ABSTRACT
BodyThere is a growing interest and use of cellular therapies in almost all fields of medicine. Mesenchymal stromal cells (MSCs) are pluripotent in their ability to differentiate in chondrocytes, adipocytes and osteoblasts. They more recently were reported to have significant immune activity, primarily by producing anti-inflammatory molecules. They can be derived from umbilical cords, adipose tissue and bone marrow primarily. Recent studies have tested their safety and efficacy in immune mediated diseases including graft versus host disease, inflammatory bowel disease and Type I diabetes among others. Reports of uncontrolled trials of MSCs in China suggest safety and efficacy of MSCs as treatment for refractory lupus. Based on encouraging results of a Phase I trial of 6 patients with lupus treated with MSCs, we initiated the first placebo- controlled trial of MSCs to treat lupus patients refractory to standard of care medications. There are nine participating centers across the US. The trial has two cohorts, one receiving low dose MSCs (one million cells/kg) and a high dose cohort of five million cells per kg, given as a one- time infusion. Patients then attend 10 follow-up visits over a year. Primary outcome is a decrease in the SRI of 4 at week 24. Inclusion criteria are patients with confirmed lupus refractory to 6 months of standard of care therapy defined by a SLEDAI of 6 or greater at screening. Exclusions were ongoing use of biologics, pregnancy, active infections, cancer, active CNS lupus or advanced renal disease. The first patient was screened in November of 2018. Patients are randomized with a 2/1 ratio of MSCs/placebo. Cohort 1 consisting of 41 patients was completed in May of 2021. We have infused 10 out of 40 patients in Cohort 2 to this point. Extensive studies of B cell, T cell, monocyte, dendritic cell and PMN number, function and phenotype are being performed. To this point there are no safety signals or concerns with DSMB reviews quarterly. There have been no SAEs attributed to the investigational product. Given the blind of the study, we cannot report on efficacy, though there are a number of participants who met the primary outcome of an SRI of 4 at 24 weeks. COVID had a profound impact on the study due to halting of enrollment for 5 months and a need for video visits due to institutional policies. A significant issue was protocol changes regarding disease activity measures in video visits. Other delays included a designed 12-week safety assessment upon completion of Cohort 1 prior to enrollment in Cohort 2 as well as a staggered start for the first six patients in Cohort 2 requiring a safety assessment by the DSMB chair at week 1 post infusion prior to the screening of the next patient. ConclusionsThere is no safety signal between the active treatment and placebo group in either Cohort to this date. Efficacy assessments await completion of the study as the two cohorts are combined for determination of efficacy. COVID has a profound impact on enrollment and management of the study. Results of the validity of assessment of different disease measures via video appointments is being assessed to inform future trials. We believe we will reach our enrollment goal and the study will answer the primary aim of whether MSCs are a potential therapeutic for patients with refractory lupus.
ABSTRACT
Background Meeting the contraceptive needs of women of reproductive age is beneficial for the health of women and children, and the economic and social empowerment of women. Higher rates of contraceptive coverage have been linked to the availability of a more diverse range of contraceptive methods. We present estimates of the contraceptive prevalence rate (CPR), modern contraceptive prevalence rate (mCPR), demand satisfied, and the method of contraception used for both partnered and unpartnered women for 5-year age groups in 204 countries and territories between 1970 and 2019. Methods We used 1162 population-based surveys capturing contraceptive use among women between 1970 and 2019, in which women of reproductive age (15-49 years) self-reported their, or their partner's, current use of contraception for family planning purposes. Spatiotemporal Gaussian process regression was used to generate estimates of the CPR, mCPR, demand satisfied, and method mix by age and marital status. We assessed how age-specific mCPR and demand satisfied changed with the Socio-demographic Index (SDI), a measure of social and economic development, using the meta-regression Bayesian, regularised, trimmed method from the Global Burden of Diseases, Injuries, and Risk Factors Study. Findings In 2019, 162middot9 million (95% uncertainty interval [UI] 155middot6-170middot2) women had unmet need for contraception, of whom 29middot3% (27middot9-30middot6) resided in sub-Saharan Africa and 27middot2% (24middot4-30middot3) resided in south Asia. Women aged 15-19 years (64middot8% [62middot9-66middot7]) and 20-24 years (71middot9% [68middot9-74middot2]) had the lowest rates of demand satisfied, with 43middot2 million (95% UI 39middot3-48middot0) women aged 15-24 years with unmet need in 2019. The mCPR and demand satisfied among women aged 15-19 years were substantially lower than among women aged 20-49 years at SDI values below 60 (on a 0-100 scale), but began to equalise as SDI increased above 60.Between 1970 and 2019, the global mCPR increased by 20middot1 percentage points (95% UI 18middot7-21middot6). During this time, traditional methods declined as a proportion of all contraceptive methods, whereas the use of implants, injections, female sterilisation, and condoms increased. Method mix differs substantially depending on age and geography, with the share of female sterilisation increasing with age and comprising more than 50% of methods in use in south Asia. In 28 countries, one method was used by more than 50% of users in 2019 Interpretation The dominance of one contraceptive method in some locations raises the question of whether family planning policies should aim to expand method mix or invest in making existing methods more accessible. Lower rates of demand satisfied among women aged 15-24 years are also concerning because unintended pregnancies before age 25 years can forestall or eliminate education and employment opportunities that lead to social and economic empowerment. Policy makers should strive to tailor family planning programmes to the preferences of the groups with the most need, while maintaining the programmes used by existing users. Copyright (C) 2022 The Author(s). Published by Elsevier Ltd.
ABSTRACT
Effective social data governance rests on a bedrock of social support. Without securing trust from the populace whose information is being collected, analyzed, and deployed, policies on which such data are based will be undermined by a lack of public confidence. The COVID-19 pandemic has accelerated digitalization and datafication by governments for the purposes of contact tracing and epidemiological investigation. However, concerns about surveillance and data privacy have stunted the adoption of such contact-tracing initiatives. This commentary analyzes Singapore's contact-tracing initiative to uncover the reasons for public resistance and efforts by the state to address them. The government's contact-tracing program encompassing its proprietary TraceTogether app and physical token initially triggered vociferous public criticisms of Big Brother style surveillance. Using a dialogic communication framework, we analyze the TraceTogether initiative to interrogate the communicative strategies that were used to overcome public resistance. We argue that these strategies reflect a top-down approach that prioritizes transactional dissemination of information, in line with Singapore's technocratic stance toward governance. We further assert that such communicative tactics represent missed opportunities to foster public confidence in social data governance through greater trust building. We propose solutions for more dialogic communicative forms that build trust, so that officials can develop a sound understanding of the public concerns, increase the level of public engagement, and incorporate public feedback into policies that govern data use.