costs (2021 US$), disability-adjusted life years (DALYs), and consumption of blood products per patient (450 mL units), for patients between 9 months and 18 years of age. We calculated cost-efectiveness as the ratio of incremental costs over incremental DALYs averted, discounted at 3Results: Hydroxyurea treatment averted an expected 1.37 DALYs and saved US$ 191 per patient if administered at the MTD, compared with SCA care without hydroxyurea. In comparison, hydroxyurea at a fxed dose averted 0.80 DALYs per patient at an incremental cost of US$ 2. The MTD strategy saved 11.2 (95% CI 11.1–11.4) units of blood per patient, compared with 9.1 (95% CI 9.0–9.2) units of blood per patient at the fxed-dose alternative. Conclusions: Hydroxyurea at MTD is likely to improve quality of life and reduce the consumption of blood products for children with SCA living in Uganda. Compared with a fxed dose regimen, treatment dosing at MTD is likely to be a cost-efective treatment for SCA, using realistic ranges of hydroxyurea costs that are relevant across SSA. Compared with no use of the drug, hydroxyurea could lead to substantial net savings per patient, while reducing the disease morbidity and mortality and increasing quality of lif

Policy mixes for incumbency: the destructive recreation of renewable energy, shale gas 'fracking,' and nuclear power in the United Kingdom

The notion of a ‘policy mix’ can describe interactions across a wide range of innovation policies, including ‘motors for creation’ as well as for ‘destruction’. This paper focuses on the United Kingdom’s (UK) ‘new policy direction’ that has weakened support for renewables and energy efficiency schemes while strengthening promotion of nuclear power and hydraulic fracturing for natural gas (‘fracking’). The paper argues that a ‘policy apparatus for incumbency’ is emerging which strengthens key regimebased technologies while arguably damaging emerging niche innovations. Basing the discussion around the three technology-based cases of renewable energy and efficiency, fracking, and nuclear power, this paper refers to this process as “destructive recreation”. Our study raises questions over the extent to which policymaking in the energy field is not so much driven by stated aims around sustainability transitions, as by other policy drivers. It investigates different ‘strategies of incumbency’ including ‘securitization’, ‘masking’, ‘reinvention’, and ‘capture.’ It suggests that analytical frameworks should extend beyond the particular sectors in focus, with notions of what counts as a relevant ‘policy maker’ correspondingly also expanded, in order to explore a wider range of nodes and critical junctures as entry points for understanding how relations of incumbency are forged and reproduced

Environmental, socio-demographic and behavioural determinants of malaria risk in the western Kenyan highlands: a case–control study

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/73660/1/j.1365-3156.2009.02370.x.pd

Epidural Analgesia Provides Better Pain Management After Live Liver Donation: A Retrospective Study

Despite the increase in surgical volumes of live liver donation, there has been very little documentation of the postoperative pain experience. The primary aim of this study was to examine the difference in acute postoperative pain intensity and adverse effects between patients who received intravenous patient-controlled analgesia (IV PCA) or patient-controlled epidural analgesia (PCEA) for pain control after live liver donation surgery. A retrospective chart review was performed of 226 consecutive patients who underwent right living donor hepatic surgery at the Toronto General Hospital, Toronto, Canada. Patients who received as their primary postoperative analgesic modality IV PCA (n = 158) were compared to patients who received PCEA (n = 68). Demographic profiles for the 2 groups were similar with respect to age, sex, and body mass index at the time of surgery. For the first 3 postoperative days, pain intensity was significantly lower in patients who received epidural analgesia (P 4) was reported more frequently in the IV PCA group (P < 0.05) along with increased sedation (P < 0.05). Pruritus was reported more frequently in the PCEA group of patients compared to the IV PCA group (P < 0.05). Significant between-group differences were not found for the incidence of postoperative vomiting, the time at which patients began fluid intake, the time to initial ambulation, or the length of hospital stay. In conclusion, epidural analgesia provides better postoperative pain relief, less sedation, but more pruritus than IV PCA after live liver donation