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Purpose: Immunotherapeutic agents produce antitumor effects by inducing cancer-specific immune responses or by modifying native immune processes. Resulting clinical response patterns extend beyond those of cytotoxic agents and can manifest after an initial increase in tumor burden or the appearance of new lesions (progressive disease). Response Evaluation Criteria in Solid Tumors or WHO criteria, designed to detect early effects of cytotoxic agents, may not provide a complete assessment of immunotherapeutic agents. Novel criteria for the evaluation of antitumor responses with immunotherapeutic agents are required.Experimental Design: The phase II clinical trial program with ipilimumab, an antibody that blocks CTL antigen-4, represents the most comprehensive data set available to date for an immunotherapeutic agent. Novel immune therapy response criteria proposed, based on the shared experience from community workshops and several investigators, were evaluated using data from ipilimumab phase II clinical trials in patients with advanced melanoma.Results: Ipilimumab monotherapy resulted in four distinct response patterns: (a) shrinkage in baseline lesions, without new lesions; (b) durable stable disease (in some patients followed by a slow, steady decline in total tumor burden); (c) response after an increase in total tumor burden; and (d) response in the presence of new lesions. All patterns were associated with favorable survival.Conclusion: Systematic criteria, designated immune-related response criteria, were defined in an attempt to capture additional response patterns observed with immune therapy in advanced melanoma beyond those described by Response Evaluation Criteria in Solid Tumors or WHO criteria. Further prospective evaluations of the immune-related response criteria, particularly their association with overall survival, are warranted. (Clin Cancer Res 2009;15(23):7412–20)

Purpose Overfishing has been a global challenge for several decades with severe impacts on biodiversity and ecosystem services. Several approaches for assessing overfishing in life cycle impact assessment exist, but do not consider scarcity in line with current policy and science-based targets. Furthermore, comparisons of results with other impact categories, e.g., climate change, are not possible with existing methods. Therefore, five approaches to assess overfishing based on the distance-to-target approach are introduced. Method Three global species-specific approaches (stock in the sea, target pressure, and fish manager) and two regional midpoint approaches were developed. For the stock in the sea, the weighting factor was derived as the relation of available biomass of the considered species to biomass at sustainable limits. Within the target pressure, the current pressure on fish stocks is set to the maximal sustainable pressure. For the fish manager, the catch is set in relation to the maximum sustainable yield. The catch is used for normalization in all three approaches. The two regional midpoint approaches consider production and consumption based catch of fish stocks in relation to the fully fished share. The overfishing indicator based on pressure on fish stocks serves as the characterization factor. Normalization occurs with the characterized catch. Results and discussion To demonstrate the applicability of the approaches, a three-level case study was derived: (i) determining ecofactors for ten specific fish species in specific oceans; (ii) deriving ecopoints for production of fish meal and oil in Europe; (iii) comparison of fish oil with rapeseed oil for the categories overfishing, climate change, land use, and marine eutrophication. The highest ecofactors for the global approaches are characterized by high normalization and weighting factors. For the regional approaches, high overfishing characterization factors determine the result. The species contribution increases with rising amounts. Main challenges are data collection and interpretation which limit the overall applicability. The sensitivity analysis shows that the overall results vary significantly depending on the composition of the fish oil and meal. Conclusions It was shown that four of the five approaches are able to account for overfishing. However, only the production-based regional midpoint approach allows for comparison with other impact categories and is therefore most suitable for integration into life cycle assessment. The developed approaches can be used for a more comprehensive assessment of environmental impacts of different diets as well as aquaculture feed solutions.

With the increasing usage of dual-mode data collection, researchers of public opinion have shown considerable interest in understanding response differences across different interview modes. Are mode effects an outcome of representation or measurement differences across modes? We conducted a dual-mode survey (web and telephone) using Florida’s voter file as the sampling frame, randomly assigning registered voters into one mode versus the other. Having a priori information about the respondents allows us to gauge whether and how sample composition differences may be driven by mode effects, and whether mode affects estimated models of political behavior. Survey mode effects are still significant for issue voting even when sampling design is similar for both modes.

The title 50.17 of Justinian’s Digest lists many juristic rules (regulae iuris). One of these juristic rules, which can be found in D. 50.17.173.3, reads as follows: dolo facit, qui petit quod redditurus est. An application of this rule is described in D. 44.4.8.1, which deals with a problem in the context of the law of succession. Due to the rule’s character as a general rule, there must have been more cases in which an exceptio doli was granted because of dolo facit, qui petit quod redditurus est. However, it is difficult to find other cases of dolo facit, qui petit quod redditurus est, as no further direct evidence was cited in the Digest of Justinian. In this paper, I examine whether or not the exceptio doli referred to in D. 21.2.73 is a consequence of dolo facit, qui petit quod redditurus est.

Florida residents have the second highest incidence of skin cancer in the nation. Sunscreen usage was found to be the one of the most effective integrative health approaches for reducing risk of skin cancer. Given the limited information on the likelihood of adopting and continuing sunscreen usage behavior, this cross-sectional study aimed to examine the correlates of initiating and sustaining sunscreen usage behavior among Florida dwellers, using the fourth-generation, multi-theory model (MTM) of behavior change. A web-based survey containing 51 questions was emailed to Florida residents aged 18 years or above, who were randomly selected from the state voter file. Psychometric validity of the survey instrument was established using structural equation modeling, and Cronbach’s alpha values were calculated for assessing the internal consistency. An independent-samples-t-test and hierarchical multiple regression tests were used to analyze the data. The results indicated that participants who engaged in sunscreen usage behavior, participatory dialogue (β = 0.062, p &lt, 0.05), behavioral confidence (β = 0.636, p &lt, 0.001), and changes in the physical environment (β = 0.210, p &lt, 0.001) were statistically significant and accounted for 73.6% of the variance in initiating sunscreen usage behavior. In addition, the constructs of emotional transformation (β = 0.486, p &lt, 0.001) and practice for change (β = 0.211, p &lt, 0.001), as well as changes in the social environment (β = 0.148, p &lt, 0.001) were significant predictors of maintaining sunscreen usage behavior and contributed to 59% of variance in sustenance. These findings offer a valuable insight regarding the applicability of MTM models to guiding public health interventions promoting sunscreen usage and preventing UV radiation risk and related skin cancer.

Anaerobic fermentation in landfill reactorcells is a biological waste treatment technique where both energy and nutrients can be recovered. The landfill reactorcell ("biocell") serves as an ecological filter, where energy is extracted as biogas while nutrients are recovered through the leachates and can be used as fertilizer in e.g. energy forests, and thus brought back to an ecological cycling. At the same time anaerobic conditions result in an effective immobilization of heavy metals and other pollutants e.g. as insoluble metal sulphides, which are immobilized in the fermentation rest. The long-lived fraction, remaining after the fermentation process has declined, containing a high content of lignin, serves as a water-holding matrix, which helps to enforce a sustainable high moisture level, and thus sustainable anaerobic conditions with heavy metals retained on a longterm bases. Also non-degradable products, like plastics, help to shield off oxygen and maintain reliable anaerobic conditions. Landfilling of organic matter is a measure to counteract the increasing concentrations of CO2 in the atmosphere, resulting from different human activities. Landfilling at anaerobic conditions means that a small fraction of the organic matter is long-term accumulated in the landfill. Accordingly landfills have similar carbon accumulating effects as natural peatlands and lake or sea sediments. With low investment costs it is possible to convert traditional landfills to well controlled biological treatment facilities. Thus the technique can be performed both in large and small scale, avoiding energy demanding road transportation.

BackgroundThe majority of clinical studies reporting on COVID-19 symptom frequencies focus on patients already hospitalized. Thus, reported symptom frequencies may not be applicable to the general population. Here we report COVID-19 symptom frequencies for the general population in a major European city. MethodsDuring a scientific collaboration between the Vienna Social Fund (FSW, Vienna, Austria), the Public Health Services of the City of Vienna (MA15) and the AI-biotech company Symptoma we recorded symptom frequencies gathered by the COVID-19 chatbot of the city government of Vienna and corresponding SARS-CoV-2 nucleic acid amplification test (NAAT) results. Chatbot users answered 13 yes/no questions about symptoms and provided information about age and sex. Subsequently a medically trained professional came to their address to take a sample and NAAT results were obtained. FindingsBetween November 2 and January 5, a total of 3011 persons experiencing flu-like symptoms had completed the chatbot-session and were subsequently tested by a NAAT. NAATs were performed by at home visitations of medical professionals. NAAT analysis was positive in 816 persons (27.1%). We compared the symptom frequencies between COVID-19 positive and negative users, and between male and female users. The symptoms (sorted by frequency) of users with positive NAATs were malaise (81.1%), fatigue (72.9%), headache (64.1%), cough (57.7%), fever (50.7%), sore throat (40.7%), rhinorrhea (31.0%), sneezing (28.4%), dysgeusia (27.1%), hyposmia (26.5%), dyspnea (11.4%) and diarrhea (10.9%) while 34.9% reported a close contact with a COVID-19 case. Among these the frequencies of cough, fever, hyposmia, dysgeusia, malaise, headache, close contact with COVID-19 case and fatigue were significantly (P < 0.01) increased in COVID-19 positive persons while the frequencies of dyspnea, diarrhea and sore throat were significantly (P < 0.01) decreased in COVID-19 positive persons. There was no significant difference for rhinorrhea and sneezing. InterpretationThis paper provides reliable COVID-19 symptom frequency statistics based on chat-bot conversations and experimental NAATs.

Introduction: Mitochondrial heart disease due to pathogenic mitochondrial DNA (mtDNA) mutations can present as hypertrophic or dilated cardiomyopathy, ventricular arrhythmias and conduction disease. It is estimated that the mutation rate of mtDNA is 10 to 20-fold higher than that of nuclear DNA genes due to damage from reactive oxygen species released as byproducts during oxidative phosphorylation. When a new mtDNA mutation arises, it creates an intracellular heteroplasmic mixture of mutant and normal mtDNAs, called heteroplasmy. Heteroplasmy levels can vary in various tissues and examining mtDNA variants in blood may not be representative for the heart. The frequency of pathogenic mtDNA variants in myocardial tissues in unknown. Hypothesis: Human ventricular tissue may contain mtDNA mutations which can lead to alterations in mitochondrial function and increase individual risk for heart failure. Methods: Mitochondrial DNA was isolated from 61 left ventricular myocardial samples obtained from failing human hearts at the time of transplantation. mtDNA was sequenced with 23 primer pairs. In silico prediction of non-conservative missense variants was performed via PolyPhen-2. Heteroplasmy levels of variants predicted to be pathogenic were quantified using allele-specific ARMS-PCR. Results: We identified 21 mtDNA non-synonymous variants predicted to be pathogenic in 17 hearts. Notably, one heart contained four pathogenic mtDNA variants (ATP6: p.M104; ND5: p.P265S; ND4: p.N390S and p.L445F). Heteroplasmy levels exceeded 90% for all four variants in myocardial tissue and were significantly lower in blood. No pathogenic mtDNA variants were identified in 44 hearts. Hearts with mtDNA mutations had higher levels of myocardial GDF-15 (growth differentiation factor-15; 6.2±2.3 vs. 1.3±0.18, p=0.045), an established serum biomarker in various mitochondrial diseases. Conclusions: Non-synonymous mtDNA variants predicted to be pathogenic are common in human left ventricular tissue and may be an important modifier of the heart failure phenotype. Future studies are necessary to correlate myocardial mtDNA mutations with cardiovascular outcomes and to assess whether serum GDF-15 allows identifying patients with myocardial mtDNA mutations.