Quantitative CT scan and response to pronation in COVID-19 ARDS.

Background: The use of the prone position (PP) has been widespread during the COVID-19 pandemic. While it has demonstrated benefits, including improved oxygenation and lung aeration, the factors influencing the response in terms of gas exchange to PP remain unclear. In particular, the association between baseline quantitative Computed Tomography (qCT) scan results and gas exchange response to PP in intubated, mechanically ventilated subjects with COVID-19 ARDS is unknown. The present study aimed to compare baseline qCT results between subjects responding to PP in terms of oxygenation or carbon dioxide (CO2) clearance and those who did not.Methods: This was a single-center, retrospective observational study, including critically ill, intubated, mechanically ventilated subjects with COVID-19 related acute respiratory distress syndrome admitted to the ICUs of Niguarda Hospital between March 2020 and November 2021. Blood-gas samples were collected before and after PP. Subjects in whom the PaO2/FiO2 increase was ≥ 20 mmHg after PP were defined as Oxygen responders (Oxy-R). CO2-responders (CO2R) were defined when the ventilatory ratio (VR) decreased during PP. Automated qCT analyses were performed to obtain tissue mass and density of the lungs.Results: One hundred twenty-five subjects were enrolled, of which 116 (93%) were Oxy-R and 51 (41%) CO2R. No difference in qCT characteristics and oxygen were observed between Oxy-R and Oxygen Non Responders (Tissue mass 1532 ±396 vs. 1654 ±304 g, p= .28; density -544±109 vs. -562±58 HU, p= .42). Similar findings were observed when dividing the population according to CO2 response (Tissue mass 1551±412 vs. 1534±377 g, p= .89; density -545±123 vs. -546±94 HU, p= .99).Conclusions: Most COVID-19 related ARDS subjects improve their oxygenation at the first pronation cycle. The study suggests that baseline qCT scan data are not associated with the response to PP in oxygenation or CO2 in mechanically ventilated COVID-19 related ARDS subjects.

Role of hemolysis on pulmonary arterial compliance and right ventricular systolic function after cardiopulmonary bypass.

BACKGROUND: Cardiopulmonary bypass (CPB) is associated with intravascular hemolysis which depletes endogenous nitric oxide (NO). The impact of hemolysis on pulmonary arterial compliance (PAC) and right ventricular systolic function has not been explored yet. We hypothesized that decreased NO availability is associated with worse PAC and right ventricular systolic function after CPB. METHODS: This is a secondary analysis of an observational cohort study in patients undergoing cardiac surgery with CPB at Massachusetts General Hospital, USA (2014-2015). We assessed PAC (stroke volume/pulmonary artery pulse pressure ratio), and right ventricular function index (RVFI) (systolic pulmonary arterial pressure/cardiac output), as well as NO consumption at 15 min, 4 h and 12 h after CPB. Patients were stratified by CPB duration. Further, we assessed the association between changes in NO consumption with PAC and RVFI between 15min and 4 h after CPB. RESULTS: PAC was lowest at 15min after CPB and improved over time (n = 50). RVFI was highest -worse right ventricular function- at CPB end and gradually decreased. Changes in hemolysis, PAC and RVFI differed over time by CPB duration. PAC inversely correlated with total pulmonary resistance (TPR). TPR and PAC positively and negatively correlated with RVFI, respectively. NO consumption between 15min and 4 h after CPB correlated with changes in PAC (-0.28 ml/mmHg, 95%CI -0.49 to -0.01, p = 0.012) and RVFI (0.14 mmHg*L-1*min, 95%CI 0.10 to 0.18, p < 0.001) after multivariable adjustments. CONCLUSION: PAC and RVFI are worse at CPB end and improve over time. Depletion of endogenous NO may contribute to explain changes in PAC and RVFI after CPB.

Successful Versus Failed Transition From Controlled Ventilation to Pressure Support Ventilation in COVID-19 Patients: A Retrospective Cohort Study.

OBJECTIVES: In patients with COVID-19 respiratory failure, controlled mechanical ventilation (CMV) is often necessary during the acute phases of the disease. Weaning from CMV to pressure support ventilation (PSV) is a key objective when the patient's respiratory functions improve. Limited evidence exists regarding the factors predicting a successful transition to PSV and its impact on patient outcomes. DESIGN: Retrospective observational cohort study. SETTING: Twenty-four Italian ICUs from February 2020 to May 2020. PATIENTS: Mechanically ventilated ICU patients with COVID-19-induced respiratory failure. INTERVENTION: The transition period from CMV to PSV was evaluated. We defined it as "failure of assisted breathing" if the patient returned to CMV within the first 72 hours. MEASUREMENTS AND MAIN RESULTS: Of 1260 ICU patients screened, 514 were included. Three hundred fifty-seven patients successfully made the transition to PSV, while 157 failed. Pao2/Fio2 ratio before the transition emerged as an independent predictor of a successful shift (odds ratio 1.00; 95% CI, 0.99-1.00; p = 0.003). Patients in the success group displayed a better trend in Pao2/Fio2, Paco2, plateau and peak pressure, and pH level. Subjects in the failure group exhibited higher ICU mortality (hazard ratio 2.08; 95% CI, 1.42-3.06; p < 0.001), an extended ICU length of stay (successful vs. failure 21 ± 14 vs. 27 ± 17 d; p < 0.001) and a longer duration of mechanical ventilation (19 ± 18 vs. 24 ± 17 d, p = 0.04). CONCLUSIONS: Our study emphasizes that the Pao2/Fio2 ratio was the sole independent factor associated with a failed transition from CMV to PSV. The unsuccessful transition was associated with worse outcomes.

Combining the Physical-Chemical Approach with Standard Base Excess to Understand the Compensation of Respiratory Acid-Base Derangements: An Individual Participant Meta-analysis Approach to Data from Multiple Canine and Human Experiments.

BACKGROUND: Several studies explored the interdependence between Paco2 and bicarbonate during respiratory acid-base derangements. The authors aimed to reframe the bicarbonate adaptation to respiratory disorders according to the physical-chemical approach, hypothesizing that (1) bicarbonate concentration during respiratory derangements is associated with strong ion difference; and (2) during acute respiratory disorders, strong ion difference changes are not associated with standard base excess. METHODS: This is an individual participant data meta-analysis from multiple canine and human experiments published up to April 29, 2021. Studies testing the effect of acute or chronic respiratory derangements and reporting the variations of Paco2, bicarbonate, and electrolytes were analyzed. Strong ion difference and standard base excess were calculated. RESULTS: Eleven studies were included. Paco2 ranged between 21 and 142 mmHg, while bicarbonate and strong ion difference ranged between 12.3 and 43.8 mM, and 32.6 and 60.0 mEq/l, respectively. Bicarbonate changes were linearly associated with the strong ion difference variation in acute and chronic respiratory derangement (ß-coefficient, 1.2; 95% CI, 1.2 to 1.3; P < 0.001). In the acute setting, sodium variations justified approximately 80% of strong ion difference change, while a similar percentage of chloride variation was responsible for chronic adaptations. In the acute setting, strong ion difference variation was not associated with standard base excess changes (ß-coefficient, -0.02; 95% CI, -0.11 to 0.07; P = 0.719), while a positive linear association was present in chronic studies (ß-coefficient, 1.04; 95% CI, 0.84 to 1.24; P < 0.001). CONCLUSIONS: The bicarbonate adaptation that follows primary respiratory alterations is associated with variations of strong ion difference. In the acute phase, the variation in strong ion difference is mainly due to sodium variations and is not paralleled by modifications of standard base excess. In the chronic setting, strong ion difference changes are due to chloride variations and are mirrored by standard base excess.

Gas Humidification During Helmet Continuous Positive Airway Pressure: A Crossover Randomized Physiologic Study in Healthy Subjects.

BACKGROUND: In the last decades, the use of the helmet interface to deliver noninvasive respiratory support has steadily increased. When delivering oxygen therapy, conditioning of inspired gas is mandatory, as the water content of medical gas is neglectable. To minimize the risk of airway damage, it is recommended to achieve an absolute humidity greater than 10 mg H2O/L. The primary aim of the study was to assess the performance of 3 different heated humidifiers to condition gas during helmet continuous positive airway pressure and to compare them with a setting without active humidification. METHODS: We performed a crossover randomized physiological study in healthy volunteers. Absolute humidity, relative humidity, and temperature were measured during 4 steps (no humidification and the 3 heated humidifiers, performed in a randomized order) and at 3 time points (after 1, 5, and 10 minutes). RESULTS: Eight subjects participated to the study. Without active humidification, absolute humidity was constantly below the recommended level. All humidifiers conditioned the inspired gases to an average absolute humidity greater than 10 mg H2O/L. Overall, the best performance, in terms of absolute humidity, was obtained with H900 (19.74 ± 0.50 mg H2O/L), followed by TurbH2O (-6.82 mg H2O/L vs H900; 95% confidence interval, -8.49 to -5.14; P < .05) and F&P 810 (-9.03 mg H2O/L vs H900; 95% confidence interval, -10.70 to -7.35; P < .05). CONCLUSIONS: Active humidification is required to achieve adequate conditioning of inspired gas during helmet continuous positive airway pressure. The choice between different humidifiers available on the market should be made according to the local needs and expertise.

Prehospital Mass Casualty Incident Response to a Fire in a Nursing Home in Milan, Italy: Actions Taken and Shortcomings.

On July 7, 2023, at 1:21 am, a fire was declared in a retirement home in Milan, Italy. The number of casualties (n = 87) according to the Simple Triage and Rapid Treatment (START) triage system was categorized as 65 green, 14 yellow, 2 red, and 6 black; 75% were women, and the mean age was 85.1 years (± 9). Most patients were unable to walk. A total of 30 basic life support (BLS) ambulances, 3 advanced cardiac life support (ACLS) teams on fast cars, 2 buses, and 1 coordination team were deployed. A scoop and run approach was adopted with patients being transported to 15 health care facilities. The event was terminated at 5:43 am. Though the local mass casualty incident (MCI) response plan was correctly applied, the evacuation of the building was difficult due to the age and comorbidities of the patients. START failed to correctly identify patients categorized as minor. Communication problems arose on site that led to the late evacuation of critical patients.

Effect of a quality improvement program on compliance to the sepsis bundle in non-ICU patients: a multicenter prospective before and after cohort study.

Objective: Sepsis and septic shock are major challenges and economic burdens to healthcare, impacting millions of people globally and representing significant causes of mortality. Recently, a large number of quality improvement programs focused on sepsis resuscitation bundles have been instituted worldwide. These educational initiatives have been shown to be associated with improvements in clinical outcomes. We aimed to evaluate the impact of a multi-faceted quality implementing program (QIP) on the compliance of a "simplified 1-h bundle" (Sepsis 6) and hospital mortality of severe sepsis and septic shock patients out of the intensive care unit (ICU). Methods: Emergency departments (EDs) and medical wards (MWs) of 12 academic and non-academic hospitals in the Lombardy region (Northern Italy) were involved in a multi-faceted QIP, which included educational and organizational interventions. Patients with a clinical diagnosis of severe sepsis or septic shock according to the Sepsis-2 criteria were enrolled in two different periods: from May 2011 to November 2011 (before-QIP cohort) and from August 2012 to June 2013 (after-QIP cohort). Measurements and main results: The effect of QIP on bundle compliance and hospital mortality was evaluated in a before-after analysis. We enrolled 467 patients in the before-QIP group and 656 in the after-QIP group. At the time of enrollment, septic shock was diagnosed in 50% of patients, similarly between the two periods. In the after-QIP group, we observed increased compliance to the "simplified rapid (1 h) intervention bundle" (the Sepsis 6 bundle - S6) at three time-points evaluated (1 h, 13.7 to 18.7%, p = 0.018, 3 h, 37.1 to 48.0%, p = 0.013, overall study period, 46.2 to 57.9%, p < 0.001). We then analyzed compliance with S6 and hospital mortality in the before- and after-QIP periods, stratifying the two patients' cohorts by admission characteristics. Adherence to the S6 bundle was increased in patients with severe sepsis in the absence of shock, in patients with serum lactate <4.0 mmol/L, and in patients with hypotension at the time of enrollment, regardless of the type of admission (from EDs or MWs). Subsequently, in an observational analysis, we also investigated the relation between bundle compliance and hospital mortality by logistic regression. In the after-QIP cohort, we observed a lower in-hospital mortality than that observed in the before-QIP cohort. This finding was reported in subgroups where a higher adherence to the S6 bundle in the after-QIP period was found. After adjustment for confounders, the QIP appeared to be independently associated with a significant improvement in hospital mortality. Among the single S6 procedures applied within the first hour of sepsis diagnosis, compliance with blood culture and antibiotic therapy appeared significantly associated with reduced in-hospital mortality. Conclusion: A multi-faceted QIP aimed at promoting an early simplified bundle of care for the management of septic patients out of the ICU was associated with improved compliance with sepsis bundles and lower in-hospital mortality.

The role of intensive care unit diaries in the grieving process: A monocentric qualitative study.

BACKGROUND: The growing importance of psychological recovery for patients and their families following intensive care unit (ICU) experiences in recent years cannot be overemphasized. The ICU diary is used to aid patients in reducing the prevalence of post-traumatic stress disorder, anxiety, and depression. The usefulness of maintaining a diary during the grieving process has not yet been thoroughly investigated. AIM: To investigate the role of ICU diaries in the grief process experienced by family members of a person who died in the intensive care unit. STUDY DESIGN: Nine family members of seven deceased ICU patients with an ICU diary were contacted and interviewed by phone using a semi-structured interview. A qualitative data analysis was performed using thematic synthesis. SETTING: Italian general intensive care unit. FINDINGS: Interviewed family members felt that the diary helped them during the grieving process. The return of diaries was desired by family members for support and to remember one's loved one. The diary helped them process their losses in various ways, including signs of evidence of care, emotional involvement, consideration, and coping with grief. Four main themes emerged from the analysis: writing the diary, reading the diary, talking about the diary, and the diary during the grieving process. CONCLUSIONS: The overall perception of the ICU diary was positive. The diary mostly helped relatives to "give back something of what we lost". This study also affirms the positive link between ICU diaries and bereavement in Italian ICU. Further studies are required to confirm the usefulness of this tool in the grieving process. RELEVANCE TO CLINICAL PRACTICE: The ICU diary can help patients' family members understand what happened to their loved one and play an important role in the grieving process. The diary served as a valuable source of information that aided in providing bereavement support to the family by helping them to gain a rational and emotional understanding of the patient's death.

Development and Validation of a New Tool to Improve the Accuracy of the Hospital Mass-Casualty Incident Response Plan Activation: The PEMAAF Score.

INTRODUCTION: Effective response to a mass-casualty incident (MCI) entails the activation of hospital MCI plans. Unfortunately, there are no tools available in the literature to support hospital responders in predicting the proper level of MCI plan activation. This manuscript describes the scientific-based approach used to develop, test, and validate the PEMAAF score (Proximity, Event, Multitude, Overcrowding, Temporary Ward Reduction Capacity, Time Shift Slot [Prossimità, Evento, Moltitudine, Affollamento, Accorpamento, Fascia Oraria], a tool able to predict the required level of hospital MCI plan activation and to facilitate a coordinated activation of a multi-hospital network. METHODS: Three study phases were performed within the Metropolitan City of Milan, Italy: (1) retrospective analysis of past MCI after action reports (AARs); (2) PEMAAF score development; and (3) PEMAAF score validation. The validation phase entailed a multi-step process including two retrospective analyses of past MCIs using the score, a focus group discussion (FGD), and a prospective simulation-based study. Sensitivity and specificity of the score were analyzed using a regression model, Spearman's Rho test, and receiver operating characteristic/ROC analysis curves. RESULTS: Results of the retrospective analysis and FGD were used to refine the PEMAAF score, which included six items-Proximity, Event, Multitude, Emergency Department (ED) Overcrowding, Temporary Ward Reduction Capacity, and Time Shift Slot-allowing for the identification of three priority levels (score of 5-6: green alert; score of 7-9: yellow alert; and score of 10-12: red alert). When prospectively analyzed, the PEMAAF score determined most frequent hospital MCI plan activation (>10) during night and holiday shifts, with a score of 11 being associated with a higher sensitivity system and a score of 12 with higher specificity. CONCLUSIONS: The PEMAAF score allowed for a balanced and adequately distributed response in case of MCI, prompting hospital MCI plan activation according to real needs, taking into consideration the whole hospital response network.

Identifying Trauma Patients in Need for Emergency Surgery in the Prehospital Setting: The Prehospital Prediction of In-Hospital Emergency Treatment (PROPHET) Study.

Prehospital field triage often fails to accurately identify the need for emergent surgical or non-surgical procedures, resulting in inefficient resource utilization and increased costs. This study aimed to analyze prehospital factors associated with the need for emergent procedures (such as surgery or interventional angiography) within 6 h of hospital admission. Additionally, our goal was to develop a prehospital triage tool capable of estimating the likelihood of requiring an emergent procedure following hospital admission. We conducted a retrospective observational study, analyzing both prehospital and in-hospital data obtained from the Lombardy Trauma Registry. We conducted a multivariable logistic regression analysis to identify independent predictors of emergency procedures within the first 6 h from admission. Subsequently, we developed and internally validated a triage score composed of factors associated with the probability of requiring an emergency procedure. The study included a total of 3985 patients, among whom 295 (7.4%) required an emergent procedure within 6 h. Age, penetrating injury, downfall, cardiac arrest, poor neurological status, endotracheal intubation, systolic pressure, diastolic pressure, shock index, respiratory rate and tachycardia were identified as predictors of requiring an emergency procedure. A triage score generated from these predictors showed a good predictive power (AUC of the ROC curve: 0.81) to identify patients requiring an emergent surgical or non-surgical procedure within 6 h from hospital admission. The proposed triage score might contribute to predicting the need for immediate resource availability in trauma patients.

Detection of patients with COVID-19 by the emergency medical services in Lombardy through an operator-based interview and machine learning models.

BACKGROUND: The regional emergency medical service (EMS) in Lombardy (Italy) developed clinical algorithms based on operator-based interviews to detect patients with COVID-19 and refer them to the most appropriate hospitals. Machine learning (ML)-based models using additional clinical and geospatial epidemiological data may improve the identification of infected patients and guide EMS in detecting COVID-19 cases before confirmation with SARS-CoV-2 reverse transcriptase PCR (rtPCR). METHODS: This was an observational, retrospective cohort study using data from October 2020 to July 2021 (training set) and October 2021 to December 2021 (validation set) from patients who underwent a SARS-CoV-2 rtPCR test within 7 days of an EMS call. The performance of an operator-based interview using close contact history and signs/symptoms of COVID-19 was assessed in the training set for its ability to determine which patients had an rtPCR in the 7 days before or after the call. The interview accuracy was compared with four supervised ML models to predict positivity for SARS-CoV-2 within 7 days using readily available prehospital data retrieved from both training and validation sets. RESULTS: The training set includes 264 976 patients, median age 74 (IQR 55-84). Test characteristics for the detection of COVID-19-positive patients of the operator-based interview were: sensitivity 85.5%, specificity 58.7%, positive predictive value (PPV) 37.5% and negative predictive value (NPV) 93.3%. Contact history, fever and cough showed the highest association with SARS-CoV-2 infection. In the validation set (103 336 patients, median age 73 (IQR 50-84)), the best-performing ML model had an AUC of 0.85 (95% CI 0.84 to 0.86), sensitivity 91.4% (95 CI% 0.91 to 0.92), specificity 44.2% (95% CI 0.44 to 0.45) and accuracy 85% (95% CI 0.84 to 0.85). PPV and NPV were 13.3% (95% CI 0.13 to 0.14) and 98.2% (95% CI 0.98 to 0.98), respectively. Contact history, fever, call geographical distribution and cough were the most important variables in determining the outcome. CONCLUSION: ML-based models might help EMS identify patients with SARS-CoV-2 infection, and in guiding EMS allocation of hospital resources based on prespecified criteria.

Severe Acute Respiratory Syndrome Coronavirus 2 and Medical Evacuation in Lombardy: Lessons Learned from an Unprecedented Pandemic.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerging infectious disease pandemic developed in Lombardy (northern Italy) during the last week of February 2020 with a progressive increase of patients presenting with serious clinical findings. Despite the efforts of the Central Italian Government, regional resources were rapidly at capacity. The solution was to plan the medical evacuation (MEDEVAC) of 119 critically ill patients (median age 61 years) to in-patient intensive care units in other Italian regions (77) and Germany (42). Once surviving patients were deemed suitable, the repatriation process concluded the assignment. The aim of this report is to underline the importance of a rapid organization and coordination process between different nodes of an effective national and international network during an emerging infectious disease outbreak and draw lessons learned from similar published reports.

Calcium-Citrate Anticoagulation during Continuous Renal Replacement Therapy in Patients with Metformin Intoxication: A Case Series, Mathematical Estimation of Citrate Accumulation, and Literature Review.

INTRODUCTION: Metformin intoxication causes lactic acidosis by inhibiting Krebs' cycle and oxidative phosphorylation. Continuous renal replacement therapy (CRRT) is recommended for metformin removal in critically ill patients. According to current guidelines, regional citrate anticoagulation (RCA) is the first-line strategy. However, since metformin also inhibits citrate metabolism, a risk of citrate accumulation could be hypothesized. In the present study, we monitored the potential citrate accumulation in metformin-associated lactic acidosis (MALA) patients treated with CRRT and RCA using the physical-chemical approach to acid-base interpretation. METHODS: We collected a case series of 3 patients with MALA. Patients were treated with continuous venovenous hemofiltration (CVVH), and RCA was performed with diluted citrate solution. Citrate accumulation was monitored through two methods: the ratio between total and ionized plasma calcium concentrations (T/I calcium ratio) above 2.5 and the strong ion gap (SIG) to identify an increased concentration of unmeasured anions. Lastly, a mathematical model was developed to estimate the expected citrate accumulation during CVVH and RCA. RESULTS: All 3 patients showed a resolution of MALA after the treatment with CVVH. The T/I calcium ratio was consistently below 2.5, and SIG decreased, reaching values lower than 6 mEq/L after 48 h of CVVH treatment. According to the mathematical model, the estimated SIG without citrate metabolism should have been around 21 mEq/L due to citrate accumulation. CONCLUSIONS: In our clinical management, no signs of citrate accumulation were recorded in MALA patients during treatment with CVVH and RCA. Our data support the safe use of diluted citrate to perform RCA during metformin intoxication.

Multidrug-Resistant Bacterial Colonization and Infections in Large Retrospective Cohort of Mechanically Ventilated COVID-19 Patients1.

Few data are available on incidence of multidrug-resistant organism (MDRO) colonization and infections in mechanically ventilated patients, particularly during the COVID-19 pandemic. We retrospectively evaluated all patients admitted to the COVID-19 intensive care unit (ICU) of Hub Hospital in Milan, Italy, during October 2020‒May 2021. Microbiologic surveillance was standardized with active screening at admission and weekly during ICU stay. Of 435 patients, 88 (20.2%) had MDROs isolated ≤48 h after admission. Of the remaining patients, MDRO colonization was diagnosed in 173 (51.2%), MDRO infections in 95 (28.1%), and non-MDRO infections in 212 (62.7%). Non-MDRO infections occurred earlier than MDRO infections (6 days vs. 10 days; p<0.001). Previous exposure to antimicrobial drugs within the ICU was higher in MDRO patients than in non-MDRO patients (116/197 [58.9%] vs. 18/140 [12.9%]; p<0.001). Our findings might serve as warnings for future respiratory viral pandemics and call for increased measures of antimicrobial stewardship and infection control.

How the Italian Formula 1 Grand Prix 2022 Mass Gathering Event Compares to the Arbon Model: A Descriptive Study.

OBJECTIVE: To describe the health-care resources implemented during the Italian Formula 1 Grand Prix (F1GP) and to calculate the patient presentation rate (PPR) based on both real data and a prediction model. METHODS: Observational and descriptive study conducted from September 9 to September 11, 2022, during the Italian F1GP hosted in Monza (Italy). Maurer's formula was applied to decide the number and type of health resources to be allocated. Patient presentation rate (PPR) was computed based on real data (PPR_real) and based on the Arbon formula (PPR_est). RESULTS: Of 336,000 attendees, n = 263 requested medical assistance with most of them receiving treatment at the advanced medical post, and n = 16 needing transport to the hospital. The PPR_real was 51 for Friday, 78 for Saturday, 134 for Sunday, and 263 when considering the whole event as a single event. The PPR_est resulted in 85 for Friday, 93 for Saturday, 97 for Sunday, and 221 for the total population. CONCLUSIONS: A careful organization of health-care resources could mitigate the impact of the Italian F1GP on local hospital facilities. The Arbon formula is an acceptable model to predict and estimate the number of patients requesting medical assistance, but further investigation needs to be conducted to implement the model and tailor it to broader categories of MGE.