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This is a transcript of a lecture course on Infinite Permutation Groups given by Peter M. Neumann (1940-2020) in Oxford during the academic year 1988-1989. The field of Infinite Permutation Groups only emerged as an independent field of study in the 1980's. Most of the results described in these notes were at the time of the lectures brand new and had either just recently appeared in print or had not appeared formally. A large part of the results described is either due to Peter himself or heavily influenced by him. These notes offer Peter's personal take on a field that he was instrumental in creating and in many cases ideas and questions that can not be found in the published literature., Comment: The text of [v1] and [v2] is identical. [v1] is formatted so that each new lecture starts at a right hand page (127+v pages) and [v2] is formatted without all the extra page breaks (93+v pages). Edited by David A. Craven (Birmingham), Dugald Macpherson (Leeds) and R\"ognvaldur G. M\"oller (Reykjav\'ik). Comments and corrections can be sent to R\"oggi M\"oller (roggi@hi.is)

Insects constitute vital components of ecosystems. There is alarming evidence for global declines in insect species diversity, abundance, and biomass caused by anthropogenic drivers such as habitat degradation or loss, agricultural practices, climate change, and environmental pollution. This raises important concerns about human food security and ecosystem functionality and calls for more research to assess insect population trends and identify threatened species and the causes of declines to inform conservation strategies. Analysis of genetic diversity is a powerful tool to address these goals, but so far animal conservation genetics research has focused strongly on endangered vertebrates, devoting less attention to invertebrates, such as insects, that constitute most biodiversity. Insects' shorter generation times and larger population sizes likely necessitate different analytical methods and management strategies. The availability of high-quality reference genome assemblies enables population genomics to address several key issues. These include precise inference of past demographic fluctuations and recent declines, measurement of genetic load levels, delineation of evolutionarily significant units and cryptic species, and analysis of genetic adaptation to stressors. This enables identification of populations that are particularly vulnerable to future threats, considering their potential to adapt and evolve. We review the application of population genomics to insect conservation and the outlook for averting insect declines. Expected final online publication date for the Annual Review of Animal Biosciences, Volume 11 is February 2023. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

Gut microbiota are known to foster pollen digestion in honey bee workers, Apis mellifera, thereby enhancing longevity and body weight gain. However, it is currently not known how longevity and body weight gain are effected when gut microbiota are reduced in bees with or without access to pollen. Here, using a hoarding cage set-up with freshly emerged summer workers, we manipulated the gut microbiota of half the bees with the antibiotic tetracycline (ABX), and left the other half untreated on a sucrose solution diet. Afterwards, all bees were assigned to either sucrose diets or sucrose plus ad libitum access to pollen (N = 4 treatments, N = 26 bees/treatment, N = 10 replicates/treatment, N = 1,040 total workers). The data confirm that pollen has a positive effect on longevity and body weight in workers with an unmanipulated gut microbiota. Surprisingly, the antibiotics alone also improved the longevity and body weight of the workers fed a strictly sucrose diet, potentially explained by the reduction of harmful bacteria. However, this positive effect was reversed from an observed antagonistic interaction between pollen and antibiotics, underscoring the innate value of natural microbiota on pollen digestion. In conclusion, a combination of adequate pollen supply and an unmanipulated gut microbiota appears crucial to honey bee worker health, calling for respective efforts to ensure both in managed colonies.

The small hive beetle (SHB), Aethina tumida, a parasite of honey bees is endemic to Sub-Saharan Africa and has become a global invasive pest. Adequate surveillance methods based on trapping methods need testing and verification of their efficacy. We tested the efficacy of top frame supplied cardboard traps. The efficacy was extremely low (0.9%) and significantly less effective than bottom board placed traps.

There is clear evidence for wild insect declines globally. Habitat loss, climate change, pests, pathogens and environmental pollution have all been shown to cause detrimental effects on insects. However, interactive effects between these stressors may be the key to understanding reported declines. Here, we review the literature on pesticide and pathogen interactions for wild bees, identify knowledge gaps, and suggest avenues for future research fostering mitigation of the observed declines. The limited studies available suggest that effects of pesticides most likely override effects of pathogens. Bees feeding on flowers and building sheltered nests, are likely less adapted to toxins compared to other insects, which potential susceptibility is enhanced by the reduced number of genes encoding detoxifying enzymes compared with other insect species. However, to date all 10 studies using a fully-crossed design have been conducted in the laboratory on social bees using Crithidia spp. or Nosema spp., identifying an urgent need to test solitary bees and other pathogens. Similarly, since laboratory studies do not necessarily reflect field conditions, semi-field and field studies are essential if we are to understand these interactions and their potential effects in the real-world. In conclusion, there is a clear need for empirical (semi-)field studies on a range of pesticides, pathogens, and insect species to better understand the pathways and mechanisms underlying their potential interactions, in particular their relevance for insect fitness and population dynamics. Such data are indispensable to drive forward robust modelling of interactive effects in different environmental settings and foster predictive science. This will enable pesticide and pathogen interactions to be put into the context of other stressors more broadly, evaluating their relative importance in driving the observed declines of wild bees and other insects. Ultimately, this will enable the development of more effective mitigation measures to protect bees and the ecosystem services they supply.

Inter-individual differences in pesticide sensitivity may trigger variability in the risk posed by pesticides. Therefore, to better inform pesticide risk assessment for bees, we studied the variability of responses to several pesticides based on endogenous (developmental stage, genetic background, caste) and exogenous factors (pesticide co-exposure). We mainly investigated the toxicity of the insecticide sulfoxaflor, the fungicide azoxystrobin and the herbicide glyphosate. We first used LD50 tests to determine the acute oral and contact toxicity of these pesticides across the different bee species, developmental stages (larva vs adult in honey bees), castes (honey bee and bumble bee workers, queens and drones), and genetic backgrounds (honey bee subspecies). We then considered the risks posed by chronic and sublethal exposures to pesticides by implementing behavioural and reproductive endpoints in the screening of pesticide toxicity. Data showed that azoxystrobin and glyphosate under the test conditions were mildly toxic to bees. However, a large variability in bee sensitivity to sulfoxaflor was found, especially across species and individuals of different castes or sex. This variability is therefore important to consider for increasing the safety margin of the risk posed by insecticides in bees. Several effects induced by sublethal concentrations or doses of pesticides are also described, such as the occurrence of a Non-Monotonic Dose-Response (NMDR) and delayed effects in honey bees, impairment of reproductive performances in bumble bees, and a decreased longevity of Osmia adult females (although no effects were found on larval development). Finally, an interaction between pesticides was found when exposure was by contact, but not under oral exposure. In conclusion, the range of effects described here provides very useful insights for better understanding the toxicity of pesticides and therefore the risks they might pose to bees. Prepared under contract from the European Commission; Grant agreement No. 773921; EU Horizon 2020 Research and Innovation action. Prepared under contract from the European Commission; Grant agreement No. 773921; EU Horizon 2020 Research and Innovation action.

This paper presents an analysis of primitive permutation groups of degree $3p$, where $p$ is a prime number, analogous to H. Wielandt's treatment of groups of degree $2p$. It is also intended as an example of the systematic use of combinatorial methods as surveyed in \S6 for distilling information about a permutation group from knowledge of the decomposition of its character. The work is organised into three parts. Part I contains the lesser half of the calculation, the determination of the decomposition of the permutation character. Part II contains a survey of the combinatorial methods and, based on these methods, the major part of the calculation. Part III ties up loose ends left earlier in the paper and gives a tabulation of detailed numerical results., Comment: Unpublished paper from 1969. Afterword by Peter J. Cameron explains the context

Within the PoshBee Project we have tested three bee species – honey bees Apis mellifera, bumble bees Bombus terrestris and solitary bees Osmia bicornis – for their sensitivity to pesticides and analysed the clearance of pesticides from bees. For each species, all castes and sexes were studied. We synthesised the mortality data (LD50 or results of limit tests) with the toxicokinetic patterns and analysed this against the background of inter- and intraspecific variation in life-histories of the tested bees. The clearance of sulfoxaflor is relatively similar across all bee species tested and in females after contact treatment it tends to be retained. The toxicity increases over time independently of the clearance from the body. The clearance of azoxystrobin was rapid in Osmia and bumble bees, as well as in honey bee queens, but in honey bee workers there was very little clearance. Similar to sulfoxaflor the toxicity increased over time, although the residues were detected at very low levels. Glyphosate tended to be retained in bumble bees after contact treatment but cleared rapidly after oral treatment. For Osmia bees only in males after contact treatment was the glyphosate almost lost. The toxicity of a pesticide is dependent on the exact dosage, but also the exposure route and time, as well as the speed of detoxification and clearance from a body. The assessment for the hazard that a less toxic pesticide might pose, can be largely dependent on the exposure route. The effects of pesticide toxicity can increase even after the molecules have been cleared out of the body. Prepared under contract from the European Commission; Grant agreement No. 773921; EU Horizon 2020 Research and Innovation action. Prepared under contract from the European Commission; Grant agreement No. 773921; EU Horizon 2020 Research and Innovation action.

Factors interfering with market-based alignment of drug prices and value make explicit value assessment necessary. The widely used quality-adjusted life year serves as a starting point because it accounts for both quality and length of life. Cost estimates could improve by accounting for drug price changes accompanying the loss of market exclusivity. Consistent use of a societal perspective when relevant would also improve value assessments. Prices should sometimes reflect government contributions to development, although such adjustments make the most sense when government facilitates late-stage research. The Institute for Clinical and Economic Review, a private group with a leading role in US value assessment, should make its analyses transparent and defer to payers regarding judgements about value. Finally, payers should embrace value-based pricing. They may not always get the lowest prices, but aligning price and value will mean society expends its resources efficiently and improves the population’s overall health.

The pharmaceutical industry has produced wondrous scientific advances, but the progress has come at a cost. US prescription drug spending has increased faster in most recent years than other categories of health and now comprises roughly one-sixth of total health expenditures. Rising costs strain already stretched public budgets. Increasing patient out-of-pocket spending for deductibles and coinsurance has created financial difficulties for many individuals and their families, particularly among the sickest patients. The dueling trends of scientific breakthroughs and ever-rising spending present enduring challenges. On its own, rising spending would not be so concerning, but evidence suggests that drug prices often do not reflect the benefits they provide. Thus, there is an imperative to measure the value of prescription drugs and incorporate such measures into drug pricing policies.

Despite its widespread acceptance, cost-effectiveness analysis, which examines an intervention’s incremental cost per unit of health gained, can run up against intuition in the context of drug coverage for conditions affecting special populations. In particular, the “rule of rescue” (i.e., spending more for populations perceived to be in immediate and great peril) may be justified for certain conditions. Examples include rare diseases and the “orphan drugs” used to treat them; cancer, with its attendant societal dread; and pediatric conditions, which are often inherited and severe. Cell and gene therapies may also challenge traditional value assessment, given their high manufacturing costs and potential for one-time, curative treatment. Health technology assessment (HTA) bodies worldwide have made exceptions for these populations by comparing cost-effectiveness ratios to higher (less stringent) benchmarks and by incorporating additional value considerations. Still, evaluating these higher-priced therapies remains a challenge for HTA and society.

This chapter recounts the evolution of methods to put a value on health benefits, a step crucial to appropriately pricing drugs. Early efforts valued life based on a worker’s productive output. “Willingness-to-pay” methods use surveys and examine real-world purchasing decisions to value life beyond productivity considerations. Cost-effectiveness analysis sidesteps explicitly pricing life by instead measuring an intervention’s cost per unit of health gained. A common currency for benefits called the quality-adjusted life year (QALY) facilitates cost-effectiveness ratio comparisons across diseases. Although controversial, the QALY packs information about longevity and quality of life, making it popular. Next, this chapter explains that economists down-weight (“discount”) future costs and benefits as less important than near term impacts. Finally, it explores the question of perspective—that is, whether an analysis should, for example, reflect only costs and benefits pertinent to health system payers or whether it should take a broader, “societal” perspective.

The Institute for Clinical and Economic Review (ICER) is not the only organization that has attempted to bring value assessment to the United States to address high pharmaceutical prices. With the federal government’s continued reluctance to embrace formal value assessment during the 2010s, other organizations introduced their own approaches. These groups included medical societies with a history of evidence-based clinical guideline development. Examples include the American Society of Clinical Oncology, National Comprehensive Cancer Network, and the American College of Cardiology/American Heart Association. Memorial Sloan Kettering Cancer Centre weighed in with its online “DrugAbacus” tool. This chapter argues that these other frameworks have serious limitations, including a focus on a single clinical area, use of arbitrary scoring systems, and a lack of transparency. ICER has therefore emerged as the dominant framework for assessment of drug pricing and coverage policy.

This chapter explores proposed solutions for high drug prices. They include measures to rein in “middlemen” pharmacy benefit managers who may artificially inflate prices; increase generic drug competition to prevent price spikes for older, off-patent drugs; enhance competition for new drugs after brand-name products reach the intended period of market protection; align US drug prices with the lower prices available in other wealthy countries; and leverage the collective bargaining power of government payers to compel drug companies to accept lower prices for their products. Policies that force drug prices down can save money but risk choking off the development of important new advances, limiting patient access to their health benefits. Moreover, the policy solutions typically offered are incremental solutions that will likely put a modest dent in the nation’s $500 billion annual drug bill. Most important, they fail to link a drug’s price to its value.

Value assessment is becoming more prominent in the United States, but challenges remain. First, should assessments include only impacts pertinent to payers or take a broader, “societal” perspective? Second, should quality adjusted life years (QALYs) be used to measure benefits? Critics complain that QALYs discriminate against people with health conditions and fail to capture aspects of health. Third, should assessments account for drug price reductions anticipated to accompany patent expirations? Prices do not always follow the expected pattern, but assuming they will not can lead to an overstatement of a drug’s true long-term cost. Fourth, how should data gaps be addressed? Outcome-based risk sharing agreements let payers and drug companies amend pricing decisions as additional data become available. Finally, who should conduct value assessments? Government agencies do so in many other countries, but that seems unlikely in the United States. For now, the Institute for Clinical and Economic Review, a private organization, has stepped into this role.

As healthcare costs increased around the world in recent decades, countries incorporated health technology assessment (HTA) into their decisions about which new technologies to pay for and how much they should pay. This chapter describes approaches for drug value assessment that are part of the HTA procedures in these countries, highlighting England and Wales’ National Institute for Health and Care Excellence, perhaps the world’s most visible HTA body. We then describe efforts since the 1980s to introduce HTA in the United States, including Oregon’s Medicaid experiment and the federally funded Office of Technology Assessment. The chapter explores the roots of resistance to these efforts, including the notion of American exceptionalism—the belief that personal and economic freedom is paramount and deep resistance to the idea of healthcare rationing. The resistance, explained at least partly by these factors, ultimately led to a scaling back of HTA in the United States.

Value-based pricing aims to optimize incentives for pharmaceutical companies making drug development investment decisions. To promote alignment of prices and value, this chapter recommends that Medicare, Medicaid, and commercial insurers build value assessment into their coverage decisions. Before doing so, it explores alternatives that purport to make this alignment unnecessary. The first, cost-recovery pricing, reimburses drug companies for only their costs, rather than for value. While cost-recovery prices can be low, they reward high internal costs rather than better drugs. Prizes and subscription plans pay a lump sum, rather than paying for each treated patient, but they still require value assessment to set the size of the prize or subscription fee. Radical alternatives suggest having the government develop new drugs. Whether the government would be effective remains unknown. Nonetheless, it would, like private companies, have to prioritize investments, requiring something like value assessment to do so.

Although its origins date to 2006, the Institute for Clinical and Economic Review (ICER) gained prominence around 2015 when it focused its health technology assessment (HTA) efforts on a new highly effective, though expensive, treatment for hepatitis C. ICER, a small, private organization, seemed to fill a void in the United States because it offered a systematic value assessment approach and made its analyses publicly accessible. Drawing inspiration from England and Wales’ HTA body, ICER has used the quality-adjusted life year (QALY) and cost-effectiveness analysis. That decision gives ICER a powerful approach applicable to a wide range of technologies, but it has also spurred controversy. The organization has responded to criticisms by revising its “value framework.” Changes include separation of budget impact analysis from value determinations, introduction of other value measures beyond the QALY, increasing consideration of contextual elements, and adoption of a “societal perspective” where data support it.

This chapter describes how prescription drug markets deviate from “normal” competitive markets. On the demand side, there is considerable uncertainty in disease prognosis and treatment effects; buyers have much less information than sellers; consumers usually do not pay directly for their prescriptions but rather have health insurance, which protects them from a drug’s full price; and physicians and insurers play a major role in consumer choices. On the supply side, firms are heavily regulated, subject to laws requiring that drugs undergo extensive testing before entering the marketplace. Monopolies are a system feature, designed to incentivize companies to invest in expensive and risky drug discovery by providing the prospect of a big payoff if the investment succeeds. Patents and market exclusivity restrict competition and provide drug developers considerable pricing power. The challenge for policymakers is how to achieve reasonable or fair drug prices in light of these market distortions.

External reference pricing is a way of controlling prescription drug costs in the U.S., but savings may erode over time due to pushback from the drug industry.

A reduction in floral resource abundance and diversity is generally observed in agro-ecosystems, along with widespread exposure to pesticides. Therefore, a better understanding on how the availability and quality of pollen diets can modulate honeybee sensitivity to pesticides is required. For that purpose, we evaluated the toxicity of acute exposure and chronic exposures to field realistic and higher concentrations of azoxystrobin (fungicide) and sulfoxaflor (insecticide) in honeybees provided with pollen diets of differing qualities (named S and BQ pollens). We found that pollen intake reduced the toxicity of the acute doses of pesticides. Contrary to azoxystrobin, chronic exposures to sulfoxaflor increased by 1.5- to 12-fold bee mortality, which was reduced by pollen intake. Most importantly, the risk of death upon exposure to a high concentration of sulfoxaflor was significantly lower for the S pollen diet when compared with the BQ pollen diet. This reduced pesticide toxicity was associated with a higher gene expression of vitellogenin, a faster sulfoxaflor metabolization and a lower concentration of the phytochemical p-coumaric acid, known to upregulate detoxification enzymes. Thus, our study revealed that pollen quality can influence the ability of bees to metabolize pesticides and withstand their detrimental effects, providing another strong argument for the restoration of suitable foraging habitat.

Within the PoshBee Project, we have worked out precise protocols for testing the toxicological endpoints and metabolisation rate of agrochemicals on and in bees. Three agrochemical classes (insecticides, fungicides and herbicides) were tested on three bee groups (honey bees, bumble bees and solitary mason bees). The specific protocols, different for each combination of the pesticide class and bee group, were designed based on the existing toxicity testing methods and modified according to the specificities of the different bee groups, their castes and the different exotoxicological features of the compounds. Sulfoxaflor, Azoxystrobin, and Glyphosate were used respectively as examples of the three pesticide classes. Apis mellifera, Bombus terrestris and Osmia bicornis were chosen as the examples of the three bee groups. The protocols for honey bees and bumble bees were designed based on the official existing guidelines edited by OECD. Nevertheless, given that the OECD guidelines provide recommendations to fit with most agrochemicals, many of the parameters are defined with low precision in order to be flexible and adapt to different categories of molecules. While OECD has no guidelines for testing solitary bees, we used information from the unpublished ring test protocols for Osmia bicornis by the ICPPR non- Apis working group. Prepared under contract from the European Commission; Grant agreement No. 773921; EU Horizon 2020 Research and Innovation action. Prepared under contract from the European Commission; Grant agreement No. 773921; EU Horizon 2020 Research and Innovation action.

Pesticides and pathogens are known drivers of declines in global entomofauna. However, interactions between pesticides and viruses, which could range from antagonistic, over additive to synergistic, are poorly understood in ants. Here, we show that in ants the impact of single and combined pesticide and virus stressors can vary across castes and at the colony level. A fully-crossed laboratory assay was used to evaluate interactions between a sublethal dose of the neonicotinoid thiamethoxam and Acute bee paralysis virus (ABPV) in black garden ants, Lasius niger. After monitoring colonies over 64 weeks, body mass, neonicotinoid residues and virus titres of workers and queens, as well as worker behavioural activity were measured. ABPV, but not thiamethoxam, reduced activity of workers. Neonicotinoid exposure resulted in reduced body mass of workers, but not of queens. Further, thiamethoxam facilitated ABPV infections in queens, but not in workers. Overall, virus exposure did not compromise detoxification and body mass, but one colony showed high virus titres and worker mortality. Although the data suggest additive effects at the level of individuals and castes, co-exposure with both stressors elicited antagonistic effects on colony size. Our results create demand for long-term holistic risk assessment of individual stressors and their interactions to protect biodiversity.

Pollen species composition of S pollen and BQ pollen blends.

Our increasing reliance on digital technology for personal, economic, and government affairs has made it essential to secure the communications and devices of private citizens, businesses, and governments. This has led to pervasive use of cryptography across society. Despite its evident advantages, law enforcement and national security agencies have argued that the spread of cryptography has hindered access to evidence and intelligence. Some in industry and government now advocate a new technology to access targeted data: client-side scanning (CSS). Instead of weakening encryption or providing law enforcement with backdoor keys to decrypt communications, CSS would enable on-device analysis of data in the clear. If targeted information were detected, its existence and, potentially, its source, would be revealed to the agencies; otherwise, little or no information would leave the client device. Its proponents claim that CSS is a solution to the encryption versus public safety debate: it offers privacy -- in the sense of unimpeded end-to-end encryption -- and the ability to successfully investigate serious crime. In this report, we argue that CSS neither guarantees efficacious crime prevention nor prevents surveillance. Indeed, the effect is the opposite. CSS by its nature creates serious security and privacy risks for all society while the assistance it can provide for law enforcement is at best problematic. There are multiple ways in which client-side scanning can fail, can be evaded, and can be abused., Comment: 46 pages, 3 figures

Direct Memory Access (DMA) attacks have been known for many years: DMA-enabled I/O peripherals have complete access to the state of a computer and can fully compromise it including reading and writing all of system memory. With the popularity of Thunderbolt 3 over USB Type-C and smart internal devices, opportunities for these attacks to be performed casually with only seconds of physical access to a computer have greatly broadened. In response, commodity hardware and operating-system (OS) vendors have incorporated support for Input-Output Memory Management Units (IOMMUs), which impose memory protection on DMA, and are widely believed to protect against DMA attacks. We investigate the state-of-the-art in IOMMU protection across OSes using a novel I/O security research platform, and find that current protections fall short when faced with a functional network peripheral that uses its complex interactions with the OS for ill intent, and demonstrate compromises against macOS, FreeBSD, and Linux, which notionally utilize IOMMUs to protect against DMA attackers. Windows only uses the IOMMU in limited cases and remains vulnerable. Using Thunderclap, an open-source FPGA research platform we built, we explore a number of novel exploit techniques to expose new classes of OS vulnerability. The complex vulnerability space for IOMMU-exposed shared memory available to DMA-enabled peripherals allows attackers to extract private data (sniffing cleartext VPN traffic) and hijack kernel control flow (launching a root shell) in seconds using devices such as USB-C projectors or power adapters. We have worked closely with OS vendors to remedy these vulnerability classes, and they have now shipped substantial feature improvements and mitigations as a result of our work.

Supplemental material for Cost-effectiveness analysis of erenumab for the preventive treatment of episodic and chronic migraine: Results from the US societal and payer perspectives by Matthew Sussman, Jennifer Benner, Peter Neumann and Joseph Menzin in Cephalalgia

Supplemental material, DS_10.1177_0272989X18798833 for Future Directions for Cost-effectiveness Analyses in Health and Medicine by Peter J. Neumann, David D. Kim, Thomas A. Trikalinos, Mark J. Sculpher, Joshua A. Salomon, Lisa A. Prosser, Douglas K. Owens, David O. Meltzer, Karen M. Kuntz, Murray Krahn, David Feeny, Anirban Basu, Louise B. Russell, Joanna E. Siegel, Theodore G. Ganiats and Gillian D. Sanders in Medical Decision Making

Hintergrund: Ziel der vorliegenden Studie war die Analyse des chirurgischen Vorgehens sowie der langfristigen klinischen Ergebnisse von Patienten mit der Diagnose kolorektaler Lebermetastasen. Methode: Es erfolgte die retrospektive populationsbasierte Analyse von 5772 Patienten mit Erstdiagnose eines kolorektalen Karzinoms im Zeitraum von 2002 bis 2007 im Einzugsbereich des Tumorzentrums Regensburg. Der Nachbearbeitungszeitraum dauerte bis einschließlich 2012. Ergebnisse: Von 5772 Patienten mit der Diagnose eines kolorektalen Karzinoms entwickelten 1426 (24,7%) Lebermetastasen, davon 1019 (71,4%) Patienten synchrone und 408 (28,5%) Patienten metachrone Lebermetastasen. Die Resektionsrate hepatischer Filiae lag bei 22,1% im Zeitraum von 2002 bis 2004 und stieg in den Folgejahren ab 2005 auf 29,7%. In zwei akademischen, auf hepatobiliäre Chirurgie spezialisierten Zentren lag die Resektionsrate im Gesamtzeitraum bei 46,6%. Es besteht ein signifikanter Überlebensvorteil (p, Background: Purpose of this study was to analyse the surgical management and long-term clinical outcome of patients diagnosed with colorectal liver metastases over a period of 10 years using data from a German tumour registry. Methods: Retrospective analysis of 5772 patients diagnosed with colorectal adenocarcinoma between 2002 and 2007 in the catchment area of Tumorzentrum Regensburg. Follow-up was continued until 2012. Results: 5772 patients diagnosed with CRC 1426 (24.7%) developed CLM. In this cohort 1019 (71.4%) patients developed synchronous CLM and 408 (28.5%) patients developed metachronous CLM. The resection of CLM was 22.1% in the period from 2002 to 2004 and increased in the following years from 2005 to 29.7%. In two academic centres specialized in hepatobiliary surgery the resection rate was at 46.6% over the whole period . There is a significant benefit of overall survival of resection irrespective of the number of metastases. Conclusions: We here present the first long-term, population-based analysis of the surgical management of CLM in Germany. Significant increase in hepatic resection rates, translating to a significant benefit in OS, was seen over years. However, a continuing, relevant surgical undersupply of colorectal liver metastases became obvious. Further studies are concerned with ways to reduce the supply gap

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The SAR of over 50 derivatives of octahydrobenzo[g]quinoline (obeline)-type somatostatin sst1 receptor antagonist 1 is presented, focusing on the modification of its arylpiperazine moiety. Sst1 affinities in this series cover a range of five orders of magnitude with the best derivatives displaying subnanomolar sst1 affinities and >10,000-fold selectivities over the sst2 receptor subtype as well as promising pharmacokinetic properties.

A novel class of non-peptide somatostatin receptor ligands bearing the octahydrobenzo[g]quinoline (obeline) structural element has been identified. SAR studies have been performed that led to the discovery of derivatives with high affinity (pK(d) r sst(1)or = 9) and selectivity (or = 150-fold for h sst(1) over h sst(2)-h sst(5)) for somatostatin receptor subtype sst(1). In a functional assay, the compounds act as antagonists at human recombinant sst(1) receptors.

International audience

This report describes the in vitro features of the first somatostatin sst 1 receptor selective non-peptide antagonist, SRA880 ([3R,4aR,10aR]-1,2,3,4,4a,5,10,10a-Octahydro-6-methoxy-1-methyl-benz[g] quinoline-3-carboxylic-acid-4-(4-nitro-phenyl)-piperazine-amide, hydrogen malonate). SRA was evaluated in a number of in vitro systems of various species, both at native and recombinant receptors, using radioligand binding and second messenger/transduction studies. SRA880 has high affinity for native rat, mouse, monkey and human cerebral cortex somatostatin sst 1 receptors (p K d =7.8−8.6) and for human recombinant sst 1 receptors (p K d =8.0−8.1). SRA880 displayed significantly lower affinity for the other human recombinant somatostatin receptors (p K d ≤6.0) or a wide range of neurotransmitter receptors, except for the human dopamine D4 receptors. SRA880 was characterized in various transduction assays: somatotropin release inhibiting factor (SRIF) induced inhibition of forskolin-stimulated cAMP accumulation, SRIF stimulated-GTPγS binding, and SRIF stimulated luciferase gene expression; in all tests, SRA880 was devoid of intrinsic activity and acted as an apparently surmountable antagonist with p K B values of 7.5–7.7. Combined with the data from binding studies, these results suggest that SRA880 acts as a competitive antagonist. Thus, SRA880 is the first non-peptide somatostatin sst 1 receptor antagonist to be reported; SRA880 will be a useful tool for the characterization of somatostatin sst 1 receptor-mediated effects both in vitro and in vivo.

A variety of "key recovery," "key escrow," and "trusted third-party" encryption requirements have been suggested in recent years by government agencies seeking to conduct covert surveillance within the changing environments brought about by new technologies. This report examines the fundamental properties of these requirements and attempts to outline the technical risks, costs, and implications of deploying systems that provide government access to encryption keys.