Publications

BACKGROUND

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.

METHODS

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.

FINDINGS

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.

INTERPRETATION

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.

FUNDING

The National Heart, Lung, and Blood Institute.

CONTEXT

Approximately 30% of the women report pain in the affected breast before breast cancer surgery.

OBJECTIVES

The purpose of this secondary analysis of our prospective study was to determine how women who experienced both preoperative and persistent postsurgical breast pain (n=107) differed from women who did not report preoperative breast pain and did (n=158) or did not (n=122) experience persistent postsurgical breast pain.

METHODS

Differences in demographic and clinical characteristics were evaluated. Linear mixed effects (LME) modeling was used to evaluate for group differences in symptom severity, function, sensation, and quality of life (QOL) over time.

RESULTS

Between-group differences in demographic and clinical characteristics as well as trajectories of shoulder function and QOL were identified. Women with both preoperative and persistent postsurgical breast pain were younger; were more likely to report swelling, strange sensations, hardness, and numbness in the affected breast before surgery; and were more likely to have reconstruction at the time of surgery. Women with both preoperative and persistent postsurgical breast pain had more biopsies in the prior year, more lymph nodes removed, and reported more severe acute postsurgical pain than women without preoperative breast pain. The LME modeling revealed significant group effects for most outcomes evaluated. Over the six months of the study, women with both preoperative and persistent postsurgical pain had persistently poorer shoulder flexion and physical well-being than women without preoperative breast pain.

CONCLUSION

Investigations of the etiology and molecular mechanisms of preoperative breast pain, as well as interventions for this high-risk group, are needed.

BACKGROUND

The malaria-specific T-cell response is believed to be important for protective immunity. Antimalarial chemoprevention may affect this response by altering exposure to malaria antigens.

METHODS

We performed interferon γ (IFNγ) ELISpot assays to assess the cellular immune response to blood-stage and pre-erythrocytic antigens longitudinally from 1 to 3 years of age in 196 children enrolled in a randomized trial of antimalarial chemoprevention in Tororo, Uganda, an area of high transmission intensity.

RESULTS

IFNγ responses to blood-stage antigens, particularly MSP1, were frequently detected, strongly associated with recent malaria exposure, and lower in those adherent to chemoprevention compared to nonadherent children and those randomized to no chemoprevention. IFNγ responses to pre-erythrocytic antigens were infrequent and similar between children randomized to chemoprevention or no chemoprevention. Responses to blood-stage antigens were not associated with subsequent protection from malaria (aHR 0.96, P = .83), but responses to pre-erythrocytic antigens were associated with protection after adjusting for prior malaria exposure (aHR 0.52, P = .009).

CONCLUSIONS

In this high transmission setting, IFNγ responses to blood-stage antigens were common and associated with recent exposure to malaria but not protection from subsequent malaria. Responses to pre-erythrocytic antigens were uncommon, not associated with exposure but were associated with protection from subsequent malaria.

BACKGROUND

Diabetes mellitus is a potent risk factor for urinary incontinence. Previous studies of incontinence in patients with diabetes have focused on younger, healthier patients. Our objective was to characterize risk factors for urinary incontinence among frail older adults with diabetes mellitus in a real-world clinical setting.

METHODS

We performed a cross-sectional analysis on enrollees at On Lok (the original Program for All-Inclusive Care of the Elderly) between October 2004 and December 2010. Enrollees were community-dwelling, nursing home-eligible older adults with diabetes mellitus (N = 447). Our outcome was urinary incontinence measures (n = 2602) assessed every 6 months as "never incontinent", "seldom incontinent" (occurring less than once per week), or "often incontinent" (occurring more than once per week). Urinary incontinence was dichotomized ("never" versus "seldom" and "often" incontinent). We performed multivariate mixed effects logistic regression analysis with demographic (age, gender and ethnicity), geriatric (dependence on others for ambulation or transferring; cognitive impairment), diabetes-related factors (hemoglobin A1c level; use of insulin and other glucose-lowering medications; presence of renal, ophthalmologic, neurological and peripheral vascular complications), depressive symptoms and diuretic use.

RESULTS

The majority of participants were 75 years or older (72%), Asian (65%) and female (66%). Demographic factors independently associated with incontinence included older age (OR for age >85, 3.13, 95% CI: 2.15-4.56; Reference: Age <75) and African American or other race (OR 2.12, 95% CI: 1.14-3.93; Reference: Asian). Geriatric factors included: dependence on others for ambulation (OR 1.48, 95% CI: 1.19-1.84) and transferring (OR 2.02, 95% CI: 1.58-2.58) and being cognitively impaired (OR 1.41, 95% CI: 1.15-1.73). Diabetes-related factors associated included use of insulin (OR 2.62, 95% CI: 1.67-4.13) and oral glucose-lowering agents (OR 1.81, 95% CI: 1.33-2.45). Urinary incontinence was not associated with gender, hemoglobin A1c level or depressive symptoms.

CONCLUSIONS

Geriatric factors such as the inability to ambulate or transfer independently are important predictors of urinary incontinence among frail older adults with diabetes mellitus. Clinicians should address mobility and cognitive impairment as much as diabetes-related factors in their assessment of urinary incontinence in this population.

Alzheimer's disease (AD) is a prevalent and currently incurable brain disease whose impact will continue to rise as the population ages. With limited treatment options, a variety of experimental therapies are currently in clinical trials. EVP-6124 (encenicline) is an α7 nicotinic acetylcholine receptor partial agonist under investigation for the symptomatic treatment of AD. EVP-6124 activates the α7 nicotinic acetylcholine receptor at low nanomolar brain concentrations and improves memory performance in rats. Treatment with EVP-6124 in Phase I and II trials involving patients with mild-to-moderate AD was well tolerated and showed statistically significant improvements compared with placebo on cognitive and functional measures. Two Phase III trials under the title COGNITIV AD will assess the efficacy and tolerability of EVP-6124 in patients with mild-to-moderate AD. Based on the completed clinical trials and proposed mechanism of action, EVP-6124 would appear to be a good candidate for therapy in combination with cholinesterase inhibitors.