Innate Immune Landscape in Early Lung Adenocarcinoma by Paired Single-Cell Analyses.

To guide the design of immunotherapy strategies for patients with early stage lung tumors, we developed a multiscale immune profiling strategy to map the immune landscape of early lung adenocarcinoma lesions to search for tumor-driven immune changes. Utilizing a barcoding method that allows a simultaneous single-cell analysis of the tumor, non-involved lung, and blood cells, we provide a detailed immune cell atlas of early lung tumors. We show that stage I lung adenocarcinoma lesions already harbor significantly altered T cell and NK cell compartments. Moreover, we identified changes in tumor-infiltrating myeloid cell (TIM) subsets that likely compromise anti-tumor T cell immunity. Paired single-cell analyses thus offer valuable knowledge of tumor-driven immune changes, providing a powerful tool for the rational design of immune therapies. VIDEO ABSTRACT.

Tissue-resident macrophages self-maintain locally throughout adult life with minimal contribution from circulating monocytes.

Despite accumulating evidence suggesting local self-maintenance of tissue macrophages in the steady state, the dogma remains that tissue macrophages derive from monocytes. Using parabiosis and fate-mapping approaches, we confirmed that monocytes do not show significant contribution to tissue macrophages in the steady state. Similarly, we found that after depletion of lung macrophages, the majority of repopulation occurred by stochastic cellular proliferation in situ in a macrophage colony-stimulating factor (M-Csf)- and granulocyte macrophage (GM)-CSF-dependent manner but independently of interleukin-4. We also found that after bone marrow transplantation, host macrophages retained the capacity to expand when the development of donor macrophages was compromised. Expansion of host macrophages was functional and prevented the development of alveolar proteinosis in mice transplanted with GM-Csf-receptor-deficient progenitors. Collectively, these results indicate that tissue-resident macrophages and circulating monocytes should be classified as mononuclear phagocyte lineages that are independently maintained in the steady state.

Rapid Implementation and Adaptation of a Telehospitalist Service to Coordinate and Optimize Care for COVID-19 Patients.

Background/Introduction: The COVID-19 pandemic poses enormous resource challenges to hospitals. Telemedicine is increasingly recognized as an attractive tool to alleviate resource strains. Herein we describe the rapid implementation and sequential process improvement (PI) of a centralized telehospitalist service to coordinate and optimize management of large number of COVID-19 patients in a tertiary and quaternary care hospital very close to the New York City epicenter. Methods: Prospective multidisciplinary PI meetings were held weekly between March 23 and May 10, 2020, and consensus service modifications were implemented for the following week. Inpatient census data, telehospitalist intervention volumes, and service utilization statistics were collected. Results/Discussion: Between March 23 and May 10, 2020, a total of 745 COVID-19 patients were admitted to the general medical wards. The telehospitalist service performed 1,136 audiovisual (AV) patient assessments, 379 best practice interventions, cohorted 108 patients, and conducted 170 remote family conversations. During the consecutive PI cycles, a number of adaptations in AV setup, care standardization, patient logistics, communication, and consultative functions were made to load balance the bedside hospitalist teams. As the COVID-19 hospital census increased to peak levels, the most value was added through facilitation of communication and collaboration between the bedside clinical teams, the infection prevention and control teams, and patient logistics team. Conclusions: A telehospitalist service can be rapidly implemented with basic telemedicine equipment. Processes/this functions can be sequentially adapted to quickly changing needs during conditions such as the COVID-19 pandemic that very quickly can place extraordinary strains on hospital resources.

Telemedicine in the ICU: clinical outcomes, economic aspects, and trainee education.

PURPOSE OF REVIEW: The evidence base for telemedicine in the ICU (tele-ICU) is rapidly expanding. The last 2 years have seen important additions to our understanding of when, where, and how telemedicine in the ICU adds value. RECENT FINDINGS: Recent publications and a recent meta-analysis confirm that tele-ICU improves core clinical outcomes for ICU patients. Recent evidence further demonstrates that comprehensive tele-ICU programs have the potential to quickly recuperate their implementation and operational costs and significantly increase case volumes and direct contribution margins particularly if additional logistics and care standardization functions are embedded to optimize ICU bed utilization and reduce complications. Even though the adoption of tele-ICU is increasing and the vast majority of today's medical graduates will regularly use some form of telemedicine and/or tele-ICU, telemedicine modules have not consistently found their way into educational curricula yet. Tele-ICU can be used very effectively to standardize supervision of medical trainees in bedside procedures or point-of-care ultrasound exams, especially during off-hours. Lastly, tele-ICUs routinely generate rich operational data, as well as risk-adjusted acuity and outcome data across the spectrum of critically ill patients, which can be utilized to support important clinical research and quality improvement projects. SUMMARY: The value of tele-ICU to improve patient outcomes, optimize ICU bed utilization, increase financial performance and enhance educational opportunities for the next generation of providers has become more evident and differentiated in the last 2 years.

A Large-Scale Multicenter Retrospective Study on Nephrotoxicity Associated With Empiric Broad-Spectrum Antibiotics in Critically Ill Patients.

BACKGROUND: Evidence regarding acute kidney injury associated with concomitant administration of vancomycin and piperacillin-tazobactam is conflicting, particularly in patients in the ICU. RESEARCH QUESTION: Does a difference exist in the association between commonly prescribed empiric antibiotics on ICU admission (vancomycin and piperacillin-tazobactam, vancomycin and cefepime, and vancomycin and meropenem) and acute kidney injury? STUDY DESIGN AND METHODS: This was a retrospective cohort study using data from the eICU Research Institute, which contains records for ICU stays between 2010 and 2015 across 335 hospitals. Patients were enrolled if they received vancomycin and piperacillin-tazobactam, vancomycin and cefepime, or vancomycin and meropenem exclusively. Patients initially admitted to the ED were included. Patients with hospital stay duration of < 1 h, receiving dialysis, or with missing data were excluded. Acute kidney injury was defined as Kidney Disease: Improving Global Outcomes stage 2 or 3 based on serum creatinine component. Propensity score matching was used to match patients in the control (vancomycin and meropenem or vancomycin and cefepime) and treatment (vancomycin and piperacillin-tazobactam) groups, and ORs were calculated. Sensitivity analyses were performed to study the effect of longer courses of combination therapy and patients with renal insufficiency on admission. RESULTS: Thirty-five thousand six hundred fifty-four patients met inclusion criteria (vancomycin and piperacillin-tazobactam, n = 27,459; vancomycin and cefepime, n = 6,371; vancomycin and meropenem, n = 1,824). Vancomycin and piperacillin-tazobactam was associated with a higher risk of acute kidney injury and initiation of dialysis when compared with that of both vancomycin and cefepime (Acute kidney injury: OR, 1.37 [95% CI, 1.25-1.49]; dialysis: OR, 1.28 [95% CI, 1.14-1.45]) and vancomycin and meropenem (Acute kidney injury: OR, 1.27 [95%, 1.06-1.52]; dialysis: OR, 1.56 [95% CI, 1.23-2.00]). The odds of acute kidney injury developing was especially pronounced in patients without renal insufficiency receiving a longer duration of vancomycin and piperacillin-tazobactam therapy compared with vancomycin and meropenem therapy. INTERPRETATION: VPT is associated with a higher risk of acute kidney injury than both vancomycin and cefepime and vancomycin and meropenem in patients in the ICU, especially for patients with normal initial kidney function requiring longer durations of therapy. Clinicians should consider vancomycin and meropenem or vancomycin and cefepime to reduce the risk of nephrotoxicity for patients in the ICU.

Effects of Telemedicine ICU Intervention on Care Standardization and Patient Outcomes: An Observational Study.

OBJECTIVES: Given the numerous recent changes in ICU practices and protocols, we sought to confirm whether favorable effects of telemedicine ICU interventions on ICU mortality and length of stay can be replicated by a more recent telemedicine ICU intervention. DESIGN SETTING AND PATIENTS: Observational before-after telemedicine ICU intervention study in seven adult ICUs in two hospitals. The study included 1,403 patients in the preintervention period (October 2014 to September 2015) and 14,874 patients in the postintervention period (January 2016 to December 2018). INTERVENTION: Telemedicine ICU implementation. MEASUREMENTS AND MAIN RESULTS: ICU and hospital mortality and length of stay, best practice adherence rates, and telemedicine ICU performance metrics. Unadjusted ICU and hospital mortality and lengths of stay were not statistically significantly different. Adjustment for Acute Physiology and Chronic Health Evaluation Version IVa score, ICU type, and ICU admission time via logistic regression yielded significantly lower ICU and hospital mortality odds ratios of 0.58 (95% CI, 0.45-0.74) and 0.66 (95% CI, 0.54-0.80), respectively. When adjusting for acuity by comparing observed-over-expected length of stay ratios through Acute Physiology and Chronic Health Evaluation IVa methodology, we found significantly lower ICU and hospital length of stay in the postintervention group. ICU mortality improvements were driven by nighttime ICU admissions (odds ratio 0.45 [95% CI, 0.33-0.61]) as compared to daytime ICU admissions (odds ratio 0.81 [95% CI, 0.55-1.20]), whereas hospital mortality improvements were seen in both subgroups but more prominently in nighttime ICU admissions (odds ratio 0.57 [95% CI, 0.44-0.74]) as compared to daytime ICU admissions (odds ratio 0.73 [95% CI, 0.55-0.97]), suggesting that telemedicine ICU intervention can effectively supplement low intensity bedside staffing hours (nighttime). CONCLUSIONS: In this pre-post observational study, telemedicine ICU intervention was associated with improvements in care standardization and decreases in ICU and hospital mortality and length of stay. The mortality benefits were mediated in part through telemedicine ICU supplementation of low intensity bedside staffing hours.

Hyperglycemia in Medically Critically Ill Patients: Risk Factors and Clinical Outcomes.

BACKGROUND: We aimed to robustly categorize glycemic control in our medical intensive care unit (ICU) as either acceptable or suboptimal based on time-weighted daily blood glucose averages of <180 mg/dL or >180 mg/dL; identify clinical risk factors for suboptimal control; and compare clinical outcomes between the 2 glycemic control categories. METHODS: This was a retrospective cohort study in an academic tertiary and quaternary medical ICU. RESULTS: Out of total of 974 unit stays over a 2-year period, 920 had complete data sets available for analysis. Of unit stays 63% (575) were classified as having acceptable glycemic control and the remaining 37% were classified (345) as having suboptimal glycemic control. Adjusting for covariables, the odds of suboptimal glycemic control were highest for patients with diabetes mellitus (odds ratio [OR] 5.08, 95% confidence interval [CI] 3.72-6.93), corticosteroid use during the ICU stay (OR 4.50, 95% CI 3.21-6.32), and catecholamine infusions (OR 1.42, 95% CI 1.04-1.93). Adjusting for acuity, acceptable glycemic control was associated with decreased odds of hospital mortality but not ICU mortality (OR 0.65, 95% CI 0.48-0.88 and OR 0.81, 95% CI 0.55-1.17, respectively). Suboptimal glycemic control was associated with increased odds of longer-than-predicted ICU and hospital stays (OR 1.76, 95% CI 1.30-2.38 and OR 1.50, 95% CI 1.12-2.01, respectively). CONCLUSIONS: In our high-acuity medically critically ill patient population, achieving time-weighted average daily blood glucose levels <180 mg/dL reliably while in the ICU significantly decreased the odds of subsequent hospital mortality. Suboptimal glycemic control during the ICU stay, on the other hand, significantly increased the odds of longer-than-predicted ICU and hospital stay.

Blood Donors on Medication - an Approach to Minimize Drug Burden for Recipients of Blood Products and to Limit Deferral of Donors.

BACKGROUND: Blood products derived from donors on medication can contain drugs which might pose a risk for the recipients or influence the quality of the product itself. MATERIAL AND METHODS: To judge the eligibility of blood donors on medication, 4 drug classes have been formed with respect to their pharmacological properties, and blood products have been divided in accordance with their single-donor plasma contents. RESULTS: For drugs with dose-dependent pharmacodynamics, no deferral periods are necessary for donation of blood products containing less than 50 ml single-donor plasma for application to adults. Waiting periods of t(max) + 5 t(1/2) were calculated for the other blood products. Teratogenic drugs do not require special considerations (exception: retinoids, thalidomide and lenalidomide, dutasteride or finasteride with waiting periods for all blood products). A deferral period of t(max) + 24 t(1/2) is proposed for every blood product from blood donors on genotoxic drugs. Drugs without systemic effects can be neglected. Irreversible inhibitors of platelet function cause a 10-day waiting period if production of platelet concentrates is intended. CONCLUSION: Donors on medication are allowed to donate blood for blood products containing less than 50 ml plasma of a single donor, like red blood cell concentrates, for the use in adults without deferral periods, except those taking retinoids, thalidomide, lenalidomide, dutasteride, finasteride, or genotoxic drugs.

Legal Perspectives on Telemedicine Part 2: Telemedicine in the Intensive Care Unit and Medicolegal Risk.

Tele-intensive care unit (tele-ICU) implementation has been shown to improve clinical and financial outcomes. The expansion of this new care delivery model has outpaced the development of its accompanying regulatory framework. In the first part of this commentary we discussed legal and regulatory issues of telemedicine in general and expanded on tele-ICU implementation in particular. Major legal and regulatory barriers to expansion remain, including uncertainty regarding license portability and reimbursement. In this second part we discuss the effects of telemedicine implementation on the various aspects of medicolegal risk and risk mitigation, with a particular focus on tele-ICU. There is a paucity of legal data regarding the effect of tele-ICU implementation on medicolegal risk. We will therefore systematically discuss the effects of tele-ICU on the various root causes of medical error. Given the substantial capital and operational investment that must be undertaken to build and run a tele-ICU, any reduction in risk adds to the financial return on investment and further decreases barriers to implementation.

Legal Perspectives on Telemedicine Part 1: Legal and Regulatory Issues.

Telemedicine is defined as the remote delivery of clinical care services through audio-visual conferencing technology. A shortage of care practitioners combined with an aging population with disproportionately increasing care utilization patterns has created a "perfect storm," which since the late 1990s has propelled telemedicine as a potential solution to bridge this supply/demand and access gap. In critical care approximately 20% of nonfederal adult intensive care unit (ICU) beds in the US today are supported by some form of tele-ICU coverage. The literature has shown with increasing clarity during the last decade that correct tele-ICU implementation improves outcomes and has the potential to significantly improve the financial performance of health care systems. As is often the case in technology-driven innovations, the legal and regulatory framework has been moving slower than the clinical adoption of this new care delivery model, which is true not just in critical care, but in other medical specialties as well. This 2-part series focuses on legal perspectives on telemedicine. The first part discusses legal and regulatory challenges of telemedicine in general, with a more in-depth focus on tele-ICU. The second part will discuss the effects of telemedicine implementation on medicolegal risk, using the litigious critical care environment as an example.

Optimizing Tele-ICU Operational Efficiency Through Workflow Process Modeling and Restructuring.

Little is known on how to best prioritize various tele-ICU specific tasks and workflows to maximize operational efficiency. We set out to: 1) develop an operational model that accurately reflects tele-ICU workflows at baseline, 2) identify workflow changes that optimize operational efficiency through discrete-event simulation and multi-class priority queuing modeling, and 3) implement the predicted favorable workflow changes and validate the simulation model through prospective correlation of actual-to-predicted change in performance measures linked to patient outcomes. SETTING: Tele-ICU of a large healthcare system in New York State covering nine ICUs across the spectrum of adult critical care. PATIENTS: Seven-thousand three-hundred eighty-seven adult critically ill patients admitted to a system ICU (1,155 patients pre-intervention in 2016Q1 and 6,232 patients post-intervention 2016Q3 to 2017Q2). INTERVENTIONS: Change in tele-ICU workflow process structure and hierarchical process priority based on discrete-event simulation. MEASUREMENTS AND MAIN RESULTS: Our discrete-event simulation model accurately reflected the actual baseline average time to first video assessment by both the tele-ICU intensivist (simulated 132.8 ± 6.7 min vs 132 ± 12.2 min actual) and the tele-ICU nurse (simulated 128.4 ± 7.6 min vs 123 ± 9.8 min actual). For a simultaneous priority and process change, the model simulated a reduction in average TVFA to 51.3 ± 1.6 min (tele-ICU intensivist) and 50.7 ± 2.1 min (tele-ICU nurse), less than the added simulated reductions for each change alone, suggesting correlation of the changes to some degree. Subsequently implementing both changes simultaneously resulted in actual reductions in average time to first video assessment to values within the 95% CIs of the simulations (50 ± 5.5 min for tele-intensivists and 49 ± 3.9 min for tele-nurses). CONCLUSIONS: Discrete-event simulation can accurately predict the effects of contemplated multidisciplinary tele-ICU workflow changes. The value of workflow process and task priority modeling is likely to increase with increasing operational complexities and interdependencies.

Low Risk Monitoring in Neurocritical Care.

Background/Rationale: Patients are admitted to Intensive care units (ICUs) either because they need close monitoring despite a low risk of hospital mortality (LRM group) or to receive ICU specific active treatments (AT group). The characteristics and differential outcomes of LRM patients vs. AT patients in Neurocritical Care Units are poorly understood. Methods: We classified 1,702 patients admitted to our tertiary and quaternary care center Neuroscience-ICU in 2016 and 2017 into LRM vs. AT groups. We compared demographics, admission diagnosis, goal of care status, readmission rates and managing attending specialty extracted from the medical record between groups. Acute Physiology, Age and Chronic Health Evaluation (APACHE) IVa risk predictive modeling was used to assess comparative risks for ICU and hospital mortality and length of stay between groups. Results: 56.9% of patients admitted to our Neuroscience-ICU in 2016 and 2017 were classified as LRM, whereas 43.1% of patients were classified as AT. While demographically similar, the groups differed significantly in all risk predictive outcome measures [APACHE IVa scores, actual and predicted ICU and hospital mortality (p < 0.0001 for all metrics)]. The most common admitting diagnosis overall, cerebrovascular accident/stroke, was represented in the LRM and AT groups with similar frequency [24.3 vs. 21.3%, respectively (p = 0.15)], illustrating that further differentiating factors like symptom duration, neurologic status and its dynamic changes and neuro-imaging characteristics determine the indication for active treatment vs. observation. Patients with intracranial hemorrhage/hematoma were significantly more likely to receive active treatments as opposed to having a primary focus on monitoring [13.6 vs. 9.8%, respectively (p = 0.017)]. Conclusion: The majority of patients admitted to our Neuroscience ICU (56.9%) had <10% hospital mortality risk and a focus on monitoring, whereas the remaining 43.1% of patients received active treatments in their first ICU day. LRM Patients exhibited significantly lower APACHE IVa scores, ICU and hospital mortality rates compared to AT patients. Observed-over-expected ICU and hospital mortality ratios were better than predicted by APACHE IVa for low risk monitored patients and close to prediction for actively treated patients, suggesting that at least a subset of LRM patients may safely and more cost effectively be cared for in intermediate level care settings.

Acute cholecystitis caused by ceftriaxone stones in an adult.

Acute cholecystitis is a major health problem. There are multiple etiologies to be considered and early recognition of the condition is important to optimize management and outcome. We report the first case in the medical literature of symptomatic acute cholecystitis triggered by ceftriaxone-associated gallbladder sludge formation and, importantly, solid ceftriaxone gallstone formation in an adult patient with underlying mineral and pigment cholecystolithiasis, necessitating cholecystectomy. This case serves as a reminder for physicians to keep this uncommon cause of cholecystolithiasis and cholecystitis in mind in patients who receive prolonged ceftriaxone therapy. These patients should be cautioned to promptly report to their physicians any signs or symptoms of cholecystitis in order to ensure timely and appropriate evaluation.

Idiopathic pleuroparenchymal fibroelastosis: an unrecognized or misdiagnosed entity?

Idiopathic pleuroparenchymal fibroelastosis is a rare recently described entity likely to be under- and misdiagnosed, as awareness of this entity is not yet widespread. We report two cases that show the need to include this disease in the differential diagnosis of patients with predominantly pleural and subpleural fibrotic processes. The condition is a fibrotic thickening of the pleura and subpleural parenchyma due to elastic fiber proliferation predominantly in the upper lobes. Performing elastic fiber stains routinely in patients with fibrosis of this distribution may, therefore, aid in establishing the diagnosis and differentiating it from usual interstitial pneumonia/idiopathic pulmonary fibrosis. These patients may be prone to the development of secondary spontaneous pneumothoraces and persistent postoperative bronchopleural fistulae. Continued study of newly diagnosed cases may uncover shared characteristics or features helpful in generating an etiologic hypothesis. Only with better understanding of this disease can we hope in the future to be able to offer treatments other than supportive care and ultimately lung transplantation, which are the only therapeutic options available today.