Cost-effectiveness of a multidimensional post-discharge disease management program for heart failure patients-economic evaluation along a one-year observation period.

OBJECTIVE: This study aimed to assess the cost-effectiveness of the telemedically assisted post-discharge management program (DMP) HerzMobil Tirol (HMT) for heart failure (HF) patients in clinical practice in Austria. METHODS: We conducted a cost-effectiveness analysis along a retrospective cohort study (2016-2019) of HMT with a propensity score matched cohort of 251 individuals in the HMT and 257 in the usual care (UC) group and a 1-year follow-up. We calculated the effectiveness (hospital-free survival, hospital-free life-years gained, and number of avoided rehospitalizations), costs (HMT, rehospitalizations), and the incremental cost-effectiveness ratio (ICER). We performed a nonparametric sensitivity analysis with bootstrap sampling and sensitivity analyses on costs of HF rehospitalizations and on costs per disease-related diagnosis (DRG) score for rehospitalizations. RESULTS: Base-case analysis showed that HMT resulted in an average of 42 additional hospital-free days, 40 additional days alive, and 0.12 avoided hospitalizations per patient-year compared with UC during follow-up. The average HMT costs were EUR 1916 per person. Mean rehospitalization costs were EUR 5551 in HMT and EUR 6943 in UC. The ICER of HMT compared to UC was EUR 4773 per life-year gained outside the hospital. In a sensitivity analysis, HMT was cost-saving when "non-HF related costs" related to the DMP were replaced with average costs. CONCLUSIONS: The economic evaluation along the cohort study showed that the HerzMobil Tirol is very cost-effective compared to UC and cost-saving in a sensitivity analysis correcting for "non-HF related costs." These findings promote a widespread adoption of telemedicine-assisted DMP for HF.

Comparative effectiveness of urine drug screening strategies alongside opioid agonist treatment in British Columbia, Canada: a population-based observational study protocol.

INTRODUCTION: Urine drug tests (UDTs) are commonly used for monitoring opioid agonist treatment (OAT) responses, supporting the clinical decision for take-home doses and monitoring potential diversion. However, there is limited evidence supporting the utility of mandatory UDTs-particularly the impact of UDT frequency on OAT retention. Real-world evidence can inform patient-centred approaches to OAT and improve current strategies to address the ongoing opioid public health emergency. Our objective is to determine the safety and comparative effectiveness of alternative UDT monitoring strategies as observed in clinical practice among OAT clients in British Columbia, Canada from 2010 to 2020. METHODS AND ANALYSIS: We propose a population-level retrospective cohort study of all individuals 18 years of age or older who initiated OAT from 1 January 2010 to 17 March 2020. The study will draw on eight linked health administrative databases from British Columbia. Our primary outcomes include OAT discontinuation and all-cause mortality. To determine the effectiveness of the intervention, we will emulate a 'per-protocol' target trial using a clone censoring approach to compare fixed and dynamic UDT monitoring strategies. A range of sensitivity analyses will be executed to determine the robustness of our results. ETHICS AND DISSEMINATION: The protocol, cohort creation and analysis plan have been classified and approved as a quality improvement initiative by Providence Health Care Research Ethics Board and the Simon Fraser University Office of Research Ethics. Results will be disseminated to local advocacy groups and decision-makers, national and international clinical guideline developers, presented at international conferences and published in peer-reviewed journals electronically and in print.

Elements in muscle tissue of three dolphin species from the east coast of South Africa.

We investigated elemental concentrations in muscle tissue of three species of dolphins incidentally bycaught off the KwaZulu-Natal coastline, South Africa. Thirty-six major, minor and trace elements were analysed in Indian Ocean humpback dolphin Sousa plumbea (n = 36), Indo-Pacific bottlenose dolphin Tursiops aduncus (n = 32) and the Common dolphin Delphinus delphis (n = 8). Significant differences in concentration between the three species were observed for 11 elements (cadmium, iron, manganese, sodium, platinum, antimony, selenium, strontium, uranium, vanadium and zinc). Mercury concentrations (maximum 29 mg/kg dry mass) were generally higher than those reported for coastal dolphin species found elsewhere. Our results reflect a combination of species differences in habitat, feeding ecology, age, and possibly species physiology and exposure to pollution levels. This study confirms the high organic pollutant concentrations documented previously for these species from the same location, and provides a well-founded case for the need to reduce pollutant sources.

Spontaneous neoplasms in harbour porpoises Phocoena phocoena.

Harbour porpoises are widely distributed in the North Atlantic and represent the most abundant cetacean species in the North and Baltic Seas. Spontaneous neoplasms are relatively rarely reported in cetaceans, and only little is known about neoplasia in harbour porpoises. Thus, archival material was reviewed for spontaneous neoplasms in harbour porpoises recorded during post-mortem examinations between 1999 and 2018. Neoplasms were identified in 7 adult porpoises: 6 animals originating from the North and Baltic Seas and investigated as part of German and Dutch systematic health monitoring programs, and 1 porpoise from Greenlandic waters. The tumours were of different histogenetic origins and further characterised by histology and immunohistochemistry. One individual had a neoplasia in the digestive tract (adenocarcinoma, n = 1); 4 animals, in the genital tract (Sertoli cell tumour, n = 1; genital leiomyoma/fibroleiomyoma, n = 3); and 2 porpoises, in endocrine organs (adrenal adenoma, n = 2). This is the first report of an adenocarcinoma in the liver, a testicular Sertoli cell tumour and adrenocortical adenomas in harbour porpoises. The cause of the tumorigenesis in examined cases remains undetermined. The involvement of endogenous factors, including mutation of cell cycle regulating genes, such as the tumour-suppressor gene p53, cannot be ruled out. The aetiopathogenetic significance of exogenous factors, such as infectious agents like liver flukes or anthropogenic factors, including persistent organic pollutants, should be the subject of future investigations.

Prevalence of comorbidities, and affective disorders in epilepsy: A latent class analysis approach.

OBJECTIVE: Epilepsies are severe chronic neurological diseases that impair several domains in life and are often accompanied by various somatic and psychiatric comorbidities. Associations between epilepsy and its comorbidities remain poorly understood. As epidemiological research mainly relies on cross-sectional designs and descriptive results, homogeneities regarding comorbidities in individuals suffering from epilepsy remain uncovered. Therefore, we aimed to identify clusters of individuals based on selected seizure-related variables and somatic comorbidities, and their respective risk of experiencing affective disorders, using a Latent Class Analysis (LCA). METHODS: Latent class analysis, is a model-driven statistical approach, which aims at latent, unobservable clusters on selected disease features. LCA has therefore the potential for uncovering previously unobservable groups or classes with similar comorbidity patterns. It allows for comparisons between those classes regarding risk or promotive factors - such as affective disorders. Our data derives from the Austrian cohort of the European Study on Burden and Care of Epilepsy (ESBACE; http://www.esbace.eu/). In ESBACE, multiple factors were collected to get a detailed picture on prevalence, epilepsy-related variables and comorbidities in a population-based cohort from the region of Salzburg, Austria. We used LCA to identify epilepsy-somatic-comorbidity-clusters and further, compared them to the observed the risk of suffering from affective disorders. RESULTS: The prevalence of epilepsy in the study region was 9.14/1000 inhabitants. LCA unveiled a three-cluster solution, of which one cluster, mainly consisting of individuals with mixed seizure types, higher age, and discrete somatic comorbidities (stroke, cardiovascular - and respiratory/pulmonary diseases) had a higher risk of experiencing affective disorders. SIGNIFICANCE: To our knowledge, this is the first large scale study that uses LCA to identify epilepsy-related comorbidity phenotypes, and therefore it might open a new way for epidemiological research.

Drivers and constraints on offshore foraging in harbour seals.

Central place foragers are expected to offset travel costs between a central place and foraging areas by targeting productive feeding zones. Harbour seals (Phoca vitulina) make multi-day foraging trips away from coastal haul-out sites presumably to target rich food resources, but periodic track points from telemetry tags may be insufficient to infer reliably where, and how often, foraging takes place. To study foraging behaviour during offshore trips, and assess what factors limit trip duration, we equipped harbour seals in the German Wadden Sea with high-resolution multi-sensor bio-logging tags, recording 12 offshore trips from 8 seals. Using acceleration transients as a proxy for prey capture attempts, we found that foraging rates during travel to and from offshore sites were comparable to offshore rates. Offshore foraging trips may, therefore, reflect avoidance of intra-specific competition rather than presence of offshore foraging hotspots. Time spent resting increased by approx. 37 min/day during trips suggesting that a resting deficit rather than patch depletion may influence trip length. Foraging rates were only weakly correlated with surface movement patterns highlighting the value of integrating multi-sensor data from on-animal bio-logging tags (GPS, depth, accelerometers and magnetometers) to infer behaviour and habitat use.

Evaluation of undetected cases during the COVID-19 epidemic in Austria.

BACKGROUND: Knowing the number of undetected cases of COVID-19 is important for a better understanding of the spread of the disease. This study analyses the temporal dynamic of detected vs. undetected cases to provide guidance for the interpretation of prevalence studies performed with PCR or antibody tests to estimate the detection rate. METHODS: We used an agent-based model to evaluate assumptions on the detection probability ranging from 0.1 to 0.9. For each general detection probability, we derived age-dependent detection probabilities and calibrated the model to reproduce the epidemic wave of COVID-19 in Austria from March 2020 to June 2020. We categorized infected individuals into presymptomatic, symptomatic unconfirmed, confirmed and never detected to observe the simulated dynamic of the detected and undetected cases. RESULTS: The calculation of the age-dependent detection probability ruled values lower than 0.4 as most likely. Furthermore, the proportion of undetected cases depends strongly on the dynamic of the epidemic wave: during the initial upswing, the undetected cases account for a major part of all infected individuals, whereas their share decreases around the peak of the confirmed cases. CONCLUSIONS: The results of prevalence studies performed to determine the detection rate of COVID-19 patients should always be interpreted with regard to the current dynamic of the epidemic wave. Applying the method proposed in our analysis, the prevalence study performed in Austria in April 2020 could indicate a detection rate of 0.13, instead of the prevalent ratio of 0.29 between detected and estimated undetected cases at that time.

The Baltic Sea: An ecosystem with multiple stressors.

This introductory chapter to our Environment International VSI does not need an abstract and therefore we just include our recommendations below in order to proceed with the resubmission. Future work should examine waterbirds as food web sentinels of multiple stressors as well as Baltic Sea food web dynamics of hazardous substances and how climate change may modify it. Also, future work should aim at further extending the new frameworks developed within BALTHEALTH for energy and contaminant transfer at the population level (Desforges et al., 2018, Cervin et al., 2020/this issue Silva et al., 2020/this issue) and their long term effects on Baltic Sea top predators, such as harbour porpoises, grey seals ringed seals, and white-tailed eagles. Likewise, the risk evaluation conducted for PCB in connection with mercury on Arctic wildlife (Dietz et al., 2019, not a BONUS BALTHEALTH product) could be planned for Baltic Sea molluscs, fish, bird and marine mammals in the future. Finally, future efforts could include stressors not covered by the BONUS BALTHEALTH project, such as food web fluxes, overexploitation, bycatches, eutrophication and underwater noise.

Habitat selection and populations of Corynosoma (Acanthocephala) in the intestines of sea otters (Enhydra lutris) and seals.

Acanthocephalans are common intestinal parasites of marine mammals, the most widespread of which is the genus Corynosoma. In this study, parasite infrapopulations of two closely related species of Corynosoma were examined: Corynosoma enhydri from sea otters (Enhydra lutris) in Alaska (n = 12) and California (n = 19), and Corynosoma strumosum from seals in Germany (n = 22). Prevalence of C. enhydri was 100% in Californian otters, with a mean abundance of 30, and 83% in Alaskan otters, with a mean abundance of 232. In seals, C. strumosum had a prevalence of 65%, with a mean abundance of 33. Female C. enhydri dominated both Californian (82%) and Alaskan (79%) infections, while, in seals, female C. strumosum made up 68% of the parasite population. Reproduction rates for C. enhydri, with 16% (California) and 18% (Alaska) of females mated, were low compared to C. strumosum in seals, of which 40% of females were mated. Habitat selection also differed significantly between the two species. Corynosoma enhydri was found most frequently in the second and third fifths of the small intestine, while C. strumosum was found most frequently in the fourth. The differences in habitat selection and prevalence analysed in this study may be related to a trade-off between growth and reproduction between the two species.

Health assessment of harbour porpoises (PHOCOENA PHOCOENA) from Baltic area of Denmark, Germany, Poland and Latvia.

Harbour porpoise (Phocoena phocoena), the only resident cetacean species of the Baltic Sea is formed of two subpopulations populations, occurring in the western Baltic, Belt Seas and Kattegat and the Baltic Proper, respectively. Harbour porpoises throughout these areas are exposed to a large number of human activities causing direct and indirect effects on individuals, that might also harm this species on a population level. From Latvia, Poland, Germany and Denmark 385 out of 1769 collected dead harbour porpoises were suitable for extensive necropsy. The animals were collected between 1990 and 2015 and were either by-caught or found dead on the coastline. Following necropsies, histopathological, microbiological, virological and parasitological investigations were conducted. Females and males were equally distributed among the 385 animals. Most animals from the different countries were juveniles between 3 months and 3 years old (varying between 46.5 and 100% of 385 animals per country). The respiratory tract had the highest number of morphological lesions, including lungworms in 25 to 58% and pneumonia in 21 to 58% of the investigated animals. Of those with pneumonia 8 to 33% were moderate or severe. The alimentary, hearing, and haematopoietic systems had inflammatory lesions and parasitic infections with limited health impact. 45.5 to 100% of the animals from the different countries were known by-caught individuals, of which 20 to 100% varying between countries had netmarks. Inflammatory lesions, especially in the respiratory tract were found in higher numbers when compared to control populations in areas with less human activities such as arctic waters. The high number of morphological changes in the respiratory tract and of bycatches especially among immature animals before reaching sexual maturity is of serious concern, as well as the low number of adult animals among the material. Data on health status and the causes of death are valuable for management. A next step in this regard will combine data from health and genetic investigations in order to detect differences between the two populations of the Baltic.

Health status of free-ranging ring-necked pheasant chicks (Phasianus colchicus) in North-Western Germany.

Being a typical ground-breeding bird of the agricultural landscape in Germany, the pheasant has experienced a strong and persistent population decline with a hitherto unexplained cause. Contributing factors to the ongoing negative trend, such as the effects of pesticides, diseases, predation, increase in traffic and reduced fallow periods, are currently being controversially discussed. In the present study, 62 free-ranging pheasant chicks were caught within a two-year period in three federal states of Germany; Lower Saxony, North Rhine-Westphalia and Schleswig-Holstein. The pheasant chicks were divided into three age groups to detect differences in their development and physical constitution. In addition, pathomorphological, parasitological, virological, bacteriological and toxicological investigations were performed. The younger chicks were emaciated, while the older chicks were of moderate to good nutritional status. However, the latter age group was limited to a maximum of three chicks per hen, while the youngest age class comprised up to ten chicks. The majority of chicks suffered from dermatitis of the periocular and caudal region of the head (57-94%) of unknown origin. In addition, intestinal enteritis (100%), pneumonia (26%), hepatitis (24%), perineuritis (6%), tracheitis (24%), muscle degeneration (1%) and myositis (1%) were found. In 78% of the cases, various Mycoplasma spp. were isolated. Mycoplasma gallisepticum (MG) was not detected using an MG-specific PCR. Parasitic infections included Philopteridae (55%), Coccidia (48%), Heterakis/Ascaridia spp. (8%) and Syngamus trachea (13%). A total of 8% of the chicks were Avian metapneumovirus (AMPV) positive using RT-PCR, 16% positive for infectious bronchitis virus (IBV) using RT-PCR, and 2% positive for haemorrhagic enteritis virus (HEV) using PCR. All samples tested for avian encephalomyelitis virus (AEV), infectious bursal disease virus (IBDV) or infectious laryngotracheitis virus (ILTV) were negative. The pool samples of the ten chicks were negative for all acid, alkaline-free and derivative substances, while two out of three samples tested were positive for the herbicide glyphosate. Pheasant chick deaths may often have been triggered by poor nutritional status, probably in association with inflammatory changes in various tissues and organs as well as bacterial and parasitic pathogens. Theses impacts may have played a major role in the decline in pheasant populations.

Improved two-stage estimation to adjust for treatment switching in randomised trials: g-estimation to address time-dependent confounding.

In oncology trials, control group patients often switch onto the experimental treatment during follow-up, usually after disease progression. In this case, an intention-to-treat analysis will not address the policy question of interest - that of whether the new treatment represents an effective and cost-effective use of health care resources, compared to the standard treatment. Rank preserving structural failure time models (RPSFTM), inverse probability of censoring weights (IPCW) and two-stage estimation (TSE) have often been used to adjust for switching to inform treatment reimbursement policy decisions. TSE has been applied using a simple approach (TSEsimp), assuming no time-dependent confounding between the time of disease progression and the time of switch. This is problematic if there is a delay between progression and switch. In this paper we introduce TSEgest, which uses structural nested models and g-estimation to account for time-dependent confounding, and compare it to TSEsimp, RPSFTM and IPCW. We simulated scenarios where control group patients could switch onto the experimental treatment with and without time-dependent confounding being present. We varied switching proportions, treatment effects and censoring proportions. We assessed adjustment methods according to their estimation of control group restricted mean survival times that would have been observed in the absence of switching. All methods performed well in scenarios with no time-dependent confounding. TSEgest and RPSFTM continued to perform well in scenarios with time-dependent confounding, but TSEsimp resulted in substantial bias. IPCW also performed well in scenarios with time-dependent confounding, except when inverse probability weights were high in relation to the size of the group being subjected to weighting, which occurred when there was a combination of modest sample size and high switching proportions. TSEgest represents a useful addition to the collection of methods that may be used to adjust for treatment switching in trials in order to address policy-relevant questions.

Intestinal displacements in older harbour and grey seals.

Intestinal displacements including volvulus, torsion and invagination have been reported in various terrestrial and marine mammals. We conducted pathological investigations on 157 seals that had either stranded on the coasts of the North or Baltic Sea between 1996 and 2015 (115 harbour seals, >19 mo old; 21 grey seals, >13 mo old) or died while in human care (18 harbour seals, >19 mo old; 3 grey seals, >13 mo old). Intestinal displacements were found in 23% of the examined free-living harbour seals, in 5% of the stranded grey seals and in 17% of the harbour seals in human care. Intestinal volvulus, found in 24 cases, was characterized by twisting of the intestine along the mesenteric axis (180-540°) resulting in vascular obstruction and haemorrhagic infarction. In harbour seals, the sex ratio of individuals suffering from volvulus tended to be biased towards females during April to June, suggesting an elevated risk for pregnant females around birth time. Invagination was detected in 11 cases, 5 of which suffered from additional volvulus. Pathological findings associated with intestinal volvulus and invagination were sero-haemorrhagic effusions in the abdominal cavity. Enteritis, parasitic infection with gastric nematodes and intestinal acanthocephalans and bacterial infection with predominantly Clostridium perfringens and Escherichia coli were observed in most of the affected animals. In total, 30 investigated harbour and grey seals suffered from intestinal displacements. Pregnant females seemed to be more vulnerable around birth time. Causes of intestinal displacements remain undetermined, but are likely multifactorial.

Morphological and Pathological Findings in the Middle and Inner Ears of Harbour Porpoises (Phocoena phocoena).

Hearing represents the major sense in harbour porpoises (Phocoena phocoena) and impairment of hearing has a great impact on the survival of these animals. In this communication, some anatomical and histological aspects of the tympanoperiotic complex of harbour porpoises are presented. In addition, the ears of 21 incidentally bycaught or stranded freshly dead harbour porpoises of different age groups and sex were investigated histologically. At the entrance to the middle ear cavity, mucosa-associated lymphoid tissue was present that was often hyperplastic in juvenile (9/10) and adult individuals (7/8). Solitary lymphoid follicles were additionally found in the corpus cavernosum and adjacent to the stapedius muscle in single porpoises. The nematode Stenurus minor represented the most common pathogen observed in the middle ear cavity of juvenile and adult harbour porpoises and the parasite was associated with chronic inflammation with metaplastic and hyperplastic epithelial changes. An unusual bone formation at the attachment of the corpus cavernosum to the perioticum was a common finding, even in young individuals. Whether this represents a normal structure or a metaplastic change remains undetermined. Acute haemorrhages in the cochlea and/or the tympanic cavity occurred in all animals and were most likely agonal changes. Single porpoises suffered from purulent otitis media, mycotic otitis media with osteolysis or chronically fractured tympanic bones, likely causing impairment of hearing that may have contributed to by-catch. There was no evidence that stranding in five porpoises was associated with the aural changes. Histological examination of the ears in harbour porpoises is a valuable part of the assessment of their health status. Damage to hearing structures may explain starvation due to impaired ability to catch prey or unusual behaviour such as stranding or entanglement in nets.

Development and validation of a loop-mediated isothermal amplification assay-a rapid and sensitive detection tool for Mycobacterium avium subsp. paratuberculosis in small ruminants.

AIMS: The aim of this study was to design an assay for the identification of Mycobacterium avium subsp. paratuberculosis (MAP) to be used in faeces and milk samples of small ruminants with a loop-mediated isothermal amplification (LAMP) system, as a time-saving and user-friendly method in contrast to real-time PCR. METHODS AND RESULTS: For the detection of MAP in milk and faeces of small ruminants, we developed a set of primers, specific for the target gene ISMap02. The analytical sensitivity of LAMP, when targeting ISMap02, showed a DNA detection limit of 10 fg µl-1 . After performing spiking experiments with two MAP reference strains, DSM 44133 and ATCC 19698T , the limit of detection, using the LAMP protocol described herein were 3·8 MAP CFU per ml milk and 12·5 MAP CFU per gram faeces. All LAMP results during the establishment of the assay were compared to those of the real-time PCR results. An internal amplification control was incorporated into the assay to exclude false-negative results produced and had no significant negative impact on the analytical sensitivity. Validation of the assay was confirmed by testing field samples of faeces and revising the results with real-time PCR. CONCLUSION: Our study conducted the first MAP detection system with a LAMP targeting ISMap02. Due to the positive results we encourage the use of LAMP in combination with ISMap02, when detecting MAP in faeces samples, as an alternative to targeting other genes as f57 or IS900. Further research on MAP detection in different matrices like raw milk, tissue or sperm with this system is recommended. SIGNIFICANCE AND IMPACT OF THE STUDY: This study provides new achievements in MAP diagnostic. Especially small ruminants do not show signs of diarrhoea until the terminal stage of the illness. The greatest task in fighting MAP is to rule out animals, which shed MAP with faeces and milk before showing symptoms of Johne's disease. Worldwide there is a need to eradicate animals, which are low MAP shedders to stop the illness spreading in animal holdings. MAP detection with LAMP is time saving, easy to use, does not need expensive equipment, as, for example, PCR kits and can be used without access to laboratories. The target gene ISMap02 was shown to be a specific insertion element for MAP and is a reliable aim in future MAP detection studies.

Two-stage estimation to adjust for treatment switching in randomised trials: a simulation study investigating the use of inverse probability weighting instead of re-censoring.

BACKGROUND: Treatment switching is common in randomised trials of oncology treatments, with control group patients switching onto the experimental treatment during follow-up. This distorts an intention-to-treat comparison of the treatments under investigation. Two-stage estimation (TSE) can be used to estimate counterfactual survival times for patients who switch treatments - that is, survival times that would have been observed in the absence of switching. However, when switchers do not die during the study, counterfactual censoring times are estimated, inducing informative censoring. Re-censoring is usually applied alongside TSE to resolve this problem, but results in lost longer-term information - a major concern if the objective is to estimate long-term treatment effects, as is usually the case in health technology assessment. Inverse probability of censoring weights (IPCW) represents an alternative technique for addressing informative censoring but has not before been combined with TSE. We aim to determine whether combining TSE with IPCW (TSEipcw) represents a valid alternative to re-censoring. METHODS: We conducted a simulation study to compare TSEipcw to TSE with and without re-censoring. We simulated 48 scenarios where control group patients could switch onto the experimental treatment, with switching affected by prognosis. We investigated various switching proportions, treatment effects, survival function shapes, disease severities and switcher prognoses. We assessed the alternative TSE applications according to their estimation of control group restricted mean survival (RMST) that would have been observed in the absence of switching up to the end of trial follow-up. RESULTS: TSEipcw performed well when its weights had a low coefficient of variation, but performed poorly when the coefficient of variation was high. Re-censored analyses usually under-estimated control group RMST, whereas non-re-censored analyses usually produced over-estimates, with bias more serious when the treatment effect was high. In scenarios where TSEipcw performed well, it produced low bias that was often between the two extremes associated with the re-censoring and non-recensoring options. CONCLUSIONS: Treatment switching adjustment analyses using TSE should be conducted with re-censoring, without re-censoring, and with IPCW to explore the sensitivity in results to these application options. This should allow analysts and decision-makers to better interpret the results of adjustment analyses.

Causal inference for long-term survival in randomised trials with treatment switching: Should re-censoring be applied when estimating counterfactual survival times?

Treatment switching often has a crucial impact on estimates of effectiveness and cost-effectiveness of new oncology treatments. Rank preserving structural failure time models (RPSFTM) and two-stage estimation (TSE) methods estimate 'counterfactual' (i.e. had there been no switching) survival times and incorporate re-censoring to guard against informative censoring in the counterfactual dataset. However, re-censoring causes a loss of longer term survival information which is problematic when estimates of long-term survival effects are required, as is often the case for health technology assessment decision making. We present a simulation study designed to investigate applications of the RPSFTM and TSE with and without re-censoring, to determine whether re-censoring should always be recommended within adjustment analyses. We investigate a context where switching is from the control group onto the experimental treatment in scenarios with varying switch proportions, treatment effect sizes, treatment effect changes over time, survival function shapes, disease severity and switcher prognosis. Methods were assessed according to their estimation of control group restricted mean survival that would be observed in the absence of switching, up to the end of trial follow-up. We found that analyses which re-censored usually produced negative bias (i.e. underestimating control group restricted mean survival and overestimating the treatment effect), whereas analyses that did not re-censor consistently produced positive bias which was often smaller in magnitude than the bias associated with re-censored analyses, particularly when the treatment effect was high and the switching proportion was low. The RPSFTM with re-censoring generally resulted in increased bias compared to the other methods. We believe that analyses should be conducted with and without re-censoring, as this may provide decision-makers with useful information on where the true treatment effect is likely to lie. Incorporating re-censoring should not always represent the default approach when the objective is to estimate long-term survival times and treatment effects.

Testicular morphology and spermatogenesis in harbour porpoises (Phocoena phocoena).

Knowledge about reproductive parameters in male harbour porpoises such as testicular histology and germ cell maturation as well as seasonal changes in spermatogenesis is scarce. Thus, the aim of the present study was to report changes in the histological appearance of the testicular morphology of neonatal and juvenile harbour porpoises during maturation, to identify stages of spermatogenesis in adult males and to detect seasonal modifications. The identification of these stages can be used to assess the developmental profile of gene expression during spermatogenesis and to identify defects in spermatogenesis arising in pathological conditions. Testes of adult male harbour porpoises from the North and Baltic Sea that became stranded or by-caught in the years 1998-2016 were histologically examined using Haematoxylin and Eosin - staining. The Periodic Acid Schiff (PAS) staining was used for spermatogenic staging and the evaluation of the development of the acrosomic cap. For the identification of changes in testes morphology and morphometry during the course of the year, histological characteristics like germ cell associations and diameter of the convoluted seminiferous tubules were noted for each month. The analysis showed that in adult males more than one stage of spermatogenesis could be found per cross section of the convoluted seminiferous tubules similar to findings in men and some ape species. This rare phenomenon is called multi-stage-arrangement. In sexually active males from the peak breeding season (June and July) eight stages of spermatogenesis were identified and all stages occurred simultaneously, while during the low breeding season (August to May) only residual spermatogenesis or constituent germ cell populations were found. Missing germ cell generations were recorded in specimens from July to September. Our investigations provide a detailed staging of spermatogenesis and give new insight into the reproductive biology of male harbour porpoises. With these new basic parameters, indicators for endocrine disruptors can be developed in the future, aiming to detect how environmental factors could affect male fertility in wildlife.

First record of Halocercus sp. (Pseudaliidae) lungworm infections in two stranded neonatal orcas (Orcinus orca).

Orca (Orcinus orca) strandings are rare and post-mortem examinations on fresh individuals are scarce. Thus, little is known about their parasitological fauna, prevalence of infections, associated pathology and the impact on their health. During post-mortem examinations of two male neonatal orcas stranded in Germany and Norway, lungworm infections were found within the bronchi of both individuals. The nematodes were identified as Halocercus sp. (Pseudaliidae), which have been described in the respiratory tract of multiple odontocete species, but not yet in orcas. The life cycle and transmission pathways of some pseudaliid nematodes are incompletely understood. Lungworm infections in neonatal cetaceans are an unusual finding and thus seem to be an indicator for direct mother-to-calf transmission (transplacental or transmammary) of Halocercus sp. nematodes in orcas.

Investigation into diseases in free-ranging ring-necked pheasants (Phasianus colchicus) in northwestern Germany during population decline with special reference to infectious pathogens.

The population of ring-necked pheasants (Phasianus colchicus) is decreasing all over Germany since the years 2008/2009. Besides impacts of habitat changes caused by current rates of land conversion, climatic influences or predators, a contribution of infectious pathogens needs also to be considered. Infectious and non-infectious diseases in free-living populations of ring-necked pheasants have been scarcely investigated so far. In the present study, carcasses of 258 deceased free-ranging pheasants of different age groups, predominantly adult pheasants, collected over a period of 4 years in the states of Lower Saxony, North Rhine-Westphalia and Schleswig-Holstein, were examined pathomorphologically, parasitologically, virologically and bacteriologically, with a focus set on infectious pathogens. A periocular and perinasal dermatitis of unknown origin was present in 62.3% of the pheasants. Additional alterations included protozoal cysts in the skeletal musculature (19.0%), hepatitis (21.7%), enteritis (18.7%), gastritis (12.6%), and pneumonia (11.7%). In single cases, neoplasms (2.6%) and mycobacteriosis (1.7%) occurred. Further findings included identification of coronaviral DNA from trachea or caecal tonsils (16.8%), siadenoviral DNA (7.6%), avian metapneumoviral RNA (6.6%), and infectious bursal disease viral RNA (3.7%). Polymerase chain reaction (PCR) on herpesvirus, avian influenza virus (AIV), paramyxovirus type 1 (PMV-1), avian encephalomyelitis virus (AEV), and chlamydia were negative. Based on the present results, there is no indication of a specific pathogen as a sole cause for population decline in adult pheasants. However, an infectious disease can still not be completely excluded as it may only affect reproduction effectivity or a certain age group of pheasants (e.g., chicks) which were not presented in the study.