Caregiver perspectives of pre-transplant evaluation in children.

BACKGROUND: Pre-transplant evaluation is mandated by Centers for Medicare and Medicaid Services, but there is wide institutional variation in implementation, and the family experience of the process is incompletely understood. Current literature largely focuses on adult transplant recipients. METHODS: This qualitative study begins to fill the knowledge gap about family experience of the pre-transplant evaluation for children through interviews with caregivers at a large pediatric transplant center. RESULTS: Prominent themes heard from caregivers include (1) the pre-transplant evaluation is overwhelming and emotional, (2) prior experiences and background knowledge frame the evaluation experience, and (3) frustration with communication among teams is common. CONCLUSIONS: These findings are relevant to efforts by transplant centers to optimize information delivery, minimize concrete barriers, and address healthcare systems issues. A higher resolution version of the Graphical abstract is available as Supplementary information.

Human lipopolysaccharide models provide mechanistic and therapeutic insights into systemic and pulmonary inflammation.

Inflammation is a key feature in the pathogenesis of sepsis and acute respiratory distress syndrome (ARDS). Sepsis and ARDS continue to be associated with high mortality. A key contributory factor is the rudimentary understanding of the early events in pulmonary and systemic inflammation in humans, which are difficult to study in clinical practice, as they precede the patient's presentation to medical services. Lipopolysaccharide (LPS), a constituent of the outer membrane of Gram-negative bacteria, is a trigger of inflammation and the dysregulated host response in sepsis. Human LPS models deliver a small quantity of LPS to healthy volunteers, triggering an inflammatory response and providing a window to study early inflammation in humans. This allows biological/mechanistic insights to be made and new therapeutic strategies to be tested in a controlled, reproducible environment from a defined point in time. We review the use of human LPS models, focussing on the underlying mechanistic insights that have been gained by studying the response to intravenous and pulmonary LPS challenge. We discuss variables that may influence the response to LPS before considering factors that should be considered when designing future human LPS studies.

A randomized controlled trial of peripheral blood mononuclear cell depletion in experimental human lung inflammation.

RATIONALE: Depletion of monocytes reduces LPS-induced lung inflammation in mice, suggesting monocytes as potential therapeutic targets in acute lung injury. OBJECTIVES: To investigate whether depletion of circulating blood monocytes has beneficial effects on markers of systemic and pulmonary inflammation in a human model of acute lung inflammation. METHODS: A total of 30 healthy volunteers were enrolled in a randomized controlled trial. Volunteers inhaled LPS at baseline, and were randomized to receive active mononuclear cell depletion by leukapheresis, or sham leukapheresis, in a double-blind fashion (15 volunteers per group). Serial blood counts were measured, bronchoalveolar lavage (BAL) was performed at 9 hours, and [(18)F]fluorodeoxyglucose positron emission tomography at 24 hours. The primary endpoint was the increment in circulating neutrophils at 8 hours. MEASUREMENTS AND MAIN RESULTS: As expected, inhalation of LPS induced neutrophilia and an up-regulation of inflammatory mediators in the blood and lungs of all volunteers. There was no significant difference between the depletion and sham groups in the mean increment in blood neutrophil count at 8 hours (6.16 × 10(9)/L and 6.15 × 10(9)/L, respectively; P = 1.00). Furthermore, there were no significant differences in BAL neutrophils or protein, positron emission tomography-derived measures of global lung inflammation, or cytokine levels in plasma or BAL supernatant between the study groups. No serious adverse events occurred, and no symptoms were significantly different between the groups. CONCLUSIONS: These findings do not support a role for circulating human monocytes in the early recruitment of neutrophils during LPS-mediated acute lung inflammation in humans.

Comparing the effectiveness of computer-aided design/computer-aided manufacturing (CAD/CAM) of insoles manufactured from foam box cast versus direct scans on patient-reported outcome measures: a protocol for a double-blinded, randomised controlled trial.

INTRODUCTION: Custom insoles are a routine treatment for many foot pathologies, and the use of computer-aided design and computer-aided manufacturing (CAD/CAM) is well established within clinical practice in the UK. The method of foot shape capture used to produce insoles varies throughout orthotic services. This trial aims to investigate the effectiveness of two common shape-capture techniques on patient-reported outcomes in people who require insoles for a foot or ankle pathology. METHODS AND ANALYSIS: This double-blinded randomised controlled trial will involve two intervention groups recruited from a National Health Service orthotic service. Participants will be randomly assigned to receive a pair of custom CAD/CAM insoles, manufactured either from a direct digital scan or a foam box cast of their feet and asked to wear the insoles for 12 weeks. The primary outcome measure will be the Foot Health Status Questionnaire (FHSQ) pain subdomain, recorded at baseline (immediately after receiving the intervention), 4, 8 and 12 weeks post intervention. Secondary outcome measures will include FHSQ foot function and foot health subdomains recorded at baseline, 4, 8 and 12 weeks. The Orthotic and Prosthetic User Survey Satisfaction with Device will be recorded at 12 weeks. The transit times associated with each arm will be measured as the number of days for each insole to be delivered after foot shape capture. Tertiary outcome measures will include participant recruitment and dropout rates, and intervention adherence measured as the daily usage of the insoles over 12 weeks. The change in FHSQ scores for the subdomains and insole usage will be compared between the groups and time points, and between group differences in time in transit, cost-time analysis and environmental impact will be compared. ETHICS AND DISSEMINATION: Ethical approval was obtained from the Health Research Authority, London Stanmore Research Ethics Committee (22/LO/0579). Study findings will be submitted for publication in peer-reviewed journals, conference presentations and webinars. TRIAL REGISTRATION NUMBER: NCT05444192.

C5a-mediated neutrophil dysfunction is RhoA-dependent and predicts infection in critically ill patients.

Critically ill patients are at heightened risk for nosocomial infections. The anaphylatoxin C5a impairs phagocytosis by neutrophils. However, the mechanisms by which this occurs and the relevance for acquisition of nosocomial infection remain undetermined. We aimed to characterize mechanisms by which C5a inhibits phagocytosis in vitro and in critically ill patients, and to define the relationship between C5a-mediated dysfunction and acquisition of nosocomial infection. In healthy human neutrophils, C5a significantly inhibited RhoA activation, preventing actin polymerization and phagocytosis. RhoA inhibition was mediated by PI3Kδ. The effects on RhoA, actin, and phagocytosis were fully reversed by GM-CSF. Parallel observations were made in neutrophils from critically ill patients, that is, impaired phagocytosis was associated with inhibition of RhoA and actin polymerization, and reversed by GM-CSF. Among a cohort of 60 critically ill patients, C5a-mediated neutrophil dysfunction (as determined by reduced CD88 expression) was a strong predictor for subsequent acquisition of nosocomial infection (relative risk, 5.8; 95% confidence interval, 1.5-22; P = .0007), and remained independent of time effects as assessed by survival analysis (hazard ratio, 5.0; 95% confidence interval, 1.3-8.3; P = .01). In conclusion, this study provides new insight into the mechanisms underlying immunocompromise in critical illness and suggests novel avenues for therapy and prevention of nosocomial infection.

A novel subpopulation of monocyte-like cells in the human lung after lipopolysaccharide inhalation.

The co-ordinated recruitment of monocyte subpopulations, neutrophils and regulatory T-cells (Tregs) during the early stages of human acute lung inflammation remains poorly understood. We therefore performed a detailed characterisation of these lineages in the blood and lungs in a model of human acute lung inflammation. Healthy volunteers inhaled lipopolysaccharide (LPS) or saline (n=6 for each group). Blood was collected at 0, 2, 4, 6 and 8 h and bronchoscopy with bronchoalveolar lavage (BAL) performed at 8 h. Multiparameter flow cytometry was used to characterise monocyte subpopulations, neutrophils and Tregs in the blood and lung. Inhalation of LPS was associated with significant blood and BAL fluid neutrophilia. Blood populations of monocyte subpopulations and Tregs were unaltered by LPS. In contrast, LPS induced an accumulation of a pulmonary monocyte-like cell (PMLC) population, which was further subdivided into "inducible" CD14(++)CD16(-) and "resident" CD14(++)CD16(+) subsets. Inducible PMLCs were significantly increased following LPS inhalation (p=0.0046), whereas resident PMLCs were unchanged. In addition, we noted a significant decrease in Tregs in BAL fluid with LPS inhalation (p=0.027). The early stages of LPS-induced inflammation in humans is characterised by pulmonary accumulation of a novel inducible monocyte-like subpopulation, accompanied by significant changes in both neutrophil and Treg numbers.

COVID-19 challenges and changes for home care agencies and providers: a scoping review protocol.

OBJECTIVE: This scoping review will explore the challenges experienced by home care agencies and home care providers during the COVID-19 pandemic and the changes made to overcome these challenges. INTRODUCTION: The COVID-19 pandemic has presented many challenges to home care agencies and providers worldwide. In response, home care agencies and providers were forced to make changes to the way they operate in order to continue providing quality care to homebound patients. INCLUSION CRITERIA: This scoping review will consider studies that explore the challenges experienced by home care agencies and providers during the COVID-19 pandemic and the changes implemented, or strategies, used to overcome the identified challenges. All geographic locations will be considered for inclusion. METHODS: This review will be conducted in accordance with the JBI methodology for scoping reviews. Key information sources will include MEDLINE, CINAHL, Embase, Scopus, and Web of Science. Sources of unpublished studies and gray literature will include ProQuest Dissertations and Theses, OpenGrey, medRxiv, and bioRxiv. The review will be limited to articles published in English, from 2020 until present day. Two independent reviewers will use a data extraction tool to collect data. Along with a narrative summary, the results will be presented in diagrammatic or tabular format in a manner that aligns with the review objective and questions.

Mitigation of SARS-CoV-2 transmission at a large public university.

In Fall 2020, universities saw extensive transmission of SARS-CoV-2 among their populations, threatening health of the university and surrounding communities, and viability of in-person instruction. Here we report a case study at the University of Illinois at Urbana-Champaign, where a multimodal "SHIELD: Target, Test, and Tell" program, with other non-pharmaceutical interventions, was employed to keep classrooms and laboratories open. The program included epidemiological modeling and surveillance, fast/frequent testing using a novel low-cost and scalable saliva-based RT-qPCR assay for SARS-CoV-2 that bypasses RNA extraction, called covidSHIELD, and digital tools for communication and compliance. In Fall 2020, we performed >1,000,000 covidSHIELD tests, positivity rates remained low, we had zero COVID-19-related hospitalizations or deaths amongst our university community, and mortality in the surrounding Champaign County was reduced more than 4-fold relative to expected. This case study shows that fast/frequent testing and other interventions mitigated transmission of SARS-CoV-2 at a large public university.

Functional characterisation of human pulmonary monocyte-like cells in lipopolysaccharide-mediated acute lung inflammation.

BACKGROUND: We have previously reported the presence of novel subpopulations of pulmonary monocyte-like cells (PMLC) in the human lung; resident PMLC (rPMLC, HLA-DR(+)CD14(++)CD16(+)cells) and inducible PMLC (iPMLC, HLA-DR(+)CD14(++)CD16(-) cells). iPMLC are significantly increased in bronchoalveolar lavage (BAL) fluid following inhalation of lipopolysaccharide (LPS). We have carried out the first functional evaluation of PMLC subpopulations in the inflamed lung, following the isolation of these cells, and other lineages, from BAL fluid using novel and complex protocols. METHODS: iPMLC, rPMLC, alveolar macrophages (AM), neutrophils, and regulatory T cells were quantified in BAL fluid of healthy subjects at 9 hours post-LPS inhalation (n = 15). Cell surface antigen expression by iPMLC, rPMLC and AM and the ability of each lineage to proliferate and to undergo phagocytosis were investigated using flow cytometry. Basal cytokine production by iPMLC compared to AM following their isolation from BAL fluid and the responsiveness of both cell types following in vitro treatment with the synthetic corticosteroid dexamethasone were assessed. RESULTS: rPMLC have a significantly increased expression of mature macrophage markers and of the proliferation antigen Ki67, compared to iPMLC. Our cytokine data revealed a pro-inflammatory, corticosteroid-resistant phenotype of iPMLC in this model. CONCLUSIONS: These data emphasise the presence of functionally distinct subpopulations of the monocyte/macrophage lineage in the human lung in experimental acute lung inflammation.