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.

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.

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.

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.

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.

Design options and methodological fallacies in the studies of reproductive failures.

Reproductive failures are at first sight well suited for epidemiologic research. The time of pregnancy is closely monitored, and failures such as spontaneous abortions and subfecundity are rather frequent. Although epidemiologists' interest in the field has been growing, there is still disappointingly little new information of relevance for prevention. A number of methodologic shortcomings may explain this. A large part of disease classification is not well suited for etiologic research, reduced fertility has diminished the populations at risk, close medical monitoring tends to mask causal links, and many scientific problems related to this area bring limitations to the research field. Still, much more could be learned from a systematic use of epidemiologic knowledge, existing registers, and the joint effort between different research groups.

Are pathologists biased by clinical information?: A blinded cross-over study of the histopathological diagnosis of mesothelial tumours versus pulmonary adenocarcinoma.

In a blinded cross-over design, we studied whether three pathologists were biased by clinical information when making histopathological diagnoses of adenocarcinoma of the lung and benign and malignant mesothelial tumours. Furthermore, the interobserver variation of these diagnoses was assessed. Forty-one cases of adenocarcinoma of the lung and mesothelial tumours were assessed by three pathologists in four rounds. In the first two rounds, slides stained by H&E and clinical information were available. Slides and information were matched so that a specific slide in one round was given clinical information suggesting adenocarcinoma and in the other round, the clinical information suggested mesothelial tumour. In the third and fourth rounds, a panel of immunohistochemical stains was added. The clinical information was matched in the same way as in the first and second rounds. Bias by clinical information was observed when the diagnoses were made on slides stained by H&E, while no bias could be demonstrated when immunohistochemical reactions were included. The reproducibility also improved significantly when these slides were available.

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.

Handling antineoplastic drugs in the European Community countries.

Alkylating antineoplastic drugs (ADs) are carcinogenic to humans and most ADs cause reproductive failures in animal experiments. Studies of occupationally exposed health personnel have shown increased risks for miscarriages (two studies), malformations (two studies) and leukaemia (two studies). During the past decade, work practice guidelines have been issued by authorities in several countries but universal agreement on a set of guidelines which would secure both the work environment and the treatment of patients is yet to come. We reviewed the existing guidelines in the European Community (EC) countries on health personnel's handling of ADs. Five countries had guidelines on the safe handling of ADs. The main principles were to use exhaust cabinets and personal protective equipment. Two sets of guidelines included recommendations for pregnant women. In general, the EC countries' guidelines were less extensive than those issued by the US Occupational Safety and Health Administration. It is argued that the existence of more uniform guidelines in all the member states would be valuable. Specifically, measures should be devised to prevent adverse effects on reproduction.

Modifications of health behaviour in response to air pollution notifications in Copenhagen.

Ambient air quality is a major issue today in large cities all over the world. On the theoretical background of the health belief model and the health locus of control model, we studied the knowledge and beliefs about air pollution and the modifications of health behaviour brought about by information to the public about projected levels of air pollution, with special emphasis on reduction of outdoor activity and avoidance of car driving. Data were collected with a questionnaire among a sample of residents in the Copenhagen area. The respondents were almost universally knowledgeable about the prime emission source and concerned about the possible health effects of the air pollution in the area. Avoidance of outdoor activity was associated with personal experiences of symptoms ascribed to the air pollution, employment status, and with female sex, but not with knowledge or beliefs about the degree or health implications of the air pollution. The willingness to avoid car driving was positively associated with the belief that one can oneself influence one's health and with female sex. Lung diseased respondents were generally more prone to protect themselves than the healthy, both by avoiding outdoor activity and by being less willing to avoid car driving. The present study was conducted in an only moderately polluted city, and it is not clear whether the findings and conclusions can be generalized to more polluted cities. The study partly supported the underlying theories of the determinants of health behaviour, but also indicated a need for a broader theoretical framework, incorporating aspects of the respondents' life situation and personal experience which would be relevant to the specific type of health behaviour under study.

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.

Underreporting of occupational cancers in Denmark.

OBJECTIVES: The goal of the study was to investigate whether the reporting of occupational cancers has improved in Denmark since 1987 and whether medical records currently have better information on occupational exposures. METHODS: All cases of pleural mesothelioma and sinonasal adenocarcinoma and 766 randomly selected adenocarcinomas of the lung diagnosed between 1983 and 1990 were identified from the Cancer Register. These cases were traced in the Register of Reported Occupational Diseases and in the records of the National Board of Industrial Injuries. Medical records for patients not reported to the Register of Reported Occupational Diseases were requested from hospitals and the data on work-related exposure were retrieved. RESULTS: For pleural mesotheliomas the frequency of reporting increased from 43% in 1983-1987 to 53% in 1988-1990. The frequency of reporting of sinonasal adenocarcinomas decreased from 34 to 20% in these periods. Of the adenocarcinomas of the lung, 1% had been reported. CONCLUSION: Overall the reporting of occupational cancer has not improved in Denmark since 1987.

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.

Reporting of occupational cancer in Denmark.

Many patients with occupational diseases fail to obtain compensation because their disease is not recognized as occupational and reported to the authorities. The present study examined the reporting of pleural mesotheliomas and sinonasal adenocarcinomas--cancers with well-known associations with occupational exposures to asbestos and wood dust--in Denmark in 1983-1987. The estimated underreporting was around 50%. Examination of the medical records of patients who had not been reported in 1986-1987 revealed that in most cases the medical records did not contain sufficiently detailed information about occupational exposures. It was recommended that a formal screening interview be carried out whenever a diagnosis is made of a potential occupational cancer. Medical associations may play a major role by issuing guidelines addressing occupational diseases within the fields of their expertise.

Musculoskeletal symptoms among sewing machine operators.

OBJECTIVES: A longitudinal study was conducted to describe the prevalences and development of musculoskeletal symptoms among sewing machine operators in relation to age and exposure and among former sewing machine operators who changed exposure by changing occupation. METHODS: Musculoskeletal symptoms were assessed among 327 sewing machine operators in 1985 with the use of the standardized Nordic questionnaire. A follow-up study in 1991 showed that approximately one-third was still working as a sewing machine operator, one-third had changed occupation, and the rest were out of employment. The exposure was assessed by a questionnaire regarding the type of machine being operated, work organization, workplace design, units produced per day, and payment system. RESULTS: High prevalences of musculoskeletal symptoms of the neck and shoulders were found, with some associations to exposure variables such as efficiency. Initially symptom-free sewing machine operators were not at a higher risk of developing symptoms when they continued sewing during the six-year follow-up when compared with those who changed to other employment. However, symptomatic sewing machine operators who quit sewing were much more likely to be relieved of their symptoms than were symptomatic operators who continued sewing, odds ratio 3.26 [95% confidence interval (95% CI) 1.38-7.72] for 12-month symptoms and odds ratio 3.90 (95% CI 1.28-11.90) for 7-day symptoms. This trend also applied to long-lasting symptoms. CONCLUSIONS: The results demonstrate that, for many sewing machine operators, neck and shoulder symptoms are reversible and may be influenced by reallocation to other worktasks.

Risk for cancer of the pharynx and oral cavity among male painters in the Nordic countries.

In an effort to evaluate a hypothesis raised by findings in Denmark that painters might experience an increased risk for pharyngeal and oral cancer, data were collected about these cancers among painters in Norway, Sweden, and Finland. The possible confounding effects of alcohol and tobacco were gauged by collecting data about cancer of the lung, larynx, esophagus, liver, and bladder, and about mortality from liver cirrhosis. Consistently increased risks for lung cancer among painters were found. The risks for cancer of the oral cavity and/or pharynx were increased in Norway, Sweden, and Finland, but not to the same extent as was observed in Denmark. The risks for cancer of the esophagus were slightly increased as were the risks for cancer of the liver and for cirrhosis of the liver in Denmark and Finland. The data from Norway, Sweden, and Finland could thus neither substantiate nor disprove the hypothesis that painters may experience an increased risk for cancer of the pharynx and oral cavity as a result of occupational exposures.

[Colorectal cancer in Denmark 1943-1988]. / Kolorektal cancer i Danmark 1943-1988.

Nation-wide incidence rates are presented of colorectal cancer in Denmark from 1943 to 1988. In Denmark notification of malignant and related diseases is mandatory. The percentage of histologically confirmed tumours is now 95. The annual incidence rate of colon cancer in Denmark has been increasing among men and women combined from 684 cases in 1943-1947 to 2020 cases in 1988. In the same period the incidence of rectal cancer has increased from 762 cases in 1943-1947 to 1108 cases in 1988. We analyzed the effects of age, calender time, and birth cohort with multiplicative Poisson models. We did not find consistent period effects in the models. We suggest an etiologic distinction between carcinoma of the rectum, the left colon and the right colon.