Cost-Effectiveness Analysis of Six Strategies to Treat Recurrent Clostridium difficile Infection

Objective

To assess the cost-effectiveness of six treatment strategies for patients diagnosed with recurrent Clostridium difficile infection (CDI) in Canada: 1. oral metronidazole; 2. oral vancomycin; 3.oral fidaxomicin; 4. fecal transplantation by enema; 5. fecal transplantation by nasogastric tube; and 6. fecal transplantation by colonoscopy.

Perspective

Public insurer for all hospital and physician services.

Setting

Ontario, Canada.

Methods

A decision analytic model was used to model costs and lifetime health effects of each strategy for a typical patient experiencing up to three recurrences, over 18 weeks. Recurrence data and utilities were obtained from published sources. Cost data was obtained from published sources and hospitals in Toronto, Canada. The willingness-to-pay threshold was $50,000/QALY gained.

Results

Fecal transplantation by colonoscopy dominated all other strategies in the base case, as it was less costly and more effective than all alternatives. After accounting for uncertainty in all model parameters, there was an 87% probability that fecal transplantation by colonoscopy was the most beneficial strategy. If colonoscopy was not available, fecal transplantation by enema was cost-effective at $1,708 per QALY gained, compared to metronidazole. In addition, fecal transplantation by enema was the preferred strategy if the probability of recurrence following this strategy was below 8.7%. If fecal transplantation by any means was unavailable, fidaxomicin was cost-effective at an additional cost of $25,968 per QALY gained, compared to metronidazole.

Conclusion

Fecal transplantation by colonoscopy (or enema, if colonoscopy is unavailable) is cost-effective for treating recurrent CDI in Canada. Where fecal transplantation is not available, fidaxomicin is also cost-effective.     

Cupric Oxide (CuO) Oxidation Detects Pyrogenic Carbon in Burnt Organic Matter and Soils

Wildfire greatly impacts the composition and quantity of organic carbon stocks within watersheds. Most methods used to measure the contributions of fire altered organic carbon–i.e. pyrogenic organic carbon (Py-OC) in natural samples are designed to quantify specific fractions such as black carbon or polyaromatic hydrocarbons. In contrast, the CuO oxidation procedure yields a variety of products derived from a variety of precursors, including both unaltered and thermally altered sources. Here, we test whether or not the benzene carboxylic acid and hydroxy benzoic acid (BCA) products obtained by CuO oxidation provide a robust indicator of Py-OC and compare them to non-Py-OC biomarkers of lignin. O and A horizons from microcosms were burned in the laboratory at varying levels of fire severity and subsequently incubated for 6 months. All soils were analyzed for total OC and N and were analyzed by CuO oxidation. All BCAs appeared to be preserved or created to some degree during burning while lignin phenols appeared to be altered or destroyed to varying extents dependent on fire severity. We found two specific CuO oxidation products, o-hydroxybenzoic acid (oBd) and 1,2,4-benzenetricarboxylic acid (BTC2) that responded strongly to burn severity and withstood degradation during post-burning microbial incubations. Interestingly, we found that benzene di- and tricarboxylic acids (BDC and BTC, respectively) were much more reactive than vanillyl phenols during the incubation as a possible result of physical protection of vanillyl phenols in the interior of char particles or CuO oxidation derived BCAs originating from biologically available classes of Py-OC. We found that the ability of these compounds to predict relative Py-OC content in burned samples improved when normalized by their respective BCA class (i.e. benzene monocarboxylic acids (BA) and BTC, respectively) and when BTC was normalized to total lignin yields (BTC:Lig). The major trends in BCAs imparted by burning persisted through a 6 month incubation suggesting that fire severity had first order control on BCA and lignin composition. Using original and published BCA data from soils, sediments, char, and interfering compounds we found that BTC:Lig and BTC2:BTC were able to distinguish Py-OC from compounds such as humic materials, tannins, etc. The BCAs released by the CuO oxidation procedure increase the functionality of this method in order to examine the relative contribution of Py-OC in geochemical samples.     

Preclinical pharmacokinetics of MHAA4549A,a human monoclonal antibody to influenza A virus,and the prediction of its efficacious clinical dose for the treatment of patients hospitalized with influenza A

MHAA4549A is a human immunoglobulin G1 (IgG1) monoclonal antibody that binds to a highly conserved epitope on the stalk of influenza A hemagglutinin and blocks the hemagglutinin-mediated membrane fusion in the endosome, neutralizing all known human influenza A strains. Pharmacokinetics (PK) of MHAA4549A and its related antibodies were determined in DBA/2J and Balb-c mice at 5 mg/kg and in cynomolgus monkeys at 5 and 100 mg/kg as a single intravenous dose. Serum samples were analyzed for antibody concentrations using an ELISA and the PK was evaluated using WinNonlin software. Human PK profiles were projected based on the PK in monkeys using species-invariant time method. The human efficacious dose projection was based on in vivo nonclinical pharmacological active doses, exposure in mouse infection models and expected human PK. The PK profiles of MHAA4549A and its related antibody showed a linear bi-exponential disposition in mice and cynomolgus monkeys. In mice, clearance and half-life ranged from 5.77 to 9.98 mL/day/kg and 10.2 to 5.76 days, respectively. In cynomolgus monkeys, clearance and half-life ranged from 4.33 to 4.34 mL/day/kg and 11.3 to 11.9 days, respectively. The predicted clearance in humans was ～2.60 mL/day/kg. A single intravenous dose ranging from 15 to 45 mg/kg was predicted to achieve efficacious exposure in humans. In conclusion, the PK of MHAA4549A was as expected for a human IgG1 monoclonal antibody that lacks known endogenous host targets. The predicted clearance and projected efficacious doses in humans for MHAA4549A have been verified in a Phase 1 study and Phase 2a study, respectively.     

Variations in nitrogen use efficiency reflect the biochemical subtype while variations in water use efficiency reflect the evolutionary lineage of C4 grasses at inter‐glacial CO2

C₄ photosynthesis evolved multiple times in diverse lineages. Most physiological studies comparing C₄ plants were not conducted at the low atmospheric CO₂ prevailing during their evolution. Here, 24 C₄ grasses belonging to three biochemical subtypes [nicotinamide adenine dinucleotide malic enzyme (NAD‐ME), phosphoenolpyruvate carboxykinase (PCK) and nicotinamide adenine dinucleotide phosphate malic enzyme (NADP‐ME)] and six major evolutionary lineages were grown under ambient (400 μL L^?1) and inter‐glacial (280 μL L^?1) CO₂. We hypothesized that nitrogen‐related and water‐related physiological traits are associated with subtypes and lineages, respectively. Photosynthetic rate and stomatal conductance were constrained by the shared lineage, while variation in leaf mass per area (LMA), leaf N per area, plant dry mass and plant water use efficiency were influenced by the subtype. Subtype and lineage were equally important for explaining variations in photosynthetic nitrogen use efficiency (PNUE) and photosynthetic water use efficiency (PWUE). CO₂ treatment impacted most parameters. Overall, higher LMA and leaf N distinguished the Chloridoideae/NAD‐ME group, while NADP‐ME and PCK grasses were distinguished by higher PNUE regardless of lineage. Plants were characterized by high photosynthesis and PWUE when grown at ambient CO₂ and by high conductance at inter‐glacial CO₂. In conclusion, the evolutionary and biochemical diversity among C₄ grasses was aligned with discernible leaf physiology, but it remains unknown whether these traits represent ecophysiological adaptation.     

Direct Nanoscale Characterization of Deep Levels in AgCuInGaSe2 Using Electron Energy‐Loss Spectroscopy in the Scanning Transmission Electron Microscope

A new experimental framework for the characterization of defects in semiconductors is demonstrated. Through the direct, energy‐resolved correlation of three analytical techniques spanning six orders of magnitude in spatial resolution, a critical mid‐bandgap electronic trap level (E_V + 0.56 eV) within Ag_0.2Cu_0.8In_1?xGa_xSe₂ is traced to its nanoscale physical location and chemical source. This is achieved through a stepwise, site‐specific correlated characterization workflow consisting of device‐scale (≈1 mm²) deep level transient spectroscopy (DLTS) to survey the traps present, scanning probe–based DLTS (scanning‐DLTS) for mesoscale‐resolved (hundreds of nanometers) mapping of the target trap state's spatial distribution, and scanning transmission electron microscope based electron energy‐loss spectroscopy (STEM‐EELS) and X‐ray energy‐dispersive spectroscopy for nanoscale energy‐, structure, and chemical‐resolved investigation of the defect source. This first demonstration of the direct observation of sub‐bandgap defect levels via STEM‐EELS, combined with the DLTS methods, provides strong evidence that the long‐suspected Cu_In/Ga substitutional defects are indeed the most likely source of the E_V + 0.56 eV trap state and serves as a key example of this approach for the fundamental identification of defects within semiconductors, in general.     

A life cycle assessment of Agaricus bisporus mushroom production in the USA

The International Journal of Life Cycle Assessment - Stakeholders across the food product supply chain are increasingly interested in understanding the environmental effects of food production....