Bayesian methods: a potential path forward for sepsis trials.

BACKGROUND: Given the success of recent platform trials for COVID-19, Bayesian statistical methods have become an option for complex, heterogenous syndromes like sepsis. However, study design will require careful consideration of how statistical power varies using Bayesian methods across different choices for how historical data are incorporated through a prior distribution and how the analysis is ultimately conducted. Our objective with the current analysis is to assess how different uses of historical data through a prior distribution, and type of analysis influence results of a proposed trial that will be analyzed using Bayesian statistical methods. METHODS: We conducted a simulation study incorporating historical data from a published multicenter, randomized clinical trial in the US and Canada of polymyxin B hemadsorption for treatment of endotoxemic septic shock. Historical data come from a 179-patient subgroup of the previous trial of adult critically ill patients with septic shock, multiple organ failure and an endotoxin activity of 0.60-0.89. The trial intervention consisted of two polymyxin B hemoadsorption treatments (2 h each) completed within 24 h of enrollment. RESULTS: In our simulations for a new trial of 150 patients, a range of hypothetical results were observed. Across a range of baseline risks and treatment effects and four ways of including historical data, we demonstrate an increase in power with the use of clinically defensible incorporation of historical data. In one possible trial result, for example, with an observed reduction in risk of mortality from 44 to 37%, the probability of benefit is 96% with a fixed weight of 75% on prior data and 90% with a commensurate (adaptive-weighting) prior; the same data give an 80% probability of benefit if historical data are ignored. CONCLUSIONS: Using Bayesian methods and a biologically justifiable use of historical data in a prior distribution yields a study design with higher power than a conventional design that ignores relevant historical data. Bayesian methods may be a viable option for trials in critical care medicine where beneficial treatments have been elusive.

Expression of TLE1 in a Carcinoid Tumor of the Lung With Spindle Cell Morphology-A Potential Diagnostic Pitfall.

Tumors of the lung with a spindle cell morphology require consideration of many entities in the differential diagnosis, including metastases. Ancillary immunohistochemical stains but also molecular studies are typically required to arrive at the proper diagnosis. We present a case of a 71-year-old woman with multiple lung nodules, mediastinal lymphadenopathy, and a history of uterine cancer who underwent endobronchial ultrasound-guided fine needle aspiration and biopsy of the lung and mediastinal lymph nodes. A sampling of the lung lesion showed a cytologically bland neoplasm with spindle cell morphology, lacking necrosis or brisk mitotic activity. In conjunction with the cytomorphology, strong and diffuse Transducin-like enhancer of split 1 (TLE1) reactivity in the tumor cells initially raised the diagnosis of synovial sarcoma; however, subsequent results of additional testing showed strong and diffuse expression with AE1/AE3, CK 8/18, TTF-1, synaptophysin and chromogranin and focal or negative staining with a large number of other antibodies. This warranted a diagnosis of a carcinoid tumor. This is the first report of TLE1 staining in a carcinoid tumor of the lung. Therefore, when evaluating tumors of the lung with spindle cell morphology in which the differential diagnosis may include both carcinoid tumor and synovial sarcoma, TLE1 expression should be interpreted with caution and in conjunction with an expanded immunohistochemical staining panel.

Tocilizumab Is Associated with Increased Risk of Fungal Infections among Critically Ill Patients with COVID-19 and Acute Renal Failure: An Observational Cohort Study.

RESEARCH QUESTION: Does treatment with tocilizumab increase the risk of a fungal infection in critically ill patients with coronavirus-19? BACKGROUND: Numerous therapies have been evaluated as possible treatments for coronavirus-2019 caused by severe acute respiratory syndrome coronavirus-2. Tocilizumab is a humanized monoclonal antibody directed against the interleukin-6 receptor that has found a role as a therapy for patients with severe coronavirus-19 pneumonia. The immunomodulatory effects of tocilizumab may have the unintended consequence of predisposing recipients to secondary infections. We sought to assess the risk of invasive fungal disease and the therapeutic impact of tocilizumab on the hospital length of stay, duration of mechanical ventilation, and intensive-care-unit length of stay in critically ill patients with severe coronavirus-19 pneumonia. METHODS: Records of critically ill patients with coronavirus-2019 admitted from March to September 2020 at our institution were reviewed. The risk for fungal infections, intensive-care-unit length of stay, hospital length of stay, and duration of mechanical ventilation in those that received tocilizumab in addition to standard coronavirus-2019 treatments was assessed. RESULTS: Fifty-six critically ill patients treated with dexamethasone and remdesivir for coronavirus-2019 were included, of which 16 patients also received tocilizumab. The majority of the cohort was African American, Asian, or of other ethnic minorities (53.6%). Invasive fungal infections occurred in 10.7% of all patients, and infection rates were significantly higher in the tocilizumab group than in the control group (31.2% vs. 2.5%, risk difference [RD] = 28.8%, p < 0.01). The increased risk in the tocilizumab group was strongly associated with renal replacement therapy. There was a dose-response relationship between the risk of fungal infection and number of tocilizumab doses received, with 2.5% of infections occurring with zero doses, 20% with a single dose (RD = 17.5%), and 50% with two doses (RD = 47.5%) (trend test p < 0.001). In addition, ICU LOS (23.4 days vs. 9.0 days, p < 0.01), the duration of mechanical ventilation (18.9 vs. 3.5 days, p = 0.01), and hospital length of stay (LOS) (29.1 vs. 15.5, p < 0.01) were increased in patients that received tocilizumab. CONCLUSIONS: Repurposed immunomodulator therapies, such as tocilizumab, are now recommended treatments for severe coronavirus-2019 pneumonia, but safety concerns remain. In this early pandemic cohort, the addition of tocilizumab to dexamethasone was associated with an increased risk of fungal infection in those that were critically ill and received renal replacement therapy. Tocilizumab use was also associated with increased ICU and hospital LOSs and duration of mechanical ventilation.

One- versus two-specimen Xpert strategy to discontinue airborne isolation in suspected pulmonary tuberculosis: systematic review and meta-analysis.

BACKGROUND: Evaluation of a patient with suspected pulmonary tuberculosis (TB) involves initiation of airborne infection isolation (AII). However, guidelines detailing discontinuation of AII utilizing the Xpert MTB/RIF provide little clarity between use of one-specimen (1-Xpert') versus two-specimens (2-Xpert'). OBJECTIVES: To evaluate the diagnostic accuracy of one-Xpert versus two-Xpert strategy in guiding discontinuation of AII. METHODS: Data sources: PubMed, Embase, and EBSCO databases. STUDY ELIGIBILITY CRITERIA: Studies providing diagnostic accuracy data for one- versus two-Xperts in discontinuation of AII. PARTICIPANTS: Adult patients with suspected TB. TESTS: Xpert MTB/RIF on one- versus two-sputum specimens. Reference standard: Solid and liquid culture media. Assessment of risk of bias: Quality Assessment of Diagnostic Accuracy Studies tool was used. Methods of data synthesis: Meta-analysis was performed to calculate the pooled sensitivities and specificities using Stata 17.2. RESULTS: Four studies were included involving 1776 patients. A total of 68% were males, 36% were HIV positive, and 80% participants belonged to the United States. In patients with suspected pulmonary TB, 7% (95% CI, 6-9%) participants were found to have culture-positive MTB. For one-Xpert strategy, the pooled sensitivity was 86% (95% CI, 75-92%; I2, 1.05%) and specificity was 100% (95% CI, 99-100%; I2, 36%). Two-Xpert strategy had a pooled sensitivity of 92% (95% CI, 84-96%; I2, 16%) and a specificity of 100% (95% CI, 98-100%; I2, 27%). There was statistically significant difference between sensitivities of one-Xpert and two-Xpert strategies (p 0.05) with no statistically significant difference in their specificities. DISCUSSION: The results of this review must be interpreted in the context of a predominantly low-TB prevalence setting. Two-Xpert strategy has an incrementally higher sensitivity when compared with one-Xpert strategy with similar specificities between the two. Obtaining a second Xpert is crucial for individuals with a continued high suspicion for TB or those at a high risk of morbidity/mortality from TB.

The yield and impact of pulmonologist-performed EUS-B-FNA of subdiaphragmatic lesions-an institutional experience.

INTRODUCTION: Pulmonologists can biopsy structures below the diaphragm using the convex curvilinear ultrasound bronchoscope via the esophagus (EUS-B). The literature with respect to the value of EUS-B, rapid on-site evaluation, and final diagnostic yield for structures below the diaphragm is limited. We review our institutional experience. MATERIALS AND METHODS: Our database was queried retrospectively for EUS-B fine needle aspirations (FNAs) from 2013 to 2021. All procedures involving EUS-B-FNA of subdiaphragmatic structures were selected for analysis. The following data elements were collected for each patient: age, gender, clinical indication, sample site, on-site adequacy (OSA), preliminary and final diagnoses, and sufficiency of cell block for ancillary studies. RESULTS: A total of 75 subdiaphragmatic sites were biopsied in 74 patients. Of which, 87% of samples subjected to rapid on-site evaluation were deemed to contain adequate material (OSA+). There were no false-positive OSAs. Six cases remained nondiagnostic at the final diagnosis. The final diagnostic yield (with cell block) was 92% (69/75 cases). Cell block was sufficient for immunohistochemistry or special stains in all applicable cases (n = 36). Molecular testing was requested for 11 cases and successful in 10 (91%). Sampling of subdiaphragmatic sites changed the stage in 67% (38/57) of lung cancer patients. CONCLUSIONS: Pulmonologists can perform EUS-B-FNA of subdiaphragmatic sites with high OSA and final diagnostic yield when assisted by cytopathologists. Strong correlations exist between OSA, cell block adequacy, and subsequent capacity to perform ancillary testing. EUS-B below the diaphragm can make an important contribution to the diagnosis of lung cancer, nonpulmonary malignancies, and other diseases.

A 72-Year-Old Woman With Dyspnea, Multiple Pulmonary Nodules, and Mediastinal Lymphadenopathy.

CASE PRESENTATION: A 72-year-old woman presented to our institution with gradually worsening shortness of breath and bilateral lower extremity edema of 3 weeks' duration. She had associated complaints of cough and intermittent hemoptysis. Her medical history was significant for hypertension and hypothyroidism. She was a former cigarette smoker with a 35 pack-year smoking history. She had no recent travel history and had a pet dog at home. Six months before the current hospitalization, evaluation for cough had revealed mediastinal lymphadenopathy at an outside institution. She underwent evaluation with an endobrachial ultrasound procedure at an outside facility 8 weeks before the current admission. The procedure demonstrated both acute and chronic inflammation, with one specimen showing few atypical cells on cytopathology and no growth on bacterial, fungal, and mycobacterial cultures. She was treated empirically with oral steroids for presumed sarcoidosis. However, this did not result in clinical benefit, and because of progressive symptoms, she presented to our institution.

A Multicenter Study Assessing Interventional Pulmonary Fellow Competency in Electromagnetic Navigation Bronchoscopy.

Background: Current medical society guidelines recommend a procedural number for obtaining electromagnetic navigational bronchoscopy (ENB) competency and for institutional volume for training. Objective: To assess learning curves and estimate the number of ENB procedures for interventional pulmonology (IP) fellows to reach competency. Methods: We conducted a prospective multicenter study of IP fellows in the United States learning ENB. A tool previously validated in a similar population was used to assess IP fellows by their local faculty and two blinded independent reviewers using virtual recording of the procedure. Competency was determined by performing three consecutive procedures with a competency score on the assessment tool. Procedural time, faculty global rating scale, and periprocedural complications were also recorded. Results: A total of 184 ENB procedures were available for review with assessment of 26 IP fellows at 16 medical centers. There was a high correlation between the two blinded independent observers (rho = 0.8776). There was substantial agreement for determination of procedural competency between the faculty assessment and blinded reviewers (kappa = 0.7074; confidence interval, 0.5667-0.8482). The number of procedures for reaching competency for ENB bronchoscopy was determined (median, 4; mean, 5; standard deviation, 3.83). There was a wide variation in the number of procedures to reach competency, ranging from 2 to 15 procedures. There were six periprocedural complications reported, four (one pneumomediastinum, three pneumothorax) of which occurred before reaching competence and two pneumothoraces after achieving competence. Conclusion: There is a wide variation in acquiring competency for ENB among IP fellows. Virtual competency assessment has a potential role but needs further studies.

Personal Protective Equipment Efficiency in Healthcare Emergencies: A Single-Center Experience.

Coronavirus disease 2019 (COVID-19) has dramatically shifted the healthcare landscape since 2020. Measures against it includes universal masking in the healthcare areas and the community, viral testing before aerosolizing procedures, and ambulatory elective surgical procedures. Some hospitals have had mandated viral testing policies even before admission to the hospital. Healthcare workers (HCWs) have been cautiously modifying all pertinent practices to avoid the transmission of the virus. Personal protective equipment (PPE), including gowns, gloves, eye protection, and properly fitted N95 respirator or powered air-purifying respirators (PAPR) while treating the suspected and confirmed COVID-19 patients were made mandatory. Similarly, we changed our aerosol-generating procedures (AGPs) protocols based on available limited data. We amended our approach to in-hospital cardiopulmonary resuscitation (basic life support (BLS)/advanced cardiovascular life support (ACLS)), given the risk of aerosol generation and transmission during the process. This article shares our experience and outcomes of PPE use in healthcare emergencies at our tertiary care academic center.

A 34-Year-Old Man With Lightheadedness and Dyspnea.

CASE PRESENTATION: A 34-year-old man presented to our institution with lightheadedness and dyspnea on exertion. His medical history included chronic pancreatitis, juvenile rheumatoid arthritis (JRA), gastroesophageal reflux disease, hypertension, lumbar degenerative disc disease, seizure disorder, anterior uveitis, and multiple vertebral fractures. In addition, he was a cigarette smoker with a 10-pack-year smoking history.

The Association of "GOOP" on Gross Examination of Fine Needle Aspiration Samples and On-Site Adequacy.

BACKGROUND: Rapid on-site cytologic evaluation (ROSE) is not always available for fine needle aspiration (FNA) specimens. We have examined the relationships between the presence of "GOOP" (defined as gooey white material) on FNA aspirates, on-site adequacy (OSA), and diagnosis. METHODS: Consecutive FNA samples obtained over the study interval were included. Samples were assessed macroscopically for the presence or absence of GOOP (GOOP+ or GOOP-). GOOP+ samples were further characterized as shiny (G+S) or cheesy (G+C). Gross descriptors were correlated with OSA and final diagnoses. RESULTS: Of the 204 sites biopsied, 102 were malignant, 94 benign, and 8 nondiagnostic. The presence of GOOP was highly predictive for adequacy (positive predictive value 98%). While these correlations for GOOP positivity were significant, the absence of GOOP did not rule out adequacy or malignancy. The presence of GOOP was also significantly correlated with a malignant diagnosis. CONCLUSIONS: We have prospectively demonstrated that the presence of GOOP correlates strongly with adequacy. This may be of value for those for whom ROSE is not available and, when available, may help prioritize specimens for on-site review.

Robotic Bronchoscopy for Peripheral Pulmonary Lesion Biopsy: Evidence-Based Review of the Two Platforms.

Despite many advancements in recent years for the sampling of peripheral pulmonary lesions, the diagnostic yield remains low. Initial excitement about the current electromagnetic navigation platforms has subsided as the real-world data shows a significantly lower diagnostic sensitivity of ~70%. "CT-to-body divergence" has been identified as a major limitation of this modality. In-tandem use of the ultrathin bronchoscope and radial endobronchial ultrasound probe has yielded only comparable results, attributable to the limited peripheral reach, device maneuverability, stability, and distractors like atelectasis. As such, experts have identified three key steps in peripheral nodule sampling-navigation (to the lesion), confirmation (of the correct location), and acquisition (tissue sampling by tools). Robotic bronchoscopy (RB) is a novel innovation that aspires to improve upon these aspects and consequently, achieve a better diagnostic yield. Through this publication, we aim to review the technical aspects, safety, feasibility, and early efficacy data for this new diagnostic modality.

Rapid On-Site Cytologic Evaluation: A Feasibility Study Using Ancillary Interventional Pulmonary Personnel.

BACKGROUND: Ancillary health professionals helping in a procedural service is a common practice everywhere. OBJECTIVES: This was a proof-of-concept study to assess feasibility of using ancillary personnel for rapid on-site cytologic evaluation (ROSE) at interventional pulmonary procedures. METHODS: After a training interval, a respiratory therapist (RT) performed ROSE on consecutive interventional pulmonary specimens. Sample sites included lymph nodes, lung, liver, and the left adrenal gland. RT findings were subsequently correlated with blinded cytopathology-performed ROSE and with final histopathology results, with primary foci of adequacy and the presence or absence of malignancy. RESULTS: Seventy consecutive cases involved 163 separate sites for ROSE analysis. Adequacy: There was a high level of concordance between RT-performed ROSE (RT-ROSE) and cytopathology ROSE (CYTO-ROSE). They agreed upon the adequacy of 159 specimens. The Cohen's κ coefficient ± asymptotic standard error (ASE) was 0.74 ± 0.175, with p < 0.0001. Malignancy: RT-ROSE concurred highly with CYTO-ROSE, with agreement on 150 (92%) of the 163 specimens. Cohen's κ coefficient ± ASE was 0.83 ± 0.045, with p < 0.0001. When the comparison was for malignancy by case rather than individual site, Cohen's κ coefficient ± ASE was 0.68 ± 0.08, with p < 0.0001. CONCLUSION: This study demonstrates that ancillary personnel supporting an interventional pulmonary service can be trained to perform initial ROSE. Cytopathology can be called after sampling and staining have produced adequate samples. This setup streamlines ROSE evaluation with regard to time and cost.

A 41-Year-Old Man Presenting With Shortness of Breath, Nausea, Vomiting, and Diarrhea.

CASE PRESENTATION: A 41-year-old man presented to our institution with shortness of breath for 1 day, and nausea, vomiting, and diarrhea for 10 days. He has a medical history of gastroesophageal reflux disease, migraines, and anxiety. He is a 10 pack-year former cigarette smoker and an active vaper. He quit smoking cigarettes in 2013 but reports vaping flavored nicotine from 2013 to 2018. Since 2018, he has been vaping tetrahydrocannabinol products of different flavors and brands. A few weeks prior to admission, the subject had changed the brand of his vaping product to "Cookies High Flyers" with a "Biscotti" flavor. The new product contains 1,000 mg (883 mg tetrahydrocannabinol and 117 mg cannabidiol) in a 0.04 oz cartridge. He vapes five times a day, taking two to three puffs every time. He had recently traveled to Texas and had a sick contact with his 18-month-old daughter. She recently recovered from a diarrheal illness of presumed viral origin. Prior to admission, the subject tested negative for influenza and completed outpatient antibiotic treatment, with no improvement.

Using a Facebook group to facilitate faculty-student interactions during preclinical medical education: a retrospective survey analysis.

BACKGROUND: Strong learner-teacher relationships are associated with more successful learning outcomes. With shortened modular curricula and increased availability of online resources, fostering faculty interaction with preclinical medical students has become more challenging. We sought to enhance learner-teacher relationships by engaging in discussion with preclinical medical students in their own online space. METHODS: We utilized a closed Facebook discussion group, where faculty and students voluntarily joined in informal discussions and shared announcements related to their courses. The closed discussion group allowed only participating students and faculty to see others' posts within the group. This provided a platform to freely interact within the confines of the group while maintaining privacy for the personal Facebook accounts of both faculty and students. We utilized the discussion group through three separate organ system-based modules for 14 weeks. Afterward, students were asked to complete an anonymous, voluntary online survey about their experience. RESULTS: 94.1% (160/170) of enrolled second-year medical students joined the voluntary FB discussion group. There were 214 posts, 628 comments, and 4166 reactions in this discussion group during the three modules. Of the students in the group, 74.4% (119/160) responded to the online survey. Overall, students strongly agreed that the Facebook discussion group fostered better rapport with faculty, helped content learning, and improved emotional well-being. Also, they felt more comfortable seeking academic help after using the discussion group. They reported a slight preference for Facebook over email as a medium for asking questions, but no preference for either as a medium for distributing announcements. Students overwhelmingly recommended that the discussion group should be continued in future years. CONCLUSION: The Facebook discussion group was a free, efficient, and effective method of cultivating the learner-teacher relationship with the preclinical medical students, resulting in reported enhancement of learning and morale.

The Performance of Diagnostic Criteria for Hemophagocytic Lymphohistiocytosis in Critically Ill Patients.

OBJECTIVE: The diagnostic criteria for secondary hemophagocytic lymphohistiocytosis (HLH) have not been validated in the critically ill adult population. We set out to evaluate the performance of diagnostic criteria and determine the ferritin cutoff in critically ill adults. DESIGN: A retrospective single-center study. SETTING AND PATIENTS: Patients admitted to intensive care unit between 2008 and March 2010. Data were collected on consecutive patients who had ferritin measured. Charts were reviewed for the diagnostic criteria of HLH and components of Hscore. MEASUREMENTS AND MAIN RESULTS: A total of 445 patients had a ferritin level measured during the study period. A diagnosis of HLH was made for 10 patients. Having 5 of 6 criteria had a specificity of 97% and a sensitivity of 70%. Hemophagocytosis was found in 41 (47.1%) of 87 bone marrow biopsies. Two hundred thirty-one patients had a ferritin level above 500 ng/dL. When determining the odds of HLH being clinically diagnosed, the optimal cut point for ferritin was 1197 ng/dL. When determining the odds of HLH based on the Hscore, the best cutoff was 143.5 (sensitivity of 90% and specificity of 90%) and patients who had HLH in our study population had an Hscore of 203.8 ± 64.9. CONCLUSION: In this cohort of critically ill patients, the HLH criteria are specific for HLH but not sensitive. Critically ill patients can have a higher incidence of hemophagocytosis without HLH. A higher ferritin cutoff in combination with 5 other clinical criteria is comparable to the Hscore for the recognition of HLH in the critically ill population.

Cocaine Use and Pulmonary Hypertension.

Evidence linking cocaine to the risk of pulmonary hypertension (PH) is limited and inconsistent. We examined whether cocaine use, in the absence of other known causes of PH, was associated with elevated systolic pulmonary artery pressure (sPAP) and increased probability of PH. We compared patients with documented cocaine use to a randomly selected age, sex, and race-matched control group without history of cocaine use. All participants had no known causes of PH and underwent echocardiography for noninvasive estimation of sPAP. We used routinely reported echocardiographic parameters and contemporary guidelines to grade the probability of PH. In 88 patients with documented cocaine use (mean age ± standard deviation 51.7 ± 9.5 years), 33% were women and 89% were of Black race. The commonest route of cocaine use was smoking (74%). Cocaine users compared with the control group had significantly higher sPAP (mean ± standard deviation, 30.1 ± 13.1 vs 22.0 ± 9.8 mm Hg, p <0.001) and greater likelihood of PH (25% vs 10%, p = 0.012). In multivariable analyses adjusted for potential confounders including left ventricular diastolic dysfunction, cocaine use conferred a fivefold greater odds of echocardiographic PH (p = 0.006). Additionally, a stepwise increase in the likelihood of PH was noted across cocaine users with negative or no drug screen on the day of echocardiography to cocaine users with a positive drug screen (multivariable p for trend = 0.008). In conclusion, cocaine use was associated with a higher sPAP and an increased likelihood of echocardiographic PH with a probable acute-on-chronic effect.

Efficacy and Safety of the Early Addition of Vasopressin to Norepinephrine in Septic Shock.

BACKGROUND: Delays in achievement of target mean arterial pressure (MAP) have been associated with increased mortality in patients with septic shock. Vasopressin may be added to norepinephrine to raise MAP or decrease norepinephrine dosage. The purpose of this study was to determine whether early initiation of vasopressin to norepinephrine resulted in a reduced time to target MAP compared to norepinephrine monotherapy. METHODS: This retrospective cohort study compared early addition of vasopressin within 4 hours of septic shock onset to norepinephrine versus initial norepinephrine monotherapy in medically, critically ill patients with septic shock admitted from May 2014 to October 2015. Time to goal MAP was compared using Student t test and examined with Kaplan-Meier curves. Changes in Sequential Organ Failure Assessment (SOFA) scores were evaluated with Wilcoxon rank sum test. RESULTS: Each group contained 48 patients. Mean arterial pressure (61.5 vs 58.6 mm Hg) and intravenous fluid volume received at vasopressor initiation (14.3 vs 25.2 hours, P = .014) were similar. Patients started on early vasopressin achieved and maintained goal MAP sooner (6.2 vs 9.9 hours, P = .023), experienced greater reductions in SOFA scores at 72 hours (-4 vs -1, P = .012), and had shorter hospital durations (343 vs 604 hours, P = .014). Not initiating early vasopressin trended toward an association with increased time to goal MAP (P = .067). CONCLUSION: Early initiation of vasopressin in patients with septic shock may achieve and maintain goal MAP sooner and resolve organ dysfunction at 72 hours more effectively than later or no initiation.