A Multipotent Progenitor Domain Guides Pancreatic Organogenesis

The mammalian pancreas is constructed during embryogenesis by multipotent progenitors, the identity and function of which remain poorly understood. We performed genome-wide transcription factor expression analysis of the developing pancreas to identify gene expression domains that may represent distinct progenitor cell populations. Five discrete domains were discovered. Genetic lineage-tracing experiments demonstrate that one specific domain, located at the tip of the branching pancreatic tree, contains multipotent progenitors that produce exocrine, endocrine, and duct cells in vivo. These multipotent progenitors are Pdx1+Ptf1a+cMycHighCpa1+ and negative for differentiated lineage markers. The outgrowth of multipotent tip cells leaves behind differentiated progeny that form the trunk of the branches. These findings define a multipotent compartment within the developing pancreas and suggest a model of how branching is coordinated with cell type specification. In addition, this comprehensive analysis of >1,100 transcription factors identified genes that are likely to control critical decisions in pancreas development and disease.Molecular and Cellular Biolog

Phosphorylated tau/amyloid beta 1-42 ratio in ventricular cerebrospinal fluid reflects outcome in idiopathic normal pressure hydrocephalus

<p>Abstract</p> <p>Background</p> <p>Idiopathic normal pressure hydrocephalus (iNPH) is a potentially reversible cause of dementia and gait disturbance that is typically treated by operative placement of a ventriculoperitoneal shunt. The outcome from shunting is variable, and some evidence suggests that the presence of comorbid Alzheimer's disease (AD) may impact shunt outcome. Evidence also suggests that AD biomarkers in cerebrospinal fluid (CSF) may predict the presence of AD. The aim of this study was to investigate the relationship between the phosphorylated tau/amyloid beta 1-42 (ptau/Aβ1-42) ratio in ventricular CSF and shunt outcome in patients with iNPH.</p> <p>Methods</p> <p>We conducted a prospective trial with a cohort of 39 patients with suspected iNPH. Patients were clinically and psychometrically assessed prior to and approximately 4 months after ventriculoperitoneal shunting. Lumbar and ventricular CSF obtained intraoperatively, and tissue from intraoperative cortical biopsies were analyzed for AD biomarkers. Outcome measures included performance on clinical symptom scales, supplementary gait measures, and standard psychometric tests. We investigated relationships between the ptau/Aβ1-42 ratio in ventricular CSF and cortical AD pathology, initial clinical features, shunt outcome, and lumbar CSF ptau/Aβ1-42 ratios in the patients in our cohort.</p> <p>Results</p> <p>We found that high ptau/Aβ1-42 ratios in ventricular CSF correlated with the presence of cortical AD pathology. At baseline, iNPH patients with ratio values most suggestive of AD presented with better gait performance but poorer cognitive performance. Patients with high ptau/Aβ1-42 ratios also showed a less robust response to shunting on both gait and cognitive measures. Finally, in a subset of 18 patients who also underwent lumbar puncture, ventricular CSF ratios were significantly correlated with lumbar CSF ratios.</p> <p>Conclusions</p> <p>Levels of AD biomarkers in CSF correlate with the presence of cortical AD pathology and predict aspects of clinical presentation in iNPH. Moreover, preliminary evidence suggests that CSF biomarkers of AD may prove useful for stratifying shunt prognosis in patients being evaluated and treated for this condition.</p

CE: A Prone Positioning Protocol for Awake, Nonintubated Patients with COVID-19

ABSTRACT: Prone positioning of critically ill patients with acute respiratory distress syndrome is an accepted therapy done to improve oxygenation and promote weaning from mechanical ventilation. But there is limited information regarding its use outside of the ICU. At one Boston hospital, the influx of patients with suspected or confirmed COVID-19 strained its resources, requiring sweeping systems changes and inspiring innovations in clinical care. This article describes how an interdisciplinary team of clinicians developed a prone positioning protocol for use with awake, nonintubated, oxygen-dependent patients with suspected or confirmed COVID-19 on medical-surgical units, with the hope of hastening their recovery and avoiding deterioration and ICU transfer. A protocol implementation plan and staff educational materials were disseminated via the hospital incident command system and supported through daily leadership huddles. Patient eligibility criteria, including indications and contraindications, and a clear nursing procedure for the implementation of prone positioning with a given patient, were key elements. Nurses\u27 feedback of their experiences with the protocol was elicited through an e-mailed survey. Nearly all respondents reported improvements in patients\u27 oxygen saturation levels, while few respondents reported barriers to protocol implementation. The prone positioning protocol was found to be both feasible for and well tolerated by awake, nonintubated patients on medical-surgical units, and can serve as an example for other hospitals during this pandemic

Update in Critical Care 2021

This article has been removed from the AJRCCM website, as it may be revised in the near future

Hospital-level variation in practices and outcomes for patients with severe acute exacerbations of idiopathic pulmonary fibrosis: a retrospective multicentre cohort study

Background In the absence of evidence-based strategies to improve patient outcomes, the management of patients with severe idiopathic pulmonary fibrosis (IPF) exacerbations may vary widely across centres. We assessed between-hospital variation in practices and mortality for patients with severe IPF exacerbations.Methods Using the Premier Healthcare Database from 1 October 2015 to 31 December 2020, we identified patients admitted to intensive care unit (ICU) or intermediate care unit with an IPF exacerbation. We assessed idiosyncratic, between-hospital variation in ICU practices (invasive mechanical ventilation (IMV), non-invasive mechanical ventilation (NIMV), corticosteroid use, and immunosuppressive and/or antioxidant use) and hospital mortality by determining median risk-adjusted hospital rates and intraclass correlation coefficients (ICCs) from hierarchical multivariable regression models. A priori, an ICC&gt;15% was deemed ‘high variation’.Results We identified 5256 critically ill patients with a severe IPF exacerbation at 385 US hospitals. Hospital median risk-adjusted rates of practices were: IMV (14% (IQR: 8.3%–26%)), NIMV (42% (31%–54%)), corticosteroid use (89% (84%–93%)), and immunosuppressive and/or antioxidant use (3.3% (1.9%–5.8%)). Model ICCs were: IMV (19% (95% CI: 18% to 21%)), NIMV (15% (13% to 16%)), corticosteroid use (9.8% (8.3% to 11%)), and immunosuppressive and/or antioxidant use (8.5% (7.1% to 9.9%)). The median risk-adjusted hospital mortality was 16% (IQR: 11%–24%) with an ICC of 7.5% (95% CI: 6.2% to 8.9%).Interpretation We observed high variation in the use of IMV and NIMV, and less variation in corticosteroid and immunosuppressant and/or antioxidant use among patients hospitalised with severe IPF exacerbations. Further research is needed to guide the decisions surrounding initiation of IMV and role of NIMV and to understand the effectiveness of corticosteroids among patients with severe IPF exacerbations

Association between Residential Segregation and Long-Term Acute Care Hospital Performance on Improvement in Function among Ventilated Patients

One in five survivors of critical illness who require prolonged mechanical ventilation are discharged to long-term acute care hospitals (LTCHs). Although disparities based on race and insurance have been described in LTCH use, studies have not evaluated equity in outcomes. Improvement in function (e.g., mobility) is a crucial recovery goal for patients requiring prolonged mechanical ventilation. Research in other areas has suggested that Black patients disproportionately receive care in lower-performing facilities. Whether LTCHs serving communities with more segregation achieve lower gains in functional outcomes is unknown. In response to the Improving Medicare Post-Acute Care Transformation Act, the Centers for Medicare and Medicaid Services mandated reporting of change in mobility among ventilated patients as an LTCH quality measure. We sought to examine the association between the racial composition of the neighborhood and county of an LTCH and performance on the functional mobility improvement measure