Phase IV head-to-head randomized controlled trial comparing ingenol mebutate 0·015% gel with diclofenac sodium 3% gel for the treatment of actinic keratosis on the face or scalp.

BACKGROUND: Ingenol mebutate (IngMeb) and diclofenac sodium (DS) are approved treatments for actinic keratosis (AK). OBJECTIVES: To compare the efficacy and safety of IngMeb 0·015% gel with DS 3% gel (NCT02406014). METHODS: Patients with 4-8 visible, discrete AK lesions on the face/scalp in a 25 cm2 contiguous area of skin were randomized 1:1 to IngMeb once-daily for three consecutive days or DS twice-daily for 90 days. Patients with AK lesions at Week 8 following IngMeb were offered a second IngMeb course. Primary end point was complete clearance of AK lesions (AKCLEAR 100) at end of first treatment course (Week 8, IngMeb; Week 17, DS). Secondary end points included AKCLEAR 100 at end of last treatment course and Week 17; adverse events (AEs) were assessed at these time points. Patients completed treatment satisfaction questionnaires for medication (TSQM; Week 17). RESULTS: AKCLEAR 100 at end of first treatment course was higher with IngMeb (34%) vs. DS (23%; P = 0·006). AKCLEAR 100 at end of last IngMeb course (53%) and Week 17 (45%) was higher than DS (both P < 0·001). The most frequent AE was application-site erythema (IngMeb 19%; DS 12%). Treatment-related AE (TRAE) duration was shorter with IngMeb. TRAE withdrawals were lower for IngMeb (2%) vs. DS (6%). TSQM scores for global satisfaction (P < 0·001) and effectiveness (P = 0·002) were higher with IngMeb, as was dosing instruction adherence (≥ 90% vs. 70%). CONCLUSIONS: AKCLEAR 100, patient treatment satisfaction and effectiveness were significantly higher with IngMeb compared with DS, demonstrating superiority of IngMeb for AK treatment on face/scalp.

Histological examination confirms clinical clearance of actinic keratoses following treatment with ingenol mebutate 0·05% gel.

BACKGROUND: To date, studies with ingenol mebutate gel have used clinical clearance, not histological clearance, as a primary efficacy endpoint. OBJECTIVES: This phase I, multicentre, single-arm, open-label study sought to confirm histologically the clinical clearance of actinic keratoses (AKs) to support a treatment effect deep in the epidermis. METHODS: Patients (n = 108) aged ≥ 18 years with histologically confirmed AK within a 25-cm2 contiguous treatment area on the trunk and extremities received ingenol mebutate 0·05% gel for two consecutive days and were followed up on day 3 and week 8. One AK was randomly preselected at day 1 for clinical and histological evaluation at week 8 and for reflectance confocal microscopy (RCM) in a subset of patients. The primary endpoint was clinical and histological clearance of AKs at week 8. RESULTS: The observed agreement rate between clinical and histological assessments of clearance of a single AK was 81·9% and the positive predictive value of a clinical assessment of clearance was 87%. Agreement between the two pathologists was 88%. The common composite 8-week complete clearance rate was 41% (95% confidence interval 32-50). Observed agreement rates between RCM and pathologist I and II assessments of clearance were 72·9% and 81·4%, respectively. Overall, 30 patients (27·8%) experienced 38 adverse events (AEs). Application-site pain (four patients, 3·7%) was the most common treatment-related AE inside the treatment area. CONCLUSIONS: Ingenol mebutate achieves histopathological clearance of AKs that correlates with observed clinical clearance. Clinical clearance is a good predictor for histological clearance.

Quantification of bovine milk protein composition and coagulation properties using infrared spectroscopy and chemometrics: A result of collinearity among reference variables.

Predicting protein fractions and coagulation properties in bovine milk using Fourier transform infrared (FT-IR) measurements is desirable. However, such predictions may rely on correlations with total protein content. The aim of this study was to show how correlations between total protein content, protein fractions, and coagulation properties are responsible for the successful prediction of protein fractions and rennet-induced coagulation properties in milk samples. This study comprised 832 bovine milk samples from 2 breeds (426 Holstein and 406 Jersey). Holstein samples were collected from 20 Danish dairy herds from October to December 2009; Jersey samples were collected from 22 Danish dairy herds from February to April 2010. All samples were from conventional herds and taken while cows were housed. The results showed that κ-CN, αS1-CN, αS1-CN with 8 phosphorylated groups attached (αS1-CN 8P), and curd firming rate could be predicted from FT-IR measurements of the milk samples (with coefficients of determination between 0.66 and 0.71). However, the success of these FT-IR-based predictions was based on indirect relationships with total protein content. Hence, the FT-IR predictions relied on covariance structures with total protein content rather than absorption bands directly associated with the protein fractions and coagulation properties. If covariance structures between the protein fractions, coagulation properties, and total protein content used to calibrate partial least squares models were not conserved in future samples, these samples would show incorrect predictions of the protein fractions and coagulation properties. We demonstrated this using samples from 1 breed to calibrate and samples from the other breed to validate partial least squares models for ß-CN. The 2 breeds had different covariance structures between ß-CN and total protein content, and the validation samples yielded incorrect predictions. This finding may limit the usefulness of FT-IR-based predictions of protein fractions in milk recording, because indirect covariance structures in the calibration set must be valid for future samples, or future samples will show incorrect predictions.

Contribution of volatiles to the antifungal effect of Lactobacillus paracasei in defined medium and yogurt.

Lactic acid bacteria with antifungal properties can be used to control spoilage of food and feed. Previously, most of the identified metabolites have been isolated from cell-free fermentate of lactic acid bacteria with methods suboptimal for detecting possible contribution from volatiles to the antifungal activity. The role of volatile compounds in the antifungal activity of Lactobacillus paracasei DGCC 2132 in a chemically defined interaction medium (CDIM) and yogurt was therefore investigated with a sampling technique minimizing volatile loss. Diacetyl was identified as the major volatile produced by L. paracasei DGCC 2132 in CDIM. When the strain was added to a yogurt medium diacetyl as well as other volatiles also increased but the metabolome was more complex. Removal of L. paracasei DGCC 2132 cells from CDIM fermentate resulted in loss of both volatiles, including diacetyl, and the antifungal activity towards two strains of Penicillium spp. When adding diacetyl to CDIM or yogurt without L. paracasei DGCC 2132, marked inhibition was observed. Besides diacetyl, the antifungal properties of acetoin were examined, but no antifungal activity was observed. Overall, the results demonstrate the contribution of diacetyl in the antifungal effect of L. paracasei DGCC 2132 and indicate that the importance of volatiles may have been previously underestimated.

Quantification of individual fatty acids in bovine milk by infrared spectroscopy and chemometrics: understanding predictions of highly collinear reference variables.

Predicting individual fatty acids (FA) in bovine milk from Fourier transform infrared (FT-IR) measurements is desirable. However, such predictions may rely on covariance structures among individual FA and total fat content. These covariance structures may change with factors such as breed and feed, among others. The aim of this study was to estimate how spectral variation associated with total fat content and breed contributes to predictions of individual FA. This study comprised 890 bovine milk samples from 2 breeds (455 Holstein and 435 Jersey). Holstein samples were collected from 20 Danish dairy herds from October to December 2009; Jersey samples were collected from 22 Danish dairy herds from February to April 2010. All samples were from conventional herds and taken while cows were housed. Moreover, in a spiking experiment, FA (C14:0, C16:0, and C18:1 cis-9) were added (spiked) to a background of commercial skim milk to determine whether signals specific to those individual FA could be obtained from the FT-IR measurements. This study demonstrated that variation associated with total fat content and breed was responsible for successful FT-IR-based predictions of FA in the raw milk samples. This was confirmed in the spiking experiment, which showed that signals specific to individual FA could not be identified in FT-IR measurements when several FA were present in the same mixture. Hence, predicted concentrations of individual FA in milk rely on covariance structures with total fat content rather than absorption bands directly associated with individual FA. If covariance structures between FA and total fat used to calibrate partial least squares (PLS) models are not conserved in future samples, these samples will show incorrect and biased FA predictions. This was demonstrated by using samples of one breed to calibrate and samples of the other breed to validate PLS models for individual FA. The 2 breeds had different covariance structures between individual FA and total fat content. The results showed that the validation samples yielded biased predictions. This may limit the usefulness of FT-IR-based predictions of individual FA in milk recording as indirect covariance structures in the calibration set must be valid for future samples. Otherwise, future samples will show incorrect predictions.

Identification of chemical markers for the sensory shelf-life of saveloy.

The aroma composition, the microbial composition and the sensory profile were measured in sliced saveloy samples packed in modified atmosphere (MA). The main objective was to identify aroma compounds with potential as chemical markers to identify the sensory changes of saveloy. The 60 aroma compounds isolated from the saveloy samples by dynamic headspace extraction and measured by Gas Chromatography Mass Spectrometry (GC-MS) were used to model the sensory attributes sour&old odour and meaty odour using partial least squares regression (PLS). 2- and 3-methylbutanal, 2- and 3-methylbutanol, acetoin and diacetyl were found to have the highest impact on both sour&old odour and meaty odour of the samples. The results show that these four aroma compounds have high potential as chemical markers for the sensory shelf-life of sliced and MA-packed saveloy.

Oligoclonal bands predict multiple sclerosis after optic neuritis: a literature survey.

BACKGROUND: Multiple sclerosis (MS) is an autoimmune disease resulting in inflammation and demyelination of neurones in the central nervous system (CNS). The first sign of MS is often monosymptomatic optic neuritis (MON). Cerebrospinal fluid from a patient with MS analysed by electrophoresis often shows a split to form so called oligoclonal bands (OCBs). OCBs consist of proteins from activated lymphocytes and plasma cell clones. OBJECTIVES: The aim of this study was to review the published literature on OCBs in MON patients and perform a meta-analysis of the studies in order to assess the utility of OCB determination in patients with MON in the prediction of their risk of MS. METHODS: Review and meta-analysis of the results of 10 published studies. RESULTS: OCBs as a predictive test had a sensitivity of 73-100% (mean 88.5%), a specificity of 41-90% (mean 57%) and OR-values between 2.75 and 171 (mean 34.2). The areal under the summary receiver operator characteristic (ROC) curve was 0.89 (unweighted) and 0.82 (weighted). The studies showed large heterogeneity in the diagnostic accuracy. CONCLUSION: This literature-based meta-analysis provides evidence that OCBs may have a high predictive value for the development of MS in patients with MON. Standardization of laboratory methods and diagnostic criteria would help bring out the full clinical potential of the test. To elucidate the predictive value of OCBs versus MRI, we recommend that a similar meta-analysis of studies of MRI in MON be performed.

A phase II study of the vitamin D analogue Seocalcitol in patients with inoperable hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a common malignant tumour, which has a poor prognosis. Surgical resection can be curative but most patients are inoperable and most chemotherapy agents have minimal activity in this disease. Seocalcitol, a vitamin D analogue, induces differentiation and inhibits growth in cancer cell lines and in vivo. The vitamin D receptor is expressed in hepatocytes and more abundantly in HCC cells. In total, 56 patients with inoperable advanced HCC were included in an uncontrolled study of oral Seocalcitol treatment for up to 1 year (with possible extension for responders). The dose was titrated according to serum calcium levels. The treatment effect was evaluated by regular CT scans. Out of 33 patients evaluable for tumour response, two had complete response (CR), 12 stable disease and 19 progressive disease. The CRs appeared after 6 and 24 months of treatment, and lasted for 29 and at least 36 months (patient still in remission when data censored). Seocalcitol was well tolerated; the most frequent toxicity was hypercalcaemia and related symptoms. Most patients tolerated a daily dose of 10 micro g of Seocalcitol. This is the first study showing activity, by reduction in tumour dimensions, of a differentiating agent in patients with an advanced bulky, solid tumour. Seocalcitol may have an effect in the treatment of HCC, especially in early disease when a prolonged treatment can be instituted. The survival benefit with or without tumour response should be determined in controlled studies.

A phase II trial of the vitamin D analogue Seocalcitol (EB1089) in patients with inoperable pancreatic cancer.

Inoperable cancer of the exocrine pancreas responds poorly to most conventional anti-cancer agents, and new agents are required to palliate this disease. Seocalcitol (EB1089), a vitamin D analogue, can inhibit growth, induce differentiation and induce apoptosis of cancer cell lines in vitro and can also inhibit growth of pancreatic cancer xenografts in vivo. Thirty-six patients with advanced pancreatic cancer received once daily oral treatment with seocalcitol with dose escalation every 2 weeks until hypercalcaemia occurred, following which patients continued with maintenance therapy. The most frequent toxicity was the anticipated dose-dependent hypercalcaemia, with most patients tolerating a dose of 10-15 microg per day in chronic administration. Fourteen patients completed at least 8 weeks of treatment and were evaluable for efficacy, whereas 22 patients were withdrawn prior to completing 8 weeks' treatment and in 20 of these patients withdrawal was due to clinical deterioration as a result of disease progression. No objective responses were observed, with five of 14 patients having stable disease in whom the duration of stable disease was 82-532 days (median=168 days). The time to treatment failure (n=36) ranged from 22 to 847 days, and with a median survival of approximately 100 days. Seocalcitol is well tolerated in pancreatic cancer but has no objective anti-tumour activity in advanced disease. Further studies are necessary to determine if this agent has any cytostatic activity in this malignancy in minimal disease states.

CHS 828, a novel pyridyl cyanoguanidine with potent antitumor activity in vitro and in vivo.

A new class of recently discovered antineoplastic agents, the pyridyl cyanoguanidines, exert a potent antitumor activity in rodents after oral administration. Optimization in vitro and in vivo has resulted in the selection of the lead candidate CHS 828 (N-(6-chlorophenoxyhexyl)-N'cyano-N"-4-pyridylguanidine). CHS 828 was found to exert potent cytotoxic effects in human breast and lung cancer cell lines, with lesser effects on normal fibroblasts and endothelial cells. In a study using a panel of cell lines with different resistance patterns, the effects of CHS 828 showed a low correlation with the activity patterns of known anticancer agents, and no sensitivity to known mechanisms of multidrug resistance was observed. In nude mice bearing human tumor xenografts, CHS 828, at doses from 20 to 50 mg/kg/day p.o., inhibited the growth of MCF-7 breast cancer tumors and caused regression of NYH small cell lung cancer tumors. Oral administration of CHS 828 once weekly improved efficacy without increasing toxicity. CHS 828 was found to compare favorably with established chemotherapeutic agents such as cyclophosphamide, etoposide, methotrexate, and paclitaxel. In mice with NYH tumors, long-term survival (>6 months) was observed after treatment with CHS 828 was stopped. In conclusion, CHS 828 is an effective new antitumor agent, with a potentially new mechanism of action. CHS 828 is presently being tested in Phase I clinical trials in collaboration with the European Organization for Research and Treatment of Cancer.

Visual analogue scales for detecting changes in symptoms of the sick building syndrome in an intervention study.

OBJECTIVES: This study tested questionnaires using visual analogue scales (VAS) in a cleaning intervention study and attempted to find a simple way of analyzing the replies to the questionnaires. METHODS: A VAS questionnaire made up of 26 questions was developed and marked once a week for 28 weeks by the room occupants in 3 buildings. A total of 1248 questionnaires was used in the analysis of the results. A simple model based on the differences between a person's average responses during 2 different periods was used in the analysis. RESULTS: No clear effect of the cleaning was found. Several significant correlations between different questions were established. Estimates for the design of future studies are given. CONCLUSIONS: The VAS questionnaire proved to be feasible for this type of study. It is suggested that each intervention period should last 4 weeks if the questionnaire is used once a week. However, the length of the period also depends on the expected latency of the symptoms, on how long it takes for environmental conditions to be affected by the intervention, and on how quickly conditions return to "normal" during control periods.

Evaluation of the revised NIOSH lifting equation. A cross-sectional epidemiologic study.

STUDY DESIGN: A cross-sectional study of the 1-year prevalence of low back pain was conducted in workers employed in manual lifting jobs. OBJECTIVES: To provide epidemiologic data to determine the correlation between the prevalence of low back pain and exposure to manual lifting stressors, measured with the lifting index component of the revised lifting equation from the National Institute for Occupational Safety and Health (NIOSH). SUMMARY OF BACKGROUND DATA: The NIOSH lifting equation has been proposed as a practical, yet valid tool for assessing the risks of low back pain caused by manual lifting. To date, however, there have been few studies in which the effectiveness of the equation to identify jobs with elevated rates of low back pain has been evaluated. METHODS: Fifty jobs from four industrial sites were evaluated with the NIOSH lifting equation. A symptom and occupational history questionnaire was administered to 204 people employed in lifting jobs and 80 people employed in nonlifting jobs. Regression analysis was used to determine whether there was a correlation between the lifting index and reported low back pain. RESULTS: As the lifting index increased from 1.0 to 3.0, the odds of low back pain increased, with a peak and statistically significant odds ratio occurring in the 2 < lifting index < or = 3 category (odds ratio = 2.45). For jobs with a lifting index higher than 3.0, however, the odds ratio was lower (odds ratio = 1.45). CONCLUSIONS: Although low back pain is a common disorder, the lifting index appears be a useful indicator for determining the risk of low back pain caused by manual lifting.

Effect of age and height on vibrotactile threshold among 1,663 U.S. workers.

Assessment of vibrotactile threshold has gained application in studies of neuropathies induced by toxic substances, compression, and vibration. The effect of age and height on vibrotactile threshold is of interest for its own sake and for the purpose of confounder control. We have studied the relation between finger and toe vibrotactile thresholds and age and height in five studies carried out by the National Institute for Occupational Safety and Health with vibrometry data (N = 1,663). A unique property of the merged data set was its wide age range from 14 to 82 years (mean 42 years). We demonstrate a J-shaped increase in finger threshold value (expressed on a log scale) with age, with no increase up to age 35 and a linear increase thereafter. For finger threshold, height was not an important predictor. The data were sparser (n = 541) for toe threshold but suggested a linear increase with both age and height. While consistent with prior data, this study provides a better understanding of the relation between vibrotactile threshold and age and height than has been available before. The greater effect of age and height on toe rather than finger threshold is consistent with the hypothesis that the length of the nerve increases susceptibility to peripheral neuropathy.

Prevalence proportion ratios: estimation and hypothesis testing.

BACKGROUND: Recent communications have argued that often it may not be appropriate to analyse cross-sectional studies of prevalent outcomes with logistic regression models. The purpose of this communication is to compare three methods that have been proposed for application to cross sectional studies: (1) a multiplicative generalized linear model, which we will call the log-binomial model, (2) a method based on logistic regression and robust estimation of standard errors, which we will call the GEE-logistic model, and (3) a Cox regression model. METHODS: Five sets of simulations representing fourteen separate simulation conditions were used to test the performance of the methods. RESULTS: All three models produced point estimates close to the true parameter, i.e. the estimators of the parameter associated with exposure had negligible bias. The Cox regression produced standard errors that were too large, especially when the prevalence of the disease was high, whereas the log-binomial model and the GEE-logistic model had the correct type I error probabilities. It was shown by example that the GEE-logistic model could produce prevalences greater than one, whereas it was proven that this could not happen with the log-binomial model. The log-binomial model should be preferred.

Injuries among domestic waste collectors.

Detailed information on occupational injuries and the precise number of injuries among waste collectors is missing. In this study, risk circumstances associated with injuries among waste collectors were analyzed and described. The study was carried out in a single company with 667 employees in 1993. For each injury, information was collected on date, time, type, and severity of the injury, injury circumstances, department of employment, external or internal registration, sex, year of birth and employment, type of employment, and a registration of where the injury happened. A total of 17% of the employees experienced injury. The number of injuries decreased with increasing seniority and age. Most injuries occurred outside the company area. More injuries occurred on Mondays and Thursdays, and there were peaks in the injury rate in May and September. Most often injured was the back, followed by the knees, hands, and feet. The job as a waste collector was associated with a high risk of experiencing an occupational injury and the number of injuries decreased with increasing seniority and nonsignificantly with increasing age. Moreover, a seasonal and weekly variation was observed.

Comparison of a self-administered questionnaire and a telephone interview of 146 Danish waste collectors.

Methods to collect epidemiologic data include, among other means, self-administered questionnaires and personal and telephone interviews. In some studies, these data collection methods are used simultaneously. However, little is known about the comparability of the data obtained, thus, the validity of pooling data. A self-administered questionnaire was completed by 146 waste collectors, who participated in a telephone interview 3 months later. The responses to health questions were compared. Agreement percentages and kappa values were calculated. An answer pattern shift was detected in a subgroup of questions with five answer options. Grouping the answer options diminished the shift in the answer pattern. The questions in a yes/no format generally showed no shift in the answer pattern. The study indicates that caution should be exercised when pooling data collected by self-administered questionnaire and telephone interview in epidemiological research. Some types of questions seem to be sensitive to the data collection method.

Comparison of the reproducibility of the WHO classifications of 1975 and 1994 of endometrial hyperplasia.

In a blinded, randomized design, six histopathologists with an interest in gynecological pathology examined the inter- and intraobserver variation of the histopathological diagnosis of endometrial hyperplasia according to the World Health Organization (WHO) classification of 1975 and the new WHO classification of 1994. On four occasions, the pathologists assessed hematoxylin/eosin-stained slides from 128 cases originally diagnosed and coded in the Snomed system as endometrial hyperplasia. In the first and third rounds, the slides were classified according to the 1975 classification and in the second and fourth rounds according to the 1994 classification. The overall interobserver agreement in the two rounds where the 1975 classification was used was 0.47 and 0.51, and the kappa values 0.24 [95% confidence interval (CI) 0.21-0.27] and 0.30 (95% CI 0.27-0.33). The overall interobserver agreement in the two rounds using the 1994 classification was 0.45 and 0.41 and the kappa values 0.25 (95% CI 0.23-0.28) and 0.20 (95% CI 0.17-0.22). Reducing the classification to two categories with clinical significance (atypical endometrial hyperplasia versus others in the 1975 classification, and atypical endometrial hyperplasia, complex versus others in the 1994 classification) increased the overall agreement of the 1975 classification in both rounds to 0.91 and of the 1994 classification to 0.92 and 0.90. The kappa values increased to 0.54 (95% CI 0.49-0.58) and 0.49 (95% CI 0.45-0.54) in the 1975 classification and to 0.59 (95% CI 0.54-0.63) and 0.42 (95% CI 0.37-0.46) in the 1994 classification. The intraobserver overall agreement for the 1975 classification ranged from 0.80 to 0.55 and the kappa values from 0.70 (95% CI 0.58-0.81) to 0.28 (95% CI 0.17-0.39). The intraobserver overall agreement for the 1994 classification ranged from 0.71 to 0.46 and the kappa values from 0.60 (95% CI 0.51-0.70) to 0.20 (95% CI 0.09-0.30). It is concluded that there is considerable inter- and intraobserver variation using both the 1975 and the 1994 classifications of endometrial hyperplasia. We propose that there is need for a specification and for a simplification of the classification.

Season, equipment, and job function related to gastrointestinal problems in waste collectors.

OBJECTIVES: Informal reports have suggested that work as a waste collector entails exposures that cause gastrointestinal symptoms--such as nausea and diarrhoea. This study explores this hypothesis by correlating data on the type of waste collected, the persons' job function, the equipment used, and the times of the week and the year of reported nausea and diarrhoea. METHODS: 1747 male waste collectors and a control group for comparison of 1111 male municipality workers answered a questionnaire on work environment, work related exposure, and health status. RESULTS: In a multivariate analysis collection of organic and residual waste (prevalence proportion ratio (PPR) 1.45) and mixed household waste (PPR 1.43) were associated with reported nausea and so was the job loader (PPR 1.51). More symptoms were reported in the summer. Multivariate analysis of diarrhoea showed that the job front runner was associated with reported diarrhoea (PPR 1.22) and so was the job loader (PPR 1.26). More symptoms occurred in the summer. The workers stated that the gastrointestinal symptoms were related to the smell of rotten waste. This may support the hypothesis that microbial compounds were the causal agents. CONCLUSION: The gastrointestinal symptoms were associated with the job of waste collector and moreover the symptoms predominantly occurred in the summer.

[Use of chemicals in Danish workplaces]. / Kemikaliebrug i danske virksomheder.

The use and distribution of hazardous products in Danish industry were investigated. An exposure estimation model was developed. Based on data collected in the investigation and on the composition of about 9400 products national numbers of chemical exposure events and national volumes of chemicals were estimated. Data are presented for 36 chemical substances with chronic toxic effects and high estimated national numbers of exposure events. Seven of the 36 substances are carcinogens, 17 reprotoxicants, 12 allergens, and 18 neurotoxicants. This cross-sectional survey on chemical exposure may serve as comparison for future surveys.