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PURPOSE Rhabdomyosarcoma is the most common soft tissue sarcoma of childhood. Despite aggressive therapy, the 5-year survival rate for patients with metastatic or recurrent disease remains poor, and beyond PAX-FOXO1 fusion status, no genomic markers are available for risk stratification. We present an international consortium study designed to determine the incidence of driver mutations and their association with clinical outcome. PATIENTS AND METHODS Tumor samples collected from patients enrolled on Children's Oncology Group trials (1998-2017) and UK patients enrolled on malignant mesenchymal tumor and RMS2005 (1995-2016) trials were subjected to custom-capture sequencing. Mutations, indels, gene deletions, and amplifications were identified, and survival analysis was performed. RESULTS DNA from 641 patients was suitable for analyses. A median of one mutation was found per tumor. In FOXO1 fusion-negative cases, mutation of any RAS pathway member was found in > 50% of cases, and 21% had no putative driver mutation identified. BCOR (15%), NF1 (15%), and TP53 (13%) mutations were found at a higher incidence than previously reported and TP53 mutations were associated with worse outcomes in both fusion-negative and FOXO1 fusion-positive cases. Interestingly, mutations in RAS isoforms predominated in infants < 1 year (64% of cases). Mutation of MYOD1 was associated with histologic patterns beyond those previously described, older age, head and neck primary site, and a dismal survival. Finally, we provide a searchable companion database ( ClinOmics ), containing all genomic variants, and clinical annotation including survival data. CONCLUSION This is the largest genomic characterization of clinically annotated rhabdomyosarcoma tumors to date and provides prognostic genetic features that refine risk stratification and will be incorporated into prospective trials.

BACKGROUND: People who are homeless have a higher burden of illness and higher rates of hospital admission and readmission compared to the general population. Identifying the factors associated with hospital readmission could help healthcare providers and policymakers improve post-discharge care for homeless patients. OBJECTIVE: To identify factors associated with hospital readmission within 90 days of discharge from a general internal medicine unit among patients experiencing homelessness. DESIGN: This prospective observational study was conducted at an urban academic teaching hospital in Toronto, Canada. Interviewer-administered questionnaires and chart reviews were completed to assess medical, social, processes of care, and hospitalization data. Multivariable logistic regression with backward selection was used to identify factors associated with a subsequent readmission and estimate odds ratios and 95% confidence intervals. PARTICIPANTS: Adults (N = 129) who were admitted to the general internal medicine service between November 2017 and November 2018 and who were homeless at the time of admission. MAIN MEASURES: Unplanned all-cause readmission to the study hospital within 90 days of discharge. KEY RESULTS: Thirty-five of 129 participants (27.1%) were readmitted within 90 days of discharge. Factors associated with lower odds of readmission included having an active case manager (adjusted odds ratios [aOR]: 0.31, 95% CI, 0.13–0.76), having informal support such as friends and family (aOR: 0.25, 95% CI, 0.08–0.78), and sending a copy of the patient’s discharge plan to a primary care physician who had cared for the patient within the last year (aOR: 0.44, 95% CI, 0.17–1.16). A higher number of medications prescribed at discharge was associated with higher odds of readmission (aOR: 1.12, 95% CI, 1.02–1.23). CONCLUSION: Interventions to reduce hospital readmission for people who are homeless should evaluate tailored discharge planning and dedicated resources to support implementation of these plans in the community. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s11606-020-06483-w.

BackgroundWe aimed to measure SARS-CoV-2 seroprevalence in a cohort of healthcare workers (HCWs) during the first UK wave of the COVID-19 pandemic, explore risk factors associated with infection, and investigate the impact of antibody titres on assay sensitivity.MethodsHCWs at Sheffield Teaching Hospitals NHS Foundation Trust (STH) were prospectively enrolled and sampled at two time points. SARS-CoV-2 antibodies were tested using an in-house assay for IgG and IgA reactivity against Spike and Nucleoprotein (sensitivity 99·47%, specificity 99·56%). Data were analysed using three statistical models: a seroprevalence model, an antibody kinetics model, and a heterogeneous sensitivity model.FindingsAs of 12th June 2020, 24·4% (n=311/1275) HCWs were seropositive. Of these, 39·2% (n=122/311) were asymptomatic. The highest adjusted seroprevalence was measured in HCWs on the Acute Medical Unit (41·1%, 95% CrI 30·0–52·9) and in Physiotherapists and Occupational Therapists (39·2%, 95% CrI 24·4–56·5). Older age groups showed overall higher median antibody titres. Further modelling suggests that, for a serological assay with an overall sensitivity of 80%, antibody titres may be markedly affected by differences in age, with sensitivity estimates of 89% in those over 60 years but 61% in those ≤30 years.InterpretationHCWs in acute medical units working closely with COVID-19 patients were at highest risk of infection, though whether these are infections acquired from patients or other staff is unknown. Current serological assays may underestimate seroprevalence in younger age groups if validated using sera from older and/or more symptomatic individuals.Research in contextEvidence before this studyWe searched PubMed for studies published up to March 6th 2021, using the terms “COVID”, “SARS-CoV-2”, “seroprevalence”, and “healthcare workers”, and in addition for articles of antibody titres in different age groups against coronaviruses using “coronavirus”, “SARS-CoV-2, “antibody”, “antibody tires”, “COVID” and “age”. We included studies that used serology to estimate prevalence in healthcare workers. SARS-CoV-2 seroprevalence has been shown to be greater in healthcare workers working on acute medical units or within domestic services. Antibody levels against seasonal coronaviruses, SARS-CoV and SARS-CoV-2 were found to be higher in older adults, and patients who were hospitalised.Added value of this studyIn this healthcare worker seroprevalence modelling study at a large NHS foundation trust, we confirm that those working on acute medical units, COVID-19 “Red Zones” and within domestic services are most likely to be seropositive. Furthermore, we show that physiotherapists and occupational therapists have an increased risk of COVID-19 infection. We also confirm that antibody titres are greater in older individuals, even in the context of non-hospitalised cases. Importantly, we demonstrate that this can result in age-specific sensitivity in serological assays, where lower antibody titres in younger individuals results in lower assay sensitivity.Implications of all the available evidenceThere are distinct occupational roles and locations in hospitals where the risk of COVID-19 infection to healthcare workers is greatest, and this knowledge should be used to prioritise infection prevention control and other measures to protect healthcare workers. Serological assays may have different sensitivity profiles across different age groups, especially if assay validation was undertaken using samples from older and/or hospitalised patients, who tend to have higher antibody titres. Future seroprevalence studies should consider adjusting for age-specific assay sensitivities to estimate true seroprevalence rates.Author Contributions

Background Looked-after children and care leavers (henceforth children in care) are young people placed under the care of local authorities, often because of a history of family abuse and/or neglect. These young people have significantly increased risk of substance use and mental health problems compared with peers. Aim The Supporting Looked After Children and Care Leavers In Decreasing Drugs, and alcohol (SOLID) trial aimed to investigate the feasibility of a definitive randomised controlled trial comparing two behaviour change interventions to reduce risky substance use (illicit drugs and alcohol) in and improve the mental health of children in care aged 12–20 years. Methods The study consisted of two phases: (1) a formative phase that adapted the motivational enhancement therapy and social behaviour and network therapy interventions for use with children in care and (2) a three-arm pilot randomised controlled trial (comparing motivational enhancement therapy, social behaviour and network therapy and usual care), and a linked process and economic (return on investment) evaluation. Trial feasibility was compared with prespecified STOP/GO criteria. Setting Six local authority areas in the north-east of England. Participants Children in care (aged 12–20 years) who screened positive for drug and/or alcohol use within the last 12 months were eligible for the trial. The formative and process evaluations included children in care, carers, social workers, and drug and alcohol workers. Outcome measures The primary outcomes were recruitment and retention rates at 12 months’ follow-up. Baseline and 12-month follow-up questionnaires measured self-reported drug and alcohol use, mental health and health-related quality of life. The process evaluation considered acceptability and engagement with the interventions and trial procedures. Results Formative findings (n = 65) highlighted the need for interventions to increase the emphasis on therapeutic relationships, use creative methods of engagement and support the identification of treatment goals wider than substance misuse. Within the randomised controlled trial, of 860 participants screened, 211 (24.5%) met the inclusion criteria. One hundred and twelve (53%) of the 211 eligible children were recruited and randomised. Just 15 of the 76 (20%) participants allocated to intervention attended any of the motivational enhancement therapy of social behaviour and network therapy sessions, and 60 (54%) participants completed the 12-month follow-up. The screening and recruitment of children in care required significantly more time and resource investment by researchers and children’s services than planned. The process evaluation (n = 116) demonstrated that, despite participants engaging in risky substance use, they did not often acknowledge this nor felt that they needed help. Children in care had complex, chaotic lives and children’s services departments were less research mature and extremely stretched; this, coupled with the multiple steps in the intervention pathway and study protocol, resulted in low adherence to the intervention and the trial. Conclusions The SOLID trial demonstrated successful engagement with children in care to adapt the motivational enhancement therapy and social behaviour and network therapy interventions. However, the pilot randomised controlled trial found that a definitive trial is not feasible. The current screen, refer and treat pathway for children in care did not work. There is an urgent need to radically rethink how we deliver therapeutic services for children in care. A pragmatic evaluation design, coupled with additional research resource for children’s services, is needed to evaluate these novel models of care at scale. Trial registration This study is registered as PROSPERO CRD42018098974 and Current Controlled Trials ISRCTN80786829. Funding This project was funded by the National Institute for Health Research (NIHR) Public Health Research programme and will be published in full in Public Health Research; Vol. 8, No. 13. See the NIHR Journals Library website for further project information.

Background Recovery Education Centres (RECs) are increasingly implemented to support the process of recovery for individuals experiencing mental health challenges. However, the evidence on key REC mechanisms and outcomes, particularly for diverse subpopulations or service delivery contexts is scant. This study identified mechanisms and outcomes of an REC focused on adults with mental health challenges transitioning from homelessness. Methods Qualitative methods were used to explore in-depth the experiences of homeless and unstably housed participants experiencing mental health challenges in Toronto, Canada. Twenty service users participated in semi-structured interviews between July 2017 and June 2018, six to 14 months following REC enrollment. A realist informed interview guide explored participants’ perspectives on key REC mechanisms and outcomes. Interviews were audio-recorded, transcribed verbatim and analyzed using inductive thematic analysis. Investigator triangulation and member checking processes enhanced analytical rigour. Results Participants perceived that program participation supported the process of recovery through several mechanisms: a judgment-free environment; supportive relationships, mutuality and role modelling; deconstruction of self-stigma; and reclaiming of one’s power. Participants described several outcomes at the personal, interpersonal and social levels, including improvements in health and well-being; self-esteem, confidence and identity; sense of empowerment, control and personal responsibility; as well as improvements in interpersonal skills, pro-social behaviours and ability to self-advocate; and increased goal development and future orientation. Conclusions Findings suggest RECs can support the process of recovery among people transitioning from homelessness and can successfully support subpopulations experiencing mental health challenges and social disadvantage.

Background Previous infection with SARS-CoV-2 affects the immune response to the first dose of the SARS-CoV-2 vaccine. We aimed to compare SARS-CoV-2-specific T-cell and antibody responses in health-care workers with and without previous SARS-CoV-2 infection following a single dose of the BNT162b2 (tozinameran; Pfizer–BioNTech) mRNA vaccine. Methods We sampled health-care workers enrolled in the PITCH study across four hospital sites in the UK (Oxford, Liverpool, Newcastle, and Sheffield). All health-care workers aged 18 years or older consenting to participate in this prospective cohort study were included, with no exclusion criteria applied. Blood samples were collected where possible before vaccination and 28 (±7) days following one or two doses (given 3–4 weeks apart) of the BNT162b2 vaccine. Previous infection was determined by a documented SARS-CoV-2-positive RT-PCR result or the presence of positive anti-SARS-CoV-2 nucleocapsid antibodies. We measured spike-specific IgG antibodies and quantified T-cell responses by interferon-γ enzyme-linked immunospot assay in all participants where samples were available at the time of analysis, comparing SARS-CoV-2-naive individuals to those with previous infection. Findings Between Dec 9, 2020, and Feb 9, 2021, 119 SARS-CoV-2-naive and 145 previously infected health-care workers received one dose, and 25 SARS-CoV-2-naive health-care workers received two doses, of the BNT162b2 vaccine. In previously infected health-care workers, the median time from previous infection to vaccination was 268 days (IQR 232–285). At 28 days (IQR 27–33) after a single dose, the spike-specific T-cell response measured in fresh peripheral blood mononuclear cells (PBMCs) was higher in previously infected (n=76) than in infection-naive (n=45) health-care workers (median 284 [IQR 150–461] vs 55 [IQR 24–132] spot-forming units [SFUs] per 106 PBMCs; pInterpretation A single dose of the BNT162b2 vaccine is likely to provide greater protection against SARS-CoV-2 infection in individuals with previous SARS-CoV-2 infection, than in SARS-CoV-2-naive individuals, including against variants of concern. Future studies should determine the additional benefit of a second dose on the magnitude and durability of immune responses in individuals vaccinated following infection, alongside evaluation of the impact of extending the interval between vaccine doses. Funding UK Department of Health and Social Care, and UK Coronavirus Immunology Consortium.

Allogeneic hematopoietic stem cell transplantation is a viable treatment for multiple hematologic diseases, but its application is often limited by graft-versus-host disease (GVHD), where donor T cells attack host tissues in the skin, liver, and gastrointestinal tract. Here, we examined the role of the cellular energy sensor AMP kinase (AMPK) in alloreactive T cells during GVHD development. Early posttransplant, AMPK activity increased more than 15-fold in allogeneic T cells, and transplantation of T cells deficient in both AMPKα1 and AMPKα2 decreased GVHD severity in multiple disease models. Importantly, a lack of AMPK lessened GVHD without compromising antileukemia responses or impairing lymphopenia-driven immune reconstitution. Mechanistically, absence of AMPK decreased both CD4+ and CD8+ effector T cell numbers as early as day 3 posttransplant, while simultaneously increasing regulatory T cell (Treg) percentages. Improvements in GVHD resulted from cell-intrinsic perturbations in conventional effector T cells as depletion of donor Tregs had minimal impact on AMPK-related improvements. Together, these results highlight a specific role for AMPK in allogeneic effector T cells early posttransplant and suggest that AMPK inhibition may be an innovative approach to mitigate GVHD while preserving graft-versus-leukemia responses and maintaining robust immune reconstitution.

Background: The SARS-CoV-2 variant B.1.1.7 was first identified in December, 2020, in England. We aimed to investigate whether increases in the proportion of infections with this variant are associated with differences in symptoms or disease course, reinfection rates, or transmissibility. Methods: We did an ecological study to examine the association between the regional proportion of infections with the SARS-CoV-2 B.1.1.7 variant and reported symptoms, disease course, rates of reinfection, and transmissibility. Data on types and duration of symptoms were obtained from longitudinal reports from users of the COVID Symptom Study app who reported a positive test for COVID-19 between Sept 28 and Dec 27, 2020 (during which the prevalence of B.1.1.7 increased most notably in parts of the UK). From this dataset, we also estimated the frequency of possible reinfection, defined as the presence of two reported positive tests separated by more than 90 days with a period of reporting no symptoms for more than 7 days before the second positive test. The proportion of SARS-CoV-2 infections with the B.1.1.7 variant across the UK was estimated with use of genomic data from the COVID-19 Genomics UK Consortium and data from Public Health England on spike-gene target failure (a non-specific indicator of the B.1.1.7 variant) in community cases in England. We used linear regression to examine the association between reported symptoms and proportion of B.1.1.7. We assessed the Spearman correlation between the proportion of B.1.1.7 cases and number of reinfections over time, and between the number of positive tests and reinfections. We estimated incidence for B.1.1.7 and previous variants, and compared the effective reproduction number, R t, for the two incidence estimates. Findings: From Sept 28 to Dec 27, 2020, positive COVID-19 tests were reported by 36 920 COVID Symptom Study app users whose region was known and who reported as healthy on app sign-up. We found no changes in reported symptoms or disease duration associated with B.1.1.7. For the same period, possible reinfections were identified in 249 (0·7% [95% CI 0·6–0·8]) of 36 509 app users who reported a positive swab test before Oct 1, 2020, but there was no evidence that the frequency of reinfections was higher for the B.1.1.7 variant than for pre-existing variants. Reinfection occurrences were more positively correlated with the overall regional rise in cases (Spearman correlation 0·56–0·69 for South East, London, and East of England) than with the regional increase in the proportion of infections with the B.1.1.7 variant (Spearman correlation 0·38–0·56 in the same regions), suggesting B.1.1.7 does not substantially alter the risk of reinfection. We found a multiplicative increase in the R t of B.1.1.7 by a factor of 1·35 (95% CI 1·02–1·69) relative to pre-existing variants. However, R t fell below 1 during regional and national lockdowns, even in regions with high proportions of infections with the B.1.1.7 variant. Interpretation: The lack of change in symptoms identified in this study indicates that existing testing and surveillance infrastructure do not need to change specifically for the B.1.1.7 variant. In addition, given that there was no apparent increase in the reinfection rate, vaccines are likely to remain effective against the B.1.1.7 variant. Funding: Zoe Global, Department of Health (UK), Wellcome Trust, Engineering and Physical Sciences Research Council (UK), National Institute for Health Research (UK), Medical Research Council (UK), Alzheimer's Society.

Background: Following a single dose of BNT162b2 mRNA vaccine, higher antibody titres are observed following prior SARS-CoV-2 infection than in infection-naive individuals, but T-cell responses are less well defined. Methods: We sampled healthcare workers (HCWs) enrolled in the UK PITCH study, before and after BNT162b2 mRNA vaccination. We measured spike-specific antibody, and quantified T-cell responses by IFNγ ELISpot assay and intracellular staining of peripheral blood mononuclear cells (PBMC), comparing SARS-CoV-2-naive individuals to those with prior infection. Findings: HCWs aged 22 to 71 years received one (n=216) or two (n=21) vaccine doses. After a single dose, the spike-specific T-cell response was six-fold higher in previously-infected vs. naive individuals (median 340 vs. 58 SFU/10 6 PBMC, p

Extension of the interval between vaccine doses for the BNT162b2 mRNA vaccine was introduced in the UK to accelerate population coverage with a single dose. In a study of 503 healthcare workers, we show that after priming following the first vaccine there is a marked decline in SARS-CoV-2 neutralizing antibody (NAb) levels, but, in contrast, a sustained T cell response to spike protein. This divergent immune profile was accompanied by robust protection from infection over this period from the circulating alpha (B.1.1.7) variant. Importantly, following the second vaccine dose, NAb levels were higher after the extended dosing interval (6-14 weeks) compared to the conventional 3-4 week regimen, accompanied by a clear enrichment of CD4+ T cells expressing IL2. These data on dynamic cellular and humoral responses indicate that extension of the dosing interval is an effective, immunogenic protocol and that antiviral T cell responses are a potential mechanism of protection.Trial Registration Details: PITCH is a sub-study of the SIREN study which is registered with ISRCTN, number ISRCTN11041050,Funding Information: This work was funded by the UK Department of Health and Social Care as part of the PITCH (Protective Immunity from T cells to Covid-19 in Health workers) Consortium, with contributions from UKRI/NIHR through the UK Coronavirus Immunology Consortium (UK-CIC), the Huo Family Foundation and The National Institute for Health Research (UKRIDHSC COVID-19 Rapid Response Rolling Call, Grant Reference Number COV19-RECPLAS).EB and PK are NIHR Senior Investigators and PK is funded by WT109965MA. SJD is funded by an NIHR Global Research Professorship (NIHR300791). TdS is funded by a Wellcome Trust Intermediate Clinical Fellowship (110058/Z/15/Z). RPP is funded by a Career Re-entry Fellowship (204721/Z/16/Z). CJAD is funded by a Wellcome Clinical Research Career Development Fellowship (211153/Z/18/Z). DS is supported by the NIHR Academic Clinical Lecturer programme in Oxford. LT is supported by the Wellcome Trust (grant number 205228/Z/16/Z) and the National Institute for Health Research Health Protection Research Unit (NIHR HPRU) in Emerging and Zoonotic Infections (NIHR200907) at University of Liverpool in partnership with Public Health England (PHE), in collaboration with Liverpool School of Tropical Medicine and the University of Oxford. DGW is supported by an NIHR Advanced Fellowship in Liverpool. LT and MC are supported by U.S. Food and Drug Administration Medical Countermeasures Initiative contract 75F40120C00085. Declaration of Interests: AJP is Chair of UK Dept. Health and Social Care’s (DHSC) Joint Committee on Vaccination & Immunisation (JCVI), but does not participate in policy decisions on COVID-19 vaccines. He is a member of the WHO’s SAGE. The views expressed in this article do not necessarily represent the views of DHSC, JCVI, or WHO. AJP is chief investigator on clinical trials of Oxford University’s COVID-19 vaccine funded by NIHR. Oxford University has entered a joint COVID-19 vaccine development partnership with AstraZeneca. Ethics Approval Statement: PITCH is a sub-study of the SIREN study which was approved by the Berkshire Research Ethics Committee, Health Research 250 Authority (IRAS ID 284460, REC reference 20/SC/0230), with PITCH recognised as a sub-study on 2 December 2020. SIREN is registered with ISRCTN (Trial ID:252 ISRCTN11041050). Some participants were recruited under aligned study protocols. In Birmingham participants were recruited under the Determining the immune response to SARS-CoV-2 infection in convalescent health care workers (COCO) study (IRAS ID: 282525). In Liverpool some participants were recruited under the “Human immune responses to acute virus infections” Study (16/NW/0170), approved by North West - Liverpool Central Research Ethics Committee on 8 March 2016, and amended on 14th September 2020 and 4th May 2021. In Oxford, participants were recruited under the GI Biobank Study 16/YH/0247, approved by the research ethics committee (REC) at Yorkshire & The Humber - Sheffield Research Ethics Committee on 29 July 2016, which has been amended for this purpose on 8 June 2020. In Sheffield, participants were recruited under the Observational Biobanking study STHObs (18/YH/0441), which was amended for this study on 10 September 2020. The study was conducted in compliance with all relevant ethical regulations for work with human participants, and according to the principles of the Declaration of Helsinki (2008) and the International Conference on Harmonization (ICH) Good Clinical Practice (GCP) guidelines. Written informed consent was obtained for all patients enrolled in the study.

IntroductionDesign of an integrated diabetes service based on needs of service users (persons living with diabetes) and community clinicians in a semirural low-income health district of the UK.Research design and methodsOne hundred and eighty-five service users engaged through public meetings, questionnaires and focus groups. General practice staff contributed views through workshops and questionnaires. Analysis of feedback indicated service user needs for better access to education, dietary advice and foot care. General practice staff endorsed these views and requested regular access to secondary care in the community. Seven hundred persons registered with diabetes attended eight well-being events in the community. From 2017 virtual practice multidisciplinary patient reviews, virtual referral of foot cases and non-face-to-face helplines were developed. A National Health Service (NHS) approved ‘App’ and web-based personalized education support for those recently diagnosed with diabetes was introduced.ResultsEngagement in education for those recently diagnosed with diabetes increased from 5% to 71%. Weight and hemoglobin A1c (HbA1c) levels before and 6 months after starting the program were 99.4±25 and 95.5±24.2 kg and 59.3±16 and 54.8±12.9 mmol/mol, respectively, p=0.00003 and 0.003. Of those engaging at well-being events, 44 had missed regular follow-up. One hundred and seventy-five cases were reviewed virtually with practice staff by the secondary care team avoiding referral to the hospital diabetic clinic. One hundred and seventy-six referrals were made to the virtual multidisciplinary diabetic foot team clinic. Major amputation incidence declined from 13 to 3 major procedures/10 000 per annum and minor amputation from 26 to 18/10 000. Percentage bed day occupancy by persons with diabetes fell significantly in the district general hospital.ConclusionsIntegrated community-based diabetes care delivery has been achieved with partially virtual reviews. Patient education, secondary care in the community, access to dietetic advice and foot care outcomes have all improved.

Background & Aims Calcineurin is a ubiquitously expressed central Ca2+-responsive signaling molecule that mediates acute pancreatitis, but little is known about its effects. We compared the effects of calcineurin expression by hematopoietic cells vs pancreas in mouse models of pancreatitis and pancreatitis-associated lung inflammation. Methods We performed studies with mice with hematopoietic-specific or pancreas-specific deletion of protein phosphatase 3, regulatory subunit B, alpha isoform (PPP3R1, also called CNB1), in mice with deletion of CNB1 (Cnb1UBC△/△) and in the corresponding controls for each deletion of CNB1. Acute pancreatitis was induced in mice by administration of caerulein or high-pressure infusion of radiocontrast into biliopancreatic ducts; some mice were also given intraductal infusions of an adeno-associated virus vector that expressed nuclear factor of activated T -cells (NFAT)–luciferase into pancreas. Pancreas, bone marrow, liver, kidney, heart, and lung were collected and analyzed by histopathology, immunohistochemistry, and immunoblots; levels of cytokines were measured in serum. Mouse and human primary pancreatic acinar cells were transfected with a vector that expressed NFAT-luciferase and incubated with an agent that blocks interaction of NFAT with calcineurin; cells were analyzed by immunofluorescence. Calcineurin-mediated neutrophil chemotaxis and reactive oxygen species production were measured in neutrophils from mice. Results Mice with hematopoietic-specific deletion of CNB1 developed the same level of local pancreatic inflammation as control mice after administration of caerulein or infusion of radiocontrast into biliopancreatic ducts. Cnb1UBC△/△ mice or mice with pancreas-specific deletion of CNB1 developed less severe pancreatitis and reduced pancreatic inflammation after administration of caerulein or infusion of radiocontrast into biliopancreatic ducts compared with control mice. NFAT was activated in pancreas of Swiss Webster mice given caerulein or infusions of radiocontrast into biliopancreatic ducts. Blocking the interaction between calcineurin and NFAT did not reduce pancreatic acinar cell necrosis in response to caerulein or infusions of radiocontrast. Mice with hematopoietic-specific deletion of CNB1 (but not mice with pancreas-specific deletion of CNB1) had reduced infiltration of lung tissues by neutrophils. Neutrophil chemotaxis and production of reactive oxygen species were decreased after incubation with a calcineurin inhibitor. Conclusions Hematopoietic and neutrophil expression of calcineurin promotes pancreatitis-associated lung inflammation, whereas pancreatic calcineurin promotes local pancreatic inflammation. The findings indicate that the protective effects of blocking or deleting calcineurin on pancreatitis are mediated by the source of its expression. This information should be used in the development of strategies to inhibit calcineurin for the prevention of pancreatitis and pancreatitis-associated lung inflammation.

Canada’s population is increasing, and aging. These demographic patterns are accompanied by a growing awareness and evidence base of the benefits to society of leading a healthy and active life. The Canadian Academy of Lifestyle Medicine (CALM) was created to fill a knowledge gap in the Canadian public: how to lead a healthier and more active life. CALM aimed to address these challenges by confronting the lack of assistance modern medicine provides. As a diverse collaborative network using a lifestyle medicine philosophy, CALM’s objective was to generate discussions and examine lifestyle medicine approaches to improving overall health and well-being for Canadians. CALM aimed to engage patients whose access to health care is through a physician and provide an innovative platform to support care and healthy decision making. Despite perceived widespread support, intense planning, and extensive development, CALM was slow to gain traction and realize its full potential. This article describes the experiences and lessons learned in creating CALM from the perspective of the leadership team. Although most CALM activities have ceased, virtual space and social media remain active so too does the work of the leadership team, striving to enable Canadians to develop behaviors that will improve their lifestyle, and their overall well-being.

Context Ultrasonography is becoming more common in clinical use, and it has been shown to have promising results when introduced into medical school curricula. Objective To determine whether the use of ultrasonography as an educational supplement can improve osteopathic medical students’ confidence and ability to locate 4 specific shoulder anatomical landmarks: the coracoid process, the transverse process of T1, the long head of the biceps within the bicipital groove, and the supraspinatus tendon. Methods In this randomized controlled study, first-year osteopathic medical students aged 18 years or older were recruited and randomly assigned to a group with exposure (ultrasonography group) or without exposure (control group) to an ultrasonography machine. First, a survey was administered to measure students’ baseline knowledge of shoulder anatomy, confidence in palpation skills, and opinion on anatomical landmark identification teaching methods. Next, students were shown presentations on shoulder anatomy and allowed to practice locating and palpating the specified landmarks. Students in the ultrasonography group were also given instruction on the use of ultrasonography. All students were asked to locate each of the 4 specified anatomical landmarks and then given a follow-up survey. A Mann Whitney U test was used to compare the confidence of the students before and after the intervention. A secondary analysis was performed to compare the degree of deviance from the correct position of the specified anatomical landmark between the ultrasonography and control groups. P values less than .05 were considered statistically significant. Results Sixty-four students participated. Compared with the control group, students in the ultrasonography group had a greater increase in confidence after the session in their ability to locate the coracoid process, bicipital tendon, and supraspinatus tendon (P=.022, P=.029, P=.44, respectively). Students in the ultrasonography group were also able to more accurately palpate the landmarks than those in the control group, with a significant difference in accurate palpation of the bicipital tendon (P=.024). The ultrasonography group showed less deviation with palpation of the other 3 landmarks compared with the control group, but these results were not significant (P=.50, P=.82, P=.29, respectively). Conclusion Ultrasonography in the preclinical curriculum may improve medical students' confidence in and accuracy of palpation.

One potential harm of nonoperative management for acute appendicitis is missed appendiceal cancer, a rare and often aggressive malignancy due to the frequency of late stage of diagnosis. Previous studies have reported an increasing incidence of appendiceal neoplasms in the population. This is a retrospective case–control study of 1007 adult patients, who presented to the University of North Carolina-Memorial Hospital (UNC-MH) between 2011 and 2015 with clinical signs and symptoms of appendicitis. We evaluated the incidence of primary appendiceal cancer in this population and determined factors that predict appendiceal cancer diagnosis using multi-variate logistic regression analysis. The overall incidence of appendiceal neoplasm for adult patients presenting to UNC-MH with appendicitis from 2011 to 2015 was 2.3 per cent (23/1007). The incidence in patients without appendiceal perforation on pathology was 1.9 per cent (16/832). Age (odds ratio (OR) 1.03), number of days of abdominal pain (OR 1.16), self-reported fever (OR 2.08), appendiceal width (OR 1.95), and appendiceal wall thickness (OR 1.30) were predictors of appendiceal neoplasm diagnosis in patients that present with acute appendicitis. We recommend that an operative approach to acute appendicitis should remain the standard of care because operative management may not only be diagnostic but potentially therapeutic.

In the 25 years since the International Conference on Population and Development (ICPD), human rights legal standards have developed significantly, and those involved in sexual and reproductive hea...

Background: The preferred timing of umbilical-cord clamping in preterm infants is unclear. Methods: We randomly assigned fetuses from women who were expected to deliver before 30 weeks of gestation to either immediate clamping of the umbilical cord (≤10 seconds after delivery) or delayed clamping (≥60 seconds after delivery). The primary composite outcome was death or major morbidity (defined as severe brain injury on postnatal ultrasonography, severe retinopathy of prematurity, necrotizing enterocolitis, or late-onset sepsis) by 36 weeks of postmenstrual age. Analyses were performed on an intention-to-treat basis, accounting for multiple births. Results: Of 1634 fetuses that underwent randomization, 1566 were born alive before 30 weeks of gestation; of these, 782 were assigned to immediate cord clamping and 784 to delayed cord clamping. The median time between delivery and cord clamping was 5 seconds and 60 seconds in the respective groups. Complete data on the primary outcome were available for 1497 infants (95.6%). There was no significant difference in the incidence of the primary outcome between infants assigned to delayed clamping (37.0%) and those assigned to immediate clamping (37.2%) (relative risk, 1.00; 95% confidence interval, 0.88 to 1.13; P=0.96). The mortality was 6.4% in the delayed-clamping group and 9.0% in the immediate-clamping group (P=0.03 in unadjusted analyses; P=0.39 after post hoc adjustment for multiple secondary outcomes). There were no significant differences between the two groups in the incidences of chronic lung disease or other major morbidities. Conclusions: Among preterm infants, delayed cord clamping did not result in a lower incidence of the combined outcome of death or major morbidity at 36 weeks of gestation than immediate cord clamping. (Funded by the Australian National Health and Medical Research Council [NHMRC] and the NHMRC Clinical Trials Centre; APTS Australian and New Zealand Clinical Trials Registry number, ACTRN12610000633088. opens in new tab.)

Donor-derived adoptive T-cell therapy is a safe and effective treatment of viral infection posttransplant, but it is limited by donor serostatus and availability and by its personalized nature. Off-the-shelf, third-party virus-specific T cells (VSTs) appear promising, but the long-term safety and durability of responses have yet to be established. We conducted a prospective study of 30 allogeneic hemopoietic stem cell transplant (HSCT) patients with persistent or recurrent cytomegalovirus (CMV) (n = 28), Epstein-Barr virus (n = 1), or adenovirus (n = 1) after standard therapy. Patients were treated with infusions of partially HLA-matched, third-party, ex vivo-expanded VSTs (total = 50 infusions) at a median of 75 days post-HSCT (range, 37 to 349 days). Safety, viral dynamics, and immune recovery were monitored for 12 months. Infusions were safe and well tolerated. Acute graft versus host disease occurred in 2 patients, despite a median HLA match between VSTs and the recipient of 2 of 6 antigens. At 12 months, the cumulative incidence of overall response was 93%. Virological control was durable in the majority of patients; the reintroduction of antiviral therapy after the final infusion occurred in 5 patients. CMV-specific T-cell immunity rose significantly and coincided with a rise in CD8+ terminal effector cells. PD-1 expression was elevated on CD8+ lymphocytes before the administration of third-party T cells and remained elevated at the time of viral control. Third-party VSTs show prolonged benefit, with virological control achieved in association with the recovery of CD8+ effector T cells possibly facilitated by VST infusion. This trial was registered at www.clinicaltrials.gov as #NCT02779439 and www.anzctr.org.au as #ACTRN12613000603718.

Clinical scores determining the likelihood of acute appendicitis (AA), including the Alvarado score, were devised using a younger population, and their efficacy in predicting AA in elderly patients is not well documented. This study's purpose is to evaluate the utility of Alvarado scores in this population. A retrospective chart review of patients >65 years old presenting with pathologically diagnosed AA from 2000 to 2010 was performed. Ninety-six patients met inclusion criteria. The average age was 73.7 ± 1.5 years and our cohort was 41.7 per cent male. The average Alvarado score was 6.9 ± 0.33. The distribution of scores was 1 to 4 in 3.7 per cent, 5 to 6 in 37.8 per cent, and 7 to 10 in 58.5 per cent of cases. There was a statistically significant increase in patients scoring 5 or 6 in our cohort versus the original Alvarado cohort (P < 0.01). Right lower quadrant tenderness (97.6%), left shift of neutrophils (91.5%), and leukocytosis (84.1%) were the most common symptoms on presentation. In conclusion, our data suggest that altering our interpretation of the Alvarado score to classify elderly patients presenting with a score of ≥5 as high risk may lead to earlier diagnosis of AA. Physicians should have a higher clinical suspicion of AA in elderly patients presenting with right lower quadrant tenderness, left shift, or leukocytosis.

Approximately 80% of patients diagnosed with Crohn’s disease will ultimately require an intestinal resection for complications relating to their inflammatory bowel disease. Unfortunately, endoscopic recurrence of disease is identified in up to 70% of patients who have undergone surgical resection within one year of the operation and nearly one-third of patients will require additional operative interventions. There is still significant room for improvement in terms of efficacy of medical therapy in preventing recurrence in patients with Crohn’s disease in surgical remission. Furthermore, recurrence is most often seen at the anastomotic site or in the neo-terminal ileum. These findings indicate that efforts should be made to identify factors associated with recurrence and optimize anastomotic technique as a key proponent in the management of this difficult disease.

Cancer development from in utero exposure has been documented for a variety of agents with the most commonly studied compounds exhibiting mutagenic and genotoxic carcinogen properties. Age-dependent adjustment factors (ADAFs) are applied by the US Environmental Protection Agency to many such carcinogens when assessing cancer risk from early postnatal (PN) exposures; however, this approach has not been widely considered for transplacental (TP) exposure. To explore this question and further evaluate prenatal susceptibility a database of early life animal studies developed by California Office of Environmental Health Hazard Assessment (OEHHA) enhanced with additional literature searching was evaluated. Nine genotoxic carcinogens and one mixture (cigarette smoke) have data available via TP only, PN only and adult-only protocols. Potency comparisons across these lifestages displayed similarly greater potency in male liver and brain compared to adult-only exposure. Both TP and PN exposures were not markedly different than adult-only for other targets such as female liver and blood-borne tumors. Similarity in TP and PN targets and potency for carcinogen action suggests that a 10-fold ADAF may be applied for TP exposure as is currently applied to PN exposure. A similar conclusion was reached by OEHHA. The implications of this heightened TP vulnerability are greatest for less-than-lifetime exposure and this approach might be used to assess the level of cancer risk from exposures during pregnancy. A case example employing a mutagenic flame retardant was used to exemplify application of a TP ADAF for evaluating risks during pregnancy.

Cyber network analysts must gather evidence from multiple sources and ultimately decide whether or not suspicious activity represents a threat to network security. Information relevant to this task is usually presented in an uncoordinated fashion, meaning analysts must manually correlate data across multiple databases. The current experiment examined whether analyst performance efficiency would be improved by coordinated displays, i.e., displays that automatically link relevant information across databases. We found that coordinated displays nearly doubled performance efficiency, in contrast to the standard uncoordinated displays, and coordinated displays resulted in a modest increase in threat detections. These results demonstrate that the benefits of coordinated displays are significant enough to recommend their inclusion in future cyber defense software.

To describe fluocinolone acetonide implant dissociations in the Multicenter Uveitis Steroid Treatment (MUST) Trial.Randomized clinical trial with extended follow-up.Review of data collected on the first implant in the eye(s) of participants. Dissociation was defined as the drug pellet no longer being affixed to the strut and categorized as spontaneous or surgically related.A total of 250 eyes (146 patients) had at least 1 implant placed. Median follow-up time after implant placement was 6 years (range 0.5-9.2 years). Thirty-four dissociations were reported in 30 participants. There were 22 spontaneous events in 22 participants; 6-year cumulative risk of a spontaneous dissociation was 4.8% (95% confidence interval [CI]: 2.4%-9.1%). The earliest event occurred 4.8 years after placement. Nine of 22 eyes with data had a decline in visual acuity ≥5 letters temporally related to the dissociation. Thirty-nine implant removal surgeries were performed, 33 with replacement. Twelve dissociations were noted during implant removal surgeries in 10 participants (26%, 95% CI 15%-48%); 5 of these eyes had a decline in visual acuity ≥5 letters after surgery. The time from implant placement to removal surgery was longer for the surgeries at which dissociated implants were identified than for those without one (5.7 vs 3.7 years, P.001). Overall, visual acuity declined 15 or more letters from pre-implant values in 22% of affected eyes; declines were frequently associated with complications of uveitis or its treatment.There is an increasing risk of dissociation of Retisert implants during follow-up; the risk is greater with removal/exchange surgeries, but the risk of both spontaneous and surgically related events increases with longevity of the implants. In 22% of affected eyes visual acuity declined by 15 letters. In the context of eyes with moderate to severe uveitis for years, this rate is not unexpected.

Background It has been established that pain is frequently undertreated in children following outpatient surgery. Very few studies, however, have investigated this phenomenon in ethnically diverse populations. Methods This study included 105 families of children aged 2 to 15 years of Hispanic origin and low income undergoing outpatient tonsillectomy and adenoidectomy surgery. Participating parents completed baseline and demographic packets. Recorded postoperative pain ratings and administration of analgesics at home for 1 week were collected during home visits. Results Despite the high (70%; 99% confidence interval [CI], 57%-82%) incidence of significant pain in the first 24 hours home, 32% (95% CI, 20%-45%) of the children received 0 to 1 dose of analgesia. Overall, 21% children (99% CI, 11%-35%) received 4 or less total doses of pain medication over the entire week after surgery. Of the total analgesic doses administered to children in the week after surgery, only 44% (99% CI, 40%-47%) were in accepted ranges. Conclusions Despite experiencing significant postoperative pain, Hispanic children assessed in this study received suboptimal analgesic therapy at home.

BackgroundYoung people in state care, often due to abuse or neglect, have a four-fold increased risk of drug and alcohol use compared to their peers.AimThe SOLID study aimed to investigate the feasibility of a definitive randomised controlled trial, comparing two behaviour change interventions to reduce risky substance use (illicit drugs and alcohol), and improve mental health, in young people in care.MethodsWe recruited young people in care aged 12-20 years, self-reporting substance use within the previous 12 months and residing in 1 of 6 participating local authority sites in the North East of England. Participants were randomised to either i. Motivational Enhancement Therapy (MET), ii. Social Behaviour and Network Therapy (SBNT) or iii. Control (usual care). All interventions were delivered by trained drug and alcohol workers. Follow-up data were collected 12 months post recruitment. Feasibility for trial progression was compared to pre-specified stop: go criteria (recruitment of 60% of eligible participants, 80% of participants attending 60% of offered sessions and retention of 70% of participants at 12 month follow up).ResultsOf 1450 eligible participants, 860 (59%) were screened for drug and alcohol use by social workers, 211 (24.5%) met inclusion criteria for the trial and 112 young people (7.7%) consented and were randomised. Sixty of these 112 participants (54%) completed 12-month follow-up questionnaires. Only 15 out of the 76 (20%) participants allocated to an intervention arm attended any of the offered MET or SBNT sessions.ConclusionBy reference to pre-specified stop: go criteria it is not feasible to conduct a definitive trial for SOLID in its current format. Despite co-designing procedures with staff and young people in care, the screening, referral and treatment pathway did not work here. Future work may require dedicated clinically embedded research resource to evaluate effectiveness of new interventions in services.

Introduction: Neurofibromatosis type 1 (NF1)-associated malignant peripheral nerve sheath tumors (MPNSTs) are malignant sarcomas occurring in approximately 15% of NF1 patients and always develop within benign precursor lesions (plexiform neurofibromas). The mortality caused by these tumors is high, approaching 100% in patients with unresectable, metastatic or recurrent disease. Targeted inhibition of the MAP kinase (MAPK) pathway has been attempted in clinical trials using MEK inhibitors (MEKi). While emerging data demonstrate effective tumor growth inhibition in benign plexiform neurofibromas, MEK inhibition blocks MPNST progression only to a limited extent. Combination strategies targeting both the MAPK and PI3K/AKT pathways (horizontal inhibition) have had limited clinical success due to excessive toxicities which precludes delivery of optimal therapeutic concentrations. Thus, novel approaches and complementary treatment strategies that are tolerable and prevent adaptive resistance mechanisms in NF1 MPNST are urgently needed. Methods: We have succeeded in establishing orthotopic in vivo models (patient-derived human xenografts-PDXs and genetically engineered mouse models- GEMMs) via implantation of tumor cells into the sciatic nerve, an approach that is critical, because it preserves the tumor microenvironment. Furthermore, we have optimized MPNST culture conditions, allowing us to establish robust primary cultures of MPNSTs while retaining key biological features of the original tumors. Summary of findings: Using this preclinical testing platform, we demonstrate that - 1. A feedback loop mediated by induction of receptor tyrosine kinase (RTK) signaling becomes hyperactivated upon MEK inhibition (MEKi). This subsequently activates the MAPK pathway to such an extent that MEKi alone is unable to completely block signaling to ERK, thereby maintaining tumor proliferation. 2. SHP2 is a protein tyrosine phosphatase (PTP) that functions as a positive signal transducer, acting between RTKs and RAS and thus, functions as physiological mediator for RAS activation. A treatment paradigm where MEKi is combined with SHP099, an allosteric SHP2 inhibitor to counteract the rebound increase in RTK mediated signaling to RAS-MEK-ERK results in effective attenuation of MEK-ERK signaling. In vivo studies demonstrate that the drug combination exhibits synergistic effects on tumor growth inhibition and significantly prolongs survival. 3. SHP099 disrupts a functional complex (SOS1/GRB2) which is essential to RAS-GTP loading and inhibits RAS-mediated downstream MAP kinase signaling in NF1 MPNST. Conclusions - Our results provide a mechanistic context for SHP2's precise role in the regulation of RAS-GTP and demonstrate that SHP2i can prevent adaptive resistance to MEKi. Given that allosteric SHP2 inhibitors are currently in clinical trials (NCT03114319), our studies can be rapidly translated into a clinical trial to evaluate a combination of SHP2i and MEKi as a novel treatment approach in NF1-MPNSTs. Citation Format: Sameer Farouk Sait, Kwan Tang, Rebecca Brown, Daochun Sun, Xunhua Xie, Benjamin Neel, Luis Parada. Allosteric inhibition of SHP2 prevents adaptive resistance to MEK inhibition in neurofibromatosis type 1 associated malignant peripheral nerve sheath tumors [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1889.

Purpose: Rhabdomyosarcoma (RMS) is the most common soft-tissue sarcoma of childhood. Despite aggressive therapy, the 5-year survival rate for patients with metastatic or recurrent disease remains poor and beyond PAX-FOXO1 fusion status, no genomic markers are available for risk stratification. We therefore performed a large-scale study through an international consortium to more accurately determine the incidence of driver mutations and their association with clinical outcome. Patients and Method: Formalin-fixed, paraffin-embedded material was collected from patients enrolled on Children’s Oncology Group trials and UK patients enrolled on MMT trials. Pathology was reviewed centrally and extracted DNA was subjected to targeted capture sequencing using a panel of 39 genes previously associated with RMS. Mutations, indels, deletions, gene amplifications, and copy number variation was called using analysis pipelines developed at the NCI. Results: DNA from six hundred and forty-one patients was suitable for analyses. A median of 1 variant call was found per tumor. Mutation of a RAS isoform was found in 29% of all fusion negative cases, mutation of a RAS pathway member was seen in greater than 50% of cases, and 24% had no putative driver mutation identified. BCOR (15%), NF1 (11%), and TP53 (12%) mutations were found at a higher incidence than previously reported. Interestingly, mutations in HRAS were notable in the infant population whereas those in NRAS were enriched in adolescents. Among infants < 1 year, 71% of cases harbored a mutation in HRAS or KRAS. In contrast, mutation of MYOD1 was associated with an older age and a head and neck primary site. Finally, 29% of the evaluated tumors harbored multiple driver mutations consistent with subclonal variation and tumor heterogeneity in fusion-negative RMS. Conclusion: This is the largest genomic characterization of clinically annotated RMS tumors to date and provides genetic features that refine risk stratification and can be incorporated into prospective trials. Citation Format: Jack Shern, Joanna Selfe, Rajesh Patidar, Young Song, Marielle Yohe, Jun Wei, Xinyu Wen, Erin Rudinski, Donald Barkauskas, David Hall, Corinne Linardic, Meriel Jenney, Julia Chisholm, Rebecca Brown, Anna Kelsey, Susanne Gatz, Stephen Skapek, Douglas Hawkins, Janet Shipley, Javed Khan. Genomic classification and prognosis in rhabdomyosarcoma: A report from the Children’s Oncology Group, the Institute of Cancer Research, and the National Cancer Institute [abstract]. In: Proceedings of the AACR Special Conference on the Advances in Pediatric Cancer Research; 2019 Sep 17-20; Montreal, QC, Canada. Philadelphia (PA): AACR; Cancer Res 2020;80(14 Suppl):Abstract nr B15.

MANIFEST is a multi-object fibre facility for the Giant Magellan Telescope that uses ‘Starbug’ robots to accurately position fibre units across the telescope’s focal plane. MANIFEST, when coupled to the telescope’s planned seeinglimited instruments, offers access to larger fields of view; higher multiplex gains; versatile focal plane reformatting of the focal plane via integral-field-units; image-slicers; and in some cases higher spatial and spectral resolution. The TAIPAN instrument on the UK Schmidt Telescope is now close to science verification which will demonstrate the feasibility of the Starbug concept. We are now moving into the conceptual development phase for MANIFEST, with a focus on developing interfaces for the telescope and for the instruments.

The 4MOST1 instrument is a multi-object-spectrograph for the ESO-VISTA telescope. The 4MOST long fiber feed links the AESOP2 fiber positioner to two low-resolution spectrographs (1624 fibers) and one high-resolution spectrograph (812 fibers). In addition to the 2436 science fibers, the system includes guide fiber bundles, metrology fiducial fibers and simultaneous calibration fibers for the spectrographs. To validate the design approaches, including fiber connectors and cable rotator, pre-production fiber cables have been built and evaluated. This paper presents the near final design of the fiber feed subsystem and its performance results pertaining to throughput homogeneity, focal ratio degradation, and connector loss of the pre-production cables.

In this paper we present recent progress on the Australian Astronomical Observatory’s AESOP2 fiber positioner for 4MOST (on VISTA). As an evolution of the Echidna “spine” technology used for FMOS (on Subaru), AESOP has challenging requirements to position 2,448 fibers in parallel, within 1 minute, to an accuracy of < 10 um RMS. AESOP successfully passed ESO’s official final design review and manufacturing has commenced. We present performance results from the first batch of newly-manufactured positioners and also report on how the AESOP project is tracking in terms of schedule, budget and risk.

In this paper we present the Australian Astronomical Observatory's concept design for Sphinx - a fiber positioned with 4332 spines on a 7.77mm pitch for CFHT's Mauna Kea Spectroscopic Explorer (MSE) Telescope. Based on the Echidna technology used with FMOS (on Subaru) and 4MOST (on VISTA), the next evolution of the tilting spine design delivers improved performance and superior allocation efficiency. Several prototypes have been constructed that demonstrate the suitability of the new design for MSE. Results of prototype testing are presented, along with an analysis of the impact of tilting spines on the overall survey efficiency. The Sphinx fiber positioned utilizes a novel metrology system for spine position feedback. The metrology design and the careful considerations required to achieve reliable, high accuracy measurements of all fibres in a realistic telescope environment are also presented., Comment: 18 pages; Proceedings of SPIE Astronomical Telescopes + Instrumentation 2018; Ground-based and Airborne Instrumentation for Astronomy VII

Background Amblyopia (lazy eye) affects the vision of approximately 2% of all children. Traditional treatment consists of wearing a patch over their ‘good’ eye for a number of hours daily, over several months. This treatment is unpopular and compliance is often low. Therefore, results can be poor. I-BiT is a system, based on stereo technology using shutter glasses, designed to treat amblyopia using dichoptic stimulation. This trial uses a redesigned system for home use and includes eye-tracking capability. Methods/design This is a randomised controlled trial involving three groups of 40 patients each, aged between 3.5 and 12 years, with a diagnosis of (1) anisometropic amblyopia, (2) mixed or strabismic amblyopia prior to strabismic surgery and (3) mixed or strabismic amblyopia who have just undergone strabismus surgery. They will be randomised in a 1:1 ratio between I-BiT and control and will receive treatment, at home over a 6-week period. Their visual acuity will be assessed independently at baseline, mid-treatment (week 3), at the end of treatment (week 6) and, for those receiving the active I-BiT treatment, 4 weeks after completing treatment (week 10). The primary endpoint will be the change in visual acuity from baseline to the end of treatment. Secondary endpoints will be additional visual acuity measures, patient acceptability, compliance and the incidence of adverse events. Discussion This is a randomised controlled trial using the redesigned I-BiT™ system to determine if this is a feasible treatment strategy for the management of anisometropic, strabismic and mixed amblyopia. Trial registration ISRCTN Number/Clinical trials.gov, ID: NCT02810847. Registered on 23 June 2016. Electronic supplementary material The online version of this article (10.1186/s13063-019-3523-0) contains supplementary material, which is available to authorized users.

Many Smart City projects are beginning to consider the role of citizens. However, current methods for engaging urban populations in participatory design (PD) activities are somewhat limited. In this article, we describe an approach taken to empower socially disadvantaged citizens, using a variety of both social and technological tools, in a Smart City project. Through analysing the nature of citizens’ concerns and proposed solutions, we explore the benefits of our approach, arguing that engaging citizens can uncover hyper-local concerns that provide a foundation for finding solutions to address citizen concerns. By reflecting on our approach, we identify four key challenges to utilising PD at an urban scale; balancing scale with the personal, who has control of the process, who is participating and integrating citizen-led work with local authorities. By addressing these challenges, we will be able to truly engage citizens as collaborators in co-designing their city.

In 2015, two strong earthquakes, as well as continuous, high magnitude aftershocks, struck Nepal. Phulpingdanda village was greatly impacted due to its lack of infrastructure and environmental remoteness. Adults from sampled households were surveyed 1-year later to examine the association between earthquake exposures and indicators of depression, post-traumatic stress disorder (PTSD), and resilience. Results showed 33% of surveyed residents screened positive for depression, 9% screened positive for severe PTSD, and 46% displayed moderate to high resilience. Additionally, participants experienced resource loss (100%), damaged home and goods (99%), and exposure to the grotesque (82%). Traumatic earthquake experiences related to personal harm were associated with symptoms of depression and PTSD and resource loss was associated with depressive symptoms. Earthquake experiences associated with less damage to home and goods, but greater exposure to the grotesque were associated with increased resilience. This research adds to our knowledge of the relationship between traumatic exposures and indicators of psychological distress and resilience following a disaster.

Extracorporeal membrane oxygenation (ECMO) is being used with increasing frequency to support patients suffering from severe cardiac or respiratory failure. In pregnancy, ECMO has resulted in favor-able maternal and fetal outcomes. However, there is a paucity of information regarding ECMO man-agement in the peripartum period, including the ideal method of delivery. A case series of four pa-tients describes 100 per cent survival of the mother and fetus where delivery was performed when the patients were on ECMO. In all of these cases, de-livery was performed via cesarean section. Further investigation has revealed that all current informa-tion available in regard to this topic describe delivery via cesarean section only. Here, we describe a case in which a vaginal delivery was successfully performed when on ECMO, without significant blood loss or circuit complication. We describe our management strategies regarding maternal anticoagulation pre- and postvaginal delivery.

Vitamin C is an essential nutrient with important antioxidant properties. Higher vitamin C intake appears to be associated with positive effects on cardiovascular risk factors in cohort studies, whereas large randomized controlled clinical trials did not confirm the benefits of supplemental vitamin C on cardiovascular disease (CVD) outcomes. In this overview of systematic reviews and meta-analyses, an “umbrella review,” we investigated the effects of vitamin C supplementation on biomarkers of cardiovascular risk, that is, arterial stiffness, blood pressure, endothelial function, glycemic control, and lipid profile. In addition, we assessed the strength of the evidence and the methodological qualities of available studies. Two independent investigators searched 4 databases (Medline, Embase, Scopus, and The Cochrane Library databases) from inception until February 2018. After full text examination, 10 systematic reviews and meta-analyses were included in the umbrella review which included 6409 participants. Three systematic reviews investigated the effects of vitamin C on endothelial function with contrasting results (2 reviews reported a significant effect, and all 3 showed a high heterogeneity [I2> 50%]); 1 systematic review reported significant improvement for each of the following risk factors: blood pressure, and blood concentrations of glucose, low-density lipoprotein cholesterol, and triglycerides. There were no overall effects of vitamin C on arterial stiffness and blood concentration of insulin, total cholesterol, and high-density lipoprotein cholesterol, but subgroup analyses revealed some evidence for significant improvements in subpopulations with higher body mass index, higher plasma concentrations of glucose or cholesterol, and low plasma concentration of vitamin C. Results from this umbrella review emphasize the weakness of the current evidence base about effects of vitamin C supplementation on markers of CVD risk. There is limited evidence that some population subgroups (older people, the obese, those with lower vitamin C status at baseline, and those at higher CVD risk) may be more responsive to vitamin C supplementation and offer opportunities for tailored nutritional interventions to improve cardiometabolic health. Future studies should implement a selective recruitment strategy that is informed by evidence-based literature synthesis.

Research shows that teammates often exhibit similarities in their physiological and behavioral responses during cooperative tasks, a phenomenon termed physio-behavioral coupling (PBC). Recently, studies have extended the examination of PBC to include electrocephalography (EEG). In this study, we examined the coupling strength of EEG Fz responses from dyadic teams performing Air Force Spaceship Simulator (AFSS – a variant of Atari Asteroids) to explore the basic utility of EEG coupling measures for the real-time monitoring of team task-load in Air Force operations (e.g., remotely piloted vehicle navigation). Specific study goals were to, a) verify that Fz coupling during AFSS was driven by the team-task environment (and not simply a chance artifact), b) determine if Fz coupling was affected by periodic transitions from low-to-high task load (TL), and c) examine the relationship between Fz coupling and team performance. Findings confirmed that Fz coupling in this task was indeed driven by the team-task environment, that Fz coupling was affected by TL transitions, and that Fz coupling exhibited a moderate relationship with team performance throughout the experiment ( r ~ -.50). Specifically, high Fz coupling was shown to be associated with low TL, whereas low Fz coupling was associated with high TL. In addition, these TL-induced changes in Fz coupling exhibited minimal lag (less than 30-seconds), although changes in Fz coupling in response to high TL were transient and inconsistent. Together, these findings verify the potential of Fz coupling as an objective and physiology-based indicator of TL that could be used in the future to monitor human performance in team Air Force operations.

The literature on alcohol consumption among university and residential college students in Australia and comparable countries shows a high incidence of heavy and/or frequent drinking. In this article, we report the findings from a study on alcohol consumption among undergraduate university students living in residential colleges in Australia. The aim of the study was to examine residents’ alcohol use as part of a broader set of institutional practices in higher education that are constructed as central to the student experience. The data were collected through in-depth semistructured interviews with 29 students from seven residential colleges. We found that inclusion of alcohol in many students’ social and extracurricular activities while residing in college is associated with heavy and/or frequent drinking. We suggest that the use of alcohol among students is shaped by the colleges’ institutional micro-processes, leading to a tension between college managements’ aim to foster alcohol citizenship and students’ liberty to engage in frequent and/or heavy drinking.

Evidence concerning the impact of abuse and neglect in the early years points to the importance of taking swift and decisive action when very young children are suffering, or likely to suffer, significant harm. The decisions made by professionals who have safeguarding responsibilities are extremely difficult and will have long-term consequences for children's life chances. This paper explores three complementary questions. Firstly, how far is there a mismatch between timeframes for early childhood development and those for responses to evidence of abuse and neglect from professionals with safeguarding responsibilities? Secondly, if a mismatch exists, why has it occurred? And thirdly, how might the issues identified be addressed? Illustrations are drawn from a prospective longitudinal study of the decision-making processes influencing the life pathways and developmental progress of an English sample of very young children who were identified as suffering, or likely to suffer, significant harm before their first birthdays and have now been followed until they are five years old.

Stiff-person syndrome (SPS) is a rare disorder that affects the central nervous system and is characterized by progressive muscle stiffness, rigidity, and spasm of axial and limb muscles. The syndrome is caused by a lack of gamma aminobutyric acid (GABA), which occurs because of antibodies against glutamic acid decarboxylase (GAD), an essential enzyme for GABA synthesis. Hence, the patients present with increased muscular activity. In this article, we will discuss two case studies of stiff-person syndrome.

Background Looked after children (LAC) and care leavers are young people who have been placed under the legal care of local authorities, in many instances due to a history of abuse and/or neglect. These young people have a significantly increased risk of substance use and mental disorder compared to their peers. The aim of the SOLID study is to assess the feasibility and acceptability of a definitive three-arm multi-centre randomised controlled trial (RCT) that compares the effectiveness of two interventions that aim to reduce risky drug and alcohol use and improve mental health among LAC aged 12 to 20 years with usual care. Methods All LAC aged 12 to 20 years residing in four local authorities in North East England will be screened by their social worker for risky drug and alcohol use using the CRAFFT (Car, Relax, Alone, Forget, Friends and Trouble) screening tool. Those who score ≥2 will be invited to take part in the trial after further eligibility checks. Informed consent will be taken and baseline data collected. Participants will then be randomised into either (i) Motivational Enhancement Therapy, (ii) Social Behaviour and Network Therapy, or (iii) control–usual care. Follow-up data will be collected 12 months post-baseline. The baseline and follow-up questionnaires will measure self-reported drug and alcohol use, mental health and well-being and health-related quality of life. The follow-up will also collect data on placement stability and self-reported sexual, antisocial and criminal behaviour. Participants will also be asked about the use of health and social services. A detailed process evaluation, using both qualitative and quantitative methods, will be conducted and involve LAC, their carers, social workers and drug and alcohol practitioners. Discussion Despite having an increased likelihood of risky substance misuse, there is a lack of evidence outlining specific interventions to decrease drug and alcohol use targeting LAC. This feasibility study will provide the information needed to develop a definitive trial. LAC will benefit from the results of this study and the further development of the interventions. Trial registration ISRCTN80786829

Stillbirth currently affects approximately 1 in every 200 pregnancies in the United Kingdom. Fetuses may exhibit signs of compromise as part of a stress response before stillbirth, including reduced fetal movements (RFM) and fetal heart rate (FHR) alterations. At present, and despite widespread use, current fetal monitoring is not associated with a reduction in perinatal mortality rate (PMR) as signs of fetal compromise are not adequately detected. This may be attributed to inaccuracies resulting from manual interpretation of results or subjective assessment of fetal activity. In addition, signs of compromise often occur only hours or days before fetal death, so may be missed by current monitoring methods, which are performed intermittently. A significant consideration is that correct identification of these signs and consequent intervention can result in the delivery of a healthy baby, thus preventing stillbirth. A hypothesis is presented, proposing prompt detection of fetal compromise with the use of 24-hour continuous objective fetal monitoring. With focus placed on obtaining long-term FHR and fetal movement data, prior interest has been found in developing devices for this purpose. However, introduction into clinical practice has not been achieved. Investigation of the hypothesis will begin with the design of a device to record the mentioned parameters, followed by an appropriate validation process. Should development and testing be successful, an eventual comparison in PMR with the use of continuous fetal monitoring vs current monitoring would address the hypothesis. It is suggested that a timely yet reliable indication of fetal wellbeing obtained via long-term monitoring would allow prompt and appropriate obstetric intervention and consequently reduce PMR.

Personal response systems are quickly becoming indispensable formative assessment tools in many college-level chemistry courses. With the use of such devices, students are provided with invaluable insights into the skills perceived by the instructor as important, while concurrently, the instructor can gather feedback as to how well students have mastered those skills. In graphically intensive subjects such as chemistry, however, their use is severely limited by the input options afforded by current devices. It is often difficult to distill graphing and structure creation tasks into questions that can be answered with short strings of numbers or via multiple choice. We have developed the uRespond system—a touch-based personal response system that allows students to use iPads or more traditional computers to draw graphs and structures—to address this critical, formative assessment gap.