Silent hypoxia: A harbinger of clinical deterioration in patients with COVID-19.

Patients infected with the SARS-CoV-2 virus can present with a wide variety of symptoms including being entirely asymptomatic. Despite having no or minimal symptoms, some patients may have markedly reduced pulse oximetry readings. This has been referred to as "silent" or "apathetic" hypoxia (Ottestad et al., 2020 [1]). We present a case of a 72-year-old male with COVID-19 syndrome who presented to the emergency department with minimal symptoms but low peripheral oxygen saturation readings. The patient deteriorated over the following days and eventually died as a result of overwhelming multi-organ system failure. This case highlights the utility of peripheral oxygen measurements in the evaluation of patients with SARS-CoV-2 infection. Self-monitoring of pulse oximetry by patients discharged from the emergency department is a potential way to identify patients needing to return for further evaluation.

Antimicrobial Therapy in Septic Shock Is Conservative During Resuscitation and Maintenance Phases.

Background: Maximal dosing of early antimicrobials with high loading and maintenance doses may optimize pharmacokinetic parameters to achieve and maintain therapeutic concentrations at the site of infection in septic shock. Little is known about the current practice of early antimicrobial dosing in septic shock. Objective: To characterize early antimicrobial dosing in patients in the resuscitation phase of septic shock. Methods: This retrospective cohort study included patients admitted to the medical intensive care unit (ICU) with septic shock. The primary outcome was the percentage of early antibiotic orders that were maximal or conservative during the resuscitation (0 to 48 hours) phase based on predefined dosing criteria. The secondary outcomes were the correlations of different dosing strategies on hospital length of stay (LOS), ICU LOS, and hospital mortality. Results: This study evaluated 161 patients and 692 antibiotic orders; 504 (72.8%) of the orders during the resuscitation phase were conservative. There were no differences in mortality (odds ratio = 0.66; 95% confidence interval = 0.35-1.25; P = .20), hospital LOS (median = 20 [interquartile range (IQR) = 10-34] vs 19 [IQR = 11-32] days; P = .93), or ICU LOS (median = 8 [IQR = 5-16] vs 9 [IQR = 5-15] days; P = .63) between maximal and conservative dosing groups, respectively, in the resuscitation phase. Limitations of this study included the use of institution-specific antimicrobial dosing guidelines and its retrospective nature. Conclusions: Early antibiotic dosing is conservative for a majority of patients in septic shock. Future studies are needed to evaluate the impact of dosing strategy on patient-centered outcomes in septic shock.

Novel Noncatalytic Substrate-Selective p38α-Specific MAPK Inhibitors with Endothelial-Stabilizing and Anti-Inflammatory Activity.

The p38 MAPK family is composed of four kinases of which p38α/MAPK14 is the major proinflammatory member. These kinases contribute to many inflammatory diseases, but the currently available p38 catalytic inhibitors (e.g., SB203580) are poorly effective and cause toxicity. We reasoned that the failure of catalytic p38 inhibitors may derive from their activity against noninflammatory p38 isoforms (e.g., p38ß/MAPK11) and loss of all p38α-dependent responses, including anti-inflammatory, counterregulatory responses via mitogen- and stress-activated kinase (MSK) 1/2 and Smad3. We used computer-aided drug design to target small molecules to a pocket near the p38α glutamate-aspartate (ED) substrate-docking site rather than the catalytic site, the sequence of which had only modest homology among p38 isoforms. We identified a lead compound, UM101, that was at least as effective as SB203580 in stabilizing endothelial barrier function, reducing inflammation, and mitigating LPS-induced mouse lung injury. Differential scanning fluorimetry and saturation transfer difference-nuclear magnetic resonance demonstrated specific binding of UM101 to the computer-aided drug design-targeted pockets in p38α but not p38ß. RNA sequencing analysis of TNF-α-stimulated gene expression revealed that UM101 inhibited only 28 of 61 SB203580-inhibited genes and 7 of 15 SB203580-inhibited transcription factors, but spared the anti-inflammatory MSK1/2 pathway. We provide proof of principle that small molecules that target the ED substrate-docking site may exert anti-inflammatory effects similar to the catalytic p38 inhibitors, but their isoform specificity and substrate selectivity may confer inherent advantages over catalytic inhibitors for treating inflammatory diseases.

Long term veno-venous extracorporeal life support without intravenous anticoagulation for diffuse alveolar hemorrhage.

INTRODUCTION: Diffuse alveolar damage is the histologic hallmark for the acute phase of acute respiratory distress syndrome and can occasionally present as diffuse alveolar hemorrhage. CASE REPORT: We report a patient with diffuse alveolar hemorrhage and acute respiratory distress syndrome requiring veno-venous extracorporeal life support for 210 days, who was successfully treated for a period of 130 consecutive days without intravenous anticoagulation. DISCUSSION: Although there are a few brief reports detailing long extracorporeal life support runs, the literature is largely devoid of data regarding long-term extracorporeal life support without full systemic anticoagulation. Regular inspection of the extracorporeal membrane oxygenation circuit is critical because externally visible thrombi may predict internal thrombus generation with the potential for systemic embolization or abrupt oxygenator failure. In our case, multiple circuit and oxygenators changes were required. CONCLUSION: We have demonstrated that a patient with a contraindication for systemic anticoagulation can safely have veno-venous extracorporeal life support for prolonged periods without catastrophic thrombotic complications.

The full-length interleukin-33 (FLIL33)-importin-5 interaction does not regulate nuclear localization of FLIL33 but controls its intracellular degradation.

Human mature IL-33 is a member of the IL-1 family and a potent regulator of immunity through its pro-T helper cell 2 activity. Its precursor form, full-length interleukin-33 (FLIL33), is an intranuclear protein in many cell types, including fibroblasts, and its intracellular levels can change in response to stimuli. However, the mechanisms controlling the nuclear localization of FLIL33 or its stability in cells are not understood. Here, we identified importin-5 (IPO5), a member of the importin family of nuclear transport proteins, as an intracellular binding partner of FLIL33. By overexpressing various FLIL33 protein segments and variants in primary human lung fibroblasts and HEK293T cells, we show that FLIL33, but not mature interleukin-33, physically interacts with IPO5 and that this interaction localizes to a cluster of charged amino acids (positions 46-56) but not to an adjacent segment (positions 61-67) in the FLIL33 N-terminal region. siRNA-mediated IPO5 knockdown in cell culture did not affect nuclear localization of FLIL33. However, the IPO5 knockdown significantly decreased the intracellular levels of overexpressed FLIL33, reversed by treatment with the 20S proteasome inhibitor bortezomib. Furthermore, FLIL33 variants deficient in IPO5 binding remained intranuclear and exhibited decreased levels, which were also restored by the bortezomib treatment. These results indicate that the interaction between FLIL33 and IPO5 is localized to a specific segment of the FLIL33 protein, is not required for nuclear localization of FLIL33, and protects FLIL33 from proteasome-dependent degradation.

Numeracy and Interpretation of Prognostic Estimates in Intracerebral Hemorrhage Among Surrogate Decision Makers in the Neurologic ICU.

OBJECTIVE: Clinicians caring for patients with intracerebral hemorrhage must often discuss prognosis and goals of care with their patients' surrogate decision makers, and may make numeric estimates of likelihood of survival and functional independence, informed by validated prediction models. Surrogates' prognostic estimates are often discordant with physicians', suggesting that physicians' numeric statements may not be accurately interpreted. We sought to assess the relationship between numeracy and interpretation of prognostic estimates in intracerebral hemorrhage among surrogate decision makers. We also assessed surrogates' application of prognostic estimates to decisions regarding goals of care. DESIGN: Single-center, survey-based, cross-sectional study. SETTING: Twenty-two-bed neurologic ICU at an urban, academic hospital. SUBJECTS: Surrogate decision makers for patients admitted to the neurologic ICU. INTERVENTIONS: Participants completed a survey containing five clinical vignettes describing patients with nontraumatic intracerebral hemorrhage. For each patient, numerical estimates of survival and functional independence were explicitly provided, based on the validated outcome risk stratification scale (intracerebral hemorrhage score) and the Prediction of Functional Outcome in Patients with Primary Intracerebral Hemorrhage score. MEASUREMENTS AND MAIN RESULTS: Participants were asked to make their own prognostic estimates, as well as to describe their preferred goals of care for each hypothetical patient. Respondent demographics were collected, and numeracy was assessed using a modified Lipkus 11-item scale. Poor numeracy was common (42 of 96 total subjects) in this relatively highly educated population. Most prognostic estimates (55%) made by surrogates were discordant with the provided estimates. High numeracy correlated with better concordance (odds ratio, 23.9 [5.57-97.64]; p < 0.001), independent of several factors, including level of education and religion. Numeracy also affected goals-of-care decisions made by surrogates. CONCLUSIONS: Poor numeracy is common among surrogate decision makers in an intensive care setting and poses a barrier to communication between surrogates and clinicians regarding prognosis and goals of care.

Sirtuin 7 is decreased in pulmonary fibrosis and regulates the fibrotic phenotype of lung fibroblasts.

Pulmonary fibrosis is a severe condition with no cure and limited therapeutic options. A better understanding of its pathophysiology is needed. Recent studies have suggested that pulmonary fibrosis may be driven by accelerated aging-related mechanisms. Sirtuins (SIRTs), particularly SIRT1, SIRT3, and SIRT6, are well-known mediators of aging; however, limited data exist on the contribution of sirtuins to lung fibrosis. We assessed the mRNA and protein levels of all seven known sirtuins in primary lung fibroblasts from patients with idiopathic pulmonary fibrosis (IPF) and systemic sclerosis-associated interstitial lung disease (SSc-ILD) in comparison with lung fibroblasts from healthy controls. These unbiased tests revealed a tendency for all sirtuins to be expressed at lower levels in fibroblasts from patients compared with controls, but the greatest decrease was observed with SIRT7. Similarly, SIRT7 was decreased in lung tissues of bleomycin-challenged mice. Inhibition of SIRT7 with siRNA in cultured lung fibroblasts resulted in an increase in collagen and α-smooth muscle actin (α-SMA). Reciprocally, overexpression of SIRT7 resulted in lower basal and TGF-ß-induced levels of COL1A1, COL1A2, COL3A1, and α-SMA mRNAs, as well as collagen and α-SMA proteins. Induced changes in SIRT7 had no effect on endogenous TGF-ß mRNA levels or latent TGF-ß activation, but overexpression of SIRT7 reduced the levels of Smad3 mRNA and protein. In conclusion, the decline in SIRT7 in lung fibroblasts has a profibrotic effect, which is mediated by changes in Smad3 levels.

Pilot Feasibility Study of Therapeutic Hypothermia for Moderate to Severe Acute Respiratory Distress Syndrome.

OBJECTIVES: Prior studies suggest hypothermia may be beneficial in acute respiratory distress syndrome, but cooling causes shivering and increases metabolism. The objective of this study was to assess the feasibility of performing a randomized clinical trial of hypothermia in patients with acute respiratory distress syndrome receiving treatment with neuromuscular blockade because they cannot shiver. DESIGN: Retrospective study and pilot, prospective, open-label, feasibility study. SETTING: Medical ICU. PATIENTS: Retrospective review of 58 patients with acute respiratory distress syndrome based on Berlin criteria and PaO2/FIO2 less than 150 who received neuromuscular blockade. Prospective hypothermia treatment in eight acute respiratory distress syndrome patients with PaO2/FIO2 less than 150 receiving neuromuscular blockade. INTERVENTION: Cooling to 34-36°C for 48 hours. MEASUREMENTS AND MAIN RESULTS: Core temperature, hemodynamics, serum glucose and electrolytes, and P/F were sequentially measured, and medians (interquartile ranges) presented, 28-day ventilator-free days, and hospital mortality were calculated in historical controls and eight cooled patients. Average patient core temperature was 36.7°C (36-37.3°C), and fever occurred during neuromuscular blockade in 30 of 58 retrospective patients. In the prospectively cooled patients, core temperature reached target range less than or equal to 4 hours of initiating cooling, remained less than 36°C for 92% of the 48 hours cooling period without adverse events, and was lower than the controls (34.35°C [34-34.8°C]; p < 0.0001). Compared with historical controls, the cooled patients tended to have lower hospital mortality (75% vs 53.4%; p = 0.26), more ventilator-free days (9 [0-21.5] vs 0 [0-12]; p = 0.16), and higher day 3 P/F (255 [160-270] vs 171 [120-214]; p = 0.024). CONCLUSIONS: Neuromuscular blockade alone does not cause hypothermia but allowed acute respiratory distress syndrome patients to be effectively cooled. Results support conducting a randomized clinical trial of hypothermia in acute respiratory distress syndrome and the feasibility of studying acute respiratory distress syndrome patients receiving neuromuscular blockade.

Ten-year Single Center Experience of Pulmonary Carcinoid Tumors and Diagnostic Yield of Bronchoscopic Biopsy.

PURPOSE: Bronchoscopic biopsy of pulmonary carcinoid tumors has been controversial, and no study to date is dedicated to investigate diagnostic yield or safety. We reviewed our single center experience with pulmonary carcinoid tumors over a 10-year time period and assessed the diagnostic yield and safety of bronchoscopic biopsy of these tumors. METHODS: A retrospective analysis was conducted of all bronchopulmonary carcinoid tumors from January 2003 through January 2014 for patients treated at or referred to our tertiary care facility, including patient and tumor characteristics, diagnostic yield, and complications of bronchoscopy. RESULTS: Forty-nine patients with bronchopulmonary carcinoid tumors were identified. 75.5 % of our patients were female, and the median age was 60.7 years. 85.7 % patients were white, and 53.1 % were smokers. 83.7 % had typical carcinoid tumors or tumorlets, and 85.7 % had centrally located tumors. The median tumor size was 2.0 cm. Thirty patients underwent bronchoscopy for diagnostic evaluation. 76.7 % were diagnosed via bronchoscopic biopsy. Bronchoscopic yield was calculated at 65.7 % yield, and two complications of moderate to severe bleeding occurred with no emergent thoracotomies, transfusions, or deaths. No other complications occurred from bronchoscopy. CONCLUSION: The diagnosis of pulmonary carcinoid tumors via bronchoscopic biopsy is safe and effective, and bronchoscopy is recommended as the initial diagnostic modality for these tumors.

Prophylactic epinephrine attenuates severe bleeding in lung transplantation patients undergoing transbronchial lung biopsy: Results of the PROPHET randomized trial.

BACKGROUND: Severe hemorrhage is an uncommon yet potentially life-threatening complication of transbronchial lung biopsy. Lung transplantation recipients undergo multiple bronchoscopies with biopsy and are considered to be at an increased risk for bleeding from transbronchial biopsy, independent of traditional risk factors. We aimed to evaluate the efficacy and safety of endobronchial administration of prophylactic topical epinephrine in attenuating transbronchial biopsy-related hemorrhage in lung transplant recipients. METHODS: The Prophylactic Epinephrine for the Prevention of Transbronchial Lung Biopsy-related Bleeding in Lung Transplant Recipients study was a 2-center, randomized, double blind, placebo-controlled clinical trial. Participants undergoing transbronchial lung biopsy were randomized to receive 1:10,000-diluted topical epinephrine vs saline placebo administered prophylactically into the target segmental airway. Bleeding was graded based on a clinical severity scale. The primary efficacy outcome was incidence of severe or very severe hemorrhage. The primary safety outcome was a composite of 3-hours all-cause mortality and an acute cardiovascular event. RESULTS: A total of 66 lung transplantation recipients underwent 100 bronchoscopies during the study period. The primary outcome of severe or very severe hemorrhage occurred in 4 cases (8%) in the prophylactic epinephrine group and in 13 cases (24%) in the control group (p = 0.04). The composite primary safety outcome did not occur in any of the study groups. CONCLUSIONS: In lung transplantation recipients undergoing transbronchial lung biopsy, prophylactic administration of 1:10,000-diluted topical epinephrine into the target segmental airway before biopsy attenuates the incidence of significant endobronchial hemorrhage without conveying a significant cardiovascular risk. (ClinicalTrials.gov identifier: NCT03126968).

Hyperthermia promotes and prevents respiratory epithelial apoptosis through distinct mechanisms.

Hyperthermia has been shown to confer cytoprotection and to augment apoptosis in different experimental models. We analyzed the mechanisms of both effects in the same mouse lung epithelial (MLE) cell line (MLE15). Exposing MLE15 cells to heat shock (HS; 42°C, 2 h) or febrile-range hyperthermia (39.5°C) concurrent with activation of the death receptors, TNF receptor 1 or Fas, greatly accelerated apoptosis, which was detectable within 30 minutes and was associated with accelerated activation of caspase-2, -8, and -10, and the proapoptotic protein, Bcl2-interacting domain (Bid). Caspase-3 activation and cell death were partially blocked by inhibitors targeting all three initiator caspases. Cells expressing the IκB superrepessor were more susceptible than wild-type cells to TNF-α-induced apoptosis at 37°C, but HS and febrile-range hyperthermia still increased apoptosis in these cells. Delaying HS for 3 hours after TNF-α treatment abrogated its proapoptotic effect in wild-type cells, but not in IκB superrepressor-expression cells, suggesting that TNF-α stimulates delayed resistance to the proapoptotic effects of HS through an NF-κB-dependent mechanism. Pre-exposure to 2-hour HS beginning 6 to16 hours before TNF-α treatment or Fas activation reduced apoptosis in MLE15 cells. The antiapoptotic effects of HS pretreatment were reduced in TNF-α-treated embryonic fibroblasts from heat shock factor-1 (HSF1)-deficient mice, but the proapoptotic effects of concurrent HS were preserved. Thus, depending on the temperature and timing relative to death receptor activation, hyperthermia can exert pro- and antiapoptotic effects through distinct mechanisms.

Febrile-range hyperthermia modifies endothelial and neutrophilic functions to promote extravasation.

Acute respiratory distress syndrome (ARDS) is a neutrophil (polymorphonuclear leukocyte; PMN)-driven lung injury that is associated with fever and heat-stroke, and involves approximately 40% mortality. In murine models of acute lung injury (ALI), febrile-range hyperthermia (FRH) enhanced PMN accumulation, vascular permeability, and epithelial injury, in part by augmenting pulmonary cysteine-x-cysteine (CXC) chemokine expression. To determine whether FRH increases chemokine responsiveness within the lung, we used in vivo and in vitro models that bypass the endogenous generation of chemokines. We measured PMN transalveolar migration (TAM) in mice after intratracheal instillations of the human CXC chemokine IL-8 in vivo, and of IL-8-directed PMN transendothelial migration (TEM) through human lung microvascular endothelial cell (HMVEC-L) monolayers in vitro. Pre-exposure to FRH increased in vivo IL-8-directed PMN TAM by 23.5-fold and in vitro TEM by 7-fold. Adoptive PMN transfer demonstrated that enhanced PMN TAM required both PMN donors and recipients to be exposed to FRH, suggesting interdependent effects on PMNs and endothelium. FRH exposure caused the activation of extracellular signal-regulated kinase (ERK) and p38 mitogen-activated protein kinase in lung homogenates and circulating PMNs, with an associated increase in HSP27 phosphorylation and stress-fiber formation. The inhibition of these signaling pathways with U0126 and SB203580 blocked the effects of FRH on PMN extravasation in vivo and in vitro. Collectively, these results (1) demonstrate that FRH augments chemokine-directed PMN extravasation through direct effects on endothelium and PMNs, (2) identify ERK and p38 signaling pathways in the effect, and (3) underscore the complex effects of physiologic temperature change on innate immune function and its potential consequences for lung injury.

Tolerance for chronic heat exposure is greater in female than male mice.

PURPOSE: Chronic heat exposure in mice has cellular and physiological effects that improve thermal tolerance [1], but also modifies innate immune responses with potential adverse consequences [2]. While male and female mice are known to respond differently to acute exposure to severe hyperthermia, sex-based differences in responses to chronic moderate heat exposure have not been reported. The major objective of this study was to compare the tolerance of male and female mice for chronic heat exposure. MATERIALS AND METHODS: We used a mouse model of 5-day moderate heat exposure (ambient temperature ∼37°C) to compare the physiological and cellular heat shock response in male and female mice. Core temperature, heart rate, and activity were monitored telemetrically and heat shock protein levels were measured in brain and lung by western blotting. RESULTS: Adult CD-1 female mice maintained a 1.2°C lower core temperature (38.31 ± 0.64 versus 39.51 ± 0.72°C; p = 0.002), experienced less weight loss (1.54 ± 0.45 versus 4.54 ± 1.97 g; p = 0.0007), and had improved survival (16/16 survived versus 13/21, p < 0.006) than male mice of the same age. After 5 days of moderate heat exposure Hsp72 levels in brain and lung increased 2.1-fold (p = 0.007) and 5-fold (p = 0.048) in male mice compared with 1.3- (p = 0.054) and 1.5-fold (p = 0.134) in female mice. CONCLUSIONS: This study reveals previously unknown and potentially important differences between male and female mice in physiological and cellular responses to chronic heat exposure, which had consequences for survival. Future studies may identify biomarkers of differential heat tolerance and treatments to improve heat tolerance in humans.

Febrile-range hyperthermia augments reversible TNF-α-induced hyperpermeability in human microvascular lung endothelial cells.

Fever commonly occurs in acute lung injury (ALI) and ALI occurs in 25% of victims of heat stroke. We have shown in mouse models of ALI that exposure to febrile-range hyperthermia (FRH), 39.5°C, increases non-cardiogenic pulmonary oedema. In this study we studied the direct effects of FRH on endothelial barrier integrity using human microvascular endothelial cells (HMVEC-Ls). We analysed the effect of exposure to culture temperatures between 38.5° and 41°C with and without tumour necrosis factor-α (TNF-α) up to 250 U/mL for 6-24 h. We found that exposure to 2.5-250 U/mL TNF-α increased HMVEC-L permeability by 4.1-15.8-fold at 37°C. Exposure to 39.5°C alone caused variable, modest, lot-specific increases in HMVEC-L permeability, however raising culture temperature to 39.5°C in the presence of TNF-α increased permeability an additional 1.6-4.5-fold compared with cells incubated with the same TNF-α concentration at 37°C. Permeability occurred without measurable cytotoxicity and was reversible upon removal of TNF-α and reduction in temperature to 37°C. Exposure to 39.5°C or TNF-α each stimulated rapid activation of p38 and ERK but the effects were not additive. Treatment with inhibitors of ERK (U0126) or p38 (SB203580) each reduced TNF-α-induced permeability in 39.5°C monolayers to levels in 37°C cells, but did not alter TNF-α-induced permeability in the 37°C cells. These results demonstrate that FRH directly increases paracellular pathway opening through a process that requires ERK and p38 MAPKs. A better understanding of this mechanism may provide new understanding about how fever may contribute to the pathogenesis of ALI and provide new therapeutic targets to improve clinical outcomes.

Demystifying idiopathic interstitial pneumonia: time for more etiology-focused nomenclature in interstitial lung disease.

INTRODUCTION: A major focus of interstitial lung disease (ILD) has centered on disorders termed idiopathic interstitial pneumonias (IIPs) which include, among others, idiopathic pulmonary fibrosis, idiopathic nonspecific interstitial pneumonia, cryptogenic organizing pneumonia, and respiratory bronchiolitis-interstitial lung disease. AREAS COVERED: We review the radiologic and histologic patterns for the nine disorders classified by multidisciplinary approach as IIP, and describe the remarkable amount of published epidemiologic, translational, and molecular studies demonstrating their associations with numerous yet definitive environmental exposures, occupational exposures, pulmonary diseases, systemic diseases, medication toxicities, and genetic variants. EXPERT OPINION: In the 21st century, these disorders termed IIPs are rarely idiopathic, but rather are well-described radiologic and histologic patterns of lung injury that are associated with a wide array of diverse etiologies. Accordingly, the idiopathic nomenclature is misleading and confusing, and may also promote a lack of inquisitiveness, suggesting the end rather than the beginning of a thorough diagnostic process to identify ILD etiology and initiate patient-centered management. A shift toward more etiology-focused nomenclature will be beneficial to all, including patients hoping for better life quality and disease outcome, general medicine and pulmonary physicians furthering their ILD knowledge, and expert ILD clinicians and researchers who are advancing the ILD field.

Distinct, gene-specific effect of heat shock on heat shock factor-1 recruitment and gene expression of CXC chemokine genes.

The heat shock (HS) response, a phylogenetically conserved ubiquitous response to stress, is generally characterized by the induced expression of heat shock protein (HSP) genes. Our earlier studies showed that the stress-activated transcription factor, heat shock factor-1 (HSF1), activated at febrile range or HS temperatures also modified expression of non-HSP genes including cytokine and chemokine genes. We also showed by in silico analysis that 28 among 29 human and mouse CXC chemokine genes had multiple putative heat shock response elements (HSEs) present in their gene promoters. To further determine whether these potential HSEs were functional and bound HSF1, we analyzed the recruitment of HSF1 to promoters of 5 human CXC chemokine genes (CXCL-1, 2, 3, 5 and 8) by chromatin immunoprecipitation (ChIP) assay and analyzed the effect of HS exposure on tumor necrosis factor-α (TNFα)-induced expression of these genes in human lung epithelial-like A549 cells. HSF1 ChIP analysis showed that HSF1 was recruited to all but one of these CXC chemokine genes (CXCL-3) and HS caused a significant increase in recruitment of HSF1 to one or multiple HSEs present in the promoters of CXCL-1, 2, 5 and 8 genes. However, the effect of HS exposure on expression of these genes showed a variable gene-specific effect. For example, CXCL8 expression was markedly enhanced (p<0.05) whereas CXCL5 expression was significantly repressed (p<0.05) in cells exposed to HS coincident with TNFα stimulation. In contrast, expression of CXCL1 and CXCL2, despite HSF1 recruitment to their promoters, was not affected by HS exposure. Our results indicate that some, if not all, putative HSEs present in the CXC chemokine gene promoters are functional and recruit HSF1 in vivo but the effects on gene expression are variable and gene specific. We speculate, the physical proximity and interactions of other transcription factors and co-regulators with HSF1 could be critical to determining the effects of HS on the expression of these genes.

Impact of Risk and Volume on Procedural Traning of Pulmonary and Critical Care Fellows.

Background: Invasive procedures are a core aspect of pulmonary and critical care practice. Procedures performed in the intensive care unit can be divided into high-risk, low-volume (HRLV) procedures and low-risk, high-volume (LRHV) procedures. HRLV procedures include cricothyroidotomy, pericardiocentesis, Blakemore tube placement, and bronchial blocker placement. LRHV procedures include arterial line placement, central venous catheter placement, thoracentesis, and flexible bronchoscopy. Despite the frequency and importance of procedures in critical care medicine, little is known about the similarities and differences in procedural training between different Pulmonary and Critical Care Medicine (PCCM) and Critical Care Medicine (CCM) training programs. Furthermore, differences in procedural training practices for HRLV and LRHV procedures have not previously been described.Objective: To assess procedural training practices in PCCM and CCM fellowship programs in the United States, and compare differences in training between HRLV and LRHV procedures.Methods: A novel survey instrument was developed and disseminated to PCCM and CCM program directors and associate program directors at PCCM and CCM fellowship programs in the United States to assess procedural teaching practices for HRLV and LRHV procedures.Results: The survey was sent to 221 fellowship programs, 168 PCCM and 34 CCM, with 70 unique respondents (31.7% response rate). Of the procedural educational strategies assessed, each strategy was used significantly more frequently for LRHV versus HRLV procedures. The majority of respondents (51.1%) report having no dedicated training for HRLV procedures versus 6.9% reporting no dedicated training for any LRHV procedure (P < 0.001). For HRLV procedures, 76.9% of respondents indicated that there was no set number of procedures required to determine competency, versus 25.3% for LRHV procedures (P < 0.001). For LRHV procedures, fellows were allowed to perform procedures independently without supervision 21.7% of the time versus 3.9% for HRLV procedures (P = 0.004). Program directors' confidence in their ability to determine fellows' competence in performing procedures was significantly lower for HRLV versus LRHV versus HRLV procedures (P < 0.001).Conclusion: Significant differences exist in procedural training education for PCCM and CCM fellows for LRHV versus HRLV procedures, and awareness of this discrepancy presents an opportunity to address this educational gap in PCCM and CCM fellowship training.

Beginning a new medical school curriculum amidst a global pandemic.

The University of Maryland School of Medicine embarked on our first major curriculum revision since 1994 with a plan to implement this Renaissance Curriculum in August 2020. However, in the Spring of 2020, the coronavirus disease (COVID-19) pandemic disrupted clinical care and medical education on a large scale requiring expeditious modifications to our Renaissance Curriculum as well as our traditional Legacy Curriculum in order to meet our goal of educating the next-generation of physicians. The rippling effects of the COVID-19 pandemic led to major changes in the delivery of the pre-clerkship curriculum, the way we assessed and evaluated students, entry into the clinical environment, length of clinical rotations, and orientation for our new medical students. We relied on "new" technology, digital medical resources, and the creativity of our educators to ensure that our learners continue to acquire the skills necessary to become skilled clinicians in these unprecedented times.

Seven-Year Follow-Up of an Online Critical Care Curriculum.

Background: In July of 2013, the University of Maryland launched MarylandCCProject.com. This free-access educational website delivers asynchronous high-quality multidisciplinary critical care education targeted at critical care trainees. The lectures, presented in real time on-site, are recorded and available on the website or as a podcast on iTunes or Android. Thus, the curriculum can be easily accessed around the world.Objective: We sought to identify the impact this website has on current and former University of Maryland critical care trainees.Methods: A 32-question survey was generated using a standard survey generation tool. The survey was e-mailed in the fall of 2019 to the University of Maryland Multi-Departmental Critical Care current and graduated trainees from the prior 7 years. Survey data were collected through December 2019. The questions focused on user demographics, overall experience with the website, scope of website use, and clinical application of the content. Anonymous responses were electronically gathered.Results: A total of 186 current trainees and graduates were surveyed, with a 39% (n = 72) response rate. Of responders, 76% (55) use the website for ongoing medical education. The majority use the website at least monthly. Most users (63%, n = 35) access the lectures directly through the website. All 55 current users agree that the website has improved their medical knowledge and is a useful education resource. Platform use has increased and includes users from around the world.Conclusion: Based on our current data, the MarylandCCProject remains a valuable and highly used educational resource, impacting patient care both during and after critical care fellowship training.