Challenges in the care of individuals with severe primary insulin-like growth factor-I deficiency (SPIGFD): an international, multi-stakeholder perspective

BACKGROUND: Severe primary insulin-like growth factor-I (IGF-I) deficiency (SPIGFD) is a rare growth disorder characterized by short stature (standard deviation score [SDS] ≤ 3.0), low circulating concentrations of IGF-I (SDS ≤ 3.0), and normal or elevated concentrations of growth hormone (GH). Laron syndrome is the best characterized form of SPIGFD, caused by a defect in the GH receptor (GHR) gene. However, awareness of SPIGFD remains low, and individuals living with SPIGFD continue to face challenges associated with diagnosis, treatment and care. OBJECTIVE: To gather perspectives on the key challenges for individuals and families living with SPIGFD through a multi-stakeholder approach. By highlighting critical gaps in the awareness, diagnosis, and management of SPIGFD, this report aims to provide recommendations to improve care for people affected by SPIGFD globally. METHODS: An international group of clinical experts, researchers, and patient and caregiver representatives from the SPIGFD community participated in a virtual, half-day meeting to discuss key unmet needs and opportunities to improve the care of people living with SPIGFD. RESULTS: As a rare disorder, limited awareness and understanding of SPIGFD amongst healthcare professionals (HCPs) poses significant challenges in the diagnosis and treatment of those affected. Patients often face difficulties associated with receiving a formal diagnosis, delayed treatment initiation and limited access to appropriate therapy. This has a considerable impact on the physical health and quality of life for patients, highlighting a need for more education and clearer guidance for HCPs. Support from patient advocacy groups is valuable in helping patients and their families to find appropriate care. However, there remains a need to better understand the burden that SPIGFD has on individuals beyond height, including the impact on physical, emotional, and social wellbeing. CONCLUSIONS: To address the challenges faced by individuals and families affected by SPIGFD, greater awareness of SPIGFD is needed within the healthcare community, and a consensus on best practice in the care of individuals affected by this condition. Continued efforts are also needed at a global level to challenge existing perceptions around SPIGFD, and identify solutions that promote equitable access to appropriate care. Medical writing support was industry-sponsored

Furin cleavage of SARS-CoV-2 Spike promotes but is not essential for infection and cell-cell fusion.

Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2) infects cells by binding to the host cell receptor ACE2 and undergoing virus-host membrane fusion. Fusion is triggered by the protease TMPRSS2, which processes the viral Spike (S) protein to reveal the fusion peptide. SARS-CoV-2 has evolved a multibasic site at the S1-S2 boundary, which is thought to be cleaved by furin in order to prime S protein for TMPRSS2 processing. Here we show that CRISPR-Cas9 knockout of furin reduces, but does not prevent, the production of infectious SARS-CoV-2 virus. Comparing S processing in furin knockout cells to multibasic site mutants reveals that while loss of furin substantially reduces S1-S2 cleavage it does not prevent it. SARS-CoV-2 S protein also mediates cell-cell fusion, potentially allowing virus to spread virion-independently. We show that loss of furin in either donor or acceptor cells reduces, but does not prevent, TMPRSS2-dependent cell-cell fusion, unlike mutation of the multibasic site that completely prevents syncytia formation. Our results show that while furin promotes both SARS-CoV-2 infectivity and cell-cell spread it is not essential, suggesting furin inhibitors may reduce but not abolish viral spread

Furin cleavage of SARS-CoV-2 Spike promotes but is not essential for infection and cell-cell fusion.

Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2) infects cells by binding to the host cell receptor ACE2 and undergoing virus-host membrane fusion. Fusion is triggered by the protease TMPRSS2, which processes the viral Spike (S) protein to reveal the fusion peptide. SARS-CoV-2 has evolved a multibasic site at the S1-S2 boundary, which is thought to be cleaved by furin in order to prime S protein for TMPRSS2 processing. Here we show that CRISPR-Cas9 knockout of furin reduces, but does not prevent, the production of infectious SARS-CoV-2 virus. Comparing S processing in furin knockout cells to multibasic site mutants reveals that while loss of furin substantially reduces S1-S2 cleavage it does not prevent it. SARS-CoV-2 S protein also mediates cell-cell fusion, potentially allowing virus to spread virion-independently. We show that loss of furin in either donor or acceptor cells reduces, but does not prevent, TMPRSS2-dependent cell-cell fusion, unlike mutation of the multibasic site that completely prevents syncytia formation. Our results show that while furin promotes both SARS-CoV-2 infectivity and cell-cell spread it is not essential, suggesting furin inhibitors may reduce but not abolish viral spread

A pragmatic cluster randomised trial evaluating three implementation interventions

Background Implementation research is concerned with bridging the gap between evidence and practice through the study of methods to promote the uptake of research into routine practice. Good quality evidence has been summarised into guideline recommendations to show that peri-operative fasting times could be considerably shorter than patients currently experience. The objective of this trial was to evaluate the effectiveness of three strategies for the implementation of recommendations about peri-operative fasting. Methods A pragmatic cluster randomised trial underpinned by the PARIHS framework was conducted during 2006 to 2009 with a national sample of UK hospitals using time series with mixed methods process evaluation and cost analysis. Hospitals were randomised to one of three interventions: standard dissemination (SD) of a guideline package, SD plus a web-based resource championed by an opinion leader, and SD plus plan-do-study-act (PDSA). The primary outcome was duration of fluid fast prior to induction of anaesthesia. Secondary outcomes included duration of food fast, patients' experiences, and stakeholders' experiences of implementation, including influences. ANOVA was used to test differences over time and interventions. Results Nineteen acute NHS hospitals participated. Across timepoints, 3,505 duration of fasting observations were recorded. No significant effect of the interventions was observed for either fluid or food fasting times. The effect size was 0.33 for the web-based intervention compared to SD alone for the change in fluid fasting and was 0.12 for PDSA compared to SD alone. The process evaluation showed different types of impact, including changes to practices, policies, and attitudes. A rich picture of the implementation challenges emerged, including inter-professional tensions and a lack of clarity for decision-making authority and responsibility. Conclusions This was a large, complex study and one of the first national randomised controlled trials conducted within acute care in implementation research. The evidence base for fasting practice was accepted by those participating in this study and the messages from it simple; however, implementation and practical challenges influenced the interventions' impact. A set of conditions for implementation emerges from the findings of this study, which are presented as theoretically transferable propositions that have international relevance. Trial registration ISRCTN18046709 - Peri-operative Implementation Study Evaluation (POISE

Six-Month Survival After Extracorporeal Membrane Oxygenation for Severe COVID-19

Objectives: The authors evaluated the outcome of adult patients with coronavirus disease 2019 (COVID-19)-related acute respiratory distress syndrome (ARDS) requiring the use of extracorporeal membrane oxygenation (ECMO). Design: Multicenter retrospective, observational study. Setting: Ten tertiary referral university and community hospitals. Participants: Patients with confirmed severe COVID-19-related ARDS. Interventions: Venovenous or venoarterial ECMO. Measurements and Main Results: One hundred thirty-two patients (mean age 51.1 +/- 9.7 years, female 17.4%) were treated with ECMO for confirmed severe COVID-19-related ARDS. Before ECMO, the mean Sequential Organ Failure Assessment score was 10.1 +/- 4.4, mean pH was 7.23 +/- 0.09, and mean PaO2/fraction of inspired oxygen ratio was 77 +/- 50 mmHg. Venovenous ECMO was adopted in 122 patients (92.4%) and venoarterial ECMO in ten patients (7.6%) (mean duration, 14.6 +/- 11.0 days). Sixty-three (47.7%) patients died on ECMO and 70 (53.0%) during the index hospitalization. Six-month all-cause mortality was 53.0%. Advanced age (per year, hazard ratio [HR] 1.026, 95% CI 1.000-1-052) and low arterial pH (per unit, HR 0.006, 95% CI 0.000-0.083) before ECMO were the only baseline variables associated with increased risk of six-month mortality. Conclusions: The present findings suggested that about half of adult patients with severe COVID-19 -related ARDS can be managed successfully with ECMO with sustained results at six months. Decreased arterial pH before ECMO was associated significantly with early mortality. Therefore, the authors hypothesized that initiation of ECMO therapy before severe metabolic derangements subset may improve survival rates significantly in these patients. These results should be viewed in the light of a strict patient selection policy and may not be replicated in patients with advanced age or multiple comorbidities. (C) 2021 The Authors. Published by Elsevier Inc.Peer reviewe

Editors' introduction: neoliberalism and/as terror

The articles in this special issue are drawn from papers presented at a conference entitled “Neoliberalism and/as Terror”, held at the Nottingham Conference Centre at Nottingham Trent University by the Critical Terrorism Studies BISA Working Group (CSTWG) on 15-16 September 2014. The conference was supported by both a BISA workshop grant and supplementary funds from Nottingham Trent University’s Politics and International Relations Department and the Critical Studies on Terrorism journal. Papers presented at the conference aimed to extend research into the diverse linkages between neoliberalism and terrorism, including but extending beyond the contextualisation of pre-emptive counterterrorism technologies and privatised securities within relevant economic and ideological contexts. Thus, the conference sought also to stimulate research into the ways that neoliberalism could itself be understood as terrorism, asking - amongst other questions - whether populations are themselves terrorised by neoliberal policy. The articles presented in this special issue reflect the conference aims in bringing together research on the neoliberalisation of counterterrorism and on the terror of neoliberalism

Precise measurement of the W-boson mass with the CDF II detector

We have measured the W-boson mass MW using data corresponding to 2.2/fb of integrated luminosity collected in proton-antiproton collisions at 1.96 TeV with the CDF II detector at the Fermilab Tevatron collider. Samples consisting of 470126 W->enu candidates and 624708 W->munu candidates yield the measurement MW = 80387 +- 12 (stat) +- 15 (syst) = 80387 +- 19 MeV. This is the most precise measurement of the W-boson mass to date and significantly exceeds the precision of all previous measurements combined

Class dynamics of development: a methodological note

This article argues that class relations are constitutive of developmental processes and central to understanding inequality within and between countries. In doing so it illustrates and explains the diversity of the actually existing forms of class relations, and the ways in which they interplay with other social relations such as gender and ethnicity. This is part of a wider project to re- vitalise class analysis in the study of development problems and experiences

1963

Trees for a Beautiful Golf Course by Philip Scott (page 1) The Golf Course\u27s Worst Enemy by Charles Amorim and Hal Haskell (2) Message from the President by James f. Gilligan (2) Turf Management Club News (3) Quotes from 1962 Freshman (4) When I consider How my Night is Spent Leonard Mailloux(5) Protection of a Golf Course by Pay Lucas Jr. (6) Safety - The Superintendents\u27 Responsibility by Gerald Peters (7) Picture - Senior Stockbridge Turf Majors (8) Picture - Freshmen Stockbridge Turf Majors (9) Kansas - In the Transition Zone by Carl Beer (10 Seeds by Don Daigle (11) Picture - Dean F. P. Jeffrey, Dr. W.G. Colby and Director J. R. Beattie (12) Picture - Graduates of Winter School for Turf Managers - 1963 (13) The Effect of Last Year\u27s Weather Upon This Year\u27s Incidence of Turf Insects by John C. Schread (A-1) Labor-Management Relations by Mortimer H. Gavin S.J. (A-4) Massachusetts Labor Laws by Andrew C. SInclair (A-7) Golf Course Budget by John Espey (A-10) Golf Course Budgets by Robert St. Thomas (A-12) Purpose & Method of Budgeting by Leon St. Pierre (A-13) The Committee Chairman, His Duties by Charles Connelly (A-16) Long-range vs. Short-range Planning by George Farber (A-18) The Golf Course Superintendent, His Duties by Sherwood Moore (A-20) The Budget by Leo Kowalski (A-25) Public Relations by Leon St. Pierre (A-26) A Study of WIlt by Harry Meusal (A-28) Specifications for a Method of Putting Green Construction by Alexander Radko (A-33) Management of Kentucky Bluegrass & Grass Mixtures for Turf by F.V. Juska (A-38) What\u27s New in Fertilizers by Geoffrey S. Cornish (A-40) Methylene Ureas by Harvey Stangel (A-42) Plastic Coated Fertilizers by Louis I. Hansen (A-44) The Role of Sewage Sludge by James Latham Jr. (A-49) The Role of Ureaforms in the Turf Fertilizer Industry by Robert T. Miller (A-51) Why Low Phosphorus & Higher Potassium by L. J. Sullivan (A-55) Uptake of Potassium by Evangel Bredakis (A-59) Responsibility of Industry & Community in Land Usage & Plantings by Joseph L. Beasley (A-61) Turf & Other Planting Problems by H. Thurston Handley Jr. (A-65) Weeds & Diseases by Dominic Marini (A-67) General Maintenacne & Equipment by Lewis Hodgkinson (A-68) Fertilizer Problems by William J. Bennett (A-70) Lawn Construction & Insect Problems by herbert C. Fordham (A-71