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Abstract Many patients exhibit persistently reduced pulmonary diffusing capacity after coronavirus disease 2019 (COVID‐19). In this study, dual test gas diffusing capacity for carbon monoxide and nitric oxide (DL,CO,NO) metrics and their relationship to disease severity and physical performance were examined in patients who previously had COVID‐19. An initial cohort of 148 patients diagnosed with COVID‐19 of all severities between March 2020 and March 2021 had a DL,CO,NO measurement performed using the single‐breath method at 5.7 months follow‐up. All patients with at least one abnormal DL,CO,NO metric (n = 87) were revaluated at 12.5 months follow‐up. The DL,CO,NO was used to provide the pulmonary diffusing capacity for nitric oxide (DL,NO), the pulmonary diffusing capacity for carbon monoxide (DL,CO,5s), the alveolar–capillary membrane diffusing capacity and the pulmonary capillary blood volume. At both 5.7 and 12.5 months, physical performance was assessed using a 30 s sit‐to‐stand test and the 6 min walk test. Approximately 60% of patients exhibited a severity‐dependent decline in at least one DL,CO,NO metric at 5.7 months follow‐up. At 12.5 months, both DL,NO and DL,CO,5s had returned towards normal but still remained abnormal in two‐thirds of the patients. Concurrently, improvements in physical performance were observed, but with no apparent relationship to any DL,CO,NO metric. The severity‐dependent decline in DL,NO and DL,CO observed at 5.7 months after COVID‐19 appears to be reduced consistently at 12.5 months follow‐up in the majority of patients, despite marked improvements in physical performance.

Abstract After COVID‐19 long term respiratory symptoms and reduced lung function including maximal inspiratory pressure (MIP) and maximal expiratory pressure (MEP) have been reported. However, no studies have looked at MIP and MEP in all disease groups and the reference materials collection methods differ substantially. We aimed to determine MIP and MEP in individuals after COVID‐19 infection with different disease severity using reference material of healthy control group obtained using the same standardized method. Patients with COVID‐19 were included March 2020–March 2021 at Rigshospitalet, Denmark. MIP and MEP were measured using microRPM. Predicted MIP and MEP were calculated using reference material obtained from 298 healthy adults aged 18–97 years using the same method. In SECURe, 145 participants were measured median 5 months after COVID‐19 diagnosis and of these 16% had reduced MIP and/or MEP. There was reduced spirometry and total lung capacity, but not reduced diffusion capacity in those with abnormal MIP and/or MEP compared with normal MIP and MEP. Of those with reduced MIP and/or MEP at 5 months, 80% still had reduced MIP and/or MEP at 12 months follow‐up. In conclusion, few have reduced MIP and/or MEP 5 months after COVID‐19 and little improvement was seen over time.

Abstract Reference materials are critical in assay development for calibrating and assessing their suitability. The devasting nature of the COVID-19 pandemic and subsequent proliferation of vaccine platforms and technologies has meant that there is even a greater need for standards for immunoassay development, which are critical to assess and compare vaccines’ responses. Equally important are the standards needed to control the vaccine manufacturing processes. Standardized vaccine characterization assays throughout process development are essential for a successful Chemistry, Manufacturing and Controls (CMC) strategy. In this perspective paper, we advocate for reference material incorporation into assays and their calibration to International Standards from preclinical vaccine development through control testing and provide insight into why this is necessary. We also provide information on the availability of WHO international antibody standards for CEPI-priority pathogens.

Abstract The end of each chromosome consists of a DNA region termed the telomeres. The telomeres serve as a protective shield against degradation of the coding DNA sequence, as the DNA strand inevitably ‒ with each cell division ‒ is shortened. Inherited genetic variants cause telomere biology disorders when located in genes (e.g. DKC1, RTEL1, TERC, TERT) playing a role in the function and maintenance of the telomeres. Subsequently patients with telomere biology disorders associated with both too short or too long telomeres have been recognized. Patients with telomere biology disorders associated with short telomeres are at increased risk of dyskeratosis congenita (nail dystrophy, oral leukoplakia, and hyper- or hypo-pigmentation of the skin), pulmonary fibrosis, hematologic disease (ranging from cytopenia to leukemia) and in rare cases very severe multiorgan manifestations and early death. Patients with telomere biology disorders associated with too long telomeres have in recent years been found to confer an increased risk of melanoma and chronic lymphocytic leukemia. Despite this, many patients have an apparently isolated manifestation rendering telomere biology disorders most likely underdiagnosed. The complexity of telomere biology disorders and many causative genes makes it difficult to design a surveillance program which will ensure identification of early onset disease manifestation without overtreatment.

Objective The renin–angiotensin system (RAS) has been shown to play a role in the pathogenesis of chronic obstructive pulmonary disease (COPD) because of the inflammatory properties of the system. Many patients with COPD use RAS-inhibiting (RASi) treatment. The aim was to determine the association between treatment with RASi and the risk of acute exacerbations and mortality in patients with severe COPD.Methods Active comparator analysis by propensity-score matching. Data were collected in Danish national registries, containing complete information on health data, prescriptions, hospital admissions and outpatient clinic visits. Patients with COPD (n=38 862) were matched by propensity score on known predictors of the outcome. One group was exposed to RASi treatment (cases) and the other was exposed to bendroflumethiazide as an active comparator in the primary analysis.Results The use of RASi was associated with a reduced risk of exacerbations or death in the active comparator analysis at 12 months follow-up (HR 0.86, 95% CI 0.78 to 0.95). Similar results were evident in a sensitivity analysis of the propensity-score-matched population (HR 0.89, 95% CI 0.83 to 0.94) and in an adjusted Cox proportional hazards model (HR 0.93, 95% CI 0.89 to 0.98).Conclusion In the current study, we found that the use of RASi treatment was associated with a consistently lower risk of acute exacerbations and death in patients with COPD. Explanations to these findings include real effect, uncontrolled biases, and—less likely—chance findings.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection may cause serious illness in lung transplant recipients. We aimed to investigate incidence and severity of SARS-CoV-2 infection in lung transplant recipients in the Omicron era. We conducted a retrospective study investigating COVID-19 incidence and outcomes among lung transplant recipients between December 27, 2021, and October 31, 2022, in Denmark. We performed COX regression analysis of potential risk factors with hospitalization as an endpoint. Among 236 included patients, 108 had a first positive SARS-CoV-2 polymerase chain reaction during a total of 133 person-years of follow-up, resulting in an incidence rate of 813 per 1000 person-years (95% confidence intervals (CI) 670–977). The cumulative incidence of hospitalization was 24.1% (95% CI 26-32.1) and admission to the intensive care unit was 3.7% (95% CI 0.1–6.3). The 30-day mortality of recipients with a SARS-CoV-2 infection was 0.9% (95% CI 0–2.7). We found that the incidence rate of patients with SARS-CoV-2 infection was markedly higher, whereas the mortality rate was lower in the omicron era compared to earlier reports for lung transplant recipients conducted in the delta era. On the other hand, a substantial proportion of patients were hospitalized, suggesting a continuous impact on this patient population.

Abstract Introduction Plexiform neurofibromas (PN) are benign nerve sheath tumours that are a frequent and potentially debilitating complication in patients with neurofibromatosis type 1 (NF1). The objective of this study was to describe the natural history of PN in children, adolescents and adults with NF1. Methods This was a nationwide, longitudinal cohort study of patients with NF1 under observation at the two national centres of NF1 expertise in Denmark between 2000 and 2020. Patient and clinical characteristics were documented from individual medical records. Results A total of 1099 patients with NF1 were included. Overall, 12% (35/296) of paediatric patients and 21% (172/803) of adult patients had ≥ 1 large PN (≥ 3 cm). Approximately half of patients with a large PN had ≥ 1 symptomatic PN. The most frequent symptoms were pain, neurological deficits, cosmetic issues, disfigurement, compression, increased psychosocial burden and vision loss. Clinical evaluations of PN size were available for 40 PN in 34 paediatric patients and 191 PN in 159 adult patients with large PN. Surgery (complete resection or debulking) was performed in 38% (15/40) of PN in paediatric patients and 45% (86/191) in adult patients. In addition, 35% of PN in paediatric patients and 33% in adult patients were inoperable. In a subgroup analysis, the overall PN size increased 1.06-fold per year. Malignant peripheral nerve sheath tumours (MPNST) were diagnosed in 21 patients (two paediatric and 19 adult patients). Conclusions This study shows that PN are common, their size and prevalence increase with age, many are often inoperable and pain and other symptoms are frequently associated. The results highlight the severe sequelae and unmet need for alternatives to analgesia and surgery in patients with PN.

Abstract Escherichia coli represents a significant challenge to the poultry industry due to compromised animal welfare, vast productivity losses, elevated mortality, and increased use of antimicrobial compounds. Therefore, effective preventive strategies and insight into the pathogenesis and disease mechanisms of colibacillosis are essential to secure a healthy poultry production. Consequently, discriminative in vivo models of colibacillosis are prerequisite tools for evaluating e.g., preventive measures, exploring novel treatments and understanding disease development. Numerous models of colibacillosis are applied for experimental studies in poultry. Yet, few studies provide a proper characterisation of the model enabling other authors to reproduce experiments or use the model in general. The present paper provides a literature review on avian in vivo models of primary colibacillosis.

Abstract Background The complexity of past trauma and ongoing post-migration stressors challenges the existing mental health treatment for trauma-affected refugees. Therefore, interventions are needed to accommodate these complex challenges in mental health treatment. This study examines the effect of an add-on integrated care intervention compared to treatment as usual (TAU) for trauma-affected refugees in a randomised controlled trial (RCT). Methods The study is carried out at a Danish outpatient clinic and will include 197 treatment-seeking refugees with post-traumatic stress disorder (PTSD) who are unemployed and affiliated with municipal employment services. Mental health TAU comprises 10 sessions with a medical doctor (pharmacological treatment and psychoeducation) and 16–20 sessions with a psychologist (manual-based cognitive behavioural therapy) for a period of 8 to 12 months. The add-on intervention strengthens coordination between mental health treatment and employment interventions with three cross-sectoral collaborative meetings during the mental health treatment. The integrated care intervention draws attention to the bidirectional impact of mental health problems and post-migration stressors and focuses on cross-sectoral shared plans. The primary outcome is functioning, measured by WHODAS 2.0, the interviewer-administered 12-item version, with secondary outcomes measuring quality of life, mental health symptoms, and post-migration stressors. Discussion The RCT is novel in intervention design for trauma-affected refugees and will bring forward new perspectives and knowledge of integrated care interventions for trauma-affected refugees. The integrated care intervention is expected to reduce post-migration stressors that negatively affect the treatment of trauma-related mental health problems, thereby improving preconditions for enhanced treatment outcomes. The intervention builds on existing practices in the Danish healthcare and employment sectors, which ensures high scalability and sustainability for future practices. Trial registration ClinicalTrials.gov Identifier: NCT04244864 , registered 28 January 2020. Protocol version: 17 September 2022, version 2.

Abstract In broiler breeders, background mortality is rarely addressed, however, it represents the death of a vast number of birds, a constant productivity loss, welfare concerns and it might affect chick quality. The study aimed to unveil lesions leading to mortality in a study population perceived as healthy, combined with whole-genome sequencing (WGS) of Escherichia coli, a well-known contributor to disease problems in poultry. Broiler breeders (n = 340) originating from three distinct, putative healthy flocks and their progeny (n = 154) were subjected to a comprehensive post-mortem examination, bacteriological sampling, and sequencing of 77 E. coli isolates. Productivity data confirmed an exemplary health status of the enrolled flocks, and post-mortem examination further verified the absence of general disease problems. Among the submitted broiler breeders, exudative peritonitis (31.2%) was the most frequent lesion linked to infectious disease, whereas airsacculitis, pericarditis, perihepatitis, and salpingitis occurred in 18.5%, 3.5%, 3.8% and 17%, respectively. Yolksacculitis occurred in 15.6% of the broilers, whilst pericarditis, perihepatitis and peritonitis were diagnosed in 9.7%, 7.1% and 9.1%, respectively. WGS revealed a diverse population where ST95 dominated the population retrieved from broiler breeders, whereas ST10 was highly prevalent among broilers. Both lineages could be isolated from extraintestinal sites of birds without lesions indicative of infection. In general, the genetic diversity within flocks was comparable to the diversity between farms, and the overall occurrence of resistance markers was low. In conclusion, a comprehensive insight into lesions associated with background mortality is presented, together with a vast diversity of E. coli isolated from extraintestinal sites during a non-outbreak situation.

Patients with pheochromocytoma and paraganglioma (PPGL) are treated with α-adrenoceptor antagonists to improve peroperative hemodynamics. However, preoperative blood pressure targets differ between institutions. We retrospectively compared per- and postoperative hemodynamics in 30 patients with PPGL that were pretreated with phenoxybenzamine aiming at different blood pressure targets at two separate endocrine departments. All patients were subsequently undergoing laparoscopic surgery at Department of Urology, Herlev University hospital. Fourteen patients were treated targeting to symptomatic and significant orthostatic hypotension and 16 patients to a seated blood pressure below 130/80 mmHg. As a control group, we included 34 patients undergoing laparoscopic adrenalectomy for other reasons. The group titrated to orthostatic hypotension required a higher dose of phenoxybenzamine to achieve the blood pressure target. This group had less intraoperative systolic and diastolic blood pressure fluctuation (Mann–Whitney U test; P < 0.05) and less periods with heart rate above 100 b.p.m. (Mann–Whitney U test; P = 0.04) as compared to the group with a preoperative blood pressure target below 130/80 mmHg. Peroperative use of intravenous fluids were similar between the two groups, but postoperatively more intravenous fluids were administered in the group with a target of ortostatism. Overall, the control group was more hemodynamic stable as compared to either group treated for PPGL. We conclude that phenoxybenzamine pretreatment targeting ortostatic hypotension may improve peroperative hemodynamic stability but causes a higher postoperative requirement for intravenous fluids. Overall, PPGL surgery is related to greater hemodynamic instability compared to adrenalectomy for other reasons.

Abstract Biomarkers of inflammation are valuable tools for health status evaluation in numerous species. However, in poultry, methods for measuring acute phase proteins (APP) are sparse and rely on manual laboratory labour reserving these parameters mainly for research studies with APP as a focus point. To extend the use of APP beyond tightly focused research studies, blood from experimentally infected and control hens was analysed using equipment available in many veterinary clinics in order to identify easily accessible biomarkers of infection. Blood samples from broiler breeders (n = 30) inoculated intratracheally with either Escherichia coli or sterile vehicle were randomly selected at 2, 4 and 7 days post-infection (dpi) and subjected to biochemical analysis. Samples for bacteriological testing were collected, and all animals were subjected to a full necropsy for disease confirmation. Significantly higher levels of serum amyloid A were evident in the infected birds at 2 and 4 dpi (p

Abstract Aims/Introduction To examine the prevalence of falls and fractures, and the association with symptoms of diabetic polyneuropathy (DPN) in patients with recently diagnosed type 2 diabetes. Materials and Methods A detailed questionnaire on neuropathy symptoms and falls was sent to 6,726 patients enrolled in the Danish Center for Strategic Research in Type 2 Diabetes cohort (median age 65 years, diabetes duration 4.6 years). Complete data on fractures and patient characteristics were ascertained from population‐based health registries. We defined possible DPN as a score ≥4 on the Michigan Neuropathy Screening Instruments questionnaire. Using Poisson regression analyses, we estimated the adjusted prevalence ratio (aPR) of falls and fractures, comparing patients with and without DPN. Results In total, 5,359 patients (80%) answered the questions on the Michigan Neuropathy Screening Instruments questionnaire and falls. Within the year preceding the questionnaire response, 17% (n = 933) reported at least one fall and 1.4% (n = 76) suffered from a fracture. The prevalence ratio of falls was substantially increased in patients with possible DPN compared with those without (aPR 2.33, 95% confidence interval [CI] 2.06–2.63). The prevalence ratio increased with the number of falls from aPR 1.51 (95% CI 1.22–1.89) for one fall to aPR 5.89 (95% CI 3.84–9.05) for four or more falls within the preceding year. Possible DPN was associated with a slightly although non‐significantly increased risk of fractures (aPR 1.32, 95% CI 0.75–2.33). Conclusions Patients with recently diagnosed type 2 diabetes and symptoms of DPN had a highly increased risk of falling. These results emphasize the need for preventive interventions to reduce fall risk among patients with type 2 diabetes and possible DPN.

Abstract Escherichia coli constitutes an immense challenge to the poultry industry due to its devastating effect on productivity, mortality, and carcass condemnations. To aid future studies on disease mechanisms and interventions, an aerogenous infection model was established in adult broiler breeders. Hens (n = 120) were randomly allocated into six groups receiving either aerosolised E. coli or vehicle, or intratracheal E. coli or vehicle. Replication of aerosol inoculation was performed on distinct days. Alternating euthanasia time points were predetermined in order to evaluate the progression of the disease. All animals were thoroughly necropsied, and bacteriological samples were collected as well as tissues for histopathology. Birds inoculated with E. coli exhibited clinical signs and developed characteristic gross and histopathological lesions of colibacillosis, including splenic fibrinoid necrosis, folliculitis, polyserositis and impaction of parabronchi with fibrinoheterophilic exudate and necrotic debris, as well as positive in situ localisation of intralesional E. coli by immunohistochemistry. This study presents a successful development of a discriminative colibacillosis model through aerosol inoculation of adult broiler breeders. Gross and histopathological lesions characteristic of colibacillosis were established in two independent experiments.

Resumé FGU er en relativt ny uddannelse skabt for at understøtte, at unge i udsatte positioner kommer videre fra folkeskole til uddannelse eller arbejde. FGU modtager elever med forskellige negative erfaringer for deltagelse i skole eller uddannelse. Der er knyttet store uddannelsespolitiske ambitioner til FGU-uddannelsen om at skabe læringsfællesskaber, der kan rumme elever med mange forskellige forudsætninger. Artiklen tager afsæt i et teoretisk begreb om læring gennem social deltagelse og sætter gennem analyser af unges perspektiver på deres deltagelse i en FGU-uddannelse fokus på, hvordan unge (igen) kommer i ’position som lærende sociale deltagere’. Der tages udgangspunkt i en forståelse af social udsathed som situeret i komplekse sociale sammenhænge, hvor ikke mindst uddannelsesmæssige deltagelsesbetingelser spiller ind. Dermed anlægges et syn på social udsathed som en livssituation i stadig forandring afhængig af skiftende sociale betingelser. Artiklen analyserer, hvordan unge tillægger skolelivets fællesskaber, læringsaktiviteter og egen indflydelse betydning. En kontekstuel tilgang knytter udsathed til positioner i social praksis og det skærper et blik for, hvordan unge overskrider oplevelser af personlig usikkerhed og sårbarhed gennem aktiv medskabelse af de uddannelsesmæssige læringsfællesskaber, de er en del af. Abstract Learning Communities seen from the Perspectives of Young Adults FGU is a relatively new education which was created for the purpose of supporting young people in exposed positions in their further path – from lower secondary school to education or work. FGU receives students with various negative experiences from school or educational participation. The FGU education is linked with considerable education-policy ambitions with respect to the creation of learning communities capable of embracing students of many different educational backgrounds. The article takes a theoretical concept on learning through social participation as its point of departure and, by way of analyses of young people’s perspectives on their participation in the FGU education, it focuses on how young people can (once again) be brought into ‘position as learning social participants’. The point of departure is an understanding of social vulnerability as situated in complex social contexts in which not least educational participation relations come into play. From a theoretical perspective on learning through social participation, the article analyses how young people will attach meaning to school-life communities, learning activities and their own influence. A contextual understanding of vulnerability which, linked with positions within social practice, offers a prospect of how young people have the possibilities of exceeding personal experiences of insecurity and vulnerability through contributing to the communities of school life.

BackgroundDigital health solutions can provide populations with musculoskeletal pain with high-reach, low-cost, easily accessible, and scalable patient education and self-management interventions that meet the time and resource restrictions. ObjectiveThe main objective of this study was to determine the effectiveness of digital health interventions for people with musculoskeletal pain conditions (ie, low back pain, neck pain, shoulder pain, knee pain, elbow pain, ankle pain, and whiplash). MethodsA systematic review and meta-analysis was conducted. We searched PubMed and Cochrane Central Register of Controlled Trials (from 1974 to August 2021) and selected randomized controlled trials of digital health interventions in the target population of patients with musculoskeletal pain with a minimum follow-up of 1 month. A total of 2 researchers independently screened and extracted the data. ResultsA total of 56 eligible studies were included covering 9359 participants, with a mean follow-up of 25 (SD 15.48) weeks. In moderate-quality evidence, digital health interventions had a small effect on pain (standardized mean difference [SMD] 0.19, 95% CI 0.06-0.32), disability (SMD 0.14, 95% CI 0.03-0.25), quality of life (SMD 0.22, 95% CI 0.07-0.36), emotional functioning (SMD 0.24, 95% CI 0.12-0.35), and self-management (SMD 0.14, 95% CI 0.05-0.24). ConclusionsModerate-quality evidence supports the conclusion that digital health interventions are effective in reducing pain and improving functioning and self-management of musculoskeletal pain conditions. Low-quality evidence indicates that digital health interventions can improve the quality of life and global treatment. Little research has been conducted on the influence of digital health on expenses, knowledge, overall improvement, range of motion, muscle strength, and implementation fidelity. Trial RegistrationPROSPERO CRD42022307504; https://tinyurl.com/2cd25hus

Cannabis sativa L. is typically propagated through micropropagation or vegetative cuttings, but the use of root-inducing hormones, such as indole-3-butyric acid (IBA), is not allowed for growing medicinal cannabis in Denmark. This study examined alternative rooting treatments, including Rhizobium rhizogenes inoculation, water-only as well as IBA treatments, in eight cannabis cultivars. PCR on root tissue suggested that 19% of R. rhizogenes-inoculated cuttings were transformed. These were derived from “Herijuana”, “Wild Thailand”, “Motherlode Kush”, and “Bruce Banner”, indicating a variation in cultivar susceptibility toward R. rhizogenes. A 100% rooting success was achieved regardless of cultivar and treatment, suggesting that alternative rooting agents are not required for efficient vegetative propagation. However, rooted cuttings differed in shoot morphology with improved shoot growth in cuttings treated with R. rhizogenes (195 ± 7 mm) or water (185 ± 7 mm) while inhibited shoot growth under IBA treatment (123 ± 6 mm). This could have advantageous economic implications should cuttings not treated with hormone reach maturity faster than those exposed to the hormone, thereby contributing to completing a full growing cycle more effectively. IBA exposure increased root length, root dry weight, and root/shoot dry weight ratio compared to cuttings treated with R. rhizogenes or water but simultaneously inhibited shoot growth compared to these.

Monitoring specific underlying causes of death in solid organ transplant (SOT) recipients is important in order to identify emerging trends and health challenges. This retrospective cohort study includes all SOT recipients transplanted at Rigshospitalet between January 1st, 2010 and December 31st, 2019. The underlying cause of death was determined using the newly developed Classification of Death Causes after Transplantation (CLASS) method. Cox regression analyses assessed risk factors for all-cause and cause-specific mortality. Of the 1774 SOT recipients included, 299 patients died during a total of 7511 person-years of follow-up (PYFU) with cancer (N = 57, 19%), graft rejection (N = 55, 18%) and infections (N = 52, 17%) being the most frequent causes of death. We observed a lower risk of all-cause death with increasing transplant calendar year (HR 0.91, 95% CI 0.86–0.96 per 1-year increase), alongside death from graft rejection (HR 0.84 per year, 95% CI 0.74–0.95) and death from infections (HR 0.86 per year, 95% CI 0.77–0.97). Further, there was a trend towards lower cumulative incidence of death from cardiovascular disease, graft failure and cancer in more recent years, while death from other organ specific and non-organ specific causes did not decrease. All-cause mortality among SOT recipients has decreased over the past decade, mainly due to a decrease in graft rejection- and infection-related deaths. Conversely, deaths from a broad range of other causes have remained unchanged, suggesting that cause of death among SOT recipients is increasingly diverse and warrants a multidisciplinary effort and attention in the future.

The performance of nine different vapor barrier systems comprising polyethylene (PE) membranes were assessed. The vapor barrier systems comprised membranes of virgin PE, 100% new PE, regenerated PE and multilayered virgin and regenerated PE. Membranes were joined either with tape suited to the individual system or an adhesive base on butyl rubber. The vapor barrier systems were evaluated and compared using standard laboratory tests. Chemical analytical techniques and physicomechanical tests were used. Mechanical properties were assessed using laboratory tests recommended by the harmonized standard EN 1385. Chemical analyses followed standard laboratory protocols performed with specialized equipment and visual examination. Chemical and mechanical properties were determined before and after exposure to an aging regime comprising 168 days at 70 °C in total. The chemical stability of the plastic present in each membrane was further evaluated after an additional exposure to an aging regime comprising 50 days followed by another 30 days at 70 °C. Additional aging indicated chemical changes in the membrane material with time. However, it was not possible to distinguish between aging properties for membranes containing virgin PE, 100% new PE, regenerated PE or multilayered virgin and regenerated PE.

Water infrastructure investment planning must consider the interdependencies within the water–energy–food nexus. Moreover, uncertain future climate, evolving socio-economic context, and stakeholders with conflicting interests, lead to a highly complex decision problem. Therefore, there is a need for decision support tools to objectively determine the value of investments, considering the impacts on different groups of actors, and the risks linked to uncertainties. We present a new open-source hydro-economic optimization model, incorporating in a holistic framework, representations of the water, agriculture, and power systems. The model represents the joint development of nexus-related infrastructure and policies and evaluates their economic impact, as well as the risks linked to uncertainties in future climate and socio-economic development. We apply the methodology in the Zambezi River basin, a major African basin shared by eight countries, in which multiple investment opportunities exist, including new hydropower plants, new or resized reservoirs, development of irrigation agriculture, and investments into the power grid. We show that it is crucial to consider the links between the different systems when evaluating the impacts of climate change and socio-economic development, which will ultimately influence investment decisions. We find that climate change could induce economic losses of up to USD 2.3 billion per year in the current system. We show that the value of the hydropower development plan is sensitive to future fuel prices, carbon pricing policies, the capital cost of solar technologies, and climate change. Similarly, we show that the value of the irrigation development plan is sensitive to the evolution of crop yields, world market crop prices, and climate change. Finally, we evaluate the opportunity costs of restoring the natural floods in the Zambezi Delta; we find limited economic trade-offs under the current climate, but major trade-offs with irrigation and hydropower generation under the driest climate change scenario.

Abstract Background Antimicrobial helper-compounds may reverse antimicrobial resistance. Sertraline, a antidepressant drug, has been suggested as a tetracycline helper-compound. Tetracycline is the preferred antimicrobial for treatment of enteric diseases in pigs. This study is the first to evaluate the potency of sertraline as a tetracycline adjuvant in pigs. Methods Forty-eight nursery pigs were divided into four treatment groups: Tetracycline, sertraline, tetracycline/sertraline or un-medicated control. Fecal and ileal samples were obtained before treatment, 48 h and nine days after five days of treatment, respectively. Colony forming units (CFU) of tetracycline resistant coliforms in each sample (ileal or fecal) and CFU of an orally inoculated tetracycline-resistant strain of Escherichia coli were determined at each sampling point. The microbiome of fecal and ileal and samples was analyzed by sequencing of the 16S V3-V4 region. Results The results did not provide evidence that sertraline in combination with tetracycline has any impact on tetracycline resistant bacteria in either fecal or ileum samples, while in the tetracycline treated group of pigs, an increase in the prevalence of a tetracycline resistant indicator strain of Escherichia coli shortly after ended five-day treatment was observed. The ileal samples obtained shortly after ended treatment showed treatment-associated changes in the composition of the microbiota in the groups of pigs treated with tetracycline (+/−) sertraline. While tetracycline treatment increased the abundance in the reads of E. coli, sertraline/tetracycline treatment led to increased abundances of Streptococcus spp. and decreased abundances of Lactobacillus spp. However, all observed differences (on CFU counts and microbiota composition) between groups shortly after treatment had diminished in less than two weeks after last treatment day. Conclusions Sertraline (+/−) tetracycline treatment did not reduce the long-term level of tetracycline-resistant bacteria in the feces or small intestine contents of piglets compared to the un-medicated control group of pigs. The result of this study reflects the importance of in vivo studies for confirmation of the antimicrobial helper-compound potential of an in vitro active compound.

Water, energy, and agricultural infrastructure investments have important inter-relations fulfilling potentially competing objectives. When shaping investment plans, decision makers need to evaluate those interactions and the associated uncertainties. We compare planning infrastructure under uncertainty with an integrated water-energy-food nexus framework and with sector-centered (silo) frameworks. We use WHAT-IF, an open-source hydroeconomic decision support tool with a holistic representation of the power and agriculture sectors. The tool is applied to an illustrative synthetic case and to a complex planning problem in the Zambezi River Basin involving reservoirs, hydropower, irrigation, transmission lines and power plant investments. In the synthetic case, the nexus framework selects investments that generate more synergies across sectors. In sector-centered frameworks, the value of investments that impact multiple sectors (like hydropower, bioenergy, and desalinization) are under- or overestimated. Furthermore, the nexus framework identifies risks related to uncertainties that are not linked to the investments respective sectors. In the Zambezi river case, we find that most investments are mainly sensitive to parameters related to their respective sectors, and that financial parameters like discount rate, capital costs or carbon taxes are driving the feasibility of investments. However, trade-offs between water for irrigation and water for hydropower are important; ignoring trade-offs in silo frameworks increases the irrigation expansion that is perceived as beneficial by 22% compared to a nexus framework that considers irrigation and hydropower jointly. Planning in a nexus framework is expected to be particularly important when projects and uncertainties can considerably affect the current equilibrium.

Abstract Background Doyne honeycomb retinal dystrophy (DHRD)/malattia leventinese (ML) is an autosomal dominant, progressive retinal disorder characterized by massive central retinal drusen often partly coalescent forming a characteristic honeycomb‐like pattern. Debut of vision loss often occurs in early to mid‐adulthood, and the degree varies. A single variant in EFEMP1: c.1033C>T (R345W) has been identified as the cause in all cases. Methods Following DNA isolation, exome sequencing was performed in seven genes associated with flecked retina. Direct sequencing was used for variant verification. Results We report the first Scandinavian case of molecular genetically verified DHRD/ML: a 57‐year‐old woman debuting with vision loss and metamorphopsia. On both eyes, ophthalmological findings included massive hard drusen in the macular region and nasal to the optic disc as well as macular hyperpigmentation. Secondary choroidal neovascularizations were identified on both eyes, and anti‐vascular endothelial growth factor was administered, without effect. Conclusion Molecular genetic investigation revealed heterozygosity for the known pathogenic missense variant in EFEMP1: c.1033C>T (R345W) previously reported in relation to DHRD/ML. Family history revealed no other cases of similar visual impairment suggesting a de novo mutation. Furthermore, there was no correlation between the unique DHRD/ML haplotypes reported in the literature and our patient.

The emergence of multidrug-resistant bacteria constitutes a significant public health issue worldwide. Consequently, there is an urgent clinical need for novel treatment solutions. It has been shown in vitro that phenothiazines can act as adjuvants to antibiotics whereby the minimum inhibitory concentration (MIC) of the antibiotic is decreased. However, phenothiazines do not perform well in vivo, most likely because they can permeate the blood-brain (BBB) barrier and cause severe side-effects to the central nervous system. Therefore, the aim of this study was to synthesize a promazine derivate that would not cross the BBB but retain its properties as antimicrobial helper compound. Surprisingly, in vitro studies showed that the novel compound, JBC 1847 exhibited highly increased antimicrobial activity against eight Gram-positive pathogens (MIC, 0.5–2 mg/L), whereas a disc diffusion assay indicated that the properties as an adjuvant were lost. JBC 1847 showed significant (P < 0.0001) activity against a Staphylococcus aureus strain compared with the vehicle, in an in vivo wound infection model. However, both in vitro and in silico analyses showed that JBC 1847 possesses strong affinity for human plasma proteins and an Ames test showed that generally, it is a non-mutagenic compound. Finally, in silico predictions suggested that the compound was not prone to pass the BBB and had a suitable permeability to the skin. In conclusion, JBC 1847 is therefore suggested to hold potential as a novel topical agent for the clinical treatment of S. aureus skin and soft tissue infections, but pharmacokinetics and pharmacodynamics need to be further investigated.

Background: Tuberculosis (TB) remains the leading cause of infectious disease-related death. Recently, a trial of BCG revaccination and vaccination with H4:IC31, a recombinant protein vaccine, in South African adolescents (Aeras C-040-404) showed efficacy in preventing sustained QuantiFERON (QFT) conversion, a proxy for Mycobacterium tuberculosis (M.tb) infection. A phase 1b trial of 84 South African adolescents was conducted, concurrent with Aeras C-040-404, to assess the safety and immunogenicity of H4:IC31, H56:IC31 and BCG revaccination, and to identify and optimize immune assays for identification of candidate correlates of protection in efficacy trials. Methods: Two doses of H4:IC31 and H56:IC31 vaccines were administered intramuscularly (IM) 56 days apart, and a single dose of BCG (2–8 × 105 CFU) was administered intradermally (ID). T-cell and antibody responses were measured using intracellular cytokine staining and binding antibody assays, respectively. Binding antibodies and CD4+/CD8+ T-cell responses to H4- and H56-matched antigens were measured in samples from all participants. The study was designed to characterize safety and immunogenicity and was not powered for group comparisons. (Clinicaltrials.gov NCT02378207). Findings: In total, 481 adolescents (mean age 13·9 years) were screened; 84 were enrolled (54% female). The vaccines were generally safe and well-tolerated, with no reported severe adverse events related to the study vaccines. H4:IC31 and H56:IC31 elicited CD4+ T cells recognizing vaccine-matched antigens and H4- and H56-specific IgG binding antibodies. The highest vaccine-induced CD4+ T-cell response rates were for those recognizing Ag85B in the H4:IC31 and H56:IC31 vaccinated groups. BCG revaccination elicited robust, polyfunctional BCG-specific CD4+ T cells, with no increase in H4- or H56-specific IgG binding antibodies. There were few antigen-specific CD8+ T-cell responses detected in any group. Interpretation: BCG revaccination administered as a single dose ID and both H4:IC31 and H56:IC31 administered as 2 doses IM had acceptable safety profiles in healthy, QFT-negative, previously BCG-vaccinated adolescents. Characterization of the assays and the immunogenicity of these vaccines may help to identify valuable markers of protection for upcoming immune correlates analyses of C-040-404 and future TB vaccine efficacy trials. Funding: NIAID and Aeras. Keywords: Mycobacterium tuberculosis, H4:IC31, H56:IC31, BCG

Lars Lund,1,2 Harry Nisen,3 Petrus Järvinen,3 Magnus Fovaeus,4 Eirikur Gudmundson,5 Bjarne Kromann-Andersen,6 Börje Ljungberg,7 Frode Nilsen,8 Pernilla Sundqvist,9 Peter E Clark,10 Christian Beisland11,12 1Department of Urology, Odense University Hospital, 2Clinical Institute, Southern University of Denmark, Odense, Denmark; 3Department of Urology, Helsinki University Hospital, Helsinki, Finland; 4Department of Urology, Sahlgrenska University Hospital, Gothenburg, Sweden; 5Department of Urology, Landspitali University Hospital, Reykjavik, Iceland; 6Department of Urology, Herlev University Hospital, Copenhagen, Denmark; 7Department of Surgical and Perioperative Sciences, Urology and Andrology, Umeå University, Umeå, Sweden; 8Department of Urology, Akershus University Hospital, Lörenskog, Norway; 9Department of Urology, Faculty of Medicine and Health, Örebro University, Örebro, Sweden; 10Department of Urology, Atrium Health, Charlotte, NC, USA; 11Department of Urology, Haukeland University Hospital, 12Department of Clinical Medicine, University of Bergen, Bergen, Norway Purpose: To examine the variation in venous thromboembolism prophylactic treatment (VTEP) among renal cancer patients undergoing surgery.Materials and methods: An Internet-based questionnaire on renal tumor management before and after surgery was mailed to all Nordic departments of urology. The questions focused on the use of VTEP and were subdivided into different surgical modalities.Results: Questionnaires were mailed to 91 institutions (response rate 53%). None of the centers used VTEP before surgery, unless the patient had a vena caval tumor thrombus. Overall, the VTEP utilized during hospitalization for patients undergoing renal surgery included early mobilization (45%), compression stockings (52%) and low-molecular-weight heparin (89%). In patients undergoing open radical Nx, 80% of institutions used VTEP during their hospitalization (23% compression stockings and 94% low-molecular-weight heparin). After leaving the hospital, the proportion and type of VTEP received varied considerably across institutions. The most common interval, used in 60% of the institutions, was for a period of 4 weeks. The restriction to the Nordic countries was a limitation and, therefore, may not reflect the practice patterns elsewhere. It is a survey study and, therefore, cannot measure the behaviors of those institutions that did not participate.Conclusion: We found variation in the type and duration of VTEP use for each type of local intervention for renal cancer. These widely disparate variations in care strongly argue for the establishment of national and international guidelines regarding VTEP in renal surgery. Keywords: venous-thrombotic-embolic prophylaxis kidney cancer, surgery, nephrectomy, mortality, complication, minimally invasive methods, thrombosis prophylaxis

Abstract Background Pigmentary mosaicism is a term that describes varied patterns of pigmentation in the skin caused by genetic heterogeneity of the skin cells. In a substantial number of cases, pigmentary mosaicism is observed alongside extracutaneous abnormalities typically involving the central nervous system and the musculoskeletal system. We have compiled information on previous cases of pigmentary mosaicism aiming to optimize the handling of patients with this condition. Our study is based on a database search in PubMed containing papers written in English, published between January 1985 and April 2017. The search yielded 174 relevant and original articles, detailing a total number of 651 patients. Results Forty-three percent of the patients exhibited hyperpigmentation, 50% exhibited hypopigmentation, and 7% exhibited a combination of hyperpigmentation and hypopigmentation. Fifty-six percent exhibited extracutaneous manifestations. The presence of extracutaneous manifestations in each subgroup varied: 32% in patients with hyperpigmentation, 73% in patients with hypopigmentation, and 83% in patients with combined hyperpigmentation and hypopigmentation. Cytogenetic analyses were performed in 40% of the patients: peripheral blood lymphocytes were analysed in 48%, skin fibroblasts in 5%, and both analyses were performed in 40%. In the remaining 7% the analysed cell type was not specified. Forty-two percent of the tested patients exhibited an abnormal karyotype; 84% of those presented a mosaic state and 16% presented a non-mosaic structural or numerical abnormality. In patients with extracutaneous manifestations, 43% of the cytogenetically tested patients exhibited an abnormal karyotype. In patients without extracutaneous manifestations, 32% of the cytogenetically tested patients exhibited an abnormal karyotype. Conclusion We recommend a uniform parlance when describing the clinical picture of pigmentary mosaicism. Based on the results found in this review, we recommend that patients with pigmentary mosaicism undergo physical examination, highlighting with Wood’s light, and karyotyping from peripheral blood lymphocytes and skin fibroblasts. It is important that both patients with and without extracutaneous manifestations are tested cytogenetically, as the frequency of abnormal karyotype in the two groups seems comparable. According to the results only a minor part of patients, especially those without extracutaneous manifestations, are tested today reflecting a need for change in clinical practice.

Abstract Background H1/IC31® is a tuberculosis (TB) subunit vaccine candidate consisting of the fusion protein of Ag85B and ESAT-6 (H1) formulated with the IC31® adjuvant. Previous trials have reported on the H1/IC31® vaccine in M. tuberculosis (Mtb)-naïve, BCG-vaccinated and previously Mtb-infected individuals. In this trial, conducted between December 2008 and April 2010, the safety and immunogenicity of H1/IC31® was assessed in participants living in Ethiopia – a highly TB-endemic area. Methods Healthy male participants aged 18–25 years were recruited into four groups. Participants in group 1 (N = 12) and group 2 (N = 12) were Tuberculin Skin Test (TST) negative and QuantiFERON-TB Gold in-tube test (QFT) negative (Mtb-naïve groups), participants in group 3 (N = 3) were TST positive and QFT negative (BCG group), and participants in group 4 (N = 12) were both TST and QFT positive (Mtb-infected group). H1 vaccine alone (group 1) or H1 formulated with the adjuvant IC31® (groups 2, 3 and 4) was administered intramuscularly on day 0 and day 56. Safety and immunogenicity parameters were evaluated for up to 32 weeks after day 0. Results The H1/IC31®vaccine was safe and generally well tolerated. There was little difference among the four groups, with a tendency towards a higher incidence of adverse events in Mtb-infected compared to Mtb-naïve participants. Two serious adverse events were reported in the Mtb-infected group where a relationship to the vaccine could not be excluded. In both cases the participants recovered without sequelae within 72 h. Immunogenicity assays, evaluated in the 29 participants who received both vaccinations, showed a stronger response to TB antigens in the Mtb-naïve group vaccinated with the adjuvant. Conclusion The trial confirmed the need for an adjuvant for the vaccine to be immunogenic and highlighted the importance of early phase testing of a novel TB vaccine candidate in TB-endemic areas. Trial registration ClinicalTrials.gov, ID: NCT01049282. Retrospectively registered on 14 January 2010.

Evidence is low regarding the choice of calcineurin inhibitor for immunosuppression after lung transplantation. We aimed to compare the use of tacrolimus once per day with ciclosporin twice per day according to the current definition of chronic lung allograft dysfunction (CLAD) after lung transplantation. ScanCLAD is an investigator-initiated, open-label, multicentre, randomised, controlled trial in Scandinavia evaluating whether an immunosuppressive protocol based on anti-thymocyte globulin induction followed by tacrolimus (once per day), mycophenolate mofetil, and corticosteroids reduces the incidence of CLAD after de novo lung transplantation compared with a protocol using ciclosporin (twice per day), mycophenolate mofetil, and corticosteroids. Patients aged 18–70 years who were scheduled to undergo double lung transplantation were randomly allocated (1:1) to receive either oral ciclosporin (2–3 mg/kg before transplantation and 3 mg/kg [twice per day] from postoperative day 1) or oral tacrolimus (0·05–0·1 mg/kg before transplantation and 0·1–0·2 mg/kg from postoperative day 1). The primary endpoint was CLAD at 36 months post transplantation, determined by repeated lung function tests and adjudicated by an independent committee, and was assessed with a competing-risks analysis with death and re-transplantation as competing events. The primary outcome was assessed in the modified intention-to-treat (mITT) population, defined as those who underwent transplantation and received at least one dose of study drug. This study is registered at ClinicalTrials.gov (NCT02936505) and EudraCT (2015-004137-27). Between Oct 21, 2016, and July 10, 2019, 383 patients were screened for eligibility. 249 patients underwent double lung transplantation and received at least one dose of study drug, and were thus included in the mITT population: 125 (50%) in the ciclosporin group and 124 (50%) in the tacrolimus group. The mITT population consisted of 138 (55%) men and 111 (45%) women, with a mean age of 55·2 years (SD 10·2), and no patients were lost to follow-up. In the mITT population, CLAD occurred in 48 patients (cumulative incidence 39% [95% CI 31–48]) in the ciclosporin group and 16 patients (13% [8–21]) in the tacrolimus group at 36 months post transplantation (hazard ratio [HR] 0·28 [95% CI 0·15–0·52], log-rank p<0·0001). Overall survival did not differ between groups at 3 years in the mITT population (74% [65–81] for ciclosporin vs 79% [70–85] for tacrolimus; HR 0·72 [95% CI 0·41–1·27], log-rank p=0·25). However, in the per protocol CLAD population (those in the mITT population who also had at least one post-baseline lung function test allowing assessment of CLAD), allograft survival was significantly better in the tacrolimus group (HR 0·49 [95% CI 0·26–0·91], log-rank p=0·021). Adverse events totalled 1516 in the ciclosporin group and 1459 in the tacrolimus group. The most frequent adverse events were infection (453 events), acute rejection (165 events), and anaemia (129 events) in the ciclosporin group, and infection (568 events), anaemia (108 events), and acute rejection (98 events) in the tacrolimus group. 112 (90%) patients in the ciclosporin group and 108 (87%) in the tacrolimus group had at least one serious adverse event. Immunosuppression based on use of tacrolimus once per day significantly reduced the incidence of CLAD compared with use of ciclosporin twice per day. These findings support the use of tacrolimus as the first choice of calcineurin inhibitor after lung transplantation. Astellas, the ALF-agreement, Scandiatransplant Organization, and Heart Centre Research Committee, Rigshospitalet, Denmark. [ABSTRACT FROM AUTHOR]

In poultry, Escherichia coli is a common cause of high-cost infections. Consequently, autogenous vaccines are often used despite limited and conflicting evidence on their effectiveness have been presented. The present study aimed to investigate the efficacy of a commonly used autogenous vaccine, previously deemed ineffective, in an aerosol model of colibacillosis. Methods: Broiler breeders (n = 47) were randomly allocated to one of four groups (vaccinated and unvaccinated birds receiving an autogenous vaccine or sterile saline intramuscularly) and challenged with either aerosolised E. coli or vehicle at 29 weeks of age. Two days following inoculation, the birds were euthanised, thoroughly necropsied, and samples for bacteriology and histopathology were collected. Results: Vaccinated birds had a significantly lower bacteriology score compared to the unvaccinated group challenged with E. coli (p < 0.01) and a lower overall air sac lesion score (p < 0.05). Overall lung and spleen lesion scores only differed significantly between the unvaccinated E. coli challenged group compared to the vehicle inoculated groups. The overall gross pathology score was 2.8 and 1.95 in the unvaccinated and vaccinated E. coli challenge groups, respectively, whereas the vaccinated vehicle group had a score of 0.9 and the unvaccinated vehicle group a score of 1. Conclusions: A protective effect of an autogenous vaccine was found utilising an aerogenous model of colibacillosis through multiple methods of evaluation. The findings encourage the continued use of autogenous vaccines and underlines the necessity of discriminative experimental models with high predictive validity when evaluating vaccine interventions.

Purpose: The purpose of this paper is to examine how students' participation in an integrated school food program was related to the development of components of food and health-related action competence (F & HRAC). These components were understood to be the knowledge, insight, motivation, ownership and social skills that made students able to take action regarding food and health in everyday life. Design/methodology/approach: Research was undertaken as a single case study of the development of an integrated education and health program called LOMA-Local Food (LOMA) in a secondary school in Denmark. Qualitative methods were applied, including an action research component, where researcher and teachers examined how students developed action competence. The program was based on a whole school approach with the aim of improving F & HRAC. As a way to obtain this, students participated in planning, preparing, cooking and serving their own school food as integrated in curriculum. The study applied the Health Promoting Schools' (HPS) conceptual framework and the Investigation, Vision, Action and Change (IVACE) approach. Findings: Students who participated in LOMA educational activities became motivated for developing a food F & HRAC, which included components such as knowledge, insight, motivation, ownership, action experience, commitment, cooperation and critical thinking. Students developed practical skills related to food and health, when they were cooking healthy school food together with professionals and peers. The study also points to the importance of capacity building among teachers. The IVACE matrix is suggested as a relevant tool for monitoring forms of participation that contributes to students' development of F & HRAC. Practical implications: There were indications of how participation in LOMA contributed to students' development of F & HRAC. The practical implication of this is that "setting" is very important for the success of food and health education initiatives. In this integrated approach the production kitchen and the dining hall are indispensable. Also the new organization of the school day and the introduction of a shared daily meal are important practical components for the improvement of the learning environment. The possibility of combining theory and practice seem conducive for students' achievement of action competence. Social implications: The current study is an example of how the IVACE matrix can be applied in order to plan, conduct and evaluate LOMA educational activities, which could be considered as a contribution to the HPS scientific community. It would be useful for other schools that intend to apply the LOMA approach. However, more research is needed, where teachers, students, staff and other stakeholders collaborate in an action research process. This could promote students' health and support other initiatives regarding public health, sustainable development and democracy. Originality/value: This research may have implications for the way that school food programs are developed and implemented if they are to make a contribution to students' development of F & HRAC. Taking the political interest for research-based interventions into account, it is important that future strategies include teachers' capacity building. Research is also needed regarding further development and test of the IVACE matrix as a method in participatory, health education approaches. This should be seen in combination with a renewed focus on integrated curricula models related to the on-going discussion on redesign of western school curricula.

Integrins are cell-surface adhesion receptors that are modulated by endo-exocytic trafficking, but existing tools to study this process can interfere with function. Here the authors develop β1 integrins carrying traceable tags in the extracellular domain; a pH-sensitive pHlourin tag or a HaloTag to facilitate dye attachment.

Abstract Background Pleural effusion (PLE) may lead to low blood pressure and reduced cardiac output. Low blood pressure and reduced cardiac output are often treated with fluid loading and vasopressors. This study aimed to determine the impact of fluid loading and norepinephrine infusion on physiologic determinants of cardiac function obtained by ultrasonography during PLE. Methods In this randomised, blinded, controlled laboratory study, 30 piglets (21.9 ± 1.3 kg) had bilateral PLE (75 mL/kg) induced. Subsequently, the piglets were randomised to intervention as follows: fluid loading (80 mL/kg/h for 1.5 h, n = 12), norepinephrine infusion (0.01, 0.03, 0.05, 0.1, 0.2 and 0.3 μg/kg/min (15 min each, n = 12)) or control (n = 6). Main outcome was left ventricular preload measured as left ventricular end-diastolic area. Secondary endpoints included contractility and afterload as well as global measures of circulation. All endpoints were assessed with echocardiography and invasive pressure-flow measurements. Results PLE decreased left ventricular end-diastolic area, mean arterial pressure and cardiac output (p values 0.05) to baseline. Left ventricular contractility increased with norepinephrine infusion (p = 0.002), but was not affected by fluid loading (p = 0.903). Afterload increased in both active groups (p values > 0.001). Overall, inferior vena cava distensibility remained unchanged during intervention (p values ≥ 0.085). Evacuation of PLE caused numerical increases in left ventricular end-diastolic area, but only significantly so in controls (p = 0.006). Conclusions PLE significantly reduced left ventricular preload. Both fluid and norepinephrine treatment reverted this effect and normalised global haemodynamic parameters. Inferior vena cava distensibility remained unchanged. The haemodynamic significance of PLE may be underestimated during fluid or norepinephrine administration, potentially masking the presence of PLE.

Abstract Although trypsin-like serine proteases have flexible surface-exposed loops and are known to adopt higher and lower activity conformations, structural determinants for the different conformations have remained largely obscure. The trypsin-like serine protease, urokinase-type plasminogen activator (uPA), is central in tissue remodeling processes and also strongly implicated in tumor metastasis. We solved five X-ray crystal structures of murine uPA (muPA) in the absence and presence of allosteric molecules and/or substrate-like molecules. The structure of unbound muPA revealed an unsuspected non-chymotrypsin-like protease conformation in which two β-strands in the core of the protease domain undergoes a major antiparallel-to-parallel conformational transition. We next isolated two anti-muPA nanobodies; an active-site binding nanobody and an allosteric nanobody. Crystal structures of the muPA:nanobody complexes and hydrogen-deuterium exchange mass spectrometry revealed molecular insights about molecular factors controlling the antiparallel-to-parallel equilibrium in muPA. Together with muPA activity assays, the data provide valuable insights into regulatory mechanisms and conformational flexibility of uPA and trypsin-like serine proteases in general.

Understanding predictors and trajectories of increased potassium may inform testing and treatment of hyperkalemia. We examined predictors for repeated hyperkalemia among patients after first-time renin angiotensin system inhibitor (RASi) prescription, chronic kidney disease (CKD), or chronic heart failure (CHF); and we also examined potassium trajectories in these patients after their first hyperkalemia event. We used Danish population-based registries to identify all patients with first-time RASi prescription, incident CKD, or incident CHF (2000-2012). For patients with a first hyperkalemia event, potassium trajectories over the following 6 months were examined. The predictors associated with repeated hyperkalemia were assessed, with repeated hyperkalemia defined as a potassium test >5.0 mmol/L after the first event within 6 months. Overall 262,375 first-time RASi users, 157,283 incident CKD patients, and 14,600 incident CHF patients were included. Of patients with a first hyperkalemia event, repeated hyperkalemia within 6 months occurred in 37% of RASi users, 40% with CKD, and 49% of patients with CHF. Predictors included severe hyperkalemia, low eGFR, diabetes, and spironolactone use. In all cohorts, the median potassium levels declined over 2-4 weeks after a hyperkalemia event for the first time, but reverted to levels higher than before the initial hyperkalemia event in those who had repeated hyperkalemia. Following hyperkalemia, discontinuation of RASi and spironolactone was common in the RASi and CHF cohorts. Repeated hyperkalemia was common among the explored cohorts. The first hyperkalemia event was an indicator of increased median potassium levels. Predictors may identify patients likely to benefit from intensified monitoring and intervention.

Astrid Christine Petersen,1 Mette Søgaard,2 Frank Mehnert,2 Erik Højkjær Larsen,3 Frede Donskov,4 Nessn H Azawi,5 Bjarne Kromann-Andersen6 1Department of Pathology, Aalborg University Hospital, Aalborg, 2Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, 3Department of Urology, Odense University Hospital, Odense, 4Department of Oncology, Aarhus University Hospital, Aarhus, 5Department of Urology, Zealand University Hospital, Roskilde, 6Department of Urology, Herlev and Gentofte Hospital, Copenhagen, Denmark Aim of the database: The main purpose of the database of the Danish Renal Cancer Group (DaRenCaData) is to improve the quality of renal cancer treatment in Denmark and secondarily to conduct observational research. Study population: DaRenCaData includes all Danish patients with a first-time diagnosis of renal cancer in the Danish National Pathology Registry since August 1, 2010. Main variables: DaRenCaData holds data on demographic characteristics, treatments, and pathology collected through linkage to central registries and online registration of a few clinical key variables. Eight quality indicators have been selected for monitoring treatment quality and outcome after renal cancer. Descriptive data: The incidence of renal cancer in Denmark has increased from 12.7 per 100,000 population-years in 2010–2011 to 15.9 per 100,000 population-years in 2014–2015. A total of 3,977 Danish patients with renal cancer have been enrolled in the database in the period August 1, 2010–July 31, 2015. The completeness of data registration has increased substantially since the first years of the database. A tendency toward smaller and less advanced tumors, less invasive surgery, and a shorter hospital stay was observed, while the postoperative morbidity and mortality remained stable. Concurrently, the 1-year survival has improved and was 84.1% in 2014–2015. Conclusion: DaRenCaData provides valuable information on quality of and outcome after renal cancer treatment. Efforts to improve collection and registration of data are ongoing. Keywords: kidney cancer, database, clinical quality, indicators, incidence, survival, observational research

The intracellular applications of STED microscopy are limited by the availability of dyes. Here the authors develop a two-colour labelling strategy based on SiR and ATTO590 dyes, and apply their strategy to image various subcellular membrane compartments.