Citations

Abstract Reciprocal epithelial–mesenchymal interactions are pivotal in lung development, homeostasis, injury, and repair. Organoids have been used to investigate such interactions, but with a major focus on epithelial responses to mesenchyme and less attention to epithelial effects on mesenchyme. In the present study, we used nascent organoids composed of human and mouse lung epithelial and mesenchymal cells to demonstrate that healthy lung epithelium dramatically represses transcriptional, contractile, and matrix synthetic functions of lung fibroblasts. Repression of fibroblast activation requires signaling via the bone morphogenetic protein (BMP) pathway. BMP signaling is diminished after epithelial injury in vitro and in vivo, and exogenous BMP4 restores fibroblast repression in injured organoids. In contrast, inhibition of BMP signaling in healthy organoids is sufficient to derepress fibroblast matrix synthetic function. Our results reveal potent repression of fibroblast activation by healthy lung epithelium and a novel mechanism by which epithelial loss or injury is intrinsically coupled to mesenchymal activation via loss of repressive BMP signaling.

Introduction: What if you could only ask one question of the patient during a clinic visit? Further, suppose the patient’s biggest concern can pragmatically be incorporated into routine clinical care and clinical pathways that can address the patient’s single biggest concern can be identified. If the principal concern can be dealt with efficiently at each visit through key stakeholder case management, positive outcomes should result. Therefore, motivated by the need for patient-centered health care visits, the Beacon electronic patient-reported outcomes (PRO) quality of life (QOL) tool was developed. Methods: Central to the tool is that at each health care visit, the patient’s biggest concern is electronically communicated to the health care team. Therefore, the tool can help catalyze important discussions between the health care team and the patient, perhaps on topics that would not have been discussed otherwise at a routine visit. In recognition of the community of resources needed to provide comprehensive care, the tool generates clinical pathways or actions that can be pursued to address the patient’s biggest concern. The concern is efficiently triaged such that members of the health care community with appropriate expertise and resources are identified to address and manage that single biggest concern signaled by the patient. A report, which can be uploaded into the patient’s medical chart, is created and provides a list of resources for a case manager to assist the patient and contains graphical presentations of the patient’s QOL and a history of prior concerns. The report also labels potentially significant changes in QOL. Discussion: The tool, which has been applied successfully in several health conditions, acts as a beacon to health care providers so that a patient’s self-reported concern can be consistently and effectively integrated into their care. Key Points: It is impractical to try to deal with every patient concern in every visit. The key to the Beacon tool is that at each visit the patient’s biggest concern is identified, clinical pathways indicated, and resources efficiently matched to address the patient’s biggest concern.

ABSTRACT Musculoskeletal infections (MSKI) remain the bane of orthopedic surgery, and result in grievous illness and inordinate costs that threaten healthcare systems. As prevention, diagnosis, and treatment has remained largely unchanged over the last 50 years, a 2nd International Consensus Meeting on Musculoskeletal Infection (ICM 2018, https://icmphilly.com ) was completed. Questions pertaining to all areas of MSKI were extensively researched to prepare recommendations, which were discussed and voted on by the delegates using the Delphi methodology. The questions, including the General Assembly (GA) results, have been published ( GA questions ). However, as critical outcomes include: (i) incidence and cost data that substantiate the problems, and (ii) establishment of research priorities; an ICM 2018 research workgroup (RW) was assembled to accomplish these tasks. Here, we present the result of the RW consensus on the current and projected incidence of infection, and the costs per patient, for all orthopedic subspecialties, which range from 0.1% to 30%, and $17,000 to $150,000. The RW also identified the most important research questions. The Delphi methodology was utilized to initially derive four objective criteria to define a subset of the 164 GA questions that are high priority for future research. Thirty‐eight questions (23% of all GA questions) achieved the requisite > 70% agreement vote, and are highlighted in this Consensus article within six thematic categories: acute versus chronic infection, host immunity, antibiotics, diagnosis, research caveats, and modifiable factors. Finally, the RW emphasizes that without appropriate funding to address these high priority research questions, a 3rd ICM on MSKI to address similar issues at greater cost is inevitable.

A 51-year-old man with a medical history of coronary artery disease and dyslipidaemia presented with acute myocardial infarction resulting in cardiogenic shock, necessitating intra-aortic balloon pump placement and extracorporeal membrane oxygenation (ECMO). His hospital course was complicated by several infectious complications including ECMO circuit Pseudomonas aeruginosa bloodstream infection and presumed infected right atrial thrombus. He subsequently underwent urgent left ventricular assist device placement and had a prolonged hospital stay. On day 100 of admission, he developed acute hypoxic respiratory distress with new pulmonary infiltrates. Sputum cultures grew Cryptococcus neoformans. Blood culture also grew C. neoformans after 96 hours of incubation and cryptococcal serum antigen was elevated at 1:20. Cerebrospinal fluid studies from a lumbar puncture were normal. He was treated with 2 weeks of combination antifungal therapy followed by life-long fluconazole suppression.

242 Background: We evaluated plasma cell free based genomic aberrations for prognosticating survival of newly diagnosed metastatic hormone sensitive prostate cancer (mHSPC) patients (pts). Methods: Plasma was collected from mHSPC pts enrolled between 2009-2014. Platelet poor plasma (PPP) fractions were processed uniformly and cell free DNA (cfDNA) extracted using Qiagen kits. Pts were followed after initiating hormonal therapy until death. Next Gen Sequencing (NGS) of cfDNA was performed using Illumina HiSeq X for a preselected panel of 128 genes (PredicineDDR-77 cancer driver genes; 29 genes in BRCA-FA homologous recombination deficiency (HRD) pathway; 22 DNA damage repair pathway genes). Statistical analyses of plasma genome based aberrations with overall survival (OS) were performed in R 3.5.1. Cox proportional-hazard models were used for survival analysis. Results: An average of 2.5 ml PPP from 99 pts yielded a median of 10.5 ng (range: 2.8-702) cfDNA per sample. 15/99 pt samples with a yield < 5 ng were excluded from sequencing; 9/99 samples failed NGS. Median follow-up time was 80.2 months (mths) (Range: 74.7, 87]); median OS was 69.1 mths (range: 54,NR). 29 pts with full NGS data had high volume metastatic disease. cfDNA yield correlated with metastatic volume (P = 0.01). Univariate analysis revealed both variables prognostic for OS (Metastatic volume: log-rank P=0.01, HR=2.1, 95% CI: 1.1-3.8; cfDNA yield: P =0.04, HR = 1.3, 95% CI: 1.03-1.7). Multivariate regression showed prognostic value of cfDNA yield remained independent of metastatic volume (P = 0.03, HR = 1.34, 95% CI: 1.02-1.76). 54/67 samples with NGS data had at least one mutation/copy number variation detected. Top mutated genes included TP53 (N=18), ATM (N=9), CHEK2 (N=7), FANCM (N=6), RB1 (N=6), BRCA2 (N=5), PIK3CA (N=4) and 37/67 pts harbored 1≥ variant in HDR pathways. These pts had a shorter survival (median: 58.6 mths) (P=0.04, HR= 2.28, 95% CI: 1.01-5.18) and pts with ATM mutations did significantly worse (median survival: 47.4 mths) (HR=4.03, P=0.0005, 95% CI: 1.73-9.37). Conclusions: Plasma cfDNA yield is prognostic for survival in newly diagnosed mHSPC state and presence of HRD pathway genomic aberrations in plasma cfDNA are associated with poor survival.