Modeling Sepsis-Associated ARDS Using a Lung Endothelial Microphysiological System.

Acute respiratory distress syndrome due to non-pulmonary causes exhibits prominent endothelial activation which is challenging to assess in critically ill patients. Preclinical in vivo models of sepsis and ARDS have failed to yield useful therapies in humans, perhaps due to interspecies differences in inflammatory responses. Use of microphysiological systems (MPS) offer improved fidelity to human biological responses and better predict pharmacological responses than traditional culture. We adapted a lung endothelial MPS based on the LumeNEXT platform to evaluate the effect of plasma from critically ill sepsis patients on endothelial permeability, adhesion molecule expression and inflammatory cytokine production. Lumens incubated with sepsis plasma exhibited areas of contraction, loss of cellular coverage, and luminal defects. Sepsis plasma-incubated lumens had significantly increased permeability compared to lumens incubated with healthy donor plasma. ICAM-1 expression increased significantly in lumens incubated with sepsis plasma compared with those incubated with healthy control plasma, while concentrations of IL-6, IL-18, and soluble VEGF-R1 increased in sepsis plasma before and after incubation in the MPS compared with healthy control plasma. Use of the lung endothelial MPS may enable interrogation of specific mechanisms of endothelial dysfunction that promote ARDS in sepsis patients.

Longitudinal Analysis of the Intestinal Microbiota among a Cohort of Children in Rural and Urban Areas of Pakistan.

The profile of the intestinal microbiota is known to be altered in malnourished young children in low- and middle-income countries. However, there are limited studies longitudinally evaluating the intestinal microbiota in malnourished young children in resource-limited settings over the first two years of life. In this longitudinal pilot study, we determined the effect of age, residential location, and intervention on the composition, relative abundance, and diversity of the intestinal microbiota in a representative sample of children under 24 months of age with no diarrhea in the preceding 72 h in the urban and rural areas of Sindh, Pakistan nested within a cluster-randomized trial evaluating the effect of zinc and micronutrients on growth and morbidity (ClinicalTrials.gov Identifier: NCT00705445). The major findings were age-related with significant changes in alpha and beta diversity with increasing age. There was a significant increase in the relative abundance of the Firmicutes and Bacteroidetes phyla and a significant decrease in that of the Actinobacteria and Proteobacteria phyla (p < 0.0001). There were significant increases in the relative abundances of the major genera Bifidobacterium, Escherichia/Shigella and Streptococcus (p < 0.0001), and no significant change in the relative abundance of Lactobacillus. Using the LEfSE algorithm, differentially abundant taxa were identified between children in the first and second years of age, between those residing in rural and urban areas, and those who received different interventions at different ages from 3 to 24 months. The numbers of malnourished (underweight, wasted, stunted) or well-nourished children at each age, in each intervention arm, and at urban or rural sites were too small to determine if there were significant differences in alpha or beta diversity or differentially abundant taxa among them. Further longitudinal studies with larger numbers of well-nourished and malnourished children are required to fully characterize the intestinal microbiota of children in this region.

Impact of Interprofessional Teamwork on Aligning Intensive Care Unit Care with Patient Goals: A Qualitative Study of Transactive Memory Systems.

Rationale: Although aligning care with patient goals is fundamental to critical care, this process is often delayed and leads to conflict among patients, families, and intensive care unit (ICU) teams. Interprofessional collaboration within ICU teams is an opportunity to improve goal-aligned care, yet this collaboration is poorly understood. A better understanding of how ICU team members work together to provide goal-aligned care may identify new strategies for improvement. Objectives: Transactive memory systems is a theory of group mind that explains how high-performing teams use a shared memory and collective cognition. We applied this theory to characterize the process of interprofessional collaboration within ICU teams and its relationship with goal-aligned care. Methods: We conducted a secondary analysis of focus group (n = 10) and semistructured interview (n = 8) transcripts, gathered during a parent study at two academic medical centers on the process of ICU care delivery in acute respiratory failure. Participants (N = 70) included interprofessional ICU and palliative care team members, surrogates, and patient survivors. We used directed content analysis, applying transactive memory systems theory and its major components (specialization, coordination, credibility) to examine ICU team collaboration. Results: Participants described each ICU profession as having a specialized role in aligning care with patient goals. Different professions have different opportunities to gather knowledge about patient goals and priorities, which results in dispersion of this knowledge among different team members. To share and use this dispersed knowledge, ICU teams rely on an informal coordination process and "side conversations." This process is a workaround for formal channels (e.g., health records, interprofessional rounds) that do not adequately convey knowledge about patient goals. This informal process does not occur if team members are discouraged from asserting their knowledge because of hierarchy or lack of psychological safety. Conversely, coordination succeeds when team members recognize each other as credible sources of valued knowledge. Conclusions: We found that ICU team members work together to align care with patient goals and priorities, using transactive memory systems. The successful function of these systems can be disrupted or promoted by ICU organizational and cultural factors, which are potential targets for efforts to increase goal-aligned care.

Systemic antibody responses to the immunodominant p23 antigen and p23 polymorphisms in children with cryptosporidiosis in Bangladesh.

Cryptosporidium is a major cause of diarrhea in children in developing countries. However, there is no vaccine available and little is known about immune responses to protective antigens. We investigated antibody responses to p23, a putative vaccine candidate, in children in Bangladesh with cryptosporidiosis and diarrhea (cases) and uninfected children with diarrhea (controls), and p23 gene polymorphisms in infecting species. Serum IgM, IgG, and IgA responses to p23 were significantly greater in cases than controls after three weeks of follow-up. Cases with acute diarrhea had significantly greater serum IgA and IgM responses than those with persistent diarrhea, which suggested an association with protection from prolonged disease. The p23 sequences were relatively conserved among infecting species and subtype families. Although most children were infected with Cryptosporidium hominis, there was a cross-reactive antibody response to C. parvum antigen. These results support further development of p23 as a vaccine candidate.