Enhanced synthesis of oxo-verdazyl radicals bearing sterically-and electronically-diverse C3-substituents.

The synthetic viability of the hydrazine- and phosgene-free synthesis of 1,5-dimethyl oxo-verdazyl radicals has been improved via a detailed study investigating the influence of the aryl substituent on tetrazinanone ring formation. Although it is well established that functionalisation at the C3 position of the tetrazinanone ring does not influence the nature of the radical, it is crucial in applications development. The synthetic route involves a 4-step sequence: Schiff base condensation of a carbohydrazide with an arylaldehyde, alkylation, ring closure then subsequent oxidation to the radical. We found that the presence of strong electron-donating substituents and electron rich heterocycles, result in a significant reduction in yield during both the alkylation and ring closure steps. This can, in part, be alleviated by milder alkylation conditions and further substitution of the aryl group. In comparison, more facile formation of the tetrazine ring was observed with examples containing electron-withdrawing groups and with meta- or para-substitution. Density functional theory suggests that the ring closure proceeds via the formation of an ion pair. Electron paramagnetic resonance spectroscopy provides insight into the precise electronic structure of the radical with small variations in hyperfine coupling constants revealing subtle differences.

Assessment of Activity of Daily Life in Mucopolysaccharidosis Type II Patients with Hematopoietic Stem Cell Transplantation.

The effectiveness of hematopoietic stem cell transplantation (HSCT) for mucopolysaccharidosis type II (MPS II, Hunter disease) remains controversial although recent studies have shown HSCT provides more clinical impact. This study aims to evaluate the long-term effectiveness of HSCT using the activity of daily living (ADL) scores in patients with MPS II. Sixty-nine severely affected MPS II patients (19 patients who received HSCT and 50 untreated patients) and 40 attenuated affected patients (five with HSCT and 35 untreated) were investigated by a simplified ADL questionnaire. The frequency of clinical findings and the scores of ADL (verbal, gross motor, and the level of care) were analyzed statistically. The mean age of onset of 19 severely affected patients who received HSCT was 1.40 years ± 1.06, which is not statistically different from that of 50 untreated patients (p = 0.11). Macroglossia, frequent airway infection, hepatosplenomegaly, joint contracture, and sleep apnea were less frequent in the HSCT-treated group of severe MPS II patients. The severe phenotype HSCT treated group reported a statistically significant higher score of verbal function and gross motor function between the ages of 10 and 15 years and a higher level of care score between 10 and 20 years. Patients with the attenuated phenotype showed high ADL scores, and all of five HSCT treated patients reported a lower frequency of frequent airway infection, coarse skin, umbilical/inguinal hernia, hepatosplenomegaly, heart valve disorders, and carpal tunnel. In conclusion, HSCT is effective, resulting in improvements in clinical features and ADL in patients with MPS II. HSCT should be re-reviewed as a therapeutic option for MPS II patients.

Understanding Trends in Pesticide Volatilization from Agricultural Fields Using the Pesticide Loss via Volatilization Model.

The Pesticide Loss via Volatilization model was developed to predict and understand pesticide volatilization rates from a planted agricultural field. The model allows the user to adjust the properties of the pesticide, various soil and plant descriptors, and climatic conditions. A useful output from the model is the 24 h cumulative percentage volatilization (CPV24h) loss. The model was validated by comparing modeled CPV24h values to measured ones compiled from the literature. Sensitivity analysis showed that the plant intercept fraction (%I), leaf area index (LAI), and leaf height (hleaf) strongly affect volatilization rates of plant- and soil-sorbed pesticides whereas LAI, hleaf, and the percent of water on the plant surface strongly affect more water-soluble pesticides. The model showed that most pesticides volatilize more readily from plants than from soil and that volatilization rates vary significantly for certain pesticides (but not all) when applied to plants at different growth stages and for different species of plants. Results are displayed on chemical space diagrams to paint a clear picture of how CPV24h varies for chemicals with different properties under different conditions.

Fate of the organophosphate insecticide, chlorpyrifos, in leaves, soil, and air following application.

A field study was conducted to further our understanding about the fate and transport of the organophosphate insecticide, chlorpyrifos, and its degradation product, chlorpyrifos oxon. Leaf, soil and air sampling was conducted for 21 days after chlorpyrifos application to a field of purple tansy (Phacelia tanacetifolia). Air samples were collected using a high-volume air sampler (HVAS) and seven battery-operated medium-volume active air samplers placed around the field and on a 500-m transect extending away from the field. Chlorpyrifos was detected every day of the sampling period in all matrices, with concentrations decreasing rapidly after application. Chlorpyrifos oxon was only detected in air samples collected with the HVAS during the first three days after application. Wind direction played a significant role in controlling the measured air concentrations in near-field samples. The SCREEN3 model and chlorpyrifos' Characteristic Travel Distance (CTD) were used to predict modelled chlorpyrifos concentrations in air along the transect. The concentration trend predicted by the SCREEN3 model was similar to that of measured concentrations whereas CTD-modelled concentrations decreased at a significantly slower rate, indicating that downwind chlorpyrifos concentrations in air were primarily controlled by air dispersion. The SCREEN3-predicted chlorpyrifos concentrations were >5 times higher than measured concentrations, indicating that simple approaches for calculating accurate pesticide volatilization fluxes from agricultural fields are still needed. Finally, we found that measured concentrations in air on Days 0-2 at locations up to 500 m from the field were at levels considered concerning for human health.

Hematopoietic Stem Cell Transplantation for Mucopolysaccharidoses: Past, Present, and Future.

Allogenic hematopoietic stem cell transplantation (HSCT) has proven to be a viable treatment option for a selected group of patients with mucopolysaccharidoses (MPS), including those with MPS types I, II, IVA, VI, and VII. Early diagnosis and timely referral to an expert in MPS are critical, followed by a complete examination and evaluation by a multidisciplinary team, including a transplantation physician. Treatment recommendations for MPS are based on multiple biological, sociological, and financial factors, including type of MPS, clinical severity, prognosis, present clinical signs and symptoms (disease stage), age at onset, rate of progression, family factors and expectations, financial burden, feasibility, availability, risks and benefits of available therapies such as HSCT, enzyme replacement therapy (ERT), surgical interventions, and other supportive care. International collaboration and data review are critical to evaluating the therapeutic efficacy and adverse effects of HSCT for MPS. Collaborative efforts to assess HSCT for MPS have been ongoing since the first attempt at HSCT in a patient with MPS reported in 1981. The accumulation of data since then has made it possible to identify early outcomes (ie, transplantation outcomes) and long-term disease-specific outcomes resulting from HSCT. The recent identification of predictive factors and the development of innovative regimens have significantly improved the outcomes of both engraftment failure and transplantation-related mortality. Assessment of long-term outcomes has considered a variety of factors, including type of MPS, type of graft, age at transplantation, and stage of disease progression, among others. Studies on long-term outcomes are considered a key factor in the use of HSCT in patients with MPS. These studies have shown the effects and limitations of HSCT on improving disease manifestations and quality of life. In this review, we summarize the efficacy, side effects, risks, and cost of HSCT for each type of MPS.

Is Canadian Healthcare Affordable? A Comparative Analysis of the Canadian Healthcare System from 2004 to 2014.

OBJECTIVE: To compare cost-related non-adherence (CRNA), serious problems paying medical bills and average annual out-of-pocket cost over time in five countries. METHODS: Repeated cross-sectional analysis of the Commonwealth Fund International Health Policy survey from 2004 to 2014. Responses were compared between Canada, the UK, Australia, New Zealand and the US. RESULTS: Compared to the UK, respondents in Canada, Australia and New Zealand were two to three times and respondents in the US were eight times more likely to experience CRNA; these odds remained stable over time. From 2004 to 2014, Canadian respondents paid US $852-1,767 out-of-pocket for care. The US reported the largest risks of serious problems paying for care (13-18.5%), highest out-of-pocket costs (US $2,060-3,319) and greatest rise in expenditures. INTERPRETATION: Over the 10-year period, financial barriers to care were identified in Canada and internationally. Such persistent challenges are of great concern to countries striving for equitable access to healthcare.

ACOs Holding Commercial Contracts Are Larger And More Efficient Than Noncommercial ACOs.

Accountable care organizations (ACOs) have diverse contracting arrangements and have displayed wide variation in their performance. Using data from national surveys of 399 ACOs, we examined differences between the 228 commercial ACOs (those with commercial payer contracts) and the 171 noncommercial ACOs (those with only public contracts, such as with Medicare or Medicaid). Commercial ACOs were significantly larger and more integrated with hospitals, and had lower benchmark expenditures and higher quality scores, compared to noncommercial ACOs. Among all of the ACOs, there was low uptake of quality and efficiency activities. However, commercial ACOs reported more use of disease monitoring tools, patient satisfaction data, and quality improvement methods than did noncommercial ACOs. Few ACOs reported having high-level performance monitoring capabilities. About two-thirds of the ACOs had established processes for distributing any savings accrued, and these ACOs allocated approximately the same amount of savings to the ACOs themselves, participating member organizations, and physicians. Our findings demonstrate that ACO delivery systems remain at a nascent stage. Structural differences between commercial and noncommercial ACOs are important factors to consider as public policy efforts continue to evolve.