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Harmful cyanobacterial blooms will be more intense and frequent in the future, contaminating surface waters with cyanotoxins and posing a threat to communities heavily reliant on surface water usage for crop irrigation. Constructed wetlands (CWs) are proposed to ensure safe crop irrigation, but more research is needed before implementation. The present study operated 28 mesocosms in continuous mode mimicking horizontal sub-surface flow CWs. Mesocosms were fed with synthetic lake water and spiked periodically with two cyanotoxins, microcystin-LR (MC-LR) and cylindrospermopsin (CYN), at environmentally relevant cyanotoxins concentrations (10 μg L -1 ). The influence of various design factors, including plant species, porous media, and seasonality, was explored. The mesocosms achieved maximum MC-LR and CYN mass removal rates of 95 % and 98 %, respectively. CYN removal is reported for the first time in CWs mimicking horizontal sub-surface flow CWs. Planted mesocosms consistently outperformed unplanted mesocosms, with Phragmites australis exhibiting superior cyanotoxin mass removal compared to Juncus effusus. Considering evapotranspiration, J. effusus yielded the least cyanotoxin-concentrated effluent due to the lower water losses in comparison with P. australis. Using the P-kC* model, different scaling-up scenarios for future piloting were calculated and discussed. Additionally, bacterial community structure was analyzed through correlation matrices and differential taxa analyses, offering valuable insights into their removal of cyanotoxins. Nevertheless, attempts to validate microcystin-LR biotransformation via the known mlrA gene degradation pathway were unfruitful, indicating alternative enzymatic degradation pathways occurring in such complex CW systems. Further investigation into the precise molecular mechanisms of removal and the identification of transformation products is needed for the comprehensive understanding of cyanotoxin mitigation in CW. This study points towards the feasibility of horizontal sub-surface flow CWs to be employed to control cyanotoxins in irrigation or recreational waters., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Pedro N. Carvalho reports financial support was provided by Independent Research Fund Denmark. Carlos A. Arias reports financial support was provided by European Commission Marie Sklodowska-Curie Actions. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

In an attempt to discover and characterize the plethora of xenobiotic substances, this study investigates chemical compounds released into the environment with wastewater effluents. A novel non-targeted screening methodology based on ultra-high resolution Orbitrap mass spectrometry and nanoflow ultra-high performance liquid chromatography together with a newly optimized data-processing pipeline were applied to effluent samples from two state-of-the-art and one small wastewater treatment facility. In total, 785 molecular structures were obtained, of which 38 were identified as single compounds, while 480 structures were identified at a putative level. Most of these substances were therapeutics and drugs, present as parent compounds and metabolites. Using R packages Phyloseq and MetacodeR, originally developed for bioinformatics, significant differences in xenobiotic presence in the wastewater effluents between the three sites were demonstrated., Competing Interests: Declaration of competing interest The authors declare no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Harmful cyanobacterial blooms have increased globally, releasing hazardous cyanotoxins that threaten the safety of water resources. Constructed wetlands (CWs) are a nature-based and low-cost solution to purify and remove cyanotoxins from water. However, bio-mechanistic understanding of the biotransformation processes expected to drive cyanotoxin removal in such systems is poor, and primarily focused on bacteria. Thus, the present study aimed at exploring the fungal contribution to microcystin-LR and cylindrospermopsin biodegradation in CWs. Based on CW mesocosms, two experimental approaches were taken: a) amplicon sequencing studies were conducted to investigate the involvement of the fungal community; and b) CW fungal isolates were tested for their microcystin-LR and cylindrospermopsin degradation capabilities. The data uncovered effects of seasonality (spring or summer), cyanotoxin exposure, vegetation (unplanted, Juncus effusus or Phragmites australis) and substratum (sand or gravel) on the fungal community structure. Additionally, the arbuscular mycorrhizal fungus Rhizophagus and the endophyte Myrmecridium showed positive correlations with cyanotoxin removal. Fungal isolates revealed microcystin-LR-removal potentials of approximately 25 % in in vitro biodegradation experiments, while the extracellular chemical fingerprint of the cultures suggested a potential intracellular metabolization. The results from this study may help us understand the fungal contribution to cyanotoxin removal, as well as their ecology in CWs., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Pedro N Carvalho reports financial support was provided by Independent Research Fund Denmark. Pedro N Carvalho, Carlos A Arias reports financial support was provided by European Commission Marie Sklodowska-Curie Actions. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

We have created two isogenic iPSC lines from fibroblasts of a healthy male donor of European ancestry. The cell lines express common pluripotency markers, are free of chromosomal aberrations and are able to differentiate into cells of all three germ layers. These iPSC are now a resource for genome editing with the aim of creating models of genetic disorders without having to depend on patient cells., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Bjoern Nowack reports financial support was provided by SensID GmbH. Bjoern Nowack reports a relationship with SensID GmbH that includes: employment and equity or stocks. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Cyanobacterial blooms releasing harmful cyanotoxins, such as microcystin (MC) and cylindrospermopsin (CYN), are prominent threats to human and animal health. Constructed wetlands (CW) may be a nature-based solution for bioremediation of lake surface water containing cyanotoxins, due to its low-cost requirement of infrastructure and environmentally friendly operation. There is recent evidence that microcystin-LR (MC-LR) can efficiently be removed in CW microcosms where CYN degradation in CW is unknown. Likewise, the mechanistic background regarding cyanotoxins transformation in CW is not yet elucidated. In the present study, the objective was to compare MC-LR and CYN degradation efficiencies by two similar microbial communities obtained from CW mesocosms, by two different experiments setup: 1) in vitro batch experiment in serum bottles with an introduced CW community, and 2) degradation in CW mesocosms. In experiment 1) MC-LR and CYN were spiked at 100 µg L -1 and in experiment 2) 200 µg L -1 were spiked. Results showed that MC-LR was degraded to ≤1 µg L -1 within seven days in both experiments. However, with a markedly higher degradation rate constant in the CW mesocosms (0.18 day -1 and 0.75 day -1 , respectively). No CYN removal was detected in the in vitro incubations, whereas around 50 % of the spiked CYN was removed in the CW mesocosms. The microbial community responded markedly to the cyanotoxin treatment, with the most prominent increase of bacteria affiliated with Methylophilaceae (order: Methylophilales, phylum: Proteobacteria). The results strongly indicate that CWs can develop an active microbial community capable of efficient removal of MC-LR and CYN. However, the CW operational conditions need to be optimized to achieve a full CYN degradation. To the best of our knowledge, this study is the first to report the ability of CW mesocosms to degrade CYN., Competing Interests: Declaration of Competing Interest Carvalho reports financial support was provided by Independent Research Fund Denmark. Pedro N Carvalho, Carlos A Arias reports financial support was provided by European Commission Marie Sklodowska-Curie Actions., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Non-Floating Harbour Syndrome (FLHS) neurodevelopmental disorder (NDD) is a recently described disorder caused by mutations in certain regions of the SRCAP gene. We generated two iPSC lines that contain truncating mutation on both alleles at the 3'-end of SRCAP using CRISPR/Cas9 technology. Both cell lines are pluripotent, differentiate into the 3 germ layers and contain no genomic aberrations or off-target modifications. The cell lines form part of a human disease model to investigate the effects of truncating mutations in different regions of SRCAP., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Locally advanced or metastatic squamous carcinoma of the anal canal (SCAC) has poor prognosis following platinum-based chemotherapy. Retifanlimab (INCMGA00012), a humanized monoclonal antibody targeting programmed death protein-1 (PD-1), demonstrated clinical activity across a range of solid tumors in clinical trials. We present results from POD1UM-202 (NCT03597295), an open-label, single-arm, multicenter, phase II study evaluating retifanlimab in patients with previously treated advanced or metastatic SCAC., Patients and Methods: Patients ≥18 years of age had measurable disease and had progressed following, or were ineligible for, platinum-based therapy. Retifanlimab 500 mg was administered intravenously every 4 weeks. The primary endpoint was overall response rate (ORR) by independent central review. Secondary endpoints were duration of response (DOR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and safety., Results: Overall, 94 patients were enrolled. At a median follow-up of 7.1 months (range, 0.9-19.4 months), ORR was 13.8% [95% confidence interval (CI) 7.6% to 22.5%], with one complete response (1.1%) and 12 partial responses (12.8%). Responses were observed regardless of human immunodeficiency virus or human papillomavirus status, programmed death ligand 1 (PD-L1) expression, or liver metastases. Stable disease was observed in 33 patients (35.1%) for a DCR of 48.9% (95% CI 38.5% to 59.5%). Median DOR was 9.5 months (range, 5.6 months-not estimable). Median (95% CI) PFS and OS were 2.3 (1.9-3.6) and 10.1 (7.9-not estimable) months, respectively. Retifanlimab safety in this population was consistent with previous experience for the PD-(L)1 inhibitor class., Conclusions: Retifanlimab demonstrated clinically meaningful and durable antitumor activity, and an acceptable safety profile in patients with previously treated locally advanced or metastatic SCAC who have progressed on or are intolerant to platinum-based chemotherapy., Competing Interests: Disclosure SR reports being an advisor or receiving honoraria from Amgen, Celgene, and Shire; travel grants from Bayer, Celgene, and Incyte Corporation. JC reports scientific consultancy role (speaker and advisory roles) for Advanced Accelerator Applications, Amgen, Bayer, Eisai, Eli Lilly, Exelixis, Hutchison MediPharma, Ipsen, Isotopen Technologien München, Merck Serono, Novartis, Pfizer, and Sanofi; research support/grants from Advanced Accelerator Applications, AstraZeneca, Bayer, Eisai, Novartis, and Pfizer. LD reports honoraria from Amgen, Sanofi, and Servier. LE reports honoraria from Merck and Servier. SK reports research funding from Bioprojet Pharma, Boehringer Ingelheim, Bristol Myers Squibb, Novartis, Pfizer, Roche, and Sanofi; advisor or honoraria from Incyte Corporation, Ipsen, Merck Sharp & Dohme, Sanofi, and Servier. MPS reports being an advisor or receiving honoraria from Amgen, Merck, and Servier. ES reports honoraria from or serves on the advisory board for Amgen, Bristol Myers Squibb, Merck Sharp & Dohme, Pierre Fabre Oncology, Roche, Sandoz, and Servier. KLS reports honoraria from Boston Scientific. AD reports consultant and advisory role for AstraZeneca, Basilea Pharmaceutica, Bayer, and Servier; research funding from Bayer. DA reports consultant or advisory role, and/or presentation honoraria from AstraZeneca, Boston Scientific, Bristol Myers Squibb, Eli Lilly, Merck Sharp & Dohme, Pierre Fabre Oncology, Sanofi, Servier, and Terumo. MF reports consultant or advisory role for Amgen, Array BioPharma, GlaxoSmithKline, Incyte Corporation, Pfizer, Seattle Genetics, and Taiho Pharmaceutical; speakers’ bureau for Guardant Health; research funding (institutional) from Amgen, AstraZeneca, Bristol Myers Squibb, and Novartis. MCo, CT, and MS report employment and stock ownership in Incyte Corporation. MCa reports former employment and stock ownership in Incyte Corporation. JPS reports honoraria from AstraZeneca, Biogaran, Bristol Myers Squibb, Eli Lilly, Gilead Sciences, Leo Pharma, Mylan, Myriad Genetics, Novartis, Pfizer, and Pierre Fabre; consulting or advisory role for Merck Sharp & Dohme and Roche; grant from MSD Avenir. All other authors have declared no conflicts of interest. Data sharing Incyte Corporation (Wilmington, DE, USA) is committed to data sharing that advances science and medicine while protecting patient privacy. Qualified external scientific researchers may request anonymized datasets owned by Incyte Corporation for the purpose of conducting legitimate scientific research. Researchers may request anonymized datasets from any interventional study (except phase I studies) for which the product and indication have been approved on or after 1 January 2020 in at least one major market (e.g. US, EU, JPN). Data will be available for request after the primary publication or 2 years after the study has ended. Information on Incyte Corporation’s clinical trial data sharing policy and instructions for submitting clinical trial data requests are available at: https://www.incyte.com/Portals/0/Assets/Compliance%20and%20Transparency/clinical-trial-data-sharing.pdf?ver=2020-05-21-132838-960, (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Assisted living (AL) has existed in the United States for decades, evolving in response to older adults' need for supportive care and distaste for nursing homes and older models of congregate care. AL is state-regulated, provides at least 2 meals a day, around-the-clock supervision, and help with personal care, but is not licensed as a nursing home. The key constructs of AL as originally conceived were to provide person-centered care and promote quality of life through supportive and responsive services to meet scheduled and unscheduled needs for assistance, an operating philosophy emphasizing resident choice, and a residential environment with homelike features. As AL has expanded to constitute half of all long-term care beds, the increasing involvement of the real estate, hospitality, and health care sectors has raised concerns about the variability of AL, the quality of AL, and standards for AL. Although the intent to promote person-centered care and quality of life has remained, those key constructs have become mired under tensions related to models of AL, regulation, financing, resident acuity, and the workforce. These tensions have resulted in a model of care that is not as intended, and which must be reimagined if it is to be an affordable care option truly providing quality, person-centered care in a suitable environment. Toward that end, 25 stakeholders representing diverse perspectives conferred during 2 half-day retreats to identify the key tensions in AL and discuss potential solutions. This article presents the background regarding those tensions, as well as potential solutions that have been borne out, paving the path to a better future of assisted living., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Today, weaner diets are optimised using digestibility coefficients obtained from grower-finisher pigs, which may overestimate the digestibility in weaners. The aim of this study was to evaluate the standardised ileal digestibility (SID) of CP and amino acids (AAs), and the intestinal morphology in pigs 0-4 weeks postweaning when fed different protein sources. The experiment included 128 pigs weaned at day 28 and the protein sources were wheat, soybean meal (SBM), enzyme-treated soybean meal (ESBM), hydrothermally treated rapeseed meal (HRSM) and casein. The experiment was conducted as a difference method study including wheat in all diets. Eight pigs were slaughtered on the day of weaning (day 0) and six pigs/treatment were slaughtered at days 7, 14, 21, and 28 postweaning. The SID of CP and AA, as average over the four weeks, was lowest for ESBM and highest for wheat and casein, with SBM and HRSM being intermediate. The SID of CP and AA increased (both linear and quadratic, P < 0.05) over time after weaning. The average SID of CP for all protein sources postweaning was 0.38, 0.59, 0.76, and 0.71 on days 7, 14, 21, and 28, respectively. These differences were significant (P < 0.05) between days 7 and 21, and between days 7 and 28 (P < 0.05), whereas there tended to be a difference between days 7 and 14 (P = 0.06). Protein source did not affect the small intestinal morphology response parameters, whereas time after weaning did. Villous height and villous height to crypt depth ratio differed (P < 0.05) between the days 0 and 7, with shorter villi and a higher ratio at day 7. Crypt depth was not altered between days 0 and 7, or between days 7 and 14. For villi density, crypt density and small intestinal length, a significant increase from days 7 to 14 was observed, but there was no further increase to or difference between days 21 and 28. In conclusion, the low SID of CP in casein on day 7 (0.50) illustrates the challenges related to protein digestion in weanling pigs. The SID of CP and AA is very low during the first two weeks postweaning and time after weaning is more important for protein digestibility, than the source of protein. Fewer mature epithelial cells and less absorptive area in the small intestine in the early postweaning period may partly explain the poor protein digestibility., (Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Near-infrared spectroscopy (NIRS) and intravascular ultrasound are promising imaging modalities to identify non-obstructive plaques likely to cause coronary-related events. We aimed to assess whether combined NIRS and intravascular ultrasound can identify high-risk plaques and patients that are at risk for future major adverse cardiac events (MACEs)., Methods: PROSPECT II is an investigator-sponsored, multicentre, prospective natural history study done at 14 university hospitals and two community hospitals in Denmark, Norway, and Sweden. We recruited patients of any age with recent (within past 4 weeks) myocardial infarction. After treatment of all flow-limiting coronary lesions, three-vessel imaging was done with a combined NIRS and intravascular ultrasound catheter. Untreated lesions (also known as non-culprit lesions) were identified by intravascular ultrasound and their lipid content was assessed by NIRS. The primary outcome was the covariate-adjusted rate of MACEs (the composite of cardiac death, myocardial infarction, unstable angina, or progressive angina) arising from untreated non-culprit lesions during follow-up. The relations between plaques with high lipid content, large plaque burden, and small lumen areas and patient-level and lesion-level events were determined. This trial is registered with ClinicalTrials.gov, NCT02171065., Findings: Between June 10, 2014, and Dec 20, 2017, 3629 non-culprit lesions were characterised in 898 patients (153 [17%] women, 745 [83%] men; median age 63 [IQR 55-70] years). Median follow-up was 3·7 (IQR 3·0-4·4) years. Adverse events within 4 years occurred in 112 (13·2%, 95% CI 11·0-15·6) of 898 patients, with 66 (8·0%, 95% CI 6·2-10·0) arising from 78 untreated non-culprit lesions (mean baseline angiographic diameter stenosis 46·9% [SD 15·9]). Highly lipidic lesions (851 [24%] of 3500 lesions, present in 520 [59%] of 884 patients) were an independent predictor of patient-level non-culprit lesion-related MACEs (adjusted odds ratio 2·27, 95% CI 1·25-4·13) and non-culprit lesion-specific MACEs (7·83, 4·12-14·89). Large plaque burden (787 [22%] of 3629 lesions, present in 530 [59%] of 898 patients) was also an independent predictor of non-culprit lesion-related MACEs. Lesions with both large plaque burden by intravascular ultrasound and large lipid-rich cores by NIRS had a 4-year non-culprit lesion-related MACE rate of 7·0% (95% CI 4·0-10·0). Patients in whom one or more such lesions were identified had a 4-year non-culprit lesion-related MACE rate of 13·2% (95% CI 9·4-17·6)., Interpretation: Combined NIRS and intravascular ultrasound detects angiographically non-obstructive lesions with a high lipid content and large plaque burden that are at increased risk for future adverse cardiac outcomes., Funding: Abbott Vascular, Infraredx, and The Medicines Company., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Floating-Harbor syndrome (FLHS) is a rare genetic disease caused by mutations in the SRCAP gene. Here, we generated an induced pluripotent stem cell line from gingival fibroblasts of a male patient with a heterozygous mutation in exon 34 of the SRCAP gene (c.7330C > T, p.Arg2444*). The iPSC colonies have an atypical morphology with diffuse borders and disintegrate quickly upon touch. Still, the cell line expresses pluripotency markers and differentiates into three germ layers. The cell line can be used as patient-specific disease model and help elucidate the molecular mechanisms involving SRCAP in the context of FLHS., (Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.)

There are few published studies on the effect of stocking density (SD) of pullets, particularly between different genetic lines. The objectives of this study were to determine if strain or SD affects musculoskeletal development of pullets and determine any impact on the productivity and keel bone health of adult hens. Lohmann Selected Leghorn Lite (LSL), Dekalb White (DW), and Lohmann Brown (LB) pullets were reared at 4 different SD (247 cm 2 /bird, 270 cm 2 /bird, 299 cm 2 /bird, and 335 cm 2 /bird) in large cages furnished with elevated perches and a platform. At 16 wk of age, the keel bone, the muscles of the breast, wings, and legs, and the long bones of the wings and legs were collected to compare keel bone development, muscle growth, and bone breaking strength (BBS) between strain (adjusted for bodyweight) and SD treatments. Stocking density did not have an effect on the metasternum length, height, or area of the keel bone, the weights of the bicep brachii, pectoralis major or pectoralis minor, or the BBS of any of the selected bones. However, strain differences were found for all keel bone characteristics, all muscle weights, and the majority of BBS measures. The keel metasternum, height, and overall area of the keel bone were found to be smaller in LB pullets compared with LSL and DW pullets (P < 0.0001); however, cartilage length and overall percentage of the cartilage present on the keel bone was greatest in LB pullets (P < 0.0001). Leg muscles were heaviest in LB pullets (P < 0.05); however, breast muscles were heavier in LSL and DW pullets (P < 0.0001). Lohmann Brown pullets had lower BBS of the tibia (P < 0.0001) and femur (P < 0.0001) compared with LSL and DW pullets, whereas DW pullets had greater BBS of the humerus (P = 0.033). Additionally, there was a higher prevalence of keel bone fractures at 50 wk of age in LB hens compared with DW (P = 0.0144). Overall, SD during rearing used in this study had little impact on the musculoskeletal growth of pullets; however, significant differences were found between strains which may reflect strain-specific behavior. Additionally, differences in keel bone development between strains may lead to differences in keel bone damage in adult hens., (Copyright © 2020. Published by Elsevier Inc.)

Bone loss is a major complication of osteomyelitis and from numerous in-vitro studies, it has been concluded that the bone lysis is caused by elevated expression of the receptor activator of nuclear factor κB ligand (RANKL), leading to increased osteoclast activity. However, we failed to find any relationship between bone loss and osseous RANKL expression in a porcine model of acute and chronic implant-associated osteomyelitis (IAO) due to Staphylococcus aureus or in chronic osteomyelitis lesions in slaughter pigs. Surprisingly, we found that the expression of RANKL was reduced during chronic bone infections. This is in line with the few studies conducted on human samples. A significant bone loss was observed in IAO lesions and in lesions from slaughter pigs, but with no indication of osteoclast involvement using histochemistry, immunohistochemistry for RANKL, receptor activator of nuclear factor kappa-B, osteoprotegerin and cathepsin K, and high-throughput quantitative real-time polymerase chain reaction on bone tissue from osteomyelitic lesions. A strong inflammatory response was seen in the infected animals and, therefore, we propose proteolytic enzymes induced by inflammation to be a major component of the bone loss. Furthermore, we found a significant upregulation of the IL26 gene in infected animals, which can inhibit RANKL-induced osteoclastogenesis, but has no homologue in mice. This finding emphasises that neither murine models nor in-vitro studies can mirror human disease development completely. The present study emphasises that the interactions between microorganisms, the immune system and bone cells in osteomyelitis are too complex to be accurately represented by an in-vitro model., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Diflufenican is used in both agricultural and urban areas to control weeds. However, in Europe pesticides are regulated using agricultural soil data only. Urban soils where the top layer is replaced by gravel (e.g. driveways, outdoor tiled areas) can evidently differ from agricultural soils in many biotic and physical properties. In the present study, we compared the degradation, mineralization, sorption and aging of diflufenican between an agricultural sandy soil to a gravel used in urban areas. Both diflufenican and its two main aerobic metabolites were investigated. Diflufenican and the metabolites degraded slower in gravel than in agricultural soil. One of the metabolites, 2-[3-(Trifluoromethyl)phenoxy]nicotinic acid (AE B107137 as identified by EFSA; further abbreviated as AE-B), was formed from the incubation of diflufenican in both soil and gravel, however, showing different formation patterns in the two materials: No accumulation of AE-B was determined in the soil, whereas in gravel, an accumulation of AE-B was determined over the full study period of 150 days. After 150 days, approximately 10% of the applied diflufenican was mineralised in the soil (cumulative), while it was not mineralised in the gravel. Diflufenican showed much stronger sorption to the soil than to the gravel, while the sorption of the metabolites was weaker than diflufenican in both soil and gravel. Within the experimental period, the influence of aging on the fate of diflufenican in soil and gravel is limited (<0.9 and <1.4%, respectively) when compared to the amount of compound still present in the soil. Overall, the results imply shortcomings in the risk assessment procedures requested for the registration of pesticides for urban areas., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: Patients with human epidermal growth factor receptor-2-negative metastatic breast cancer (MBC), whose disease progressed on prior chemotherapy, have a poor prognosis. Eribulin, a microtubule dynamics inhibitor, extends overall survival in previously treated MBC. The most common adverse event associated with eribulin is neutropenia, which may result in dose interruptions or reductions. A modified biweekly dosing schedule of eribulin was assessed for efficacy as well as improvements in hematologic toxicity., Patients and Methods: In this open-label, single-arm, multicenter, phase II study, previously treated (2-5 chemotherapy regimens for metastatic disease) patients with human epidermal growth factor receptor-2-negative MBC received intravenous eribulin 1.4 mg/m 2 over 2 to 5 minutes on days 1 and 15 of each 28-day cycle. The primary study endpoints were objective response rate (ORR; complete response [CR] + partial responses [PR]) and disease control rate (DCR; CR + PR + stable disease [SD])., Results: Among 58 treated patients, the ORR was 12% (95% confidence interval [CI], 5%-24%), DCR (CR, n = 1; PR, n = 6; SD, n = 30) was 65%, and the median progression-free survival was 3.6 months (95% CI, 2.9-4.1 months). Grade 3 or 4 neutropenia was 31%; 50% of all patients, and 78% of patients with neutropenia (all grades), received hematopoietic growth-factor support., Conclusion: The efficacy and safety results obtained with a biweekly eribulin schedule in this phase II trial appear similar to those associated with the approved eribulin schedule (1.4 mg/m 2 on days 1 and 8 of a 21-day cycle) reported in the EMBRACE study., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Nicosulfuron sorption/desorption kinetics were studied through batch sorption studies in ten volcanic ash-derived Andisol and Ultisol soils with acidic pH and variable surface charge. Two different kinetic models were used to fit the experimental data: i) Models to establish kinetic parameters (Pseudo-First and Pseudo-Second-Order), and ii) Models to describe solute transport mechanisms of organic compounds on sorbents (Intraparticle Diffusion, Dimensionless Intraparticle, Boyd, and Two-Site Nonequilibrium). Sorption kinetic data best fit the pseudo-second-order model. Application of these models to describe solute transport suggests that underlying mechanisms are complex in all soils due to: i) surface sorption, with mass transfers controlling sorption kinetics across the boundary layer; and ii) pore diffusion (i.e. intraparticle diffusion into macropores and micropores). The Freundlich model explained equilibrium sorption data in all cases (R 2 > 0.9979) with K f values higher than those reported for different class of soils (6.85-16.08 μg 1-1/n  mL 1/n  g -1 ). The hysteresis was significant in all studied soils. The lower sorption rate on Ultisols must be considered in regards to Nicosulfuron leaching potential., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: Preterm birth is a known risk factor for infant development but it is less clear whether fetal growth restriction (FGR) and early term birth between 37 and 39 weeks gestation are associated with risks for infant development., Aims: This study investigated risk factors for adverse developmental outcomes at 12 months of age in a population-based birth cohort., Study Design: Cohort study., Subjects: Participants in the Raine Study, which recruited 2900 women at 18 weeks of gestation (Gen1) and followed up infants longitudinally (Gen2). At 12 months, 1773 mothers provided developmental data for their infants., Outcome Measure: The Ages and Stages Questionnaire (ASQ) was used to measure gross and fine motor, communication, adaptability and personal social development. Multivariate logistic regression analyses were used to estimate associations between FGR, gestational age, sex, breast feeding, parental age, socioeconomic factors and developmental delay at 12 months of age as measured with the ASQ., Results: The risk of any delay at 12 months of age, as well as gross motor, fine motor and adaptive delay, was slightly increased for infants born FGR. Preterm and early term birth and male sex were associated with poorer development at 12 months. Breast feeding was protective of developmental status., Conclusions: Developmental assessment using the ASQ of infants with FGR was mostly comparable to those born without FGR at 12 months, although finer-grained neurobehavioural assessments may yield capacity for earlier identification of developmental risk. Our data provide weight to the argument that surveillance of early term infants could enable earlier intervention for children at risk., Competing Interests: Declaration of competing interest Authors have no competing interest to declare., (Crown Copyright © 2020. Published by Elsevier B.V. All rights reserved.)

Groundwater extracted for drinking water production is commonly treated by aeration and sand filtration. However, this simple treatment is typically unable to remove pesticide residues. As a solution, bioaugmentation of sand filter units (i.e., the addition of specific degrader strains) has been proposed as an alternative "green" technology for targeted pesticide removal. However, the introduced degraders are challenged by (i) micropollutant levels of target residue, (ii) the oligotrophic environment and (iii) competition and predation by the native microorganisms, leading to loss of population and degradation potential. To overcome these challenges, we propose the introduction of a novel hybrid treatment step to the overall treatment process in which reverse osmosis filtration and biodegradation are combined to remove a target micropollutant. Here, the reverse osmosis produces a concentrated retentate that will act as a feed to a dedicated biofilter unit, intended to promote biodegradation potential and stability of an introduced degrader. Subsequently, the purified retentate will be re-mixed with the permeate from reverse osmosis, for re-mineralization and downstream consumption. In our study, we investigated the effect of reverse osmosis retentates on the degradation potential of an introduced degrader. This paper provides the first promising results of this hybrid concept using the 2,6-dichlorobenzamide (BAM)-degrading bacteria Aminobacter sp. MSH1 in batch experiments, spiked with radiolabeled BAM. The results showed an increased degradation potential of MSH1 in retentate waters versus untreated water. Colony-forming units and qPCR showed a stable MSH1 population, despite higher concentrations of salts and metals, and increased growth of native bacteria., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Glyphosate is used extensively worldwide, but current evidence suggests detrimental effects on the environment, pollinators, and human health. Glyphosate adsorption kinetics and adsorption/desorption were studied through batch sorption experiments in ten typical volcanic ash-derived soils from Andisol and Ultisol orders. Two kinetic models were used to fit the experimental data: i. Models that allowed establishment of principally kinetic parameters and modeling of the adsorption process, and ii. Models described solute transport mechanisms commonly used for remediation purposes. Adsorption kinetic data were best fitted by the pseudo-second-order kinetic model and Two-Site Nonequilibrium model. These models suggest that mechanisms are complex due to rapid surface adsorption in ultisols with mass transfer controlling adsorption kinetics across the boundary layer, as indicated by the highhand lowt 1/2 values. High intraparticle diffusion into macropores and micropores was observed for Andisols. The Freundlich model accurately represented adsorption equilibrium data in all cases (R 2 > 0.9580) with comparatively higher adsorption capacity on Andisols. K f values (2.50-52.28 μg 1-1/n  mL 1/n  g -1 ) and hysteresis were significant in all studied soils. Taken together, these data suggest that Glyphosate may be adsorbed more on Andisol soils in comparison to Ultisols., (Copyright © 2019 Elsevier B.V. All rights reserved.)

This study investigates copper ore tailings deposited in Repparfjorden, Norway in the 1970's. Bathymetric show that the tailings deposit still occurs as a series of cone-shapes and has retained its original shape for four decades. Analytical data of 51 chemical elements show that some of the tailings are spreading, affecting fjord surface sediments in the inner part of the fjord. The deposited tailings are clearly enriched on the elements Ba, Bi, Cu, Hf and Zr and depleted of Ca, Li, Nb, Pb, Sc, V and Y. A hard pan horizon occurs at 20 cm sediment depth in large parts of the inner inlet, which seems to have precipitated during the deposition of tailings. New tailings were fabricated from the two local mineralisations and these display varying chemical results from each other but also in respect to the old, deposited tailings. Therefore, caution should be taken when making chemical predictions for a future deposit., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: As older gastric cancer patients are often excluded from randomized clinical trials, the most appropriate treatment strategy for these patients remains unclear. The current study aimed to gain more insight in treatment strategies and relative survival of older patients with resectable gastric cancer across Europe., Methods: Population-based cohorts from Belgium, Denmark, The Netherlands, Norway, and Sweden were combined. Patients ≥70 years with resectable gastric cancer (cT1-4a, cN0-2, cM0), diagnosed between 2004 and 2014 were included. Resection rates, administration of chemotherapy (irrespective of surgery), and relative survival within a country according to stage were determined., Results: Overall, 6698 patients were included. The percentage of operated patients was highest in Belgium and lowest in Sweden for both stage II (74% versus 56%) and stage III disease (57% versus 25%). For stage III, chemotherapy administration was highest in Belgium (44%) and lowest in Sweden (2%). Three year relative survival for stage I, II, and III disease in Belgium was 67.8% (95% CI:62.8-72.6), 41.2% (95% CI:37.3-45.2), 17.8% (95% CI:12.5-24.0), compared with 56.7% (95% CI:51.5-61.7), 31.3% (95% CI:27.6-35.2), 8.2% (95% CI:4.4-13.4) in Sweden. There were no significant differences in treatment strategies of patients with stage I disease., Conclusion: Substantial treatment differences are observed across North European countries for patients with stages II and III resectable gastric cancer aged 70 years or older. In the present comparison, treatment strategies with a higher proportion of patients undergoing surgery seemed to be associated with higher survival rates for patients with stages II or III disease., (Copyright © 2018. Published by Elsevier Ltd.)

Background & Aims: Intestinal insufficiency and intestinal failure are conditions associated with malabsorption of micro- and macronutrients. Consequently, malnutrition and ensuing alterations in body composition are common in this context and patients may have an increased risk of progressive loss of skeletal muscle mass and function (i.e. sarcopenia). We investigated the prevalence of sarcopenia in patients with intestinal insufficiency and intestinal failure and identified associated risk factors., Methods: This was a cross-sectional study including 113 clinically stable outpatients with intestinal insufficiency or intestinal failure. Body composition was assessed using bioelectrical impedance analysis and muscle function (strength or performance) using a handheld dynamometer and a timed up-and-go test. Sarcopenia was classified using the European Working Group on Sarcopenia in Older People criteria. Several parameters, including smoking, alcohol, and concurrent morbidities, were analyzed for association with sarcopenia., Results: The prevalence of sarcopenia was 53.1% (95% CI; 43.8 to 62.2) in the combined patient group. In patients with intestinal failure the prevalence of sarcopenia was 72.7% (95% CI; 59.3 to 83.0) compared to 34.5% (95% CI; 23.3 to 47.8) in those with intestinal insufficiency (OR 5.07 [95% CI; 2.27 to 11.31]; p < 0.001). Excessive alcohol consumption (OR 7.69 [95% CI; 1.50 to 39.34]; p = 0.014), intestinal failure (OR 4.16 [95% CI; 1.69 to 10.28]; p = 0.002), and inflammatory activity (OR 3.83 [95% CI; 1.06 to 12.84]; p = 0.041), were identified as independent risk factors of sarcopenia. A trend was observed for hypermetabolism in multivariate analysis (OR 7.55 [95% CI; 0.79 to 72.03]; p = 0.079)., Conclusions: Patients with intestinal insufficiency and intestinal failure are at immense risk of developing sarcopenia. Associated risk factors are excessive alcohol consumption, intestinal failure, and inflammatory activity., (Copyright © 2017 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)

Background & Aims: Intestinal insufficiency and intestinal failure are associated with malabsorption of micro- and macronutrients that may negatively influence bone metabolism and increase the risk for developing osteoporosis. However, information regarding prevalence and contribution of individual risk factors is scarce. We investigated the prevalence of osteoporosis in patients with intestinal insufficiency and intestinal failure and identified associated risk factors., Methods: This was a retrospective cross-sectional study including 167 clinically stable outpatients with intestinal insufficiency or intestinal failure. Bone mineral density (BMD) was measured by dual X-ray absorptiometry and the prevalence of osteoporosis was compared to a gender and age matched population. Several clinical and demographic parameters, including body mass index (BMI), vitamin-D, smoking habits and medications, were analyzed for association with BMD., Results: The prevalence of osteoporosis was 56.9% in the combined patient group compared to 24.1% in the control group (OR 4.2 [95% CI, 2.3 to 7.7]; p < 0.001). BMD in the hip was independently associated with BMI (0.13 [95% CI, 0.09 to 0.18]; p < 0.001) and vitamin-D levels (-0.41 [95% CI, -0.76 to -0.06]; p = 0.03). Similar associations were seen for BMD in the spine (0.15 [95% CI, 0.08 - 0.22]; p < 0.001) and (-0.60 [95% CI, -0.76 to -0.06]; p = 0.02), respectively. Trends for low BMD were observed in smokers, and in patients using glucocorticoids, opioids, and proton pump inhibitors., Conclusions: Patients with intestinal insufficiency and intestinal failure are at immense risk of developing osteoporosis. Low BMI and vitamin-D deficiency were identified as independent risk factors., (Copyright © 2017 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)

Treatment of post-traumatic and implant-associated osteomyelitis (IAO) includes surgical debridement, removal of implants and long-term antibiotic therapy. The success of antibiotic therapy relies not only on activity towards the infecting pathogen, but also on sufficient penetration of the target site. The aim of the present study was to characterize the local pathological changes associated with reduced penetration of cefuroxime to infected bone implant cavities. Previously, reduced penetration of systemically administrated cefuroxime was demonstrated in the implant cavity of 10 pigs with Staphylococcus aureus IAO present for 5 days. In the present study, a comprehensive histopathological characterization of the peri-implant bone tissue was performed and correlated with the reduced penetration of cefuroxime. In two pigs, the levels of oxygen, pyruvate and lactate was estimated in the implant cavity. A peri-implant pathological bone area (PIBA) developed with a width of 1.2 up to 3.8 mm. PIBAs included: (1) suppuration, resulting in destruction of the implant cavity contour, and (2) a non-vascular zone of primarily necrotic bone tissue. A strong negative correlation was seen between PIBA width and cefuroxime area under the concentration time curves (AUC [0-last] ) and peak concentration of cefuroxime (C max ). All metabolic measurements demonstrated hypoxia. In conclusion, subacute suppurative bone inflammation with local tissue destruction can result in decreased penetration of antibiotics and insufficient oxygen supply., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Objective: To identify factors associated with long-term treatment success after catheter-directed thrombolysis (CDT) for acute deep venous thrombosis (DVT) involving the ilio-femoral vein., Material and Methods: This was a non-randomised observational cohort study. From 1999 to 2013, 191 consecutive patients (203 limbs) attending a tertiary vascular centre at Gentofte University Hospital, Denmark underwent CDT. All patients had ultrasonically verified acute ilio-femoral DVT with open distal popliteal vein and calf veins. Patients were seen in the outpatient clinic 6 weeks, 3, 6, and 12 months, and annually thereafter following the DVT. Successful outcome was defined as patent deep veins without reflux on Duplex ultrasound scanning (DUS). Data were collected prospectively as per protocol and analysed retrospectively., Results: Median age was 27 years (range 14-74 years) and overall median lysis time was 56 h (range 22-146 h). A stent was placed in 106 limbs (52%). Six patients had major bleeding. The median follow-up was 5 years (range 1 month-14.3 years). The cumulative rate of patients with deep patent veins without reflux at 7 years was 79%. Multivariate Cox regression analyses showed that symptom duration >2 weeks (hazard ratio (HR) 2.78, 95% CI 1.14-6.73) and chronic post-thrombotic lesions (HR 19.3, 95% CI 7.29-51.2) were significantly associated with poorer outcome, while the pulse-spray technique (HR 0.15, 95% CI 0.05-0.48) was associated with better outcome. Age, gender, side, IVC atresia, stenting, and lysis duration did not affect outcome., Conclusion: In this observational study of CDT for ilio-femoral DVT it was demonstrated that symptom duration less than 2 weeks, absence of chronic post-thrombotic lesions and use of the pulse-spray technique for CDT resulted in better primary patency including normal valve function in the long term., (Copyright © 2016 European Society for Vascular Surgery. Published by Elsevier Ltd. All rights reserved.)

Aims: Outcomes for patients with oesophago-gastric cancer are variable across Europe. The reasons for this variability are not clear. The aim of this study was to describe and analyse clinical pathways to understand differences in service provision for oesophageal and gastric cancer in the countries participating in the EURECCA Upper GI group., Methods: A questionnaire was devised to assess clinical presentation, diagnosis, staging, treatment, pathology, follow-up and service frameworks across Europe for patients with oesophageal and gastric cancer. The questionnaire was issued to experts from 14 countries. The responses were analysed quantitatively and qualitatively and compared., Results: The response rate was (10/14) 71.4%. The approach to diagnosis was similar. Most countries established a diagnosis within 3 weeks of presentation. However, there were different approaches to staging with variable use of endoscopic ultrasound reflecting availability. There has been centralisation of treatments in most countries for oesophageal surgery. The most consistent area was the approach to pathology. There were variations in access to specialist nurse and dietitian support. Although most countries have multidisciplinary teams, their composition and frequency of meetings varied. The two main areas of significant difference were research and audit and overall service provision. Observations on service framework indicated that limited resources restricted many of the services., Conclusion: The principle approaches to diagnosis, treatment and pathology were similar. Factors affecting the quality of patient experience were variable. This may reflect availability of resources. Standard pathways of care may enhance both the quality of treatment and patient experience., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Background & Aim: Patients with intestinal failure (IF) are dependent on parenteral nutrition delivered through central access such as Hickman™ catheters. The peripherally inserted central catheter (PICC) is becoming increasingly popular for the purpose. The aim of the present study was to compare complication rates between the two types of catheters., Patients and Methods: Over a six-year period (2008-2014), we included 136 patients with IF receiving home parenteral nutrition (HPN). These patients had a total of 295 catheters (169 Hickman™ catheters and 126 PICCs). Data were collected by reviewing their medical records. Incidences are given per 1000 catheter days. Data are given as means ± standard deviation (SD) and compared using independent student's t-tests, Mann-Whitney-Wilcoxon, and X(2)-tests. A survival analysis for time to the first infection was conducted using Cox regression., Results: The total number of catheter days was 54,912 days for Hickman™ catheters (mean dwell time 325 ± 402) and 15,974 days for PICCs (mean dwell time 127 ± 121), respectively. The incidence of catheter-related blood stream infection (CRBSI) per 1000 catheter days was significantly lower for Hickman™ catheters compared to PICCs (0.56 vs. 1.63, p < 0.05). The mean time to first CRBSI was significantly shorter for PICCs compared to Hickman™ catheters (84 ± 94 days vs. 297 ± 387 days, p < 0.05), which was confirmed with a cox analysis corrected for age and gender. A total of 75 catheters were removed due to CRBSI, 49 Hickman™ catheters and 26 PICCs respectively. In addition, PICCs were more often removed due to local infection/phlebitis and mechanical causes (p < 0.001)., Conclusion: We found a higher risk and shorter time to first CRBSI in PICCs compared to Hickman catheters supporting that PICCs should mainly be chosen for planned HPN up to 3-6 months. We therefore conclude that the choice of catheter must still be determined on an individual basis., (Copyright © 2015 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)

Purpose: To provide an initial assessment of the safety of a recombinant adeno-associated virus vector expressing RPE65 (rAAV2-CB-hRPE65) in adults and children with retinal degeneration caused by RPE65 mutations., Design: Nonrandomized, multicenter clinical trial., Participants: Eight adults and 4 children, 6 to 39 years of age, with Leber congenital amaurosis (LCA) or severe early-childhood-onset retinal degeneration (SECORD)., Methods: Patients received a subretinal injection of rAAV2-CB-hRPE65 in the poorer-seeing eye, at either of 2 dose levels, and were followed up for 2 years after treatment., Main Outcome Measures: The primary safety measures were ocular and nonocular adverse events. Exploratory efficacy measures included changes in best-corrected visual acuity (BCVA), static perimetry central 30° visual field hill of vision (V30) and total visual field hill of vision (VTOT), kinetic perimetry visual field area, and responses to a quality-of-life questionnaire., Results: All patients tolerated subretinal injections and there were no treatment-related serious adverse events. Common adverse events were those associated with the surgical procedure and included subconjunctival hemorrhage in 8 patients and ocular hyperemia in 5 patients. In the treated eye, BCVA increased in 5 patients, V30 increased in 6 patients, VTOT increased in 5 patients, and kinetic visual field area improved in 3 patients. One subject showed a decrease in BCVA and 2 patients showed a decrease in kinetic visual field area., Conclusions: Treatment with rAAV2-CB-hRPE65 was not associated with serious adverse events, and improvement in 1 or more measures of visual function was observed in 9 of 12 patients. The greatest improvements in visual acuity were observed in younger patients with better baseline visual acuity. Evaluation of more patients and a longer duration of follow-up will be needed to determine the rate of uncommon or rare side effects or safety concerns., (Copyright © 2016 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Background: Gilles de la Tourette syndrome (GTS) is a complex neuropsychiatric disorder with a strong genetic influence where copy number variations are suggested to play a role in disease pathogenesis. In a previous small-scale copy number variation study of a GTS cohort (n = 111), recurrent exon-affecting microdeletions of four genes, including the gene encoding arylacetamide deacetylase (AADAC), were observed and merited further investigations., Methods: We screened a Danish cohort of 243 GTS patients and 1571 control subjects for submicroscopic deletions and duplications of these four genes. The most promising candidate gene, AADAC, identified in this Danish discovery sample was further investigated in cohorts from Iceland, the Netherlands, Hungary, Germany, and Italy, and a final meta-analysis, including a total of 1181 GTS patients and 118,730 control subjects from these six European countries, was performed. Subsequently, expression of the candidate gene in the central nervous system was investigated using human and mouse brain tissues., Results: In the Danish cohort, we identified eight patients with overlapping deletions of AADAC. Investigation of the additional five countries showed a significant association between the AADAC deletion and GTS, and a final meta-analysis confirmed the significant association (p = 4.4 × 10(-4); odds ratio = 1.9; 95% confidence interval = 1.33-2.71). Furthermore, RNA in situ hybridization and reverse transcription-polymerase chain reaction studies revealed that AADAC is expressed in several brain regions previously implicated in GTS pathology., Conclusions: AADAC is a candidate susceptibility factor for GTS and the present findings warrant further genomic and functional studies to investigate the role of this gene in the pathogenesis of GTS., (Copyright © 2016 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Background: Biliary tract cancer is an uncommon cancer with a poor outcome. We assembled data from the National Cancer Research Institute (UK) ABC-02 study and 10 international studies to determine prognostic outcome characteristics for patients with advanced disease., Methods: Multivariable analyses of the final dataset from the ABC-02 study were carried out. All variables were simultaneously included in a Cox proportional hazards model, and backward elimination was used to produce the final model (using a significance level of 10%), in which the selected variables were associated independently with outcome. This score was validated externally by receiver operating curve (ROC) analysis using the independent international dataset., Results: A total of 410 patients were included from the ABC-02 study and 753 from the international dataset. An overall survival (OS) and progression-free survival (PFS) Cox model was derived from the ABC-02 study. White blood cells, haemoglobin, disease status, bilirubin, neutrophils, gender, and performance status were considered prognostic for survival (all with P < 0.10). Patients with metastatic disease {hazard ratio (HR) 1.56 [95% confidence interval (CI) 1.20-2.02]} and Eastern Cooperative Oncology Group performance status (ECOG PS) 2 had worse survival [HR 2.24 (95% CI 1.53-3.28)]. In a dataset restricted to patients who received cisplatin and gemcitabine with ECOG PS 0 and 1, only haemoglobin, disease status, bilirubin, and neutrophils were associated with PFS and OS. ROC analysis suggested the models generated from the ABC-02 study had a limited prognostic value [6-month PFS: area under the curve (AUC) 62% (95% CI 57-68); 1-year OS: AUC 64% (95% CI 58-69)]., Conclusion: These data propose a set of prognostic criteria for outcome in advanced biliary tract cancer derived from the ABC-02 study that are validated in an international dataset. Although these findings establish the benchmark for the prognostic evaluation of patients with ABC and confirm the value of longheld clinical observations, the ability of the model to correctly predict prognosis is limited and needs to be improved through identification of additional clinical and molecular markers., (© The Author 2015. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

There is much debate in the pharmaceutical industry on how to translate the current guidelines on immunogenicity testing for biotherapeutics into a testing strategy that suits the specific requirements of individual drug candidates. In this paper, member companies from the European immunogenicity platform (EIP) present a consensus view on the essential requirements for immunogenicity testing of a biotherapeutic throughout the various phases of drug development, to ensure patient safety and to enable successful market entry. Our aim is to open the debate and provoke discussion on this important topic which is unique to biotherapeutic drug development. The scope of this paper is limited to aspects relevant to biotherapeutic drug development and does not include fundamental academic studies of immunogenicity. Here, we propose two pre-defined testing strategies for the detection and characterization of anti-drug antibody (ADA) responses where the different strategies are based on the phase of development for a biotherapeutic, a. without (category 1) and b. with (category 2) the expected potential to elicit ADA mediated severe clinical consequences. The harm of a potential ADA response determines which of the two testing strategies is adopted. Rather than replacing the overall risk assessment which is known to be challenging and multi-factorial, the testing strategy selection is a starting point for immunogenicity testing which adapts throughout drug development as more information becomes available. The scientific rationale on which the "case-by-case" approach advocated in white papers and guidance documents may be translated for each individual drug development program is provided and, underpins the recommendations made here., (Copyright © 2015 Elsevier B.V. All rights reserved.)