The James Webb Space Telescope Mission

Twenty-six years ago a small committee report, building on earlier studies, expounded a compelling and poetic vision for the future of astronomy, calling for an infrared-optimized space telescope with an aperture of at least $4m$. With the support of their governments in the US, Europe, and Canada, 20,000 people realized that vision as the $6.5m$ James Webb Space Telescope. A generation of astronomers will celebrate their accomplishments for the life of the mission, potentially as long as 20 years, and beyond. This report and the scientific discoveries that follow are extended thank-you notes to the 20,000 team members. The telescope is working perfectly, with much better image quality than expected. In this and accompanying papers, we give a brief history, describe the observatory, outline its objectives and current observing program, and discuss the inventions and people who made it possible. We cite detailed reports on the design and the measured performance on orbit.Comment: Accepted by PASP for the special issue on The James Webb Space Telescope Overview, 29 pages, 4 figure

Bi-allelic Loss-of-Function CACNA1B Mutations in Progressive Epilepsy-Dyskinesia.

The occurrence of non-epileptic hyperkinetic movements in the context of developmental epileptic encephalopathies is an increasingly recognized phenomenon. Identification of causative mutations provides an important insight into common pathogenic mechanisms that cause both seizures and abnormal motor control. We report bi-allelic loss-of-function CACNA1B variants in six children from three unrelated families whose affected members present with a complex and progressive neurological syndrome. All affected individuals presented with epileptic encephalopathy, severe neurodevelopmental delay (often with regression), and a hyperkinetic movement disorder. Additional neurological features included postnatal microcephaly and hypotonia. Five children died in childhood or adolescence (mean age of death: 9 years), mainly as a result of secondary respiratory complications. CACNA1B encodes the pore-forming subunit of the pre-synaptic neuronal voltage-gated calcium channel Cav2.2/N-type, crucial for SNARE-mediated neurotransmission, particularly in the early postnatal period. Bi-allelic loss-of-function variants in CACNA1B are predicted to cause disruption of Ca2+ influx, leading to impaired synaptic neurotransmission. The resultant effect on neuronal function is likely to be important in the development of involuntary movements and epilepsy. Overall, our findings provide further evidence for the key role of Cav2.2 in normal human neurodevelopment.MAK is funded by an NIHR Research Professorship and receives funding from the Wellcome Trust, Great Ormond Street Children's Hospital Charity, and Rosetrees Trust. E.M. received funding from the Rosetrees Trust (CD-A53) and Great Ormond Street Hospital Children's Charity. K.G. received funding from Temple Street Foundation. A.M. is funded by Great Ormond Street Hospital, the National Institute for Health Research (NIHR), and Biomedical Research Centre. F.L.R. and D.G. are funded by Cambridge Biomedical Research Centre. K.C. and A.S.J. are funded by NIHR Bioresource for Rare Diseases. The DDD Study presents independent research commissioned by the Health Innovation Challenge Fund (grant number HICF-1009-003), a parallel funding partnership between the Wellcome Trust and the Department of Health, and the Wellcome Trust Sanger Institute (grant number WT098051). We acknowledge support from the UK Department of Health via the NIHR comprehensive Biomedical Research Centre award to Guy's and St. Thomas' National Health Service (NHS) Foundation Trust in partnership with King's College London. This research was also supported by the NIHR Great Ormond Street Hospital Biomedical Research Centre. J.H.C. is in receipt of an NIHR Senior Investigator Award. The research team acknowledges the support of the NIHR through the Comprehensive Clinical Research Network. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, Department of Health, or Wellcome Trust. E.R.M. acknowledges support from NIHR Cambridge Biomedical Research Centre, an NIHR Senior Investigator Award, and the University of Cambridge has received salary support in respect of E.R.M. from the NHS in the East of England through the Clinical Academic Reserve. I.E.S. is supported by the National Health and Medical Research Council of Australia (Program Grant and Practitioner Fellowship)

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

Digital Visitor Evaluations at the NHA

The goal of this project was to create technology-assisted surveys for the Nantucket Historical Association (NHA). After researching industry best practices and consulting with NHA staff, the student team used web-based software to create a 2014 NHA Programs Survey and Museum Survey. The team conducted public testing to gauge impressions of the digital technology, and analyzed response data from the implemented surveys. With the instruments developed, the NHA will be able to collect more in-depth visitor feedback that will help the NHA improve its administrative decision-making and adjust its practices to better meet its patrons’ needs. It is our hope that the NHA continues to use and create digital surveys to further enhance visitor experiences

Unmet needs in the management of immune‐mediated thrombotic thrombocytopenic purpura and the potential role of caplacizumab in the UK—A modified‐Delphi study

Abstract Immune‐mediated thrombotic thrombocytopenic purpura (iTTP) is an ultra‐rare, blood‐clotting disorder. Management historically relies on plasma exchange and immunosuppression; however, a 10%–20% mortality rate is still observed. Caplacizumab binds to von Willebrand factor and directly inhibits platelet aggregation; addition of caplacizumab to historical treatment induced faster resolution of platelet count in clinical trials. In 2019, a modified‐Delphi study was conducted with UK experts, to develop consensus statements on management of acute TTP and the potential role of caplacizumab. An unmet need was acknowledged, and areas requiring improvement included: time to diagnosis and treatment initiation; time to platelet normalisation (TTPN) during which patients remain at risk of persistent microvascular thrombosis and organ damage; and incidence of subsequent exacerbations and relapses. Caplacizumab addition to historical treatment within 24 h (after confirmatory ADAMTS13 [a disintegrin and metalloproteinase with thrombospondin type 1 motif, member 13] assay) would significantly reduce TTPN, which directly influences acute outcomes, with manageable bleeding risk and reduced burden on healthcare systems. Expert panellists agree that poor outcomes in iTTP largely result from failure to rapidly control microvascular thrombosis. Use of caplacizumab during a confirmed iTTP episode could offer better control and may plausibly improve long‐term outcomes. However, this consensus must be validated with further clinical trials and robust real‐world evidence

Understanding and mitigating the impacts of major dietary changes on dairy cows

© 2019 Dr Victoria Marie RussoFour experiments were conducted to investigate the effects of major dietary changes on ruminal pH, ruminal fluid composition, eating behaviour, feed intake and milk production of dairy cows. The impacts of both diet composition and management strategies were evaluated. The initial experiment investigated the impact of early adaptation when instigating a complete dietary change from one forage to another at calving, as is common practice in Irish dairy farming. Three weeks prior to their expected calving date, 14 spring calving dairy cows were assigned to one of two treatments: pasture silage pre-partum followed by fresh cut perennial ryegrass (PRG) post-partum, or fresh PRG both pre and post-partum. There were no differences in dry matter intake (DMI), body condition score, energy balance or milk yield and composition between the treatments. The results of the initial experiment suggested that early adaptation to avoid a major dietary change at calving did not result in health or production benefits. This was speculated to be due to the similarities of the two diets, creating little challenge for the rumen to adapt. The second experiment focused on a more challenging dietary change, incorporating a large amount of concentrate into a forage-only diet. Thirty-two lactating dairy cows were initially fed 100% lucerne hay cubes, wheat was then gradually substituted in until it comprised 40% of total dry matter (DM) and lucerne hay cubes, the remainder. Wheat was substituted for lucerne cubes via one of four strategies, (1) in six small increments (each 6.7% of total DM) over 6 days; (2) in six small increments (each 6.7% of total DM) over 11 days; (3) in three large increments (each 13.3% of total DM) over 6 days; or (4) in three large increments (each 13.3% of total DM) over 11 days. The 6-day strategies are considered rapid for the dairy industry yet none of the treatments resulted in ruminal fluid pH values that would have compromised ruminal function, nor were there differences in DMI or energy corrected milk (ECM) yields. Furthermore, there were no differences between ruminal fluid volatile fatty acid (VFA), lactate or ammonia concentrations. It is speculated that the properties of the lucerne cubes helped the ruminal contents resist the pronounced declines in pH often seen with the fermentation of large amounts of wheat. These results suggested that changes to rumen function are driven not only by the characteristics of the concentrate being introduced but also by those of the forage. The third experiment aimed to investigate the role of forages in grain adaptation. Twenty-eight lactating dairy cows were fed either PRG hay or lucerne hay and wheat was gradually substituted for forage in three equal increments, over 6 or 11 days, until wheat made up 40% of DM (~ 8 kg DM/cow per day). The results varied significantly with forage type. Cows fed lucerne hay ate more, produced more ECM and had lower ruminal pH values. Furthermore, of the cows fed lucerne hay, those adapted to wheat in the shorter time frame (6 days) exhibited significantly lower mean ruminal pH values. Despite the ruminal pH of these cows declining to levels typically considered low, none of their other measured parameters indicated compromised fermentation or acidosis. Rather, it was these same cows that had the greatest ECM yields, producing an average of 1.5 kg ECM/cow per day more than their 11-day counterparts. The 6-day adaptation strategy allowed for a rapid increase in metabolisable energy, while the hay promoted adequate buffering within the rumen. No difference was seen between adaptation strategies when PRG hay was fed. This was due to the higher metabolisable energy concentration and lower intake of the PRG hay resulting in a less pronounced increase in metabolisable energy intake with the wheat substitution. The greater intakes of cows fed the lucerne hay likely contributed to their greater ECM yields and lower ruminal pH values. However, both forages allowed the rumen contents to resist the large declines in ruminal pH that are typically seen during rapid grain adaptation. The final experiment aimed to further evaluate the role that forage plays in ruminal, behavioural and production responses to the incorporation of large amounts of wheat grain into the diet. Sixteen dairy cows in early lactation were fed a forage only diet of either lucerne hay, PRG hay or one of two cultivars of fresh PRG pasture (cultivar Bealey or Base) for three weeks. The forage-only diet was then supplemented with crushed wheat grain at a rate of 8 kg DM/cow per day, with no adaptation period. Wheat comprised between 32 and 43% of total DMI and was fed over two meals, followed by forage, for one day only. Feeding fresh pasture resulted in lower ruminal pH values, with pH remaining below 6.0 for longer each day. Following supplementation of wheat, cows fed pasture exhibited ruminal fluid pH levels associated with sub-acute ruminal acidosis. Hay created a ruminal environment that was better able to cope with the influx of acid produced as wheat was digested. A combination of increased ruminating time and a decreased rate of fermentation are likely responsible for the higher ruminal fluid pH values. The ruminal environment of cows fed lucerne hay remained most stable throughout the grain challenge, with ruminal fluid spending the least amount of time below pH 6.0. Reducing the introductory time for concentrates into a dairy cow’s diet means an ability to rapidly increase the energy content of a diet, resulting in milk production benefits. However, this thesis highlights the importance of forage choice when determining introduction strategies. Traditional, gradual adaptation strategies must still be employed when feeding highly digestible fresh forages. However, more aggressive adaptation strategies can be implemented when hays are used as the base forage. In situations where high energy grains are substituted for a low energy, high fibre basal forage, rapid introduction can have milk production benefits over gradual strategies

Design and Optimization of a Micro-Aerial Vehicle

AIAA’s 2016 Design/Build/Fly Competition required the construction of two separate systems to complete distributive manufacturing missions. The team had to develop a production aircraft to carry a 1 kg payload and a manufacturing support aircraft which could carry the production aircraft internally. Aircraft designs were finalized using merit analyses and iterative design techniques to make quantitative decisions. The team selected a flying wing design for the production aircraft nested inside the wing of a conventional design manufacturing support aircraft as final configurations. The aircraft were manufactured and tested to ensure designs would complete mission requirements while maintaining the highest possible score by retaining minimal components and a low aircraft weight

Bridging the Chasm between Pregnancy and Health over the Life Course: A National Agenda for Research and Action

BackgroundMany pregnant people find no bridge to ongoing specialty or primary care after giving birth, even when clinical and social complications of pregnancy signal need. Black, indigenous, and all other women of color are especially harmed by fragmented care and access disparities, coupled with impacts of racism over the life course and in health care.MethodsWe launched the initiative "Bridging the Chasm between Pregnancy and Health across the Life Course" in 2018, bringing together patients, advocates, providers, researchers, policymakers, and systems innovators to create a National Agenda for Research and Action. We held a 2-day conference that blended storytelling, evidence analysis, and consensus building to identify key themes related to gaps in care and root causes of inequities. In 2019, more than 70 stakeholders joined six working groups to reach consensus on strategic priorities based on equity, innovation, effectiveness, and feasibility.FindingsWorking groups identified six key strategic areas for bridging the chasm. These include: 1) progress toward eliminating institutional and interpersonal racism and bias as a requirement for accreditation of health care institutions, 2) infrastructure support for community-based organizations, 3) extension of holistic team-based care to the postpartum year and beyond, with integration of doulas and community health workers on the team, 4) extension of Medicaid coverage and new quality and pay-for-performance metrics to link maternity care and primary care, 5) systems to preserve maternal narratives and data across providers, and 6) alignment of research with women's lived experiences.ConclusionsThe resulting agenda presents a path forward to remedy the structural chasms in women's health care, with key roles for advocates, policymakers, researchers, health care leaders, educators, and the media

The SunBEAm birth cohort: Protocol design

Background: Food allergy (FA) and atopic dermatitis (AD) are common conditions that often present in the first year of life. Identification of underlying mechanisms and environmental determinants of FA and AD is essential to develop and implement effective prevention and treatment strategies. Objectives: We sought to describe the design of the Systems Biology of Early Atopy (SunBEAm) birth cohort. Methods: Funded by the National Institute of Allergy and Infectious Diseases (NIAID) and administered through the Consortium for Food Allergy Research (CoFAR), SunBEAm is a US population-based, multicenter birth cohort that enrolls pregnant mothers, fathers, and their newborns and follows them to 3 years. Questionnaire and biosampling strategies were developed to apply a systems biology approach to identify environmental, immunologic, and multiomic determinants of AD, FA, and other allergic outcomes. Results: Enrollment is currently underway. On the basis of an estimated FA prevalence of 6%, the enrollment goal is 2500 infants. AD is defined on the basis of questionnaire and assessment, and FA is defined by an algorithm combining history and testing. Although any FA will be recorded, we focus on the diagnosis of egg, milk, and peanut at 5 months, adding wheat, soy, cashew, hazelnut, walnut, codfish, shrimp, and sesame starting at 12 months. Sampling includes blood, hair, stool, dust, water, tape strips, skin swabs, nasal secretions, nasal swabs, saliva, urine, functional aspects of the skin, and maternal breast milk and vaginal swabs. Conclusions: The SunBEAm birth cohort will provide a rich repository of data and specimens to interrogate mechanisms and determinants of early allergic outcomes, with an emphasis on FA, AD, and systems biology

The revised Approved Instructional Resources score:An improved quality evaluation tool for online educational resources

BACKGROUND: Free Open-Access Medical education (FOAM) use among residents continues to rise. However, it often lacks quality assurance processes and residents receive little guidance on quality assessment. The Academic Life in Emergency Medicine Approved Instructional Resources tool (AAT) was created for FOAM appraisal by and for expert educators and has demonstrated validity in this context. It has yet to be evaluated in other populations.OBJECTIVES: We assessed the AAT's usability in a diverse population of practicing emergency medicine (EM) physicians, residents, and medical students; solicited feedback; and developed a revised tool.METHODS: As part of the Medical Education Translational Resources: Impact and Quality (METRIQ) study, we recruited medical students, EM residents, and EM attendings to evaluate five FOAM posts with the AAT and provide quantitative and qualitative feedback via an online survey. Two independent analysts performed a qualitative thematic analysis with discrepancies resolved through discussion and negotiated consensus. This analysis informed development of an initial revised AAT, which was then further refined after pilot testing among the author group. The final tool was reassessed for reliability.RESULTS: Of 330 recruited international participants, 309 completed all ratings. The Best Evidence in Emergency Medicine (BEEM) score was the component most frequently reported as difficult to use. Several themes emerged from the qualitative analysis: for ease of use-understandable, logically structured, concise, and aligned with educational value. Limitations include deviation from questionnaire best practices, validity concerns, and challenges assessing evidence-based medicine. Themes supporting its use include evaluative utility and usability. The author group pilot tested the initial revised AAT, revealing a total score average measure intraclass correlation coefficient (ICC) of moderate reliability (ICC = 0.68, 95% confidence interval [CI] = 0 to 0.962). The final AAT's average measure ICC was 0.88 (95% CI = 0.77 to 0.95).CONCLUSIONS: We developed the final revised AAT from usability feedback. The new score has significantly increased usability, but will need to be reassessed for reliability in a broad population.</p