Exploring Determinants of Execution in Early Phase Clinical Studies with Cell Therapies in Stroke

Background Stroke is associated with a significant disease burden across the world (1). Ischaemic stroke accounts for over 80% of the total number of strokes and specifically refers to central nervous system infarction accompanied by overt symptoms (2). Cell therapies (CTs) represent a composite of different cell types being investigated in different phases of stroke, with use of different dose and delivery regimens (2). Preliminary evidence for meaningful clinical translation is now available with CTs in stroke, as early studies have demonstrated safety and a trend towards functional improvement over a longer time window of application (2). Research Aims This research aimed to analyse study design, regulatory policy, ethical and economic considerations, as well as to describe their impact on the quality of execution of early-phase clinical CTs studies in stroke Methods The thesis is a compendium of subprojects that evaluated these considerations for efficient implementation of early phase CTs studies, using a mixed methodology approach. Results Study design considerations: a systematic review of early phase clinical studies with CTs in ischaemic stroke indicated a trend towards improvement across varied domains of functional impairment and reasonable safety and feasibility, in patients with stroke receiving CTs (2). A high level of heterogeneity was observed, in terms of differences in cell types used and route, dose and time of administration, use of randomised control design and selection of trial endpoints. Most studies reported temporal changes in global endpoints such as those measured by the National Institutes of Health Stroke Scale (NIHSS), Barthel Index (BI) or Modified Rankin scale (mRS). Regulatory considerations: a narrative review examined different national regulatory provisions and described standardization of research terminology and access to expertise in manufacturing as the key determinants critical to the execution of early phase studies with CTs in stroke. Ethical considerations: a qualitative study was undertaken to understand the perspective of stroke survivors on the research design of a proposed early phase clinical study with adult human dental pulp stem cells in chronic ischaemic stroke. The study found that patients considered outcomes such as recovery in social participation and decreased dependence on carers as most meaningful to them. Whilst improved motor function was important, the impact on cognition, memory, mood, pain and fatigue were bigger determinants of their perception of benefit. The perception of risk versus benefit was influenced by the time elapsed since stroke. Health economic considerations: a systematic review reported that there is limited evidence for economic evaluation at early stage of research in CTs. Only three studies have been published to date. All studies undertook a cost utility analysis of CTs versus current standard of care using decision analytical modelling and reported that CTs could provide meaningful cost savings in terms of direct costs of disease management accrued to the government (healthcare bodies and social services). Discussion Successful clinical translation of CTs in stroke requires efficient development strategies potentially comprising the use of adaptive trial designs and the use of domain specific endpoints for efficacy evaluation (8, 9). Addressing regulatory requirements and patients’ preferences in research design can significantly improve the eventual clinical relevance of data generated within these trials (11, 12). Collection of data on cost-effectiveness of their use from the early phase of research is critical, as these therapies are likely to be expensive (13). Conclusions Development of a practical framework comprising key elements of study design and regulatory policy, as well as ethical and health economic considerations that is available to different research groups can potentially accelerate clinical translation of CTs in stroke.Thesis (Ph.D.) -- University of Adelaide, Adelaide Medical School, 201

Monoclonal antibodies to gonadotropin-releasing hormone (GnRH) inhibit binding of the hormone to its receptor

Monoclonal antibodies (MAbs) specific to gonadotropin-releasing hormone (GnRH) were obtained using different strategies of conjugation of the peptide to carrier protein and immunization. Of several antibodies obtained, two, namely F1D3C5 and E2D2 bound GnRH in solution phase. Though the epitopes corresponding to the two overlapped, there was a one amino acid shift in the core epitope. These two antibodies were characterized with respect to inhibition of GnRH induced responses in rat pituitary cultures and α -T3.1 mouse gonadotrope cell line

Safety and effectiveness of stem cell therapies in early-phase clinical trials in stroke: a systematic review and meta-analysis

Abstract Stem cells have demonstrated encouraging potential as reparative therapy for patients suffering from post-stroke disability. Reperfusion interventions in the acute phase of stroke have shown significant benefit but are limited by a narrow window of opportunity in which they are beneficial. Thereafter, rehabilitation is the only intervention available. The current review summarises the current evidence for use of stem cell therapies in stroke from early-phase clinical trials. The safety and feasibility of administering different types of stem cell therapies in stroke seem to be reasonably proven. However, the effectiveness needs still to be established through bigger clinical trials with more pragmatic clinical trial designs that address the challenges raised by the heterogeneous nature of stroke per se, as well those due to unique characteristics of stem cells as therapeutic agents

Additional file 1: of Safety and effectiveness of stem cell therapies in early-phase clinical trials in stroke: a systematic review and meta-analysis

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COVID-19 in Patients with Multiple Sclerosis: Associations with Disease-Modifying Therapies

Background Disease-modifying therapies (DMTs) for multiple sclerosis (MS) target immunity and have the potential to increase the risk of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection and alter its clinical course. We assessed these risks in patients with MS (PwMS). Objective The objective of this study was to describe the overall risk of coronavirus disease 2019 (COVID-19) infection, severe disease course, and potential population-level predictors of COVID-19 infection in PwMS, and to provide a context using a cohort of patients with systemic lupus erythematosus (SLE). In addition, the association of different MS DMTs with the incidence and clinical course of COVID-19 was evaluated. Safety data from the Biogen Global Safety Database are also presented on reported cases of COVID-19 in patients treated with Biogen MS therapies. Methods The IBM(R) Explorys electronic health record database of > 72,000,000 patients from US healthcare networks identified patients with MS or SLE, with and without polymerase chain reaction-confirmed COVID-19. COVID-19 cumulative incidence, hospitalization, and deaths among DMT classes were compared using logistic regression (adjusted for age, sex, body mass index, comorbidities, and race/ethnicity). As a secondary data source to assess safety data, COVID-19 reports for Biogen MS therapies were extracted and described from Biogen's Global Safety Database. Results 30,478 PwMS with an open DMT prescription were identified within Explorys; 344 were COVID-19 positive. The most significant risk factors for acquiring COVID-19 were comorbidity score >= 1, body mass index >= 30, and Black/African ancestry. Similar risk factors were also identified for patients with SLE. Patients with MS were less likely to develop COVID-19 when treated with interferons (0.61%) and glatiramer acetate (0.51%), vs all other MS DMTs (both p < 0.001); anti-CD20 therapy was associated with the highest risk (3.45%; p < 0.0001). In the Biogen Global Safety Database, we identified 1217 patients who were COVID-19 positive treated with intramuscular interferon beta-1a, peginterferon beta-1a, natalizumab, dimethyl fumarate, diroximel fumarate, or fampridine. Conclusions Comorbidities, obesity, and Black/African ancestry, but not age, were associated with a higher risk of SARS-CoV-2 infection in PwMS. Interferons and glatiramer acetate were associated with a reduced COVID-19 risk, whereas anti-CD20 therapies were associated with an increased risk, within the treated MS cohort. COVID-19 safety reports for patients receiving Biogen MS therapies were consistent with the Explorys database and MS literature, illustrating the replicability and power of this approach

The journal of cardiovascular computed tomography: A year in review: 2022.

This review aims to summarize key articles published in the Journal of Cardiovascular Computed Tomography (JCCT) in 2022, focusing on those that had the most scientific and educational impact. The JCCT continues to expand; the number of submissions, published manuscripts, cited articles, article downloads, social media presence, and impact factor continues to grow. The articles selected by the Editorial Board of the JCCT in this review highlight the role of cardiovascular computed tomography (CCT) to detect subclinical atherosclerosis, assess the functional relevance of stenoses, and plan invasive coronary and valve procedures. A section is dedicated to CCT in infants and other patients with congenital heart disease, in women, and to the importance of training in CT. In addition, we highlight key consensus documents and guidelines published in JCCT last year. The Journal values the tremendous work by authors, reviewers, and editors to accomplish these contributions

The Journal of cardiovascular computed tomography: A year in review 2021

This review aims to summarize original articles published in the Journal of Cardiovascular Computed Tomography (JCCT) for the year 2021, focusing on those that had the most scientific and educational impact. The JCCT continues to expand; the number of submissions, published manuscripts, cited articles, article downloads, social media presence, and impact factor continues to increase. The articles selected by the Editorial Board of the JCCT in this review focus on coronary artery disease, coronary physiology, structural heart disease, and technical advances in cardiovascular CT. In addition, we highlight key consensus documents and guidelines published in the Journal in 2021. The Journal recognizes the tremendous work done by each author and reviewer this year - thank you

Child neurodevelopment after multidomain interventions from preconception through early childhood

ImportanceMultidomain interventions in pregnancy and early childhood have improved child neurodevelopment, but little is known about the effects of additional preconception interventions.ObjectiveTo evaluate the effect of a multifaceted approach including health; nutrition; water, sanitation, and hygiene (WASH); and psychosocial support interventions delivered during the preconception period and/or during pregnancy and early childhood on child neurodevelopment.Design, Setting, and ParticipantsIn this randomized trial involving low- and middle-income neighborhoods in Delhi, India, 13 500 participants were assigned to preconception interventions or routine care for the primary outcome of preterm births and childhood growth. Participants who became pregnant were randomized to pregnancy and early childhood interventions or routine care. Neurodevelopmental assessments, the trial’s secondary outcome reported herein, were conducted in a subsample of children at age 24 months, including 509 with preconception, pregnancy, and early childhood interventions; 473 with preconception interventions alone; 380 with pregnancy and early childhood interventions alone; and 350 with routine care. This study was conducted from November 1, 2020, through February 25, 2022.InterventionsHealth, nutrition, psychosocial care and support, and WASH interventions delivered during preconception, pregnancy, and early childhood periods.Main Outcomes and MeasuresCognitive, motor, language, and socioemotional performance at age 24 months, assessed using the Bayley Scales of Infant and Toddler Development 3 tool.ResultsThe mean age of participants at enrollment was 23.8 years (SD, 3.0 years). Compared with the controls at age 24 months, children in the preconception intervention groups had higher cognitive scores (mean difference [MD], 1.16; 98.3% CI, 0.18-2.13) but had similar language, motor, and socioemotional scores as controls. Those receiving pregnancy and early childhood interventions had higher cognitive (MD, 1.48; 98.3% CI, 0.49-2.46), language (MD, 2.29; 98.3% CI, 1.07-3.50), motor (MD, 1.53; 98.3% CI, 0.65-2.42), and socioemotional scores (MD, 4.15; 98.3% CI, 2.18-6.13) than did controls. The pregnancy and early childhood group also had lower incidence rate ratios (RRs) of moderate to severe delay in cognitive (incidence RR, 0.62; 98.3% CI, 0.40-0.96), language (incidence RR, 0.73; 98.3% CI, 0.57-0.93), and socioemotional (incidence RR, 0.49; 98.3% CI, 0.24-0.97) development than did those in the control group. Children in the preconception, pregnancy, and early childhood intervention group had higher cognitive (MD, 2.60; 98.3% CI, 1.08-4.12), language (MD, 3.46; 98.3% CI, 1.65-5.27), motor (MD, 2.31; 98.3% CI, 0.93-3.69), and socioemotional (MD, 5.55; 98.3% CI, 2.66-8.43) scores than did those in the control group.Conclusions and RelevanceMultidomain interventions during preconception, pregnancy and early childhood led to modest improvements in child neurodevelopment at 24 months. Such interventions for enhancing children’s development warrant further evaluation

Worldwide Disparities in Recovery of Cardiac Testing 1 Year Into COVID-19

BACKGROUND The extent to which health care systems have adapted to the COVID-19 pandemic to provide necessary cardiac diagnostic services is unknown.OBJECTIVES The aim of this study was to determine the impact of the pandemic on cardiac testing practices, volumes and types of diagnostic services, and perceived psychological stress to health care providers worldwide.METHODS The International Atomic Energy Agency conducted a worldwide survey assessing alterations from baseline in cardiovascular diagnostic care at the pandemic's onset and 1 year later. Multivariable regression was used to determine factors associated with procedure volume recovery.RESULTS Surveys were submitted from 669 centers in 107 countries. Worldwide reduction in cardiac procedure volumes of 64% from March 2019 to April 2020 recovered by April 2021 in high- and upper middle-income countries (recovery rates of 108% and 99%) but remained depressed in lower middle- and low-income countries (46% and 30% recovery). Although stress testing was used 12% less frequently in 2021 than in 2019, coronary computed tomographic angiography was used 14% more, a trend also seen for other advanced cardiac imaging modalities (positron emission tomography and magnetic resonance; 22%-25% increases). Pandemic-related psychological stress was estimated to have affected nearly 40% of staff, impacting patient care at 78% of sites. In multivariable regression, only lower-income status and physicians' psychological stress were significant in predicting recovery of cardiac testing.CONCLUSIONS Cardiac diagnostic testing has yet to recover to prepandemic levels in lower-income countries. Worldwide, the decrease in standard stress testing is offset by greater use of advanced cardiac imaging modalities. Pandemic-related psychological stress among providers is widespread and associated with poor recovery of cardiac testing. (C) 2022 The Authors. Published by Elsevier on behalf of the American College of Cardiology Foundation