Recent technological advances and deployments are creating a new landscape in access networks, with an integration of wireless and fiber technologies a key supporting technology. In the past, a ...separation between those with fiber in the access networks and those with wireless networks, the relatively low data-rate requirements of backhaul and the relatively large cell sites, have all combined to keep fiber deployment low in wireless backhaul. As fiber has penetrated the access network and the latest wireless standards have demanded smaller, higher bandwidth cells, fiber connectivity has become key. Choices remain as to where the demarcation between key elements should be in the network and whether fiber should be used as just a high data-rate backhaul path or if a transition to radio-over-fiber techniques can afford benefits. This paper will explore the network options available in particular those demonstrated in recent European Union (EU) projects, how they can be integrated with existing access networks and how techniques such as radio-over-fiber can be deployed to offer increased functionality.
Immunologic responses to anti-PD-1 therapy in melanoma patients occur rapidly with pharmacodynamic T cell responses detectable in blood by 3 weeks. It is unclear, however, whether these early ...blood-based observations translate to the tumor microenvironment. We conducted a study of neoadjuvant/adjuvant anti-PD-1 therapy in stage III/IV melanoma. We hypothesized that immune reinvigoration in the tumor would be detectable at 3 weeks and that this response would correlate with disease-free survival. We identified a rapid and potent anti-tumor response, with 8 of 27 patients experiencing a complete or major pathological response after a single dose of anti-PD-1, all of whom remain disease free. These rapid pathologic and clinical responses were associated with accumulation of exhausted CD8 T cells in the tumor at 3 weeks, with reinvigoration in the blood observed as early as 1 week. Transcriptional analysis demonstrated a pretreatment immune signature (neoadjuvant response signature) that was associated with clinical benefit. In contrast, patients with disease recurrence displayed mechanisms of resistance including immune suppression, mutational escape, and/or tumor evolution. Neoadjuvant anti-PD-1 treatment is effective in high-risk resectable stage III/IV melanoma. Pathological response and immunological analyses after a single neoadjuvant dose can be used to predict clinical outcome and to dissect underlying mechanisms in checkpoint blockade.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Exhausted CD8
T (T
) cells in chronic infections and cancer have limited effector function, high co-expression of inhibitory receptors and extensive transcriptional changes compared with effector (T
...) or memory (T
) CD8
T cells. T
cells are important clinical targets of checkpoint blockade and other immunotherapies. Epigenetically, T
cells are a distinct immune subset, with a unique chromatin landscape compared with T
and T
cells. However, the mechanisms that govern the transcriptional and epigenetic development of T
cells remain unknown. Here we identify the HMG-box transcription factor TOX as a central regulator of T
cells in mice. TOX is largely dispensable for the formation of T
and T
cells, but it is critical for exhaustion: in the absence of TOX, T
cells do not form. TOX is induced by calcineurin and NFAT2, and operates in a feed-forward loop in which it becomes calcineurin-independent and sustained in T
cells. Robust expression of TOX therefore results in commitment to T
cells by translating persistent stimulation into a distinct T
cell transcriptional and epigenetic developmental program.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
The fungal pathogen Candida albicans is frequently associated with catheter-based infections because of its ability to form resilient biofilms. Prior studies have shown that the transcription factor ...Bcr1 governs biofilm formation in an in vitro catheter model. However, the mechanistic role of the Bcr1 pathway and its relationship to biofilm formation in vivo are unknown. Our studies of biofilm formation in vitro indicate that the surface protein Als3, a known adhesin, is a key target under Bcr1 control. We show that an als3/als3 mutant is biofilm-defective in vitro, and that ALS3 overexpression rescues the biofilm defect of the bcr1/bcr1 mutant. We extend these findings with an in vivo venous catheter model. The bcr1/bcr1 mutant is unable to populate the catheter surface, though its virulence suggests that it has no growth defect in vivo. ALS3 overexpression rescues the bcr1/bcr1 biofilm defect in vivo, thus arguing that Als3 is a pivotal Bcr1 target in this setting. Surprisingly, the als3/als3 mutant forms a biofilm in vivo, and we suggest that additional Bcr1 targets compensate for the Als3 defect in vivo. Indeed, overexpression of Bcr1 targets ALS1, ECE1, and HWP1 partially restores biofilm formation in a bcr1/bcr1 mutant background in vitro, though these genes are not required for biofilm formation in vitro. Our findings demonstrate that the Bcr1 pathway functions in vivo to promote biofilm formation, and that Als3-mediated adherence is a fundamental property under Bcr1 control. Known adhesins Als1 and Hwp1 also contribute to biofilm formation, as does the novel protein Ece1.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Peer-to-peer logistics platforms coordinate independent drivers to fulfill requests for last mile delivery and ridesharing. To balance demand-side performance with driver autonomy, a new stochastic ...methodology provides drivers with a small but personalized menu of requests to choose from. This creates a Stackelberg game, in which the platform leads by deciding what menu of requests to send to drivers, and the drivers follow by selecting which request(s) they are willing to fulfill from their received menus. Determining optimal menus, menu size, and request overlaps in menus is complex as the platform has limited knowledge of drivers’ request preferences. Exploiting the problem structure when drivers signal willingness to participate, we reformulate our problem as an equivalent single-level Mixed Integer Linear Program (MILP) and apply the Sample Average Approximation (SAA) method. Computational tests recommend a training sample size for inputted SAA scenarios and a test sample size for completing performance analysis. Our stochastic optimization approach performs better than current approaches, as well as deterministic optimization alternatives. A simplified formulation ignoring ‘unhappy drivers’ who accept requests but are not matched is shown to produce similar objective values with a fraction of the runtime. A ridesharing case study of the Chicago Regional transportation network provides insights for a platform wanting to provide driver autonomy via menu creation. The proposed methods achieved high demand performance as long as the drivers are well compensated (e.g., even when drivers are allowed to reject requests, on average over 90% of requests are fulfilled when 80% of the fare goes to drivers; this drops to below 60% when only 40% of the fare goes to drivers). Thus, neither the platform nor the drivers benefit from low driver compensation due to its resulting low driver participation and thus low request fulfillment. Finally, for the cases tested, a maximum menu size of 5 is recommended as it produces good quality platform solutions without requiring much driver selection time.
•Drivers in ridesharing/crowdsourced delivery platforms autonomously make selections.•A special case yields single-level MILP equivalent to bilevel model.•Personalized driver menus are optimized for drivers’ stochastic selections.•Platform benefits from offering multiple items to drivers with stochastic selection.•Computational study provides menu and performance insights.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The Pediatric Cardiac Genomics Consortium (PCGC) designed the Congenital Heart Disease Genetic Network Study to provide phenotype and genotype data for a large congenital heart defects (CHDs) cohort. ...This article describes the PCGC cohort, overall and by major types of CHDs (e.g., conotruncal defects) and subtypes of conotrucal heart defects (e.g., tetralogy of Fallot) and left ventricular outflow tract obstructions (e.g., hypoplastic left heart syndrome). Cases with CHDs were recruited through ten sites, 2010-2014. Information on cases (N = 9,727) and their parents was collected through interviews and medical record abstraction. Four case characteristics, eleven parental characteristics, and thirteen parent-reported neurodevelopment outcomes were summarized using counts and frequencies and compared across CHD types and subtypes. Eleven percent of cases had a genetic diagnosis. Among cases without a genetic diagnosis, the majority had conotruncal heart defects (40%) or left ventricular outflow tract obstruction (21%). Across CHD types, there were significant differences (p<0.05) in the distribution of all four case characteristics (e.g., sex), four parental characteristics (e.g., maternal pregestational diabetes), and five neurodevelopmental outcomes (e.g., learning disabilities). Several characteristics (e.g., sex) were also significantly different across CHD subtypes. The PCGC cohort is one of the largest CHD cohorts available for the study of genetic determinants of risk and outcomes. The majority of cases do not have a genetic diagnosis. This description of the PCGC cohort, including differences across CHD types and subtypes, provides a reference work for investigators who are interested in collaborating with or using publically available resources from the PCGC.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
BACKGROUND:The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of a rapidly spreading illness, Coronavirus Disease 2019 (COVID-19), affecting thousands of people ...around the world. Urgent guidance for clinicians caring for the sickest of these patients is needed.
METHODS:We formed a panel of 36 experts from 12 countries. All panel members completed the World Health Organization conflict of interest disclosure form. The panel proposed 53 questions that are relevant to the management of COVID-19 in the ICU. We searched the literature for direct and indirect evidence on the management of COVID-19 in critically ill patients in the ICU. We identified relevant and recent systematic reviews on most questions relating to supportive care. We assessed the certainty in the evidence using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach, then generated recommendations based on the balance between benefit and harm, resource and cost implications, equity, and feasibility. Recommendations were either strong or weak, or in the form of best practice recommendations.
RESULTS:The Surviving Sepsis Campaign COVID-19 panel issued 54 statements, of which four are best practice statements, nine are strong recommendations, and 35 are weak recommendations. No recommendation was provided for six questions. The topics were1) infection control, 2) laboratory diagnosis and specimens, 3) hemodynamic support, 4) ventilatory support, and 5) COVID-19 therapy.
CONCLUSION:The Surviving Sepsis Campaign COVID-19 panel issued several recommendations to help support healthcare workers caring for critically ill ICU patients with COVID-19. When available, we will provide new evidence in further releases of these guidelines.
Background
The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of a rapidly spreading illness, Coronavirus Disease 2019 (COVID-19), affecting thousands of people ...around the world. Urgent guidance for clinicians caring for the sickest of these patients is needed.
Methods
We formed a panel of 36 experts from 12 countries. All panel members completed the World Health Organization conflict of interest disclosure form. The panel proposed 53 questions that are relevant to the management of COVID-19 in the ICU. We searched the literature for direct and indirect evidence on the management of COVID-19 in critically ill patients in the ICU. We identified relevant and recent systematic reviews on most questions relating to supportive care. We assessed the certainty in the evidence using the
Grading of Recommendations, Assessment, Development and Evaluation
(GRADE) approach, then generated recommendations based on the balance between benefit and harm, resource and cost implications, equity, and feasibility. Recommendations were either strong or weak, or in the form of best practice recommendations.
Results
The Surviving Sepsis Campaign COVID-19 panel issued 54 statements, of which 4 are best practice statements, 9 are strong recommendations, and 35 are weak recommendations. No recommendation was provided for 6 questions. The topics were: (1) infection control, (2) laboratory diagnosis and specimens, (3) hemodynamic support, (4) ventilatory support, and (5) COVID-19 therapy.
Conclusion
The Surviving Sepsis Campaign COVID-19 panel issued several recommendations to help support healthcare workers caring for critically ill ICU patients with COVID-19. When available, we will provide new recommendations in further releases of these guidelines.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Being the lifeblood of socioeconomic progress, engineering is implicated in the unprecedented challenge of sustainability. The global engineering community devised sustainable engineering as a ...conceptual departure from conventional engineering practices. However, the extent to which the sustainability worldview has permeated the Nigerian engineering community remains unanswered. This paper is an attempt to answer the question of how sustainability literate are the members of the Nigerian engineering community. The paper undertakes an assessment of the sustainability literacy of the community with the aid of a stakeholder survey and a devised sustainability literacy test. Three criteria that are used to gauge the stakeholders’ sustainability literacy are awareness of the UN Decade of Education for Sustainable Development, score on the sustainability literacy test, and self-assessment of sustainability knowledge. Survey participants were recruited mainly from two federally-run Nigerian higher education institutions, and engineering professional associations. The assessment reveals an unsatisfactory performance of the Nigerian engineering stakeholders on all three sustainability literacy criteria. The results show that the majority of the students (81%), educators (67%), and practitioners (64%) were unaware of the UNDESD. The paper therefore highlights the need to improve the sustainability literacy of the Nigerian engineering community, possibly through a sustainability education intervention.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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