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Objective: To determine the frequency of mutations known to cause autosomal dominant Parkinson disease (PD) in a series with more than 10% of Sweden's estimated number of PD patients. Methods: The Swedish Parkinson Disease Genetics Network was formed as a national multicenter consortium of clinical researchers who together have access to DNA from a total of 2,206 PD patients; 85.4% were from population-based studies. Samples were analyzed centrally for known pathogenic mutations in SNCA (duplications/triplications, p.Ala30Pro, p.Ala53Thr) and LRRK2 (p.Asn1437His, p.Arg1441His, p.Tyr1699Cys, p.Gly2019Ser, p.Ile2020Thr). We compared the frequency of these mutations in Swedish patients with published PD series and the gnomAD database. Results: A family history of PD in first- and/or second-degree relatives was reported by 21.6% of participants. Twelve patients (0.54%) carried LRRK2 p.(Gly2019Ser) mutations, one patient (0.045%) an SNCA duplication. The frequency of LRRK2 p.(Gly2019Ser) carriers was 0.11% in a matched Swedish control cohort and a similar 0.098% in total gnomAD, but there was a marked difference between ethnicities in gnomAD, with 42-fold higher frequency among Ashkenazi Jews than all others combined. Conclusions: In relative terms, the LRRK2 p.(Gly2019Ser) variant is the most frequent mutation among Swedish or international PD patients, and in gnomAD. SNCA duplications were the second most common of the mutations examined. In absolute terms, however, these known pathogenic variants in dominant PD genes are generally very rare and can only explain a minute fraction of familial aggregation of PD. Additional genetic and environmental mechanisms may explain the frequent co-occurrence of PD in close relatives.

Contains fulltext : 209315.pdf (Publisher’s version ) (Closed access), The apparent efficacy of d-cycloserine (DCS) for enhancing exposure treatment for anxiety disorders appears to have declined over the past 14 years. We examined whether variations in how DCS has been administered can account for this "declining effect". We also investigated the association between DCS administration characteristics and treatment outcome to find optimal dosing parameters. We conducted a secondary analysis of individual participant data obtained from 1047 participants in 21 studies testing the efficacy of DCS-augmented exposure treatments. Different outcome measures in different studies were harmonized to a 0-100 scale. Intent-to-treat analyses showed that, in participants randomized to DCS augmentation (n = 523), fewer DCS doses, later timing of DCS dose, and lower baseline severity appear to account for this decline effect. More DCS doses were related to better outcomes, but this advantage leveled-off at nine doses. Administering DCS more than 60 minutes before exposures was also related to better outcomes. These predictors were not significant in the placebo arm (n = 521). Results suggested that optimal DCS administration could increase pre-to-follow-up DCS effect size by 50%. In conclusion, the apparent declining effectiveness of DCS over time may be accounted for by how it has been administered. Optimal DCS administration may substantially improve outcomes. Registration: The analysis plan for this manuscript was registered on Open Science Framework (https://osf.io/c39p8/).

The circumstances under which different ecosystem service benefits can be realized differ. The benefits tend to be coproduced and to be enabled by multiple interacting social, ecological, and technological factors, which is particularly evident in cities. As many cities are undergoing rapid change, these factors need to be better understood and accounted for, especially for those most in need of benefits. We propose a framework of three systemic filters that affect the flow of ecosystem service benefits: the interactions among green, blue, and built infrastructures; the regulatory power and governance of institutions; and people's individual and shared perceptions and values. We argue that more fully connecting green and blue infrastructure to its urban systems context and highlighting dynamic interactions among the three filters are key to understanding how and why ecosystem services have variable distribution, continuing inequities in who benefits, and the long-term resilience of the flows of benefits.

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© 2018 Elsevier Ltd Industrial energy efficiency is crucial for energy cost saving and sustainable competitiveness, but its potential is not exploited due to several barriers. Previous literature has pointed out that, among the most effective means, energy management in industrial companies could bring a valuable contribution. Therefore, it is crucial to assess and evaluate the energy management status in an organisation so to undertake the most appropriate improvement actions. So far, literature has neither described the fundamental characteristics of energy management practices, nor specifically developed an assessment model to support industrial decision-makers. Stemming from those research gaps, the present work presents and discusses an innovative energy management assessment model based on a novel characterization of energy management practices. We validated and applied the model through case studies among large Italian and Swedish manufacturing companies, both proving the model to be able to thoroughly describe the energy management status and benchmarking the adoption level of energy management practices with respect to specific baselines. The model highlights both strengths and critical areas in an industrial company's energy management, thus offering a valuable support to drive further improvement activities. The work concludes with interesting suggestions for industrial decision-makers and policy-makers, sketching also some further research avenues.

Oral PresentationsMeeting Abstract: 7.3-O6

This paper investigates the role of caregiver mental health and parenting practices as predictors of attachment in children with intellectual disability/developmental delay, comparing between children with ASD (n = 29) and children with other developmental disabilities (n = 20). Parents reported that children with ASD had high levels of anxiety and stress, and attachment insecurity in children (less closeness and more conflict in attachment relationships, and more inhibited attachment behaviours) compared with children with other developmental disabilities. Children's attachment quality was associated with parenting practices and the presence of an ASD diagnosis. These results highlight the bidirectional nature of the quality of caregiving environments and attachment in children with ASD, and also provide a strong rationale for targeting children's attachment quality in early interventions.Copyright © 2018, Springer Science+Business Media, LLC, part of Springer Nature.

T-cell prolymphocytic leukemia (T-PLL) is a rare and poor-prognostic mature T-cell malignancy. Here we integrated large-scale profiling data of alterations in gene expression, allelic copy number (CN), and nucleotide sequences in 111 well-characterized patients. Besides prominent signatures of T-cell activation and prevalent clonal variants, we also identify novel hot-spots for CN variability, fusion molecules, alternative transcripts, and progression-associated dynamics. The overall lesional spectrum of T-PLL is mainly annotated to axes of DNA damage responses, T-cell receptor/cytokine signaling, and histone modulation. We formulate a multi-dimensional model of T-PLL pathogenesis centered around a unique combination of TCL1 overexpression with damaging ATM aberrations as initiating core lesions. The effects imposed by TCL1 cooperate with compromised ATM toward a leukemogenic phenotype of impaired DNA damage processing. Dysfunctional ATM appears inefficient in alleviating elevated redox burdens and telomere attrition and in evoking a p53-dependent apoptotic response to genotoxic insults. As non-genotoxic strategies, synergistic combinations of p53 reactivators and deacetylase inhibitors reinstate such cell death execution.

T-cell prolymphocytic leukemia (T-PLL) is a rare and aggressive neoplasm of mature T-cells with an urgent need for rationally designed therapies to address its notoriously chemo-refractory behavior. The median survival of T-PLL patients is <2 years and clinical trials are difficult to execute. Here we systematically explored the diversity of drug responses in T-PLL patient samples using an ex vivo drug sensitivity and resistance testing platform and correlated the findings with somatic mutations and gene expression profiles. Intriguingly, all T-PLL samples were sensitive to the cyclin-dependent kinase inhibitor SNS-032, which overcame stromal-cell-mediated protection and elicited robust p53-activation and apoptosis. Across all patients, the most effective classes of compounds were histone deacetylase, phosphoinositide-3 kinase/ AKT/mammalian target of rapamycin, heat-shock protein 90 and BH3-family protein inhibitors as well as p53 activators, indicating previously unexplored, novel targeted approaches for treating T-PLL. Although Janus-activated kinase-signal transducer and activator of transcription factor (JAK-STAT) pathway mutations were common in T-PLL (71% of patients), JAK-STAT inhibitor responses were not directly linked to those or other T-PLL-specific lesions. Overall, we found that genetic markers do not readily translate into novel effective therapeutic vulnerabilities. In conclusion, novel classes of compounds with high efficacy in T-PLL were discovered with the comprehensive ex vivo drug screening platform warranting further studies of synergisms and clinical testing.

Urban green infrastructure (UGI) is a promising concept when developing multifunctional green space systems to address major challenges of urbanisation such as increasing social cohesion, promoting the transition to a green economy, adaptation to climate change and conservation of biodiversity. In response to the European Commission’s Communication on Green Infrastructure from 2013, the GREEN SURGE project aimed to further advance the development of UGI in European cities by (i) strengthening the conceptual foundations of UGI, (ii) developing improved methods and tools for assessment of its state, benefits and governance and, (iii) applying these to build a stronger evidence base. This paper aims to provide an overall synthesis of the project’s main achievements.GREEN SURGE adopted an inter- and transdisciplinary approach. Urban Learning Labs and focal Learning Alliances in five cities were instrumental for intensive collaboration between disciplines and across science and practice. Pan-European surveys, e.g. of planning and governance practice or human-nature interactions established the state-of-the-art across the continent and identified good practices.The project consolidated green infrastructure planning and governance conceptually, and it mapped opportunities for better linking government-led planning with bottom-up initiatives for creating and managing UGI. It also introduced a framework for knowledge integration to support UGI valuation. Importantly, development and application of the concept of biocultural diversity gave new insights into human–nature relationships in multicultural urban societies. The results strongly call for more context-sensitive development of UGI that addresses the different needs and diverse cultural practices of people engaging with nature.In a nutshell, GREEN SURGE showed that UGI indeed can make a major contribution to sustainable and resilient urbanisation. Transdisciplinary research in urban labs, if well-conceived, has shown to

BACKGROUND: Patients with aneurysmal subarachnoid hemorrhage (aSAH) have poor outcome. Studies on outcome beyond 1 year post-aSAH are few, and late recovery is poorly investigated, initiating this prospective outcome study on patients 12-15 years after an aSAH. We hypothesized to find; functional improvement > 1 year post-ictus; increased long-term mortality in aSAH patients vs matched controls, and finally to present; predictors of long-term favorable outcome (GOS 4-5). METHODS: We prospectively investigated patients, admitted 2000-2003 to the Sahlgrenska University Hospital, 1 year post-ictus using Glasgow Outcome Scale (GOS). The patients were revalidated 12-15 years post-aSAH by structured-telephone interviews (GOS), followed by statistical analysis. RESULTS: A total of 158 patients were included, (women n = 114, men n = 44), with a mean age of 55 years at aSAH. Patients treated with surgical clipping had lower mortality. At the follow-up 12-15 years post-aSAH, all 103 survivors (65.2%) were categorized as having; good recovery (39.9%), moderate disability (15.2%), or severe disability (10.1%). Within the patient cohort, 23.6% improved GOS over time. Fifty-five patients died, median at 4 years post-ictus. aSAH patients had 3.5 times increased mortality 12-15 years post-ictus vs matched controls (P < .0001). Patients with favorable outcome at 1 year (67.3%, n = 101) had similar survival probability as control patients. Prognostic indicators of long-term favorable outcome were low age and high GOS at 1-year follow-up, (AUCROC, 0.79). CONCLUSIONS: Individual functional improvement was found >1 year post-ictus. Patients with favorable outcome at 1 year had similar long-term life expectancy as the general population. Indicators of long-term favorable prognosis were low age at ictus and high GOS at 1-year follow-up.