Cost Effectiveness of Metal Stents in Relieving Obstructive Jaundice in Patients with Pancreatic Cancer.

BACKGROUND: ASGE and ESGE guidelines recommend endoscopic metal stent placement for pancreatic carcinoma patients with biliary obstruction, and whose estimated life expectancy is greater than 6 months. Because median overall survival (OS) of metastatic pancreatic adenocarcinoma until recently has been less than 6 months, plastic biliary stents were preferentially placed rather than metal due to the greater upfront cost of the latter. Recent advances in the treatment of metastatic pancreatic cancer have extended median OS beyond the 6-month range. Given this improvement in OS, we performed a cost-effectiveness analysis of initial metal biliary versus plastic stent placement in metastatic pancreatic cancer patients with biliary obstruction. METHODS: A Markov model was developed to predict lifetime costs, quality-adjusted life years (QALYs), and cost effectiveness of metal compared with plastic stents. Adult patients entered the model with locally advanced cancer and underwent endoscopic retrograde cholangiopancreatography (ERCP) with placement of metal or plastic stents. A targeted literature search was conducted to identify published sources, which were used to estimate clinical, cost, utility, and event rate inputs to the model. Results were estimated from the third-party payer perspective in 2012 US dollars per QALY. One-way and probabilistic sensitivity analyses were conducted to assess the impact on model outcomes resulting from uncertainty among inputs. RESULTS: Our analysis found that initial placement of metal stents was more cost effective than plastic biliary stents with lower overall costs due to lower restenting rates while at the same time associated with a better quality of life. Based on model projections, placement of metal stents could save approximately $1450 per patient over a lifetime, while simultaneously improving quality of life. These findings were robust in sensitivity analyses. CONCLUSIONS: Placement of metal biliary stents at initial onset of obstructive jaundice in adult patients with metastatic pancreatic carcinoma with an expected OS greater than 6 months was found to be a more cost-effective strategy than plastic stents. These results reinforce guidelines' suggestions for metal stent placement.

The application of an industry level participatory ergonomics approach in developing MSD interventions.

Participatory ergonomics projects are traditionally applied within one organisation. In this study, a participative approach was applied across the New Zealand meat processing industry, involving multiple organisations and geographical regions. The purpose was to develop interventions to reduce musculoskeletal disorder (MSD) risk. This paper considers the value of an industry level participatory ergonomics approach in achieving this. The main rationale for a participative approach included the need for industry credibility, and to generate MSD interventions that address industry level MSD risk factors. An industry key stakeholder group became the primary vehicle for formal participation. The study resulted in an intervention plan that included the wider work system and industry practices. These interventions were championed across the industry by the key stakeholder group and have extended beyond the life of the study. While this approach helped to meet the study aim, the existence of an industry-supported key stakeholder group and a mandate for the initiative are important prerequisites for success.

The role of organisational support in teleworker wellbeing: a socio-technical systems approach.

The prevalence of telework and other forms of mobile working enabled by digital technology is increasing markedly. Following a socio-technical systems approach, this study aims to examine the role of organisational social support and specific support for teleworkers in influencing teleworker wellbeing, the mediating role of social isolation, potentially resulting from a person-environment mismatch in these relationships, and possible differences in these relationships between low-intensity and hybrid teleworkers. Teleworkers' (n = 804) perceptions of support and telework outcomes (psychological strain, job satisfaction, and social isolation) were collected using an on-line survey of teleworking employees distributed within 28 New Zealand organisations where knowledge work was undertaken. Organisational social support and teleworker support was associated with increased job satisfaction and reduced psychological strain. Social isolation mediated the relationship between organisational social support and the two outcome variables, and some differences were observed in the structural relationships for hybrid and low-intensity teleworker sub-samples. These findings suggest that providing the necessary organisational and teleworker support is important for enhancing the teleworker-environment fit and thereby ensuring desirable telework outcomes.

Calculated third order rate constants for interpreting the mechanisms of hydrolyses of chloroformates, carboxylic Acid halides, sulfonyl chlorides and phosphorochloridates.

Hydrolyses of acid derivatives (e.g., carboxylic acid chlorides and fluorides, fluoro- and chloroformates, sulfonyl chlorides, phosphorochloridates, anhydrides) exhibit pseudo-first order kinetics. Reaction mechanisms vary from those involving a cationic intermediate (SN1) to concerted SN2 processes, and further to third order reactions, in which one solvent molecule acts as the attacking nucleophile and a second molecule acts as a general base catalyst. A unified framework is discussed, in which there are two reaction channels-an SN1-SN2 spectrum and an SN2-SN3 spectrum. Third order rate constants (k3) are calculated for solvolytic reactions in a wide range of compositions of acetone-water mixtures, and are shown to be either approximately constant or correlated with the Grunwald-Winstein Y parameter. These data and kinetic solvent isotope effects, provide the experimental evidence for the SN2-SN3 spectrum (e.g., for chloro- and fluoroformates, chloroacetyl chloride, p-nitrobenzoyl p-toluenesulfonate, sulfonyl chlorides). Deviations from linearity lead to U- or V-shaped plots, which assist in the identification of the point at which the reaction channel changes from SN2-SN3 to SN1-SN2 (e.g., for benzoyl chloride).

Revised sample preparation for the analysis of oxysterols by enzyme-assisted derivatisation for sterol analysis (EADSA).

Sterols, and specifically oxysterols, play important roles in the biosynthesis of bile acids and steroid hormones as well as possessing biological activities in their own right. Analysis of oxysterols is complicated due to their low abundance in biological systems and poor ionisation characteristics in mass spectrometry. Over the past decade, we have developed a liquid chromatography-mass spectrometry method termed enzyme-assisted derivatisation for sterol analysis (EADSA). Our derivatisation procedure relies on two solid-phase extraction steps to (i) separate cholesterol from oxysterols and (ii) remove excess derivatisation reagents. Recent inter-batch variation in C18 reversed-phase cartridges has led us to experiment with alternative columns. Here, we present our findings and report an improved sample preparation procedure using polymeric hydrophilic-lipophilic balanced reversed-phase cartridges.

Quantitative charge-tags for sterol and oxysterol analysis.

BACKGROUND: Global sterol analysis is challenging owing to the extreme diversity of sterol natural products, the tendency of cholesterol to dominate in abundance over all other sterols, and the structural lack of a strong chromophore or readily ionized functional group. We developed a method to overcome these challenges by using different isotope-labeled versions of the Girard P reagent (GP) as quantitative charge-tags for the LC-MS analysis of sterols including oxysterols. METHODS: Sterols/oxysterols in plasma were extracted in ethanol containing deuterated internal standards, separated by C18 solid-phase extraction, and derivatized with GP, with or without prior oxidation of 3ß-hydroxy to 3-oxo groups. RESULTS: By use of different isotope-labeled GPs, it was possible to analyze in a single LC-MS analysis both sterols/oxysterols that naturally possess a 3-oxo group and those with a 3ß-hydroxy group. Intra- and interassay CVs were <15%, and recoveries for representative oxysterols and cholestenoic acids were 85%-108%. By adopting a multiplex approach to isotope labeling, we analyzed up to 4 different samples in a single run. Using plasma samples, we could demonstrate the diagnosis of inborn errors of metabolism and also the export of oxysterols from brain via the jugular vein. CONCLUSIONS: This method allows the profiling of the widest range of sterols/oxysterols in a single analytical run and can be used to identify inborn errors of cholesterol synthesis and metabolism.

Descriptive data on cardiovascular and metabolic risk factors in ambulatory and non-ambulatory adults with cerebral palsy.

Forty-two participants with cerebral palsy were recruited for a study examining traditional and novel indicators of cardiovascular risk (McPhee et al., 2015 [1]). Data pertaining to the prevalence of obesity, smoking, hypertension, and metabolic risk are provided. These data are presented along with the scoring methods used in evaluation of the study participants. Percentages are included for comparative purposes with the existing literature.

An implementation evaluation of a qualitative culture assessment tool.

Safety culture has been identified as a critical element of healthy and safe workplaces and as such warrants the attention of ergonomists involved in occupational health and safety (OHS). This study sought to evaluate a tool for assessing organisational safety culture as it impacts a common OHS problem: musculoskeletal disorders (MSD). The level of advancement across nine cultural aspects was assessed in two implementation site organisations. These organisations, in residential healthcare and timber processing, enabled evaluation of the tool in contrasting settings, with reported MSD rates also high in both sectors. Interviews were conducted with 39 managers and workers across the two organisations. Interview responses and company documentation were compared by two researchers to the descriptor items for each MSD culture aspect. An assignment of the level of advancement, using a five stage framework, was made for each aspect. The tool was readily adapted to each implementation site context and provided sufficient evidence to assess their levels of advancement. Assessments for most MSD culture aspects were in the mid to upper levels of advancement, although the levels differed within each organisation, indicating that different aspects of MSD culture, as with safety culture, develop at a different pace within organisations. Areas for MSD culture improvement were identified for each organisation. Reflections are made on the use and merits of the tool by ergonomists for addressing MSD risk.

Evaluation of novel derivatisation reagents for the analysis of oxysterols.

Oxysterols are oxidised forms of cholesterol that are intermediates in the synthesis of bile acids and steroid hormones. They are also ligands to nuclear and G protein-coupled receptors. Analysis of oxysterols in biological systems is challenging due to their low abundance coupled with their lack of a strong chromophore and poor ionisation characteristics in mass spectrometry (MS). We have previously used enzyme-assisted derivatisation for sterol analysis (EADSA) to identify and quantitate oxysterols in biological samples. This technique relies on tagging sterols with the Girard P reagent to introduce a charged quaternary ammonium group. Here, we have compared several modified Girard-like reagents and show that the permanent charge is vital for efficient MS(n) fragmentation. However, we find that the reagent can be extended to include sites for potential stable isotope labels without a loss of performance.

Effect of the 12-gene colon cancer assay results on adjuvant treatment recommendations in patients with stage II colon cancer.

INTRODUCTION: The 12-gene colon cancer Recurrence Score assay is a clinically validated predictor of recurrence risk in stage II colon cancer patients. A survey was performed characterizing the assay's impact on treatment recommendations for these patients. METHODS: US medical oncologists (n = 346) who ordered the assay for ≥3 stage II colon cancer patients were asked to complete a web-based survey regarding their most recent such patient. Physicians surveyed represented users of the assay within the first 2 years of commercial availability which may include 'early adopters'. RESULTS: Most of 116 eligible physicians were in community practice (86%), with median 14.5 years' experience (range = 2-40). Mean patient age was 61 years (range = 32-85); 81% had T3 disease, and 38% had comorbidities. Of 76 patients tested for mismatch-repair/microsatellite-instability (MMR/MSI), 13 (17%) were MMR-deficient/MSI-high; 46 (61%) MMR-proficient/MSI-low; and 17 (22%) unknown. Most patients (84%) had ≥12 nodes examined. Median Recurrence Score result was 20 (range = 1-77). Before assay, treatment recommendations were specified for 92 (79%) patients, with no recommendation for 24 (21%). Of the 92 with pre-assay recommendations, chemotherapy was planned for 52 (57%) and observation for 40 (43%); the assay changed recommendations for 27 (29%). Treatment intensity decreased for 18 (67%) and increased for nine (33%) patients; it was more likely to decrease for lower Recurrence Score values and increase for higher values (p < 0.001). CONCLUSION: For stage II colon cancer patients receiving Recurrence Score testing, 29% of treatment recommendations were changed. Use of the assay may lead to reductions in treatment intensity. Study limitations include retrospective design, data gathering during the first 2 years of assay availability only, and potential non-representativeness of respondents.

Methods for improving efficiency in quality measurement: the example of pain screening.

OBJECTIVE: Collecting unnecessary data when assessing quality of care wastes valuable resources. We evaluated three approaches for estimating quality-measure adherence and determined minimum visit data required to achieve accurate estimates. DESIGN: We abstracted medical records for calculating physician-level pain screening rates as: visit-specific, using single-visit data for each patient; visit-level average, using data for all patients and visits; and patient-level average, using data from a subset of patients and visits. SETTING: VA Greater Los Angeles Health-care System, 2006. PARTICIPANTS: One hundred and six patients with Stage IV solid tumors. INTERVENTION: Pain screening at every medical encounter, measured by a 0-10 numeric rating scale and reported to the national Medicare insurance program under a 'pay-for-reporting' program. MAIN OUTCOME MEASURES: Amount of visit data needed to reach the smallest 95% confidence interval (CI) and stable pain screening estimates. RESULTS: Pain screening occurred at 22% (23/106; 95% CI: 14-30%) of initial visits and 50% (8/16; 95% CI: 25-75%) of single visits. Across all visits, screening adherence averaged 34% when estimated at the visit-level precision and 30% at the patient level. Maximum patient-level precision was reached at visit 4 (95% CI: ± 8%) and visit level at visit 14 (95% CI: ± 6%). Using patient-level and visit-level approaches, estimates stabilized at visits 8 and 11, respectively, and reached within 1 percentage point of the steady-state value at visits 4 and 9. CONCLUSION: To address low-pain screening among cancer patients, an oncology pain screening measure may be most efficiently evaluated with data from a sample of patients and visits. This approach may be valid for visit-level quality measures in other settings.

Nucleophilicity parameters for amines, amino acids and peptides in water. Variations in selectivities for quinone methides.

Second order rate constants for reactions of 4,4'-dimethylaminobenzhydrylium cations with amines and other nucleophiles in water define a scale of nucleophilicity (N(+)'' = log k + 2.63). The N(+)'' scale can be extended by linking directly to an established N(+) scale based on reactions of methyl vinyl pyridinium cations with amine nucleophiles. Logarithms of rate constants for other benzhydrylium ions and quinone methides (QMs) are correlated by the equation: log k = s(E)N(+)'' + constant, having a nucleophilicity parameter (N(+)'' defined as in the Ritchie N(+) equation with N(+)'' = 4.75 for hydroxide ion), and an electrophile's response (selectivity) parameter (s(E), as in the Swain-Scott equation). Correlations for other benzhydrylium cations require only one slope and one intercept per cation, and fit data for up to 54 amines, amino acids and peptide nucleophiles; the slope s(E) increases as the reactivity of the cation decreases. Contrary to recent reports, s(E) is significantly less than unity for reactions of o- and p-benzoquinone methides. As the reactivities of QMs decrease, s(E) increases and the response of s(E) to changes in reactivity is larger for QMs than for cations.

An analysis of sprain and strain injury data for the New Zealand meat processing industry from national and industry injury surveillance databases.

Data on musculoskeletal disorders (MSD) in meat processing and the tasks in which they occur is limited in the literature. This paper provides a summary of such data from the New Zealand industry. Despite the high incidence of MSD in meat processing in New Zealand, little research has been undertaken to identify and assess high-risk tasks and develop interventions to address them. This paper reports on the initial stages of a 2-year government funded project to address these issues. Findings are presented from the analysis of data from two injury surveillance databases. Accident Compensation Corporation national data claims assisted in defining the industry and indicated factors for further assessment, including consideration of claimants' gender, ethnicity and geographical region. National Injury Database industry data claims helped to identify specific tasks in which MSD are more likely to occur by departments and for the two main animal species processed. These factors have helped shape the assessment of high-risk tasks currently undertaken in the meat processing industry.

Characterization of a resistance locus (Pfs-1) to the spinach downy mildew pathogen (Peronospora farinosa f. sp. spinaciae) and development of a molecular marker linked to Pfs-1.

Downy mildew is a destructive disease of spinach worldwide. There have been 10 races described since 1824, six of which have been identified in the past 10 years. Race identification is based on qualitative disease reactions on a set of diverse host differentials which include open-pollinated cultivars, contemporary hybrid cultivars, and older hybrid cultivars that are no longer produced. The development of a set of near-isogenic open-pollinated spinach lines (NILs), having different resistance loci in a susceptible and otherwise common genetic background, would facilitate identification of races of the downy mildew pathogen, provide a tool to better understand the genetics of resistance, and expedite the development of molecular markers linked to these disease resistance loci. To achieve this objective, the spinach cv. Viroflay, susceptible to race 6 of Peronospora farinosa f. sp. spinaciae, was used as the recurrent susceptible parent in crosses with the hybrid spinach cv. Lion, resistant to race 6. Resistant F(1) progeny were subsequently backcrossed to Viroflay four times with selection for race 6 resistance each time. Analysis of the segregation data showed that resistance was controlled by a single dominant gene, and the resistance locus was designated Pfs-1. By bulk segregant analysis, an amplified fragment length polymorphism (AFLP) marker (E-ACT/M-CTG) linked to Pfs-1 was identified and used to develop a co-dominant Sequence characterized amplified region (SCAR) marker. This SCAR marker, designated Dm-1, was closely linked ( approximately 1.7 cM) to the Pfs-1 locus and could discriminate among spinach genotypes that were homozygous resistant (Pfs-1Pfs-1), heterozygous resistant (Pfs-1pfs-1), or homozygous susceptible (pfs-1pfs-1) to race 6 within the original mapping population. Evaluation of a wide range of commercial spinach lines outside of the mapping population indicated that Dm-1 could effectively identify Pfs-1 resistant genotypes; the Dm-1 marker correctly predicted the disease resistance phenotype in 120 out of 123 lines tested. In addition, the NIL containing the Pfs-1 locus (Pfs-1Pfs-1) was resistant to multiple races of the downy mildew pathogen indicating Pfs-1 locus may contain a cluster of resistance genes.

The role of contextual factors for musculoskeletal disorders in the New Zealand meat processing industry.

Musculoskeletal disorders (MSD) are the leading cause of occupational injury internationally. In New Zealand, the highest incidence of MSD is in meat processing, accounting for over half the injury compensation costs for the sector. MSD in meat processing have proven highly resistant to physical, micro-level interventions, suggesting a new approach is required. This paper reports on part of a 2-year study looking at MSD in the New Zealand meat processing industry. The qualitative study involved interviews with 237 workers, management, union and safety personnel in 28 processing sites. These data were summarised into a list of contextual factors, which, it is postulated, may create conditions under which greater exposure to physical and psychosocial factors can occur in meat processing. Some of the contextual factors are recognised as problematic by the industry, but have not previously been associated with MSD risk. The paper concludes by reflecting on conducting MSD research with a focus on contextual factors and how this may influence MSD prevention. The manuscript provides industry-based data on MSD risk and outlines the approach used in its collection. Identifying contextual factors and understanding their role in creating MSD risk may help improve the acceptance and effectiveness of MSD interventions in industry.

Structural effects on the solvolytic reactivity of carboxylic and sulfonic acid chlorides. Comparisons with gas-phase data for cation formation.

Kinetic data for solvolyses of 28 acid chlorides in 97% w/w trifluoroethanol (TFE)-water spanning over 10 (9) in rate constant at 25 degrees C are obtained directly or by short extrapolation from published values. G3 calculations of the energy required for cation formation in the gas phase are validated from proton affinities and from other experimental data. G3 calculations of heterolytic bond dissociation enthalpies (HBDEs) for formation of cations from acid chlorides in the gas phase show the following trends when compared with the solvolysis rate constants: (i) electron-rich sulfonyl chlorides and most carboxylic acid chlorides, including thione derivatives, give a satisfactory linear correlation with a significant negative slope; (ii) most sulfonyl chlorides and some chloroformates and thio derivatives have higher HBDEs and fit another correlation with a small, negative slope. A significant deviation is observed for the acyl series (RCOCl), for which both solvolysis rates and HBDEs increase in the order R = Bu ( t ) < Pr ( i ) < Et < Me. The deviation may be explained either by a prior hydration mechanism or preferably by electrostatic effects on the formation of small cations. The above results of structural effects support independent evidence from solvent effects that cationic ionization reaction pathways (with nucleophilic solvent assistance or S N2 character) are involved in the solvolyses of acid chlorides.

Additivity rules using similarity models for chemical reactivity: calculation and interpretation of electrofugality and nucleofugality.

A recently proposed, multi-parameter correlation: log k (25 degrees C)=s(f) (Ef + Nf), where Ef is electrofugality and Nf is nucleofugality, for the substituent and solvent effects on the rate constants for solvolyses of benzhydryl and substituted benzhydryl substrates, is re-evaluated. A new formula (Ef=log k (RCl/EtOH/25 degrees C) -1.87), where RCl/EtOH refers to ethanolysis of chlorides, reproduces published values of Ef satisfactorily, avoids multi-parameter optimisations and provides additional values of Ef. From the formula for Ef, it is shown that the term (sfxEf) is compatible with the Hammett-Brown (rho+sigma+) equation for substituent effects. However, the previously published values of N(f) do not accurately account for solvent and leaving group effects (e.g. nucleofuge Cl or X), even for benzhydryl solvolyses; alternatively, if the more exact, two-parameter term, (sfxNf) is used, calculated effects are less accurate. A new formula (Nf=6.14 + log k(BX/any solvent/25 degrees C)), where BX refers to solvolysis of the parent benzhydryl as electrofuge, defines improved Nf values for benzhydryl substrates. The new formulae for Ef and Nf are consistent with an assumption that sf=1.00(,) and so improved correlations for benzhydryl substrates can be obtained from the additive formula: log k(RX/any solvent/25 degrees C)=(Ef + Nf). Possible extensions of this approach are also discussed.

Unsubstituted bicyclo[1.1.0]but-2-ylcarbinyl cations.

A synthesis for the unsubstituted bicyclo[1.1.0]but-2-ylmethanols (endo- and exo-9) from 1,3-butadiene has been developed. Solvolyses of their sulfonates 10 and 11 took entirely different courses, as the endo compound 10 gave rise exclusively to rearranged products such as cyclopent-3-en-1-ol (14), while the exo compound 11 underwent only the substitution of the tosylate group with complete retention of the exo-bicyclo[1.1.0]but-2-ylmethyl skeleton. Under solvolytic conditions, 10 reacted at very similar rates to the corresponding monocyclic substrate, that is, cyclopropylcarbinyl mesylate (19); in contrast, 11 reacted only three times as fast as n-butyl tosylate and about 1000-fold slower than 10. The nature of the bicyclo[1.1.0]but-2-ylcarbinyl cations has been probed by quantum chemical calculations. Whereas, the exo isomer (exo-18) corresponds to a local energy minimum, the endo isomer is only a transition state [endo-18(TS)] for an automerization of the nonclassical cyclopent-3-en-1-yl cation (13) and converts into 13 by a Wagner-Meerwein rearrangement. The most favorable isomerization of exo-18 also leads to 13 but via a transition state resembling the 2-vinylcycloprop-1-yl cation [25(TS)]. On the introduction of methyl groups at positions 1 and 3 of exo-18, the cation is no longer an energy minimum and it becomes a transition state [27(TS)] for an automerization of the nonclassical 1,3-dimethylcyclopent-3-en-1-yl cation (28). The large effect of the methyl substitution rationalizes the puzzling results of the previous product and rate studies, which utilized various substituted derivatives of bicyclo[1.1.0]but-2-ylcarbinyl sulfonates as substrates.

Mechanisms of solvolyses of acid chlorides and chloroformates. Chloroacetyl and phenylacetyl chloride as similarity models.

[reaction: see text] Rate constants and product selectivities (S = ([ester product]/[acid product]) x ([water]/[alcohol solvent]) are reported for solvolyses of chloroacetyl chloride (3) at -10 degrees C and phenylacetyl chloride (4) at 0 degrees C in ethanol/ and methanol/water mixtures. Additional kinetic data are reported for solvolyses in acetone/water, 2,2,2-trifluoroethanol(TFE)/water, and TFE/ethanol mixtures. Selectivities and solvent effects for 3, including the kinetic solvent isotope effect (KSIE) of 2.18 for methanol, are similar to those for solvolyses of p-nitrobenzoyl chloride (1, Z = NO(2)); rate constants in acetone/water are consistent with a third-order mechanism, and rates and products in ethanol/ and methanol/water mixtures can be explained quantitatively by competing third-order mechanisms in which one molecule of solvent (alcohol or water) acts as a nucleophile and another acts as a general base (an addition/elimination reaction channel). Selectivities increase for 3 as water is added to alcohol. Solvent effects on rate constants for solvolyses of 3 are very similar to those of methyl chloroformate, but acetyl chloride shows a lower KSIE, and a higher sensitivity to solvent-ionizing power, explained by a change to an S(N)2/S(N)1 (ionization) reaction channel. Solvolyses of 4 undergo a change from the addition/elimination channel in ethanol to the ionization channel in aqueous ethanol (<80% v/v alcohol). The reasons for change in reaction channels are discussed in terms of the gas-phase stabilities of acylium ions, calculated using Gaussian 03 (HF/6-31G(d), B3LYP/6-31G(d), and B3LYP/6-311G(d,p) MO theory).