Incorporating Systems Engineering Methodologies to Increase the Transferability of Journey Planners

AbstractOne characteristic that is highly desired in transportation-related applications, and particularly journey planners, is transferability – i.e., the capacity to be used with minimal modification in different locations. To achieve transferability, the initial design must take into account all factors that may diverge between locations, including existing modes of transport, the availability of required data, the technological habits of users, etc. In consequence, a highly transferable system is difficult and expensive to develop and maintain. A very flexible initial design, one ensuring low-cost adaptability of the system for different cities, regions, or countries, might not be cost-effective. On the other hand, a rigid design, tailored for a specific location, might act as a barrier to implementing the system elsewhere. This dilemma has motivated researchers to seek a structured process for selecting the most promising design, one that will realize the benefits of transferability while minimizing development costs.One of the fundamental building blocks of structured design in SE is requirements-design exploration. This paper evaluates the use of Multi-Attribute Tradespace Exploration (MATE), a leading design exploration process, for the effective design of journey planners.We examine the process of changeability assessment (e.g., transferability) in light of the goals of journey planning from the point of view of different stakeholders: travelers, private developers, and transport authorities. The analysis demonstrates how tradespace exploration can also be used to identify specific designs that bridge the gap between the public and private sectors and provide value over time to all parties. Moreover, when specific concerns of public authorities are not met, tradespace exploration can reveal measures the public sector can take (financial or others) for making their preferred design attractive to the private sector as well

Implementing best practice occupational therapist-led environmental assessment and modification to prevent falls: A qualitative study of two regional and rural public health services in Australia

Background: Occupational therapist-led environmental assessment and modification (EAM) is effective in reducing falls for populations at high risk. Two regional and rural public health services in Queensland devised an implementation strategy to embed best practice occupational therapist-led EAM. Methods: A qualitative study was conducted to compare the determinants of implementation success across the different health services, using the COM-B model of behaviour change. Six semi-structured interviews were completed with occupational therapists involved at each site, following 12 months of implementation. Interview data were triangulated with minutes from three combined site steering committee meetings, eight local steering committee meetings, and field notes. Thematic analysis was completed to compare barriers and facilitators to best practice uptake of EAM and differences in outcomes between the two sites. Results: Both sites commenced implementation with similar states of capability and motivation. After 12 months, one site considered that practice change had been embedded as noted in steering committee minutes and comments; however, the other site observed limited progress. According to the COM-B analysis, opportunity (the factors that lie outside the individual’s control) had a significant influence on how both sites were able to respond to the practice change and navigate some of the unexpected challenges that emerged, including the COVID-19 pandemic. Existing team structure, multiple responsibilities of key stakeholders, differences in access to resources, and lack of connection between complementary services meant that COVID-19 disruptions were only a catalyst for unveiling other systemic issues. Conclusion: This study highlights the power of external factors on influencing behaviour change for best practice implementation. Learnings from the study will provide deeper understanding of completing implementation projects in regional and rural contexts and support the future implementation of EAM in occupational therapy clinical settings

An international survey of adherence to Surviving Sepsis Campaign Guidelines 2016 regarding fluid resuscitation and vasopressors in the initial management of septic shock

BACKGROUND: Our survey aimed to evaluate adherence to Surviving Sepsis Campaign (SSC) Guidelines 2016 among intensive care practitioners and to identify issues that remain controversial or lack clarity. METHODS: Members of the European Society of Intensive Care Medicine (ESICM) were surveyed using an anonymous web-based survey written by an international group of experts. The primary outcome measure was the rate of adherence to specific recommendations. Secondary outcomes were to describe areas of controversy and lack of data and to associate specific practices with clinician characteristics. RESULTS: Overall 820 questionnaires were completed. The SCC recommendations 2016 most adhered to were the choice of norepinephrine as first-line vasoactive drug (96.5%), vasopressor prescription based on therapeutic goal rather than dose (83.4%), targeting a specific mean arterial blood pressure during vasopressor use (77.9%), monitoring of blood pressure invasively (62.8%) and adding vasopressin or epinephrine as a second vasoactive agent (83.4%). We identified an internal conflict with regards to parallel versus sequential administration of fluids and vasoactive drugs and regional differences in practice that may be related to drug availabilities. CONCLUSION: The use of vasopressors and fluid use in septic shock is largely compliant with current guidelines but several controversies should be addressed in future guideline iterations

Cognitive Information Processing

Contains research objectives and summary of research on fourteen research projects and reports on four research projects.Joint Services Electronics Program (Contract DAAB07-75-C-1346)National Science Foundation (Grant EPP74-12653)National Science Foundation (Grant ENG74-24344)National Institutes of Health (Grant 2 PO1 GM19428-04)Swiss National Funds for Scientific ResearchM.I.T. Health Sciences Fund (Grant 76-11)National Institutes of Health (Grant F03 GM58698)National Institutes of Health (Biomedical Sciences Support Grant)Associated Press (Grant

Macrophage-derived IL-1β and TNF-α regulate arginine metabolism in neuroblastoma

© 2018 American Association for Cancer Research. Neuroblastoma is the most common childhood solid tumor, yet the prognosis for high-risk disease remains poor. We demonstrate here that arginase 2 (ARG2) drives neuroblastoma cell proliferation via regulation of arginine metabolism. Targeting arginine metabolism, either by blocking cationic amino acid transporter 1 (CAT-1)-dependent arginine uptake in vitro or therapeutic depletion of arginine by pegylated recombinant arginase BCT-100, significantly delayed tumor development and prolonged murine survival. Tumor cells polarized infiltrating monocytes to an M1-macrophage phenotype, which released IL1b and TNFa in a RAC-alpha serine/threonine-protein kinase (AKT)-dependent manner. IL1b and TNFa established a feedback loop to upregulate ARG2 expression via p38 and extracellular regulated kinases 1/2 (ERK1/2) signaling in neuroblastoma and neural crest-derived cells. Proteomic analysis revealed that enrichment of IL1b and TNFa in stage IV human tumor microenvironments was associated with a worse prognosis. These data thus describe an immune-metabolic regulatory loop between tumor cells and infiltrating myeloid cells regulating ARG2, which can be clinically exploited

A Feature-Based Approach to Modeling Protein–DNA Interactions

Transcription factor (TF) binding to its DNA target site is a fundamental regulatory interaction. The most common model used to represent TF binding specificities is a position specific scoring matrix (PSSM), which assumes independence between binding positions. However, in many cases, this simplifying assumption does not hold. Here, we present feature motif models (FMMs), a novel probabilistic method for modeling TF–DNA interactions, based on log-linear models. Our approach uses sequence features to represent TF binding specificities, where each feature may span multiple positions. We develop the mathematical formulation of our model and devise an algorithm for learning its structural features from binding site data. We also developed a discriminative motif finder, which discovers de novo FMMs that are enriched in target sets of sequences compared to background sets. We evaluate our approach on synthetic data and on the widely used TF chromatin immunoprecipitation (ChIP) dataset of Harbison et al. We then apply our algorithm to high-throughput TF ChIP data from mouse and human, reveal sequence features that are present in the binding specificities of mouse and human TFs, and show that FMMs explain TF binding significantly better than PSSMs. Our FMM learning and motif finder software are available at http://genie.weizmann.ac.il/

Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans

Genome-wide association studies (GWAS) have identified numerous common prostate cancer (PrCa) susceptibility loci. We have fine-mapped 64 GWAS regions known at the conclusion of the iCOGS study using large-scale genotyping and imputation in 25 723 PrCa cases and 26 274 controls of European ancestry. We detected evidence for multiple independent signals at 16 regions, 12 of which contained additional newly identified significant associations. A single signal comprising a spectrum of correlated variation was observed at 39 regions; 35 of which are now described by a novel more significantly associated lead SNP, while the originally reported variant remained as the lead SNP only in 4 regions. We also confirmed two association signals in Europeans that had been previously reported only in East-Asian GWAS. Based on statistical evidence and linkage disequilibrium (LD) structure, we have curated and narrowed down the list of the most likely candidate causal variants for each region. Functional annotation using data from ENCODE filtered for PrCa cell lines and eQTL analysis demonstrated significant enrichment for overlap with bio-features within this set. By incorporating the novel risk variants identified here alongside the refined data for existing association signals, we estimate that these loci now explain ∼38.9% of the familial relative risk of PrCa, an 8.9% improvement over the previously reported GWAS tag SNPs. This suggests that a significant fraction of the heritability of PrCa may have been hidden during the discovery phase of GWAS, in particular due to the presence of multiple independent signals within the same regio

Effect of Hydrocortisone on Mortality and Organ Support in Patients With Severe COVID-19: The REMAP-CAP COVID-19 Corticosteroid Domain Randomized Clinical Trial.

Importance: Evidence regarding corticosteroid use for severe coronavirus disease 2019 (COVID-19) is limited. Objective: To determine whether hydrocortisone improves outcome for patients with severe COVID-19. Design, Setting, and Participants: An ongoing adaptive platform trial testing multiple interventions within multiple therapeutic domains, for example, antiviral agents, corticosteroids, or immunoglobulin. Between March 9 and June 17, 2020, 614 adult patients with suspected or confirmed COVID-19 were enrolled and randomized within at least 1 domain following admission to an intensive care unit (ICU) for respiratory or cardiovascular organ support at 121 sites in 8 countries. Of these, 403 were randomized to open-label interventions within the corticosteroid domain. The domain was halted after results from another trial were released. Follow-up ended August 12, 2020. Interventions: The corticosteroid domain randomized participants to a fixed 7-day course of intravenous hydrocortisone (50 mg or 100 mg every 6 hours) (n = 143), a shock-dependent course (50 mg every 6 hours when shock was clinically evident) (n = 152), or no hydrocortisone (n = 108). Main Outcomes and Measures: The primary end point was organ support-free days (days alive and free of ICU-based respiratory or cardiovascular support) within 21 days, where patients who died were assigned -1 day. The primary analysis was a bayesian cumulative logistic model that included all patients enrolled with severe COVID-19, adjusting for age, sex, site, region, time, assignment to interventions within other domains, and domain and intervention eligibility. Superiority was defined as the posterior probability of an odds ratio greater than 1 (threshold for trial conclusion of superiority >99%). Results: After excluding 19 participants who withdrew consent, there were 384 patients (mean age, 60 years; 29% female) randomized to the fixed-dose (n = 137), shock-dependent (n = 146), and no (n = 101) hydrocortisone groups; 379 (99%) completed the study and were included in the analysis. The mean age for the 3 groups ranged between 59.5 and 60.4 years; most patients were male (range, 70.6%-71.5%); mean body mass index ranged between 29.7 and 30.9; and patients receiving mechanical ventilation ranged between 50.0% and 63.5%. For the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively, the median organ support-free days were 0 (IQR, -1 to 15), 0 (IQR, -1 to 13), and 0 (-1 to 11) days (composed of 30%, 26%, and 33% mortality rates and 11.5, 9.5, and 6 median organ support-free days among survivors). The median adjusted odds ratio and bayesian probability of superiority were 1.43 (95% credible interval, 0.91-2.27) and 93% for fixed-dose hydrocortisone, respectively, and were 1.22 (95% credible interval, 0.76-1.94) and 80% for shock-dependent hydrocortisone compared with no hydrocortisone. Serious adverse events were reported in 4 (3%), 5 (3%), and 1 (1%) patients in the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively. Conclusions and Relevance: Among patients with severe COVID-19, treatment with a 7-day fixed-dose course of hydrocortisone or shock-dependent dosing of hydrocortisone, compared with no hydrocortisone, resulted in 93% and 80% probabilities of superiority with regard to the odds of improvement in organ support-free days within 21 days. However, the trial was stopped early and no treatment strategy met prespecified criteria for statistical superiority, precluding definitive conclusions. Trial Registration: ClinicalTrials.gov Identifier: NCT02735707

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570