No effective pharmacotherapy for acute respiratory distress syndrome (ARDS) exists, and mortality remains high. Preclinical studies support the efficacy of mesenchymal stem (stromal) cells (MSCs) in ...the treatment of lung injury. We aimed to test the safety of a single dose of allogeneic bone marrow-derived MSCs in patients with moderate-to-severe ARDS.
The STem cells for ARDS Treatment (START) trial was a multicentre, open-label, dose-escalation, phase 1 clinical trial. Patients were enrolled in the intensive care units at University of California, San Francisco, CA, USA, Stanford University, Stanford, CA, USA, and Massachusetts General Hospital, Boston, MA, USA, between July 8, 2013, and Jan 13, 2014. Patients were included if they had moderate-to-severe ARDS as defined by the acute onset of the need for positive pressure ventilation by an endotracheal or tracheal tube, a PaO2:FiO2 less than 200 mm Hg with at least 8 cm H2O positive end-expiratory airway pressure (PEEP), and bilateral infiltrates consistent with pulmonary oedema on frontal chest radiograph. The first three patients were treated with low dose MSCs (1 million cells/kg predicted bodyweight PBW), the next three patients received intermediate dose MSCs (5 million cells/kg PBW), and the final three patients received high dose MSCs (10 million cells/kg PBW). Primary outcomes included the incidence of prespecified infusion-associated events and serious adverse events. The trial is registered with ClinicalTrials.gov, number NCT01775774.
No prespecified infusion-associated events or treatment-related adverse events were reported in any of the nine patients. Serious adverse events were subsequently noted in three patients during the weeks after the infusion: one patient died on study day 9, one patient died on study day 31, and one patient was discovered to have multiple embolic infarcts of the spleen, kidneys, and brain that were age-indeterminate, but thought to have occurred before the MSC infusion based on MRI results. None of these severe adverse events were thought to be MSC-related.
A single intravenous infusion of allogeneic, bone marrow-derived human MSCs was well tolerated in nine patients with moderate to severe ARDS. Based on this phase 1 experience, we have proceeded to phase 2 testing of MSCs for moderate to severe ARDS with a primary focus on safety and secondary outcomes including respiratory, systemic, and biological endpoints.
The National Heart, Lung, and Blood Institute.
To compare two long-term remission maintenance strategies for antineutrophil cytoplasmic antibody (ANCA) vasculitis.
We conducted a prospective, single-centre, open-label, randomised controlled trial ...of patients with ANCA vasculitis in remission after completing at least 2 years of fixed-schedule rituximab. In the B cell arm, rituximab was reinfused upon B cell repopulation; in the ANCA arm, rituximab was reinfused upon significant rise in ANCA level. Evaluations were conducted every 3 months. The primary endpoint was clinical relapse, defined as a modified BVAS/WG >0 by 36 months. Secondary endpoints included serious adverse events (SAEs) and rituximab exposure.
115 patients were enrolled. Median follow-up time was 4.1 years (IQR 2.5-5.0). By Kaplan-Meier analysis, 4.1% (95% CI 1.0 to 15.6) of patients had a clinical relapse in the B cell arm, compared with 20.5% (95% CI 11.9 to 34.1) in the ANCA arm, at 3 years after study entry (log-rank p=0.045). Total SAEs, including infectious SAEs, and deaths did not differ. The number of SAEs due to COVID-19 was higher in the B cell arm (p=0.049). In the B cell arm, patients received a mean of 3.6 (SD 2.4) infusions (3.6 g) per person over the median study follow-up time of 4.1 years, compared with 0.5 (SD 1.4) infusions (0.5 g) per patient in the ANCA arm (p<0.001).
Rituximab dosed for B cell repopulation results in fewer clinical relapses than when dosed for a rise in ANCA level in maintenance of remission for ANCA vasculitis. Overall safety was equivalent; SAEs due to COVID-19 and rituximab exposure were higher with the B cell strategy.
NCT02749292.
Individuals with primary and pharmacologic B cell deficiencies have high rates of severe disease and mortality from coronavirus disease 2019 (COVID-19), but the immune responses and clinical outcomes ...after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and vaccination have yet to be fully defined. Here, we evaluate the cellular immune responses after both SARS-CoV-2 infection and vaccination in patients receiving the anti-CD20 therapy rituximab (RTX) and those with low B cell counts due to common variable immune deficiency (CVID) disease. Assessment of effector and memory CD4
and CD8
T cell responses to SARS-CoV-2 revealed elevated reactivity and proliferative capacity after both infection and vaccination in B cell-deficient individuals, particularly within the CD8
T cell compartment, in comparison with healthy controls. Evaluation of clinical outcomes demonstrates that vaccination of RTX-treated individuals was associated with about 4.8-fold reduced odds of moderate or severe COVID-19 in the absence of vaccine-induced antibodies. Analysis of T cell differentiation demonstrates that RTX administration increases the relative frequency of naïve CD8
T cells, potentially by depletion of CD8
CD20
T cells, which are primarily of an effector memory or terminal effector memory (TEMRA) phenotype. However, this also leads to a reduction in preexisting antiviral T cell immunity. Collectively, these data indicate that individuals with B cell deficiencies have enhanced T cell immunity after both SARS-CoV-2 infection and vaccination that potentially accounts for reduced hospitalization and severe disease from subsequent SARS-CoV-2 infection.
Background
Despite advances in supportive care, moderate-severe acute respiratory distress syndrome (ARDS) is associated with high mortality rates, and novel therapies to treat this condition are ...needed. Compelling pre-clinical data from mouse, rat, sheep and ex vivo perfused human lung models support the use of human mesenchymal stem (stromal) cells (MSCs) as a novel intravenous therapy for the early treatment of ARDS.
Methods
This article describes the study design and challenges encountered during the implementation and phase 1 component of the START (STem cells for ARDS Treatment) trial, a phase 1/2 trial of bone marrow-derived human MSCs for moderate-severe ARDS. A trial enrolling 69 subjects is planned (9 subjects in phase 1, 60 subjects in phase 2 treated with MSCs or placebo in a 2:1 ratio).
Results
This report describes study design features that are unique to a phase 1 trial in critically ill subjects and the specific challenges of implementation of a cell-based therapy trial in the ICU.
Conclusions
Experience gained during the design and implementation of the START study will be useful to investigators planning future phase 1 clinical trials based in the ICU, as well as trials of cell-based therapy for other acute illnesses.
Trial registration
Clinical Trials Registration:
NCT01775774
and
NCT02097641
.
Recent studies suggest discrepancies between patients and providers around perceptions of hemodialysis prognosis. Such data are lacking for continuous renal replacement therapy (CRRT). We aim to ...assess patient and provider understanding of outcomes around CRRT.
From February 1 to August 31, 2013, a triad of (1) a patient on CRRT (or health care proxy HCP), (2) physician and (3) primary nurse from the intensive care unit (ICU) team were surveyed. Univariate chi-square and qualitative analysis techniques were used.
Ninety-six total participants (32 survey triads) were completed. Ninety one percent of patients/HCPs correctly identified that CRRT replaced the function of the kidneys. Six percent of patients/HCPs, 44 % of physicians, and 44 % of nurses identified rates of survival to hospital discharge that were consistent with published literature. Both physicians and nurses were more likely than patients/HCPs to assess survival consistently with published data (p = 0.001). Patients/HCPs were more likely to overestimate survival rates than physicians and nurses (p < 0.001). Thirty eight percent of patients/HCPs, 38 % of physicians, and 28 % of nurses identified rates of lifelong dialysis-dependence among surviving patients that were consistent with published literature.
There is mismatch between patients, HCPs, and providers around prognosis of CRRT. Patients/HCPs are more likely to overestimate chances of survival than physicians or nurses. Further intervention is needed to improve this knowledge gap.
Growing demand for public involvement in environmental governance combined with recognition that top-down approaches often are not well suited to dealing with local concerns has led to increased use ...of collaborative approaches. The consensus-seeking partnership is becoming a common tool in the landscape of collaborative water governance. These arrangements typically are used to provide advice on water management to policy makers. Partnership models based on consensus are grounded in a number of assumptions, including cooperation amongst multi-stakeholder participants, fair and high quality decision outcomes, and commitment to implement the results produced during the consensus seeking process.
Conflicting research on the consensus model and its use as a collaborative decision-making tool indicates that these assumptions are difficult to achieve. This thesis investigates these assumptions through a study of the outcomes of consensus in collaborative advisory partnerships and the procedures necessary for ensuring success with the consensus partnership model. Data were derived from analysis of documents and interviews with study participants involved in water partnerships in Southern Alberta. The research revealed that a number of conditions are needed in consensus-based approaches to avoid negative outcomes such as lowest common denominator decisions. While the analysis focuses on experiences in Alberta, the lessons learned are broadly transferable and provide practitioners in water management a more accurate representation of the use of consensus in collaborative water partnerships.
Two of Canada's blue-chip law firms, Fraser Milner of Toronto and Byers Casgrain of Montreal, are in serious merger talks, legal sources said yesterday. Fraser Milner was created about a year ago in ...a merger of Fraser Beatty and Fenerty Milner. At the time, the newly formed firm said its goal was to become a national player. Byers Casgrain has been in play since its association with Toronto's McMillan Binch and Vancouver-based Bull Housser dissolved about two months ago. Fraser Milner has about 350 lawyers in offices in Vancouver, Calgary, Edmonton, Ottawa and Toronto. With the additional 100 Byers Casgrain staffers in Montreal, the merged company would rank among the five largest law firms in Canada, by employees.
Two of Canada's blue-chip law firms, Fraser Milner of Toronto and Byers Casgrain of Montreal, are in serious merger talks, legal sources said yesterday. Fraser Milner was created about a year ago in ...a merger of Fraser Beatty and Fenerty Milner. At the time, the newly formed firm said its goal was to become a national player. Byers Casgrain has been in play since its association with Toronto's McMillan Binch and Vancouver-based Bull Housser dissolved about two months ago. Fraser Milner has about 350 lawyers in offices in Vancouver, Calgary, Edmonton, Ottawa and Toronto. With the additional 100 Byers Casgrain staffers in Montreal, the merged company would rank among the five largest law firms in Canada, by employees.
Vitiligo is impacted by environmental triggers. We studied the contribution of the microbiome in FH mice, in which depigmentation is mediated by tyrosinase-reactive T cells. The mice received oral ...antibiotics and were monitored for depigmentation. The microbiome was studied in fecal and skin samples using 16S rRNA analysis. The resulting T-cell distributions were evaluated. In untreated mice, pigment loss did not expand to the pelage, whereas mice in the ampicillin group were approximately 1/3 depigmented at 30 weeks. In contrast to models of autoimmunity that are less dependent on IFN-γ, ampicillin but not neomycin treatment correlated with accelerated disease and reduced bacteria in the fecal pellets. Modified cytokine patterns in the tissue and serum suggest a response that transcends the gut. Ampicillin-induced depigmentation was accompanied by gut but not skin dysbiosis, and reduced T cell numbers in both sites. Neomycin induced a redistribution of gut T cells and an accumulation of skin regulatory T cells. This treatment spurred a Bacteroides-dominated population of fecal bacteria. Reduced diversity is prominent particularly after ampicillin treatment, when the gut is dominated by Pseudomonas species. In line with current concepts relating the microbiome and the immune system, we predict that dietary measures might promote skin health and delay vitiligo onset.
Abstract
Background
Quantifying the amount and diversity of antibiotic use in United States hospitals assists antibiotic stewardship efforts but is hampered by limited national surveillance. Our ...study aimed to address this knowledge gap by examining adult antibiotic use across 576 hospitals and nearly 12 million encounters in 2016–2017.
Methods
We conducted a retrospective study of patients aged ≥ 18 years discharged from hospitals in the Premier Healthcare Database between 1 January 2016 and 31 December 2017. Using daily antibiotic charge data, we mapped antibiotics to mutually exclusive classes and to spectrum of activity categories. We evaluated relationships between facility and case-mix characteristics and antibiotic use in negative binomial regression models.
Results
The study included 11 701 326 admissions, totaling 64 064 632 patient-days, across 576 hospitals. Overall, patients received antibiotics in 65% of hospitalizations, at a crude rate of 870 days of therapy (DOT) per 1000 patient-days. By class, use was highest among β-lactam/β-lactamase inhibitor combinations, third- and fourth-generation cephalosporins, and glycopeptides. Teaching hospitals averaged lower rates of total antibiotic use than nonteaching hospitals (834 vs 957 DOT per 1000 patient-days; P < .001). In adjusted models, teaching hospitals remained associated with lower use of third- and fourth-generation cephalosporins and antipseudomonal agents (adjusted incidence rate ratio 95% confidence interval, 0.92 .86–.97 and 0.91 .85–.98, respectively). Significant regional differences in total and class-specific antibiotic use also persisted in adjusted models.
Conclusions
Adult inpatient antibiotic use remains high, driven predominantly by broad-spectrum agents. Better understanding reasons for interhospital usage differences, including by region and teaching status, may inform efforts to reduce inappropriate antibiotic prescribing.
Quantifying the volume and diversity of antibiotic use in United States hospitals assists antibiotic stewardship efforts but is hampered by limited national surveillance. Our study examined adult antibiotic use across 576 hospitals and nearly 12 million encounters in 2016–2017.
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