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Two key goals for sustainable spatial planning are to promote low-carbon travel in daily life and to enhance human wellbeing through diverse human-environment interactions. Yet, the integration of these goals has been underexplored. This study investigates the potential for experiential diversity via active travel in different residential contexts within the Gävle city-region, Sweden. Over 15 months, we collected spatiotemporal data from 165 participants, analyzing 4,362 reported experiences and 13,192 GPS-derived travel trajectories. Our analysis uncovered a significant spatial discrepancy: while the travelled distances to locations of positive experiences typically ranged from 1.5 km to 5 km, active travel predominated only within 1.5 km. This discrepancy persisted across urban, suburban, and peripheral contexts. Although residents in different contexts reported the same types of experiences, urban dwellers travelled about 50 % farther for nature experiences compared with other positive experiences, whereas peripheral dwellers travelled twice the distance for urbanicity experiences compared with other positive experiences. Consequently, urban residents mostly relied on active travel for urbanicity experiences and motorised travel for nature experiences, with the reverse trend observed among peripheral dwellers. These results illustrate the importance of spatial scale for promoting diverse positive experiences via active travel, regardless of residential context. Effective planning strategies may include enhancing environmental diversity near homes and developing infrastructure that favours active over motorised travel for short to moderate distances.

Fume hoods in laboratories consume the energy equivalent of up to four American households per hood; however, closing a modern hood’s sash completely can save up to 75% of that energy. Past efforts have attempted to harness this potential energy reduction by reminding users to close the sash when a hood is not in use. In this work, we developed a device to measure the efficacy of these energy-saving methods. The device records the position of the sash and detects motion to determine whether a user is present, and, when fitted with a piezoelectric buzzer, can audibly alert users to close the sash when not in use. We installed this device in laboratories to quantify the energy and cost savings resulting from real-time audible feedback and found that the alarm reduced wasted energy by 87 to 98%. In addition, the platform demonstrated here can be used to quantitatively test other energy-saving methods that rely on user behavioral change in future work. Keywords: Energy savings, Behavioral modification, Active feedback, Motion detection

Background: With continued increase in the use of mechanical circulatory support, the incidence of device thrombus remains a challenge. This study is a retrospective analysis of data at a single center to assess the safety and efficacy of thrombolytic use in durable mechanical assist devices. Methods: Data was analyzed retrospectively from 154 patients who underwent left ventricular assist device (LVAD) implantation from 1/1/2005 to 6/30/2014. The HMII device was implanted in 131 patients while 23 received the HVAD. LVAD thrombus was diagnosed when lactate dehydrogenase levels exceeded 1000 units/l accompanied by clinical signs of hemolysis and heart failure, echocardiographic data and surges in pump power. TPA (tissue plasminogen activator) protocol consisted of a 5 mg intravenous bolus followed by 3 mg/h infusion in normal saline for 10 h. If symptoms persisted another cycle of TPA at 1 mg/h was continued up to 48 h. Results: The TPA group had a 70% success rate. Success was defined as complete resolution of hemolysis and clinical symptoms with no requirement for LVAD exchange at 30 days. 95% survival was noted at 30 days and 90% were free of a hemorrhagic stroke in the TPA group. The rates of hemorrhagic strokes in the TPA group and the control group were not different (OR = 0.92). Conclusion: The TPA protocol described here was successful consistently. Though this study is limited by its size and retrospective nature it leads the way for larger studies to generate more robust comparisons between different types of mechanical assist devices as well as the tailored use of thrombolytics in this patient population.

Background & Aims: Angiocrine signaling by liver sinusoidal endothelial cells (LSECs) regulates hepatic functions such as growth, metabolic maturation, and regeneration. Recently, we identified GATA4 as the master regulator of LSEC specification during development. Herein, we studied the role of endothelial GATA4 in the adult liver and in hepatic pathogenesis., Methods: We generated adult Clec4g-icre tg/0 xGata4 fl/fl (Gata4 LSEC-KO ) mice with LSEC-specific depletion of Gata4. Livers were analyzed by histology, electron microscopy, immunohistochemistry/immunofluorescence, in situ hybridization, and LSECs were isolated for gene expression profiling, ChIP- and ATAC-sequencing. Partial hepatectomy was performed to assess regeneration. We used choline-deficient, l-amino acid-defined (CDAA) diet and chronic carbon tetrachloride exposure to model liver fibrosis. Human single cell RNA-seq data sets were analyzed for endothelial alterations in healthy and cirrhotic livers., Results: Genetic Gata4 deficiency in LSECs of adult mice caused perisinusoidal liver fibrosis, hepatopathy and impaired liver regeneration. Sinusoidal capillarization and LSEC-to-continuous endothelial transdifferentiation were accompanied by a profibrotic angiocrine switch involving de novo endothelial expression of hepatic stellate cell-activating cytokine PDGFB. Increased chromatin accessibility and amplification by activated MYC mediated angiocrine Pdgfb expression. As observed in Gata4 LSEC-KO livers, CDAA diet-induced perisinusoidal liver fibrosis was associated with GATA4 repression, MYC activation and a profibrotic angiocrine switch in LSECs. Comparison of CDAA-fed Gata4 LSEC-KO and control mice demonstrated that endothelial GATA4 indeed protects against dietary-induced perisinusoidal liver fibrosis. In human cirrhotic livers, GATA4-positive LSECs and endothelial GATA4 target genes were reduced, while non-LSEC endothelial cells and MYC target genes including PDGFB were enriched., Conclusions: Endothelial GATA4 protects against perisinusoidal liver fibrosis by repressing MYC activation and profibrotic angiocrine signaling at the chromatin level. Therapies targeting the GATA4/MYC/PDGFB/PDGFRβ axis offer a promising strategy for prevention and treatment of liver fibrosis., Lay Summary: The liver vasculature is supposed to play a major role in the development of liver fibrosis and cirrhosis, which can lead to liver failure and liver cancer. Herein, we discovered that structural and transcriptional changes induced by genetic deletion of the transcription factor GATA4 in the hepatic endothelium were sufficient to cause liver fibrosis. Activation of the transcription factor MYC and de novo expression of the "angiocrine" growth factor PDGFB were identified as downstream drivers of fibrosis and as potential therapeutic targets for this potentially fatal disease., Competing Interests: Conflict of interest The authors declare no competing interests. Please refer to the accompanying ICMJE disclosure forms for further details., (Copyright © 2020 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Downregulation of ubiquitin (Ub) ligase activity prevents premature ubiquitination and is critical for cellular homeostasis. Nedd4 Ub ligases share a common domain architecture and yet are regulated in distinct ways through interactions of the catalytic HECT domain with the N-terminal C2 domain or the central WW domain region. Smurf1 and Smurf2 are two highly related Nedd4 ligases with ~70% overall sequence identity. Here, we show that the Smurf1 C2 domain interacts with the HECT domain and inhibits ligase activity in trans. However, in contrast to Smurf2, we find that full-length Smurf1 is a highly active Ub ligase, and we can attribute this striking difference in regulation to the lack of one WW domain (WW1) in Smurf1. Using NMR spectroscopy and biochemical assays, we identified the WW1 region as an additional inhibitory element in Smurf2 that cooperates with the C2 domain to enhance HECT domain binding and Smurf2 inhibition. Our work provides important insights into Smurf regulation and highlights that the activities of highly related proteins can be controlled in distinct ways., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Biologic therapies have shown high efficacy in psoriasis, but individual response varies and is poorly understood. To inform biomarker discovery in the Psoriasis Stratification to Optimise Relevant Therapy (i.e., PSORT) study, we evaluated a comprehensive array of omics platforms across three time points and multiple tissues in a pilot investigation of 10 patients with severe psoriasis, treated with the tumor necrosis factor (TNF) inhibitor, etanercept. We used RNA sequencing to analyze mRNA and small RNA transcriptome in blood, lesional and nonlesional skin, and the SOMAscan platform to investigate the serum proteome. Using an integrative systems biology approach, we identified signals of treatment response in genes and pathways associated with TNF signaling, psoriasis pathology, and the major histocompatibility complex region. We found association between clinical response and TNF-regulated genes in blood and skin. Using a combination of differential expression testing, upstream regulator analysis, clustering techniques, and predictive modeling, we show that baseline samples are indicative of patient response to biologic therapies, including signals in blood, which have traditionally been considered unreliable for inference in dermatology. In conclusion, our pilot study provides both an analytical framework and empirical basis to estimate power for larger studies, specifically the ongoing PSORT study, which we show as powered for biomarker discovery and patient stratification., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

JNJ-63623872 (formally known as VX-787; referred to here as JNJ872) is an orally bioavailable compound, which is in phase II clinical trials for the treatment of influenza A virus (IAV) infections. Here we show that JNJ872 inhibits at nanomolar concentrations the transcription of viral RNA in IAV-infected human macrophages by targeting a highly conserved site on the cap-snatching domain of influenza polymerase basic 2 protein (PB2). Furthermore, even lower concentrations of JNJ872 protected macrophages from IAV-mediated death when given in combination with 100 nM gemcitabine, which also attenuated transcription and replication of viral RNA. Importantly, treating human macrophages with JNJ872 allowed expression of many immune-related and other genes, involved in antiviral responses, such as indoleamine 2,3-dioxygenase 1 (IDO), and cytosolic 5'-nucleotidase 3A (NT5C3A). Moreover, our targeted metabolomics analysis indicate that treatment with JNJ782 did not interfere with metabolic responses to infection, which further supported our transcriptomics results. Thus, VX-737 alone or in combination with other drugs could be beneficial for treating IAV infected patients, because it would allow the development of antiviral responses and, thereby, protect individuals from current and future infections with closely related IAV strains., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Objective: In chronic inflammation, prevention of cAMP degradation by phosphodiesterase-4 (PDE4) inhibition can be anti-inflammatory therapy. However, PDE4 inhibition was uneffective in rheumatoid arthritis (RA). Recent studies demonstrated that PDE4/β-arrestin interaction at β-adrenoceptors resulted in switching from Gαs to Gαi signaling and ERK1/2 activation. Such a switch in signaling might elicit proinflammatory effects. We aimed to investigate this possible Gαs to Gαi signaling switch in RA and osteoarthritis (OA) mixed synoviocytes., Methods: Synoviocytes were treated alone or with combinations of adrenergic, dopaminergic, and adenosinergic drugs, rolipram (PDE4 inhibitor), inhibitors of Gαi signaling (pertussis toxin), and blockers of protein kinase A (PKA). Under normoxic or hypoxic conditions, proinflammatory TNF was the readout-parameter. We investigated co-expression and interaction of PDE4 and β-arrestin by imaging techniques. Expression of pERK1/2 was analyzed by western blotting., Results: Mixed synoviocytes in RA and OA possessed all major Gαs-coupled neurotransmitter receptors. Under hypoxia, particularly in RA cells, Gαs-coupled receptor agonists unexpectedly increased TNF and respective antagonists decreased TNF. Under hypoxia, rolipram alone or rolipram plus Gαs agonists increased TNF, which was reversed by pertussis toxin or PKA inhibition. Co-localization and interaction of PDE4 and β-arrestin in synovial tissue and cells was demonstrated. Gαs agonists or rolipram plus Gαs agonists increased pERK1/2 expression., Conclusions: This study in human arthritic synovial tissue presents an unexpected proinflammatory switch from Gαs to Gαi signaling, which depends on PDE4/β-arrestin interaction. This phenomenon is most probably responsible for reduced efficacy of PDE4 inhibitors and Gαs agonists in RA., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Quality of pork from pigs raised either traditionally (outdoor access or bedded settings with no sub-therapeutic antibiotics or growth promotants in feed) or conventionally (commercial indoor) was evaluated. Pork loins (m. longissimus thoracis et lumborum, LTL) from four hundred pigs from either traditional or conventional production systems (n=200) fed commercially formulated diets ad libitum were harvested at slaughter. Intramuscular crude fat content and lean color (L* and b*) values were significantly decreased in conventional pork loins. LTL from conventionally-raised pig carcasses showed increased (P<0.05) mean pH, moisture content and reduced cooking loss and shear force values and had increased tenderness and juiciness scores compared to those from traditionally-raised pig carcasses. Results indicated that pork from conventionally raised pigs was superior to that from traditionally raised pigs in terms of tenderness and juiciness, suggesting that consumers may value pork from traditionally raised pigs on the basis of factors other than eating quality and appearance., (© 2013.)

A qualitative interview based study on ways of addressing and managing domestic violence (DV) by general practitioners (GPs) is presented. Problem centred semi-structured topic-guided interviews were conducted with 10 male and nine female GPs. Transcribed passages were analysed with the deductive approach of qualitative content analysis. Female doctors gave broader definitions of DV. Addressing of DV by a patient was perceived as a demand to act by all doctors. Documentation of injuries was considered to be important. Time constraints, feelings of being ashamed and helpless were described as barriers in addressing DV. Female doctors reported being anxious about losing their professional distance in cases of female victims. While female participants tend to take an 'acting' role in managing cases of DV by being responsible for treatment and finding a solution in collaboration with the patient, male doctors preferred an 'organising' role, assisting patients finding further help. Definitions of DV and differences in addressing the issue seemed to be strongly affected by personal professional experience. Definitions of DV, personal barriers in addressing the subject and understanding of the own role in management and treatment of DV cases differed between male and female doctors. Pre-existing definitions of DV, personal experience and gender aspects have to be taken into account when planning educational programmes for GPs on the issue of DV., (Copyright © 2013 Elsevier Ltd and Faculty of Forensic and Legal Medicine. All rights reserved.)

Recent discoveries relating depression to inflammation and immune function may help to solve an important evolutionary puzzle: If depression carries with it so many negative consequences, including notable costs to survival and reproduction, then why is it common and heritable? What countervailing force or compensatory advantage has allowed susceptibility genes for depression to persist in the population at such high rates? A priori, compensatory advantages in combating infection are a promising candidate, given that infection has been the major cause of mortality throughout human history. Emerging evidence on deeply rooted bidirectional pathways of communication between the nervous and immune systems further supports this notion. Here we present an updated review of the "infection-defense hypothesis" of depression, which proposes that moods-with their ability to orchestrate a wide array of physical and behavioral responses-have played an adaptive role throughout human history by helping individuals fight existing infections, as well as helping both individuals and their kin avoid new ones. We discuss new evidence that supports several key predictions derived from the hypothesis, and compare it with other major evolutionary theories of depression. Specifically, we discuss how the infection-defense hypothesis helps to explain emerging data on psychoimmunological features of depression, as well as depression's associations with a diverse array of conditions and illnesses-including nutritional deficiencies, seasonal changes, hormonal fluctuations, and chronic diseases-that previous evolutionary theories of depression have not accounted for. Finally, we note the potential implications of the hypothesis for the treatment and prevention of depression., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Background: Surgical safety checklists, such as the perioperative time-out, have been shown to improve performance on a variety of patient safety measures. A variety of methods have been used to assess compliance with the perioperative time-out, but no standardized methodology with a reliable observer group currently exists. An observation-based methodology was used to assess time-out compliance at an academic medical center., Methods: A single observer group made up of medical students and nurses recorded compliance with each of the 11 standardized items of the time-out. A total of 193 time-out procedures were observed, 48 by medical students and 145 by nurses., Results: One item (procedure to be performed) achieved > 95% compliance. Three items (surgical site; availability of necessary blood products, implants, devices; and start of antibiotics) achieved 80%-95% compliance. Seven items achieved < 80% compliance (presence of required members of procedure team, presence of person who marked patient, patient identity, side marking, relevant images, allergies, and discussion of relevant special considerations). Compliance with the four core time-out items was 78.2%. Of the 11 items on the time-out being evaluated, there was a statistically significant difference between medical student and nursing observations for 10 items (p < .05)., Conclusions: In our cohort of observed time-outs, the compliance rate was low, calling into question time-out quality, and, more importantly, patient safety. Measures must be taken by large hospitals to regularly audit time-out compliance and create effective programming to improve performance. Although observational assessment is an effective method to assess compliance with surgical safety checklists, observer group bias has the potential to skew results.

Empathy is the ability to perceive and understand other people's emotions and to react appropriately. This ability is a necessary prerequisite for successful interpersonal interaction. Empathy is a multifaceted construct including low-level mechanisms like emotional contagion as well as high-level processes like perspective-taking. The ability to empathize varies between individuals and is considered a stable personality trait: some people are generally more successful in empathizing than others. In this chapter we will first present different conceptualizations of the construct of empathy, and refer to empathy-regulating processes as well as to the relationship between empathy and social behavior. Then, we will review peripheral physiological and brain imaging studies pertaining to low- and high-level empathic processes, empathy-modulating processes, and the link between empathy and social behavior. Further, we will present evidence regarding interindividual differences in these processes as an important source of information for solving the conundrum of how the comprehension of others' emotions is achieved by our brains.

Advances in electronic medical record capabilities enable clinical reminders to inform providers when recommended actions are "due" for a patient. Despite evidence that they improve adherence to guidelines, the Veteran's Health Administration (VHA) has experienced challenges in having providers consistently use clinical reminders as intended. In this paper, we describe how multiple methods were used to opportunistically triangulate, or "bootstrap," an understanding of barriers to the effective use of clinical reminders in the VHA. In an initial study using ethnographic observations and semi-structured interviews of HIV clinical reminders, we identified six barriers to effective use: workload, time to remove inapplicable reminders, false alarms, training, reduced eye contact, and the use of paper forms rather than software. In a second study, we collected open-ended and closed-ended data regarding barriers and facilitators to the use of clinical reminders in general in the VHA through a survey of 261 participants at a national informatics meeting, where 104 of 142 VHA health care facilities were represented. The findings from the second study extended our understanding of the previously identified barriers. In addition, four new barriers were identified: ease of use issues, accessibility of workstations, resident physicians and trainees, and administration benefiting more than providers from clinical reminder use. We discuss potential implications regarding the similarities and differences in study findings for factors to consider in planning interventions to improve clinical reminder use.

BM-40 (Osteonectin, SPARC) is the most abundant glycoprotein secreted by human osteoblasts. In situ hybridization studies on the expression of BM-40 mRNA in murine tissues have demonstrated the highest levels of transcripts in bone, but expression was also observed in several other mesenchymal tissues. In contrast, little is known about the expression of BM-40 in human tissues, especially in skin. Total RNA obtained from normal human skin was analyzed by northern blotting and revealed a marked expression of BM-40. To analyze its expression in vivo, in situ hybridization was performed, demonstrating that BM-40 is expressed in fibroblasts, smooth muscle, and endothelial cells in the dermis. Interestingly, BM-40 mRNA was also detected throughout the basal, spinous, and granular layers in the epidermis of adult human skin. Further analysis by immunohistochemistry revealed a marked deposition in the dermis that was most intense directly below the basement membrane in the papillary dermis and around vascular as well as glandular structures. In the epidermis, BM-40 protein could be detected intercellularly in suprabasal layers. This finding is further supported by the intercellular deposition of BM40 detected by immunofluorescence in cultured keratinocytes. This study demonstrates that BM-40 that has previously been thought to be exclusively expressed in extracellular matrix producing cells may in fact play a role in differentiation and maintenance of the epidermis.