A novel framework is presented that aims to guide practitioners and decision makers toward a better understanding of the role of nature-based solutions (NBS) in the enhancement of resources ...management in cities, and the mainstreaming of NBS in the urban fabric. Existing frameworks describing the use of NBS to address urban challenges do not specifically consider circularity challenges. Thus, the new framework provides the following: (1) a comprehensive set of Urban Circularity Challenges (UCCs); (2) a set of more than fifty NBS units and NBS interventions thoroughly assessed in terms of their potential to address UCCs; and (3) an analysis of input and output resource streams, which are both required for and produced during operation of NBS. The new framework aims to facilitate the coupling of individual NBS units and NBS interventions with NBS that enable circular economy solutions.
Nature-Based Solutions (NBS) have been proven to effectively mitigate and solve resource depletion and climate-related challenges in urban areas. The COST (Cooperation in Science and Technology) ...Action CA17133 entitled “Implementing nature-based solutions (NBS) for building a resourceful circular city” has established seven urban circularity challenges (UCC) that can be addressed effectively with NBS. This paper presents the outcomes of five elucidation workshops with more than 20 European experts from different backgrounds. These international workshops were used to examine the effectiveness of NBS to address UCC and foster NBS implementation towards circular urban water management. A major outcome was the identification of the two most relevant challenges for water resources in urban areas: ‘Restoring and maintaining the water cycle’ (UCC1) and ‘Water and waste treatment, recovery, and reuse’ (UCC2). s Moreover, significant synergies with ‘Nutrient recovery and reuse’, ‘Material recovery and reuse’, ‘Food and biomass production’, ‘Energy efficiency and recovery’, and ‘Building system recovery’ were identified. Additionally, the paper presents real-life case studies to demonstrate how different NBS and supporting units can contribute to the UCC. Finally, a case-based semi-quantitative assessment of the presented NBS was performed. Most notably, this paper identifies the most typically employed NBS that enable processes for UCC1 and UCC2. While current consensus is well established by experts in individual NBS, we presently highlight the potential to address UCC by combining different NBS and synergize enabling processes. This study presents a new paradigm and aims to enhance awareness on the ability of NBS to solve multiple urban circularity issues.
River systems have undergone a massive transformation since the Anthropocene. The natural properties of river systems have been drastically altered and reshaped, limiting the use of management ...frameworks, their scientific knowledge base and their ability to provide adequate solutions for current problems and those of the future, such as climate change, biodiversity crisis and increased demands for water resources. To address these challenges, a socioecologically driven research agenda for river systems that complements current approaches is needed and proposed. The implementation of the concepts of social metabolism and the colonisation of natural systems into existing concepts can provide a new basis to analyse the coevolutionary coupling of social systems with ecological and hydrological (i.e., ‘socio-ecohydrological’) systems within rivers. To operationalize this research agenda, we highlight four initial core topics defined as research clusters (RCs) to address specific system properties in an integrative manner. The colonisation of natural systems by social systems is seen as a significant driver of the transformation processes in river systems. These transformation processes are influenced by connectivity (RC 1), which primarily addresses biophysical aspects and governance (RC 2), which focuses on the changes in social systems. The metabolism (RC 3) and vulnerability (RC 4) of the social and natural systems are significant aspects of the coupling of social systems and ecohydrological systems with investments, energy, resources, services and associated risks and impacts. This socio-ecohydrological research agenda complements other recent approaches, such as ‘socio-ecological’, ‘socio-hydrological’ or ‘socio-geomorphological’ systems, by focusing on the coupling of social systems with natural systems in rivers and thus, by viewing the socioeconomic features of river systems as being just as important as their natural characteristics. The proposed research agenda builds on interdisciplinarity and transdisciplinarity and requires the implementation of such programmes into the education of a new generation of river system scientists, managers and engineers who are aware of the transformation processes and the coupling between systems.
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•River systems have been massively transformed and are socio-ecohydrological systems.•A socio-ecohydrologically driven approach provides insights into coevolutionary processes.•Social metabolism and the colonisation of natural systems are underlying concepts.•Four research clusters analyse the transformation and coupling of society and nature.•Interdisciplinary and transdisciplinary approaches support the operationalization of the research agenda.
Multiple lepidopteran larvae feed successfully on plants containing glucosinolates despite the diverse array of toxic and deterrent breakdown products, such as isothiocyanates (ITCs), formed upon ...plant damage. While much is known about how specialist lepidopterans metabolize and tolerate glucosinolates, there is little information about the metabolic fate of these plant defense compounds in specialized herbivores. Employing
C- and
C-labeled 4-methylsulfinylbutyl glucosinolate (glucoraphanin), we identified and quantified the major detoxification products of glucosinolates and ITCs in selected specialized and generalist larvae. While specialists prevented glucosinolate hydrolysis or diverted hydrolysis to form nitriles, hydrolysis in generalists proceeded to toxic ITCs, of which a portion were conjugated to glutathione. However, a large amount of ITCs remained unmodified, which may have led to the observed negative effects on growth and development. The performance of two generalist-feeding caterpillars,
(African cotton leafworm) and
(cabbage moth) on
Col-0 and various glucosinolate-deficient mutants was investigated from hatching until pupation. We found that glucosinolates negatively affected larval growth and development, but not survival, with aliphatic glucosinolates having stronger effects than indolic glucosinolates, and the combination of the two glucosinolate types being even more detrimental to growth and development. Curiously, last instar larvae grew better on wild type than on non-glucosinolate-containing plant lines, but this could not be attributed to a change in detoxification rate or feeding behavior. Glucosinolates thus appear to be effective defenses against generalist lepidopteran herbivores at least during most stages of larval development. Nevertheless, the reversal of negative effects in the oldest instar is intriguing, and further investigation of this phenomenon may shed light on how generalists adjust their physiology to feed on diets with many different types of plant defense compounds.
Conservation science is a rapidly developing discipline, and the knowledge base it generates is relevant for practical applications. It is therefore crucial to monitor biases and trends in ...conservation literature, to track the progress of the discipline and re-align efforts where needed. We evaluated past and present trends in the focus of the conservation literature, and how they relate to conservation needs. We defined the focus of the past literature from 13 published reviews referring to 18,369 article classifications, and the focus of the current literature by analysing 2553 articles published between 2011–2015. We found that some of the historically under-studied biodiversity elements are receiving significantly more attention today, despite being still under-represented. The total proportion of articles on invertebrates, genetic diversity, or aquatic systems is 50%–60% higher today than it was before 2010. However, a disconnect between scientific focus and conservation needs is still present, with greater attention devoted to areas or taxa less rich in biodiversity and threatened biodiversity. In particular, a strong geographical bias persists, with 40% of studies carried out in USA, Australia or the UK, and only 10% and 6% respectively in Africa or South East Asia. Despite some changing trends, global conservation science is still poorly aligned with biodiversity distribution and conservation priorities, especially in relation to threatened species. To overcome the biases identified here, scientists, funding agencies and journals must prioritise research adaptively, based on biodiversity conservation needs. Conservation depends on policy makers and practitioners for success, and scientists should actively provide those who make decisions with the knowledge that best addresses their needs.
Background
Antithyroid antibodies increase the likelihood of developing overt hypothyroidism, but their clinical utility remains unclear. No large randomized controlled trial (RCT) has assessed ...whether older adults with subclinical hypothyroidism (SHypo) caused by autoimmune thyroid disease derive more benefits from levothyroxine treatment (LT4).
Objective
To determine whether older adults with SHypo and positive antibodies derive more clinical benefits from LT4 than those with negative antibodies.
Methods
We pooled individual participant data from two RCTs, Thyroid Hormone Replacement for Untreated Older Adults with Subclinical Hypothyroidism and IEMO 80+. Participants with persistent SHypo were randomly assigned to receive LT4 or placebo. We compared the effects of LT4 versus placebo in participants with and without anti–thyroid peroxidase (TPO) at baseline. The two primary outcomes were 1‐year change in Hypothyroid Symptoms and Tiredness scores on the Thyroid‐Related Quality‐of‐Life Patient‐Reported Outcome Questionnaire.
Results
Among 660 participants (54% women) ≥65 years, 188 (28.5%) had positive anti‐TPO. LT4 versus placebo on Hypothyroid Symptoms lead to an adjusted between‐group difference of −2.07 (95% confidence interval: −6.04 to 1.90) for positive antibodies versus 0.89 (−1.76 to 3.54) for negative antibodies (p for interaction = 0.31). Similarly, there was no treatment effect modification by baseline antibody status for Tiredness scores—adjusted between‐group difference 1.75 (−3.60 to 7.09) for positive antibodies versus 1.14 (−1.90 to 4.19) for negative antibodies (p for interaction = 0.98). Positive anti‐TPO were not associated with better quality of life, improvement in handgrip strength, or fewer cardiovascular outcomes with levothyroxine treatment.
Conclusions
Among older adults with SHypo, positive antithyroid antibodies are not associated with more benefits on clinical outcomes with LT4.
IntroductionMultimorbidity and polypharmacy are important risk factors for drug-related hospital admissions (DRAs). DRAs are often linked to prescribing problems (overprescribing and ...underprescribing), as well as non-adherence with drug regimens for different reasons. In this trial, we aim to assess whether a structured medication review compared with standard care can reduce DRAs in multimorbid older patients with polypharmacy.Methods and analysisOPtimising thERapy to prevent Avoidable hospital admissions in Multimorbid older people is a European multicentre, cluster randomised, controlled trial. Hospitalised patients ≥70 years with ≥3 chronic medical conditions and concurrent use of ≥5 chronic medications are included in the four participating study centres of Bern (Switzerland), Utrecht (The Netherlands), Brussels (Belgium) and Cork (Ireland). Patients treated by the same prescribing physician constitute a cluster, and clusters are randomised 1:1 to either standard care or Systematic Tool to Reduce Inappropriate Prescribing (STRIP) intervention with the help of a clinical decision support system, the STRIP Assistant. STRIP is a structured method performing customised medication reviews, based on Screening Tool of Older People’s Prescriptions/Screening Tool to Alert to Right Treatment criteria to detect potentially inappropriate prescribing. The primary endpoint is any DRA where the main reason or a contributory reason for the patient’s admission is caused by overtreatment or undertreatment, and/or inappropriate treatment. Secondary endpoints include number of any hospitalisations, all-cause mortality, number of falls, quality of life, degree of polypharmacy, activities of daily living, patient’s drug compliance, the number of significant drug–drug interactions, drug overuse and underuse and potentially inappropriate medication.Ethics and disseminationThe local Ethics Committees in Switzerland, Ireland, The Netherlands and Belgium approved this trial protocol. We will publish the results of this trial in a peer-reviewed journal.Main fundingEuropean Union’s Horizon 2020 programme.Trial registration number NCT02986425 , SNCTP000002183 , NTR6012, U1111-1181-9400.
Although adoptive T‐cell therapy has shown remarkable clinical efficacy in haematological malignancies, its success in combating solid tumours has been limited. Here, we report that PTPN2 deletion in ...T cells enhances cancer immunosurveillance and the efficacy of adoptively transferred tumour‐specific T cells. T‐cell‐specific PTPN2 deficiency prevented tumours forming in aged mice heterozygous for the tumour suppressor p53. Adoptive transfer of PTPN2‐deficient CD8+ T cells markedly repressed tumour formation in mice bearing mammary tumours. Moreover, PTPN2 deletion in T cells expressing a chimeric antigen receptor (CAR) specific for the oncoprotein HER‐2 increased the activation of the Src family kinase LCK and cytokine‐induced STAT‐5 signalling, thereby enhancing both CAR T‐cell activation and homing to CXCL9/10‐expressing tumours to eradicate HER‐2+ mammary tumours in vivo. Our findings define PTPN2 as a target for bolstering T‐cell‐mediated anti‐tumour immunity and CAR T‐cell therapy against solid tumours.
Synopsis
This study reveals a role for protein tyrosine phosphatase N2 (PTPN2) in cancer immunosurveillance and T‐cell infiltration into solid tumours. Antagonizing PTPN2 thus represents a promising therapeutic strategy for adoptive T‐cell therapy.
T‐cell‐specific PTPN2 deletion prevents tumour formation in p53+/− mice without exacerbating inflammation.
PTPN2 deletion enhances LCK‐mediated CAR T‐cell cytotoxicity.
PTPN2 deletion promotes STAT5‐mediated CXCR3 expression and CAR T‐cell homing.
PTPN2‐deficient CAR T cells eradicate solid tumours in vivo.
PTPN2 inhibition enhances the activity of human CAR T cells.
Protein tyrosine phosphatase N2 inhibits tumour T‐cell infiltration and CAR T‐cell cytotoxicity and may thus be a therapeutic target to enhance solid‐tumour immunotherapy.
A multiproxy (pollen, microcharcoal, loss-on-ignition, magnetic susceptibility and geochemistry) sequence from Lough Cullin, southeast Ireland, supported by a high-resolution radiocarbon chronology, ...modelled using Bayesian approaches, provides a record of environmental change for much of the Holocene. Following the establishment of mixed deciduous woodland, climatic deterioration was likely responsible for pronounced vegetation change and erosion, 7615–6500 cal. BC to 6245–5575 cal. BC, evidence for the ‘8.2 Kyr’ BP climate event. The so-called ‘elm decline’ is dated to 4220–3980 cal. BC and whilst there are possible indications of an anthropogenic cause, clear evidence of woodland clearance with cereal pollen is recorded at 3900–3700 cal. BC, 3790–3580 cal. BC and 3760–3650 cal. BC, during a period of clearance and farming of 320–450 years duration. A reduction in farming/settlement and woodland regeneration during the Middle Neolithic parallels the archaeological record, with low levels of activity during the Late Neolithic/Chalcolithic after 2960–2525 cal. BC, prior to increases during the Bronze Age then woodland clearance and agriculture between 1500–1410 and 1275–1000 cal. BC, corresponding with the archaeological evidence. A subsequent ‘step-wise’ reduction in human activity follows, from the latter date to 815–685 cal. BC, and a brief but pronounced cessation at 690–535 cal. BC. Renewed woodland clearance and agriculture commenced until 415–250 cal. BC. From the latter date until cal. AD 390–540, the Late Iron Age/Early Medieval period, a phase of woodland recovery is attested, followed by renewed landscape disturbance and arable agriculture in particular, continuing to the close of the record at cal. AD 780–1035.
Introduction
Inhibitors develop less frequently in haemophilia B (HB) than haemophilia A (HA). However, when present, the success of tolerization by immune tolerance induction (ITI) therapy is lower ...and the risk of complications higher.
Aim
To evaluate the use and outcome of ITI in patients with HB and inhibitors.
Methods
Subjects include singletons or siblings with a current/history of inhibitors enrolled in B‐Natural—an observational study designed to increase understanding of clinical management of patients with HB. Patients were followed for 6 months and information on demographics, medical and social history, and treatment were recorded.
Results
Twenty‐nine patients with severe HB and inhibitors were enrolled in 24 centres. Twenty‐two underwent one or more courses of ITI with or without immune suppression. Eight patients (36.4%) were successfully tolerized after the first course of ITI. One of these successes (12.5%) experienced allergic manifestations, whereas the corresponding number for the 10 treatment failures was five (50%). One of seven (14.2%) patients with large deletions and three of eight (37.5%) with nonsense mutations were tolerized at the first attempt, and all patients experiencing nephrosis either failed or were on‐going. At study end, 11 (50%) were considered successfully tolerized after one or more ITI courses, three were unsuccessful, and eight were still undergoing treatment.
Conclusion
Our data underscore the possibilities and difficulties of achieving tolerization in patients with HB with inhibitors. The type of mutation and complications appear to correlate with ITI outcome, but more accurate definitions of successful ITI are warranted.
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