Comparing Patient-Reported Outcomes Among Anti-TNF-Experienced Patients with Crohn's Disease Initiating Vedolizumab Versus Ustekinumab.

BACKGROUND: Primary and secondary non-response to anti-tumor necrosis factor (TNF) therapy is common in patients with Crohn's disease (CD), yet limited research has compared the effectiveness of subsequent biological therapy. OBJECTIVE: We sought to compare the effectiveness of vedolizumab and ustekinumab in anti-TNF-experienced patients with CD, focusing on patient-prioritized patient-reported outcomes (PROs). METHODS: We conducted a prospective, internet-based cohort study nested within IBD Partners. We identified anti-TNF-experienced patients initiating with CD vedolizumab or ustekinumab and analyzed PROs reported approximately 6 months later (minimum 4 months, maximum 10 months). Co-primary outcomes were Patient-Reported Outcome Measurement Information System (PROMIS) domains of Fatigue and Pain Interference. Secondary outcomes included patient-reported short Crohn's disease activity index (sCDAI), treatment persistence, and corticosteroid use. Inverse probability of treatment weighting (IPTW) was used to control for a number of potential confounders and incorporated into linear and logistic regression models for continuous and categorical outcomes, respectively. RESULTS: Overall, 141 vedolizumab and 219 ustekinumab initiators were included in our analysis. After adjustment, we found no differences between treatment groups in our primary outcomes of Pain Interference or Fatigue or the secondary outcome of sCDAI. However, vedolizumab was associated with lower treatment persistence (OR 0.4, 95% CI 0.2-0.6) and higher corticosteroid use at follow-up assessment (OR 1.7, 95% CI 1.1-2.6). DISCUSSION: Among anti-TNF experienced patients with CD, Pain Interference or Fatigue was not significantly different 4-10 months after starting ustekinumab or vedolizumab. However, reduced steroid use and increased persistence suggest superiority of ustekinumab for non-PRO outcomes.

Residents' self-perceived errors in transitions of care in the emergency department.

BACKGROUND: The Accreditation Council for Graduate Medical Education requirements for systems-based practice state residents are expected to participate in identifying system errors and implementing potential systems solutions. The objective of this study was to determine the numbers of perceived errors occurring from patient pass offs between resident physicians in our emergency department. METHODS: Using a prospective observational study, we queried emergency medicine residents about perceived errors in the transition of care using trained research assistants and a standardized protocol. Transition of care was defined as the transfer of responsibility to evaluate and treat and disposition of a patient in the emergency department from 1 resident physician to a second oncoming emergency department resident physician. Mean resident-perceived errors per shift and per patient transfer of care were calculated. Additionally, the mean number of perceived errors impacting patients was calculated. RESULTS: Emergency medicine residents on 107 shifts reported receiving 713 patients in pass off with a mean of 7 patients per physician per shift, with 40% of patients passed off needing some intervention (mean of 2.8 patients per provider per shift). Nineteen of the 107 shifts (17.8%) during which a resident took patients from a prior provider had a perceived error in at least 1 patient signed off. Of the 713 patients transitioned, the receiving physician perceived an error related to the transition of care for 23. Two of the 23 errors were determined by reviewing emergency medicine attendings to not be errors, and for 9 the receiving physician perceived an impact on the patient. All were delays in care or disposition. CONCLUSION: Our data suggest emergency medicine residents were able to perceive errors related to transitions of care, describe the types of pass-off errors, and, to a lesser degree, describe the impact these errors have on patients.

GaInSn usage in the research laboratory.

GaInSn, a eutectic alloy, has been successfully used in the Magneto-Thermofluid Research Laboratory at the University of California-Los Angeles and at the Princeton Plasma Physics Laboratory for the past six years. This paper describes the handling and safety of GaInSn based on the experience gained in these institutions, augmented by observations from other researchers in the liquid metal experimental community. GaInSn is an alloy with benign properties and shows considerable potential in liquid metal experimental research and cooling applications.

Mortality of employees of a perfluorooctanesulphonyl fluoride manufacturing facility.

AIM: To evaluate the mortality experience of a cohort of employees of a perfluorooctanesulphonyl fluoride (POSF) based fluorochemical production facility. METHODS: A retrospective cohort mortality study followed all workers with at least one year of cumulative employment at the facility. The jobs held by cohort members were assigned to one of three exposure subgroups; high exposed, low exposed, and non-exposed, based on biological monitoring data for perfluorooctane sulphonate (PFOS). RESULTS: A total of 145 deaths were identified in the 2083 cohort members. Sixty five deaths occurred among workers ever employed in high exposed jobs. The overall mortality rates for the cohort and the exposure subcohorts were lower than expected in the general population. Two deaths from liver cancer were observed in the workers with at least one year of high or low exposure (standardised mortality ratio (SMR) 3.08, 95% CI 0.37 to 11.10). The risk of death from bladder cancer was increased for the entire cohort (three observed, SMR 4.81, 95% CI 0.99 to 14.06). All three bladder cancers occurred among workers who held a high exposure job (SMR 12.77, 95% CI 2.63 to 37.35). The bladder cancer cases primarily worked in non-production jobs, including maintenance and incinerator and wastewater treatment plant operations. CONCLUSION: Workers employed in high exposure jobs had an increased number of deaths from bladder cancer; however it is not clear whether these three cases can be attributed to fluorochemical exposure, an unknown bladder carcinogen encountered during the course of maintenance work, and/or non-occupational exposures. With only three observed cases the possibility of a chance finding cannot be ruled out.

Synthesis and characterization of six new quaternary actinide thiophosphate compounds: Cs(8)U(5)(P(3)S(10))(2)(PS(4))(6)(,) K(10)Th(3)(P(2)S(7))(4)(PS(4))(2), and A(5)An(PS(4))(3), (A = K, Rb, Cs; An = U, Th).

Six new actinide metal thiophosphates have been synthesized by the reactive flux method and characterized by single-crystal X-ray diffraction: Cs(8)U(5)(P(3)S(10))(2)(PS(4))(6) (I), K(10)Th(3)(P(2)S(7))(4)(PS(4))(2) (II), K(5)U(PS(4))(3) (III), K(5)Th(PS(4))(3) (IV), Rb(5)Th(PS(4))(3) (V), and Cs(5)Th(PS(4))(3) (VI). Compound I crystallizes in the monoclinic space group P2(1)/c with a = 33.2897(1) A, b = 14.9295(1) A, c = 17.3528(2) A, beta = 115.478(1) degrees, Z = 8. Compound II crystallizes in the monoclinic space group C2/c with a = 32.8085(6) A, b = 9.0482(2) A, c = 27.2972(3) A, beta = 125.720(1) degrees, Z = 8. Compound III crystallizes in the monoclinic space group P2(1)/c with a = 14.6132(1) A, b = 17.0884(2) A, c = 9.7082(2) A, beta = 108.63(1) degrees, Z = 4. Compound IV crystallizes in the monoclinic space group P2(1)/n with a = 9.7436(1) A, b = 11.3894(2) A, c = 20.0163(3) A, beta = 90.041(1) degrees, Z = 4, as a pseudo-merohedrally twinned cell. Compound V crystallizes in the monoclinic space group P2(1)/c with a = 13.197(4) A, b = 9.997(4) A, c = 18.189(7) A, beta = 100.77(1) degrees, Z = 4. Compound VI crystallizes in the monoclinic space group P2(1)/c with a = 13.5624(1) A, b = 10.3007(1) A, c = 18.6738(1) A, beta = 100.670(1) degrees, Z = 4. Optical band-gap measurements by diffuse reflectance show that compounds I and III contain tetravalent uranium as part of an extended electronic system. Thorium-containing compounds are large-gap materials. Raman spectroscopy on single crystals displays the vibrational characteristics expected for [PS(4)](3)(-), [P(2)S(7)](4-), and the new [P(3)S(10)](5)(-) building blocks. This new thiophosphate building block has not been observed except in the structure of the uranium-containing compound Cs(8)U(5)(P(3)S(10))(2)(PS(4))(6).

Plasma cholecystokinin and hepatic enzymes, cholesterol and lipoproteins in ammonium perfluorooctanoate production workers.

Ammonium perfluorooctanoate is a potent synthetic surfactant used in industrial applications. It rapidly dissociates in biologic media to perfluorooctanoate [CF3(CF2)6CO2-], which is the anion of perfluorooctanoic acid [PFOA, CF3(CF2)6COOH]. PFOA is a peroxisome proliferator known to increase the incidence of hepatic, pancreas and Leydig cell adenomas in rats. The pancreas acinar cell adenomas may be the consequence of a mild but sustained increase of cholecystokinin as a result of hepatic cholestasis. Although no significant clinical hepatic toxicity was observed, PFOA was reported to have modulated hepatic responses to obesity and alcohol consumption among production workers. To further assess these hypotheses, we examined medical surveillance data of male workers involved in ammonium perfluorooctanoate production in 1993 (n=111), 1995 (n=80) and 1997 (n=74). Serum PFOA was measured by high-performance liquid chromatography mass spectrometry methods. Plasma cholecystokinin was measured (only in 1997) by the use of direct radioimmunoassay. Serum biochemical tests included hepatic enzymes, cholesterol and lipoproteins. Serum PFOA levels, by year, were: 1993 (mean 5.0 ppm, SD 12.2, median 1.1 ppm, range 0.0-80.0 ppm); 1995 (mean 6.8 ppm, SD 16.0, median 1.2 ppm, range 0.0-114.1 ppm); and 1997 (mean 6.4 ppm, SD 14.3, median 1.3 ppm, range 0.1-81.3 ppm). Cholecystokinin values (mean 28.5 pg/ml, SD 17.1, median 22.7 pg/ml, range 8.8-86.7 pg/ml) approximated the assay's reference range (up to 80 pg/ml) for a 12 hour fast and were negatively, not positively, associated with employees' serum PFOA levels. Our findings continue to suggest there is no significant clinical hepatic toxicity associated with PFOA levels as measured in this workforce. Unlike a previously reported observation, PFOA did not appear to modulate hepatic responses to either obesity or alcohol consumption. Limitations of these findings include: 1) the cross-sectional design as only 17 subjects were common for the three surveillance years; 2) the voluntary participation that ranged between 50 and 70 percent; and 3) the few subjects with serum levels > or = 10 ppm.

Serum perfluorooctane sulfonate and hepatic and lipid clinical chemistry tests in fluorochemical production employees.

The 3M Company manufactures fluorochemicals, which have as a precursor perfluorooctane sulfonyl fluoride (C8F17SO2F). These compounds may be expected to transform metabolically, to an undetermined degree, to perfluorooctane sulfonate (PFOS, C8F17SO3-) as an end-stage metabolite. Subchronic studies in rats and primates indicate a potential for cumulative toxicity with PFOS with the primary effect related to metabolic wasting with hypolipidemia as a consistent finding. Biennial medical surveillance has been offered to the company's fluorochemical production workers located in Decatur, Alabama, and Antwerp, Belgium. In 1995, the mean serum PFOS level, as measured by high-performance liquid chromatography mass spectrometry, for 178 male employees was 2.19 parts per million (ppm; range, 0.00 to 12.83 ppm), and in 1997, for 149 male employees, it was 1.75 ppm (0.10 to 9.93 ppm). Our analyses suggest that among these production employees, there were no substantial changes in serum hepatic enzymes, cholesterol, or lipoproteins associated with PFOS levels less than 6 ppm. It was not possible to derive inferences from the few employees who had serum PFOS levels > or = 6 ppm. These results may be due to the lower levels of serum PFOS measured among these production employees, compared to those suspected to cause effects in laboratory animals.

Reversible nephrotoxicity of onconase and effect of lysine pH on renal onconase uptake.

PURPOSE: To examine the histopathology of the kidney in mice following repeated injections of the antitumor drug onconase, and to determine whether lysine, which reportedly blocks kidney uptake of other basic proteins, blocks the high renal uptake of onconase. METHODS: Mice received repeated intraperitoneal onconase injections over 3 weeks. Kidneys were examined by light microscopy after 1 week, 3 weeks, and 5 weeks (2 weeks after cessation of injections) and compared to kidneys from animals receiving a similar schedule of PBS injections. Renal uptake of radioiodinated onconase was measured in animals receiving intraperitoneal injections of lysine solutions of acidic and neutral pH given at -30, 0 and + 5 min relative to intravenous onconase injection. Renal onconase uptake was also measured in animals made metabolically acidotic by ingestion of ammonium chloride, arginine chloride or lysine dihydrochloride from the drinking water. RESULTS: Onconase caused acute moderate multifocal proximal renal tubular necrosis, and this toxicity was reversed by 2 weeks after drug withdrawal. Intraperitoneal injections of lysine dihydrochloride in PBS (pH 1.5) reduced renal onconase uptake at 15 min from 67.9+/-13.4% to 17.0+/-3.8% of the injected dose without affecting the plasma concentration and also reduced the fraction of degraded onconase in the urine. However, neutral solutions of lysine dihydrochloride at pH 7.4 or lysine acetate at pH 7.1 were ineffective at blocking renal onconase uptake. Furthermore, renal onconase uptake was minimally or not affected by a state of metabolic acidosis. CONCLUSIONS: Proximal tubular toxicity of onconase was reversible. Renal onconase uptake was blocked by lysine at pH 1.5 but not at neutral pH.

The Human Genome Project after a decade: policy issues.

The Human Genome Project began a decade ago, its early momentum fueled by two reports. A report from the National Research Council (NRC) in February 1998 endorsed the project and provided the basis for the first joint plan by the National Institutes of Health (NIH) and the Department of Energy (DOE). A report from the Office of Technology Assessment (OTA) in April 1988, provided Congress with a means to assess the roles of NIH and DOE. Both reports highlighted the importance of genomics and emphasized the need for a concerted research program. The committees did not predict the large investment of private funds or the extensive patenting of sequences, and they underestimated the rate of progress. Overall, though, the consensus-building provided by the committees helped to set the blueprint for one of the great success stories in modern biology.

An epidemiologic investigation of reproductive hormones in men with occupational exposure to perfluorooctanoic acid.

Perfluorooctanoic acid (PFOA), a potent synthetic surfactant used in industrial applications, is a peroxisome proliferator that has resulted in dose-related increases in hepatic, pancreatic acinar, and Leydig cell adenomas in laboratory animals. In addition, PFOA increased serum estradiol levels through the induction of hepatic aromatase activity. In 1993 and 1995, we conducted two cross-sectional studies of 111 and 80 production workers, respectively, and specifically measured their serum PFOA in relation to several reproductive hormones to determine whether such an effect occurs in humans. PFOA was not significantly associated with estradiol or testosterone in either year's study. A 10% increase in mean estradiol levels was observed among employees who had the highest levels of serum PFOA, although this association was confounded by body mass index. Neither was PFOA consistently associated with the other measured hormones. Our results provide reasonable assurance that, in this production setting, there were no significant hormonal changes associated with PFOA at the serum levels measured. Limitations of this investigation include its cross-sectional design, the few subjects exposed at the highest levels, and the lower levels of serum PFOA measured, compared with those levels reported to cause effects in laboratory animal studies.

Absenteeism among employees who participated in a workplace influenza immunization program.

To assess the effectiveness of a free workplace immunization program at 3M's St. Paul, Minnesota locations, we examined the difference in sick leave hours taken from November 15, 1996, through March 15, 1997, for employees who had and did not have an influenza vaccination prior to the previous year's four-month influenza season (November 15, 1995-March 15, 1996). Among the 2,622 employees who self-reported that they were not immunized in the previous year, there were, on average, 1.2 fewer hours of sick leave taken during the 1996-1997 influenza season than the comparable time period one year earlier (P < 0.05), although the exact reason for the absenteeism was not determined. In particular, we observed that female employees younger than 50 years of age with two or more children took 3.1 hours less sick leave in the year they were immunized, compared with the preceding year (P < 0.0001). Among the 895 subjects who were immunized in both years, employees took 0.7 hours more sick leave during the 1996-1997 influenza season than the previous year (P = 0.46). Based on our findings, consideration should be given to workplace immunization programs. However, we urge caution in applying a "one-size fits all" approach to any cost-savings analysis from a company-sponsored immunization program because the workplace is not a homogeneous [corrected] environment, with regard to employees' age, gender, medical history, and home environment. All of these factors may directly or indirectly contribute to the risk of acquiring influenza and any of its complications.

Diaphragm shortening and intrathoracic pressure during hypercapnia in rats.

The purpose of this study was to determine the relationship between intrathoracic pressure (delta ITP) and diaphragm shortening (DS) during the development of diaphragm fatigue. Fatigue of the diaphragm was produced by having rats breath 15% CO2 in O2. Diaphragm shortening increased significantly to 178% of control during the first 5 min of hypercapnia and then decreased to 86% of control at approximately 80 min. Twenty minutes after terminating hypercapnia, DS increased to 115% of the prehypercapnic value. delta ITP increased to 199% of control following 5 min of hypercapnia and continued to increase, reaching 267% of control at the end of the hypercapnic period. Twenty minutes later, delta ITP was 147% of control. These results illustrate that during increased respiratory work, DS can decrease while intrathoracic pressure remains increased. These findings suggest that intrathoracic pressure may not always reflect the contractile status of the diaphragm. These findings are consistent with other studies indicating that as the diaphragm fatigues, accessory respiratory muscle activity increases to maintain delta ITP.

Action spectrum for photocross-linking of human lens proteins.

The action spectrum for photocross-linking was measured for human lens beta gamma-crystallins from young adult noncataractous lenses at wavelengths of 297, 302, 313, 334 and 365 nm. The action spectrum had a maximal effectiveness at 297 nm that sharply decreased in effectiveness up to 313 nm, then remained flat until 334 nm and decreased markedly as wavelength increased to 365 nm. Radiation at 297 nm was 36 times more effective in producing cross-linking than 302 nm radiation. The 297 nm radiation was 220, 195 and 1300 times more effective than 313, 334 and 365 nm radiation, respectively. The action spectrum had a shape similar to the absorption spectrum of the lens proteins but the response was lower than expected from the absorption data, suggesting that some of the absorptions are not effective at cross-linking. Because most animal experimentation and epidemiological studies include broadband radiation, these studies would be useful in predicting the biological response of the lens to environmental UV stress.

Lidar technique for remote measurement of temperature by use of vibrational-rotational Raman spectroscopy.

Atmospheric temperature can be measured remotely by a lidar system that measures the ratio of backscattered signals from vibrational-rotational Raman scattering by N(2) to pure vibrational Raman scattering. We present simulations of the performance of an airborne lidar system (based on the Goddard Airborne Raman lidar) that employs this technique.