9 research outputs found

    Protocol for an open label: phase I trial within a cohort of foetal cell transplants in people with Huntington’s disease

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    Huntington’s disease is a progressive neurodegenerative disorder characterised by motor, cognitive and psychiatric symptoms. Currently, no disease-modifying therapies are available to slow or halt disease progression. Huntington’s disease is characterised by relatively focal and specific loss of striatal medium spiny neurons, which makes it suitable for cell replacement therapy, a process involving the transplantation of donor cells to replace those lost due to disease. TRIDENT (TRIal DEsigns for delivery of Novel Therapies in neurodegeneration) is a phase I Trial Within a Cohort (TWiC) designed to assess safety and feasibility of transplanting human fetalstriatal cells into the striatum of people with Huntington’s disease. A minimum of 18 participants will be enrolled in the study cohort, and up to five eligible participants will be randomly selected to undergo transplantation of 12-22 million fetal cells in a dose escalation paradigm. Independent reviewers will assess safety outcomes (lack of significant infection, bleeding or new neurological deficit) four weeks after surgery, and ongoing safety will be established before conducting each subsequent surgery. All participants will undergo detailed clinical and functional assessment at baseline, 6 and 12 months. Surgery will be performed one month after baseline, and transplant participants will undergo regular clinical follow-up for at least 12 months. Evaluation of trial processes will also be undertaken. Transplant participants and their carers will be interviewed approximately one month before and after surgery. Interviews will also be conducted with non-transplanted participants and healthcare staff delivering the intervention and involved in the clinical care of participants. Evaluation of clinical and functional efficacy outcomes and intervention costs will be carried out to explore plausible trial designs for subsequent randomised controlled trials aimed at evaluating efficacy and cost-effectiveness of cell replacement therapy. TRIDENT will enable the assessment of the safety, feasibility, acceptability and cost of fetalcell transplants in people with Huntington’s disease. The data collected will inform trial designs for complex intracranial interventions in a range of neurodegenerative conditions and facilitate the development of stable surgical pipelines for delivery of future stem cell trials

    Cultivating a culture of inclusivity in heliophysics

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    A large number of heliophysicists from across career levels, institution types, and job titles came together to support a poster at Heliophysics 2050 and the position papers for the 2024 Heliophysics decadal survey titled “Cultivating a Culture of Inclusivity in Heliophysics,” “The Importance of Policies: It’s not just a pipeline problem,” and “Mentorship within Heliophysics.” While writing these position papers, the number of people who privately shared disturbing stories and experiences of bullying and harassment was shocking. The number of people who privately expressed how burned out they were was staggering. The number of people who privately spoke about how they considered leaving the field for their and their family’s health was astounding. And for as much good there is in our community, it is still a toxic environment for many. If we fail to do something now, our field will continue to suffer. While acknowledging the ongoing growth that we as individuals must work toward, we call on our colleagues to join us in working on organizational, group, and personal levels toward a truly inclusive culture, for the wellbeing of our colleagues and the success of our field. This work includes policies, processes, and commitments to promote: accountability for bad actors; financial security through removing the constant anxiety about funding; prioritization of mental health and community through removing constant deadlines and constant last-minute requests; a collaborative culture rather than a hyper-competitive one; and a community where people can thrive as whole persons and do not have to give up a healthy or well-rounded life to succeed

    Finishing the euchromatic sequence of the human genome

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    The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∌99% of the euchromatic genome and is accurate to an error rate of ∌1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

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

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    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

    DataSheet1_Recommendations on simple but transformative diversity, equity, and inclusion measures in Heliophysics over the next decade.PDF

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    It is well established that, in order to perform at their peak ability, a person must feel accepted, safe, and valued at work. Therefore, it is imperative to bring Diversity, Equity, and Inclusion (DEI) efforts to the forefront of Heliophysics over the next decade and well beyond. This position paper outlines three specific recommendations to make the Heliophysics community more diverse, equitable, and inclusive by improving the accessibility and accountability. These recommendations are: performing consistent collection and analysis of demographic data across different agencies, reimagining undergraduate Heliophysics internships using the SOARS¼ model, and providing conference funding for DEI speakers whose expertise lies outside the field of Heliophysics. These targeted recommendations have a well-documented positive impact, are simple to implement, and follow other scientific communities’ recent recommendations for making the science, technology, engineering, and mathematics fields more diverse, equitable, and inclusive.</p

    Effect of Antiplatelet Therapy on Survival and Organ Support–Free Days in Critically Ill Patients With COVID-19

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