Establishment and characterization of an iPSC line (UCLi023-A) derived from a Late-Onset Retinal Degeneration patient carrying a founder mutation in C1QTNF5

Late-Onset Retinal Degeneration (L-ORD) is a rare autosomal dominant macular disease, with most cases being caused by a founder mutation in C1QTNF5. Initial symptoms, which generally occur during or after the sixth decade, include abnormal dark adaptation and changes in peripheral vision. Over time, the build-up of sub-retinal pigment epithelium (RPE) deposits leads to macular atrophy and bilateral central vision loss1. Here, we describe the generation of a human induced pluripotent stem cell (iPSC) line from dermal fibroblasts of a 61-year-old L-ORD Caucasian male patient carrying the founder mutation (c.489C>G, p.Ser163Arg), using episomal reprogramming

Cycling of lithogenic marine particles in the US GEOTRACES North Atlantic transect

© The Author(s), 2014. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Deep Sea Research Part II: Topical Studies in Oceanography 116 (2015): 283-302, doi:10.1016/j.dsr2.2014.11.019.In this paper, we present, describe, and model the first size-fractionated (0.8–51 µm; >51 µm) water-column particulate trace metal results from the US GEOTRACES North Atlantic Zonal Transect in situ pumping survey, with a focus on the lithogenic tracer elements Al, Fe and Ti. This examination of basin-wide, full-depth distributions of particulate elements elucidates many inputs and processes—some for bulk lithogenic material, others element-specific—which are presented via concentration distributions, elemental ratios, size-fractionation dynamics, and steady-state inventories. Key lithogenic inputs from African dust, North American boundary interactions, the Mediterranean outflow, hydrothermal systems, and benthic nepheloid layers are described. Using the refractory lithogenic tracer Ti, we develop a 1-D model for lithogenic particle distributions and test the sensitivities of size-fractionated open-ocean particulate Ti profiles to biotically driven aggregation, disaggregation rates, vertical sinking speeds, and dust input rates. We discuss applications of this lithogenic model to particle cycling in general, and to POC cycling specifically.International and US GEOTRACES Offices (OCE-0850963 and OCE-1129603), and fellowship assistance from the Williams College Tyng Fellowship and MIT/WHOI Academic Programs Office to DCO

The quantified self: what counts in the neoliberal workplace

Implementation of quantified self technologies in workplaces relies on the ontological premise of Cartesian dualism with mind dominant over body. Contributing to debates in new materialism, we demonstrate that workers are now being asked to measure our own productivity and health and wellbeing in art-houses and warehouses alike in both the global north and south. Workers experience intensified precarity, austerity, intense competition for jobs, and anxieties about the replacement of labour-power with robots and other machines as well as, ourselves replaceable, other humans. Workers have internalized the imperative to perform, a subjectification process as we become observing, entrepreneurial subjects and observed, objectified labouring bodies. Thinking through the implications of the use of wearable technologies in workplaces, this article shows that these technologies introduce a heightened Taylorist influence on precarious working bodies within neoliberal workplaces

Early impacts of the COVID-19 pandemic on mental health care and on people with mental health conditions: framework synthesis of international experiences and responses

PURPOSE: The COVID-19 pandemic has many potential impacts on people with mental health conditions and on mental health care, including direct consequences of infection, effects of infection control measures and subsequent societal changes. We aimed to map early impacts of the pandemic on people with pre-existing mental health conditions and services they use, and to identify individual and service-level strategies adopted to manage these. METHODS: We searched for relevant material in the public domain published before 30 April 2020, including papers in scientific and professional journals, published first person accounts, media articles, and publications by governments, charities and professional associations. Search languages were English, French, German, Italian, Spanish, and Mandarin Chinese. Relevant content was retrieved and summarised via a rapid qualitative framework synthesis approach. RESULTS: We found 872 eligible sources from 28 countries. Most documented observations and experiences rather than reporting research data. We found many reports of deteriorations in symptoms, and of impacts of loneliness and social isolation and of lack of access to services and resources, but sometimes also of resilience, effective self-management and peer support. Immediate service challenges related to controlling infection, especially in inpatient and residential settings, and establishing remote working, especially in the community. We summarise reports of swiftly implemented adaptations and innovations, but also of pressing ethical challenges and concerns for the future. CONCLUSION: Our analysis captures the range of stakeholder perspectives and experiences publicly reported in the early stages of the COVID-19 pandemic in several countries. We identify potential foci for service planning and research

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

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

Challenges and opportunities for conducting a vaccine trial during the COVID-19 pandemic in the United Kingdom

The COVID-19 pandemic has resulted in unprecedented challenges for healthcare systems worldwide. It has also stimulated research in a wide range of areas including rapid diagnostics, novel therapeutics, use of technology to track patients and vaccine development. Here, we describe our experience of rapidly setting up and delivering a novel COVID-19 vaccine trial, using clinical and research staff and facilities in three National Health Service Trusts in Cambridgeshire, United Kingdom. We encountered and overcame a number of challenges including differences in organisational structures, research facilities available, staff experience and skills, information technology and communications infrastructure, and research training and assessment procedures. We overcame these by setting up a project team that included key members from all three organisations that met at least daily by teleconference. This group together worked to identify the best practices and procedures and to harmonise and cascade these to the wider trial team. This enabled us to set up the trial within 25 days and to recruit and vaccinate the participants within a further 23 days. The lessons learned from our experiences could be used to inform the conduct of clinical trials during a future infectious disease pandemic or public health emergency

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

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

Spaces for Participatory Design Innovation

This paper presents a model to guide the design of participatory design (PD) projects, which was generated through methodological reflection on a programme of digital health and care research. Building on wide use of the term spaces within PD literature and theory, the model comprises seven spaces that can be designed to support diverse stakeholders to engage in a PD process. The model encourages reflection on the capacity of participants to critically and creatively engage with the concepts being proposed, in order to design a process to scaffold participation. Aiming to support PD practitioners and researchers to identify the combination and sequence of hybrid spaces required to move participants and concepts towards resolved designs, the model guides the careful design of each space supported by examples of practice. The model is also designed to enable reflective practice and articulation of PD processes to support integration within multidisciplinary collaborations

Leadership and management in UK medical school curricula

Purpose Although medical leadership and management (MLM) is increasingly being recognised as important to improving healthcare outcomes, little is understood about current training of medical students in MLM skills and behaviours in the UK. The paper aims to discuss these issues. Design/methodology/approach This qualitative study used validated structured interviews with expert faculty members from medical schools across the UK to ascertain MLM framework integration, teaching methods employed, evaluation methods and barriers to improvement. Findings Data were collected from 25 of the 33 UK medical schools (76 per cent response rate), with 23/25 reporting that MLM content is included in their curriculum. More medical schools assessed MLM competencies on admission than at any other time of the curriculum. Only 12 schools had evaluated MLM teaching at the time of data collection. The majority of medical schools reported barriers, including overfilled curricula and reluctance of staff to teach. Whilst 88 per cent of schools planned to increase MLM content over the next two years, there was a lack of consensus on proposed teaching content and methods. Research limitations/implications There is widespread inclusion of MLM in UK medical schools’ curricula, despite the existence of barriers. This study identified substantial heterogeneity in MLM teaching and assessment methods which does not meet students’ desired modes of delivery. Examples of national undergraduate MLM teaching exist worldwide, and lessons can be taken from these. Originality/value This is the first national evaluation of MLM in undergraduate medical school curricula in the UK, highlighting continuing challenges with executing MLM content despite numerous frameworks and international examples of successful execution