Systemic AA Amyloidosis Associated With Intravenous Injection of Oral Prescription Opioids-An Autopsy Case Report.

ABSTRACT: There are reports of AA amyloidosis associated with intravenous and/or subcutaneous injection of street drugs, such as heroin and cocaine. Most reports describe patients with substance use disorder, renal amyloidosis and concurrent viral infections, such as hepatitis and/or human immunodeficiency virus. Herein, we present a case of systemic AA amyloidosis and sepsis in a 34-year-old woman with a history of intravenous injection of oral prescription medications (as evidenced by excipient lung disease) who had no known history of human immunodeficiency virus nor of hepatitis B or C. Our case shows the broader spectrum of pathology that can occur with the misuse of prescription medications.

Resuscitating Resuscitation: Advanced Therapies for Resistant Ventricular Dysrhythmias.

BACKGROUND: More than 640,000 combined in-hospital and out-of-hospital cardiac arrests occur annually in the United States. However, survival rates and meaningful neurologic recovery remain poor. Although "shockable" rhythms (i.e., ventricular fibrillation (VF) and pulseless ventricular tachycardia (VT)) have the best outcomes, many of these ventricular dysrhythmias fail to return to a perfusing rhythm (resistant VF/VT), or recur shortly after they are resolved (recurrent VF/VT). OBJECTIVE: This review discusses 4 emerging therapies in the emergency department for treating these resistant or recurrent ventricular dysrhythmias: beta-blocker therapy, dual simultaneous external defibrillation, stellate ganglion blockade, and extracorporeal cardiopulmonary resuscitation. We discuss the underlying physiology of each therapy, review relevant literature, describe when these approaches should be considered, and provide evidence-based recommendations for these techniques. DISCUSSION: Esmolol may mitigate some of epinephrine's negative effects when used during resuscitation, improving both postresuscitation cardiac function and long-term survival. Dual simultaneous external defibrillation targets the region of the heart where ventricular fibrillation typically resumes and may apply a more efficient defibrillation across the heart, leading to higher rates of successful defibrillation. Stellate ganglion blocks, recently described in the emergency medicine literature, have been used to treat patients with recurrent VF/VT, resulting in significant dysrhythmia suppression. Finally, extracorporeal cardiopulmonary resuscitation is used to provide cardiopulmonary support while clinicians correct reversible causes of arrest, potentially resulting in improved survival and good neurologic functional outcomes. CONCLUSION: These emerging therapies do not represent standard practice; however, they may be considered in the appropriate clinical scenario when standard therapies are exhausted without success.

Equipoise in Appropriate Initial Volume Resuscitation for Patients in Septic Shock With Heart Failure: Results of a Multicenter Clinician Survey.

PURPOSE: International clinical practice guidelines call for initial volume resuscitation of at least 30 mL/kg body weight for patients with sepsis-induced hypotension or shock. Although not considered in the guidelines, preexisting cardiac dysfunction may be an important factor clinicians weigh in deciding the quantity of volume resuscitation for patients with septic shock. METHODS: We conducted a multicenter survey of clinicians who routinely treat patients with sepsis to evaluate their beliefs, behaviors, knowledge, and perceived structural barriers regarding initial volume resuscitation for patients with sepsis and concomitant heart failure with reduced ejection fraction (HFrEF) <40%. Initial volume resuscitation preferences were captured as ordinal values, and additional testing for volume resuscitation preferences was performed using McNemar and Wilcoxon signed rank tests as indicated. Univariable logistic regression models were used to identify significant predictors of ≥30 mL/kg fluid administration. RESULTS: A total of 317 clinicians at 9 US hospitals completed the survey (response rate 47.3%). Most respondents were specialists in either internal medicine or emergency medicine. Substantial heterogeneity was found regarding sepsis resuscitation preferences for patients with concomitant HFrEF. The belief that patients with septic shock and HFrEF should be exempt from current sepsis bundle initiatives was shared by 39.4% of respondents. A minimum fluid challenge of ∼30 mL/kg or more was deemed appropriate in septic shock by only 56.4% of respondents for patients with concomitant HFrEF, compared to 89.1% of respondents for patients without HFrEF (P < .01). Emergency medicine physicians were most likely to feel that <30 mL/kg was most appropriate in patients with septic shock and HFrEF. CONCLUSIONS: Clinical equipoise exists regarding initial volume resuscitation for patients with sepsis-induced hypotension or shock and concomitant HFrEF. Future studies and clinical practice guidelines should explicitly address resuscitation in this subpopulation.

Female Physician Leadership During Cardiopulmonary Resuscitation Is Associated With Improved Patient Outcomes.

OBJECTIVES: A recently published simulation study suggested that women are inferior leaders of cardiopulmonary resuscitation efforts. The aim of this study was to compare female and male code leaders in regard to cardiopulmonary resuscitation outcomes in a real-world clinical setting. DESIGN: Retrospective cohort review. SETTING: Two academic, urban hospitals in San Diego, California. SUBJECTS: One-thousand eighty-two adult inpatients who suffered cardiac arrest and underwent cardiopulmonary resuscitation. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We analyzed whether physician code leader gender was independently associated with sustained return of spontaneous circulation and survival to discharge and with markers of quality cardiopulmonary resuscitation. Of all arrests, 327 (30.1%) were run by female physician code leaders with 251 (76.8%) obtaining return of spontaneous circulation, and 122 (37.3%) surviving to discharge. Male physicians ran 757 codes obtaining return of spontaneous circulation in 543 (71.7%) with 226 (29.9%) surviving to discharge. When adjusting for variables, female physician code leader gender was independently associated with a higher likelihood of return of spontaneous circulation (odds ratio, 1.36; 95% CI, 1.01-1.85; p = 0.049) and survival to discharge (odds ratio, 1.53; 95% CI, 1.15-2.02; p < 0.01). Additionally, the odds ratio for survival to discharge was 1.62 (95% CI, 1.13-2.34; p < 0.01) for female physicians with a female code nurse when compared with male physician code leaders paired with a female code nurse. Gender of code leader was not associated with cardiopulmonary resuscitation quality. CONCLUSIONS: In contrast to data derived from a simulated setting with medical students, real life female physician leadership of cardiopulmonary resuscitation is not associated with inferior outcomes. Appropriately, trained physicians can lead high-quality cardiopulmonary resuscitation irrespective of gender.

Shock subtypes by left ventricular ejection fraction following out-of-hospital cardiac arrest.

BACKGROUND: Post-resuscitation hemodynamic instability following out-of-hospital cardiac arrest (OHCA) may occur from myocardial dysfunction underlying cardiogenic shock and/or inflammation-mediated distributive shock. Distinguishing the predominant shock subtype with widely available clinical metrics may have prognostic and therapeutic value. METHODS: A two-hospital cohort was assembled of patients in shock following OHCA. Left ventricular ejection fraction (LVEF) was assessed via echocardiography or cardiac ventriculography within 1 day post arrest and used to delineate shock physiology. The study evaluated whether higher LVEF, indicating distributive-predominant shock physiology, was associated with neurocognitive outcome (primary endpoint), survival, and duration of multiple organ failures. The study also investigated whether volume resuscitation exhibited a subtype-specific association with outcome. RESULTS: Of 162 patients with post-resuscitation shock, 48% had normal LVEF (> 40%), consistent with distributive shock physiology. Higher LVEF was associated with less favorable neurocognitive outcome (OR 0.74, 95% CI 0.58-0.94 per 10% increase in LVEF; p = 0.01). Higher LVEF also was associated with worse survival (OR 0.81, 95% CI 0.67-0.97; p = 0.02) and fewer organ failure-free days (ß = - 0.67, 95% CI - 1.28 to - 0.06; p = 0.03). Only 51% of patients received a volume challenge of at least 30 ml/kg body weight in the first 6 h post arrest, and the volume received did not differ by LVEF. Greater volume resuscitation in the first 6 h post arrest was associated with favorable neurocognitive outcome (OR 1.59, 95% CI 0.99-2.55 per liter; p = 0.03) and survival (OR 1.44, 95% CI 1.02-2.04; p = 0.02) among patients with normal LVEF but not low LVEF. CONCLUSIONS: In post-resuscitation shock, higher LVEF-indicating distributive shock physiology-was associated with less favorable neurocognitive outcome, fewer days without organ failure, and higher mortality. Greater early volume resuscitation was associated with more favorable neurocognitive outcome and survival in patients with this shock subtype. Additional studies with repeated measures of complementary hemodynamic parameters are warranted to validate the clinical utility for subtyping post-resuscitation shock.

Favorable Neurocognitive Outcome with Low Tidal Volume Ventilation after Cardiac Arrest.

RATIONALE: Neurocognitive outcome after out-of-hospital cardiac arrest (OHCA) is often poor, even when initial resuscitation succeeds. Lower tidal volumes (Vts) attenuate extrapulmonary organ injury in other disease states and are neuroprotective in preclinical models of critical illness. OBJECTIVE: To evaluate the association between Vt and neurocognitive outcome after OHCA. METHODS: We performed a propensity-adjusted analysis of a two-center retrospective cohort of patients experiencing OHCA who received mechanical ventilation for at least the first 48 hours of hospitalization. Vt was calculated as the time-weighted average over the first 48 hours, in milliliters per kilogram of predicted body weight (PBW). The primary endpoint was favorable neurocognitive outcome (cerebral performance category of 1 or 2) at discharge. MEASUREMENTS AND MAIN RESULTS: Of 256 included patients, 38% received time-weighted average Vt greater than 8 ml/kg PBW during the first 48 hours. Lower Vt was independently associated with favorable neurocognitive outcome in propensity-adjusted analysis (odds ratio, 1.61; 95% confidence interval [CI], 1.13-2.28 per 1-ml/kg PBW decrease in Vt; P = 0.008). This finding was robust to several sensitivity analyses. Lower Vt also was associated with more ventilator-free days (ß = 1.78; 95% CI, 0.39-3.16 per 1-ml/kg PBW decrease; P = 0.012) and shock-free days (ß = 1.31; 95% CI, 0.10-2.51; P = 0.034). Vt was not associated with hypercapnia (P = 1.00). Although the propensity score incorporated several biologically relevant covariates, only height, weight, and admitting hospital were independent predictors of Vt less than or equal to 8 ml/kg PBW. CONCLUSIONS: Lower Vt after OHCA is independently associated with favorable neurocognitive outcome, more ventilator-free days, and more shock-free days. These findings suggest a role for low-Vt ventilation after cardiac arrest.

A Conceptual Framework to Reduce Inpatient Preventable Deaths.

BACKGROUND: Efforts to reduce preventable deaths in the in-hospital setting should target both cardiopulmonary arrest (CPA) prevention and optimal resuscitation. This requires consideration of a broad range of clinical issues and processes. A comprehensive, integrated system of care (SOC) that links data collection with a modular education program to reduce preventable deaths has not been defined. METHODS: This study was conducted in two urban university hospitals from 2005 to 2009. The Advanced Resuscitation Training (ART) program was implemented in 2007, incorporating hands-on resuscitative skills and in-hospital-specific training with an institutional resuscitation database. Linkage between the database and training modules occurs via the ART Matrix, which classifies all CPA events into the following etiologies: sepsis, hemorrhage, pulmonary embolus, heart failure, tachyarrhythmias, bradyarrhythmias, acute respiratory distress syndrome, non-intubated pulmonary disease, obstructive apnea, traumatic brain injury, ischemic brain injury, and intracranial mass lesions. This taxonomy was validated using descriptive statistics, before-and-after analysis evaluating CPA incidence, and multivariate logistic regression to predict CPA survival. RESULTS: A total of 336 inpatients suffered a cardiopulmonary arrest during the study period-187 in the pre-ART period and 149 in the post-ART period. The vast majority of CPA events were categorized using the ART Matrix with high inter-observer reliability. As anticipated, changes in CPA incidence and survival were observed for some Matrix categories but not others following ART implementation. In addition, multivariate logistic regression revealed strong independent associations between taxonomy classifications and outcome. CONCLUSION: A novel SOC using a unique taxonomy for arrest classification appears to be effective at reducing inpatient CPA incidence and outcome.

Preliminary report of a mathematical model of ventilation and intrathoracic pressure applied to prehospital patients with severe traumatic brain injury.

BACKGROUND: Inadvertent hyperventilation is associated with poor outcomes from traumatic brain injury (TBI). Hypocapnic cerebral vasoconstriction is well described and causes an immediate and profound decrease in cerebral perfusion. The hemodynamic effects of positive-pressure ventilation (PPV) remain incompletely understood but may be equally important, particularly in the hypovolemic patient with TBI. OBJECTIVE: Preliminary report on the application of a previously described mathematical model of perfusion and ventilation to prehospital data to predict intrathoracic pressure. METHODS: Ventilation data from 108 TBI patients (76 ground transported, 32 helicopter transported) were used for this analysis. Ventilation rate (VR) and end-tidal carbon dioxide (PetCO2) values were used to estimate tidal volume (VT). The values for VR and estimated VT were then applied to a previously described mathematical model of perfusion and ventilation. This model allows input of various lung parameters to define a pressure-volume relationship, then derives mean intrathoracic pressure (MITP) for various VT and VR values. For this analysis, normal lung parameters were utilized. Separate analyses were performed assuming either fixed or variable PaCO2-PetCO2 differences. Ground and air medical patients were compared with regard to VR, PetCO2, estimated VT, and predicted MITP. RESULTS: A total of 10,647 measurements were included from the 108 TBI patients, representing about 13 minutes of ventilation per patient. Mean VR values were higher for ground patients versus air patients (21.6 vs. 19.7 breaths/min; p < 0.01). Estimated VT values were similar for ground and air patients (399 mL vs. 392 mL; p = NS) in the fixed model but not the variable (636 vs. 688 mL, respectively; p < 0.01). Mean PetCO2 values were lower for ground versus air patients (30.6 vs. 33.8 mmHg; p < 0.01). Predicted MITP values were higher for ground versus air patients, assuming either fixed (9.0 vs. 8.1 mmHg; p < 0.01) or variable (10.9 vs. 9.7 mmHg; p < 0.01) PaCO2-PetCO2 differences. CONCLUSIONS: Predicted MITP values increased with ventilation rates. Future studies to externally validate this model are warranted.

Ransomware Cyberattack Associated With Cardiac Arrest Incidence and Outcomes at Untargeted, Adjacent Hospitals.

OBJECTIVES: Healthcare ransomware cyberattacks have been associated with major regional hospital disruptions, but data reporting patient-oriented outcomes in critical conditions such as cardiac arrest (CA) are limited. This study examined the CA incidence and outcomes of untargeted hospitals adjacent to a ransomware-infected healthcare delivery organization (HDO). DESIGN SETTING AND PATIENTS: This cohort study compared the CA incidence and outcomes of two untargeted academic hospitals adjacent to an HDO under a ransomware cyberattack during the pre-attack (April 3-30, 2021), attack (May 1-28, 2021), and post-attack (May 29, 2021-June 25, 2021) phases. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Emergency department and hospital mean daily census, number of CAs, mean daily CA incidence per 1,000 admissions, return of spontaneous circulation, survival to discharge, and survival with favorable neurologic outcome were measured. The study evaluated 78 total CAs: 44 out-of-hospital CAs (OHCAs) and 34 in-hospital CAs. The number of total CAs increased from the pre-attack to attack phase (21 vs. 38; p = 0.03), followed by a decrease in the post-attack phase (38 vs. 19; p = 0.01). The number of total CAs exceeded the cyberattack month forecast (May 2021: 41 observed vs. 27 forecasted cases; 95% CI, 17.0-37.4). OHCA cases also exceeded the forecast (May 2021: 24 observed vs. 12 forecasted cases; 95% CI, 6.0-18.8). Survival with favorable neurologic outcome rates for all CAs decreased, driven by increases in OHCA mortality: survival with favorable neurologic rates for OHCAs decreased from the pre-attack phase to attack phase (40.0% vs. 4.5%; p = 0.02) followed by an increase in the post-attack phase (4.5% vs. 41.2%; p = 0.01). CONCLUSIONS: Untargeted hospitals adjacent to ransomware-infected HDOs may see worse outcomes for patients suffering from OHCA. These findings highlight the critical need for cybersecurity disaster planning and resiliency.

Epidemiology, risk factors and outcomes associated with in-hospital reflex-mediated cardiac arrest.

Aim of the study: Overactivation of the parasympathetic nervous system can lead to reflex syncope (RS) and, in extreme cases, trigger an unusual and underrecognized form of cardiac arrest. We characterized the epidemiology and prognosis of reflex-mediated cardiac arrest (RMCA) and hypothesized it is associated with intervenable patient factors. Methods: This retrospective case-control study examined RMCAs at two academic hospitals from 1/2016 to 6/2022 using a resuscitation quality improvement database. RMCA cases were identified as cardiac arrests preceded by vagal trigger(s). Cases of RS, defined as syncope with bradycardia and hypotension preceded by vagal trigger(s), between 1/2021 and 12/2021 were used as controls. For the secondary analysis, RMCA outcomes were compared to in-hospital cardiac arrest (IHCA) of other causes. Results: We identified 46 RMCA and 67 RS cases. Compared to RS patients, RMCA patients were more likely to have spinal cord injury (13.0% vs 1.5%, p = 0.02). Airway clearance i.e., coughing and suctioning triggered a higher proportion of RMCA events than RS events (23.9% vs 3.0%, p < 0.01). Compared to 1,021 IHCAs of other causes, RMCAs had 100% return of spontaneous circulation, were more likely to survive to discharge (84.8% vs 36.2%, p < 0.001) and have favorable neurological outcomes (cerebral performance category 1 or 2, 58.7% vs 26.9%, p < 0.001). Conclusions: RMCA has a favorable prognosis compared to other IHCAs and is potentially preventable. Spinal cord injury and airway clearance were patient factors significantly associated with RMCA.

Preservation of the Subtalar Joint Determines Outcomes in a 10-Year Evaluation of Ankle Arthrodesis.

Posttraumatic osteoarthritis may lead to surgical fusion of the ankle joint if non-surgical therapy fails. The indication for a fusion of the joint is based on the pain and disability of the patient, radiographic imaging, and surgeon experience, with no strict guidelines. We aimed to compare outcomes after tibiotalocalcaneal arthrodesis (TTCA) and tibiotalar arthrodesis (TTA) to highlight the functional importance of the subtalar joint. In total, 432 patients with ankle arthrodesis were retrospectively enrolled. Group A (n = 216) underwent TTCA; group B (n = 216) underwent TTA. Demographics, Olerud & Molander Ankle Score (OMAS), Foot Function Index (FFI-D), and Short Form-12 Questionnaire (SF-12) were recorded at a mean follow-up of 6.2 years. The mean OMAS was 50.7; the mean FFI-D was 68.9; the mean SF-12 physical component summary was 39.1. These scores differed significantly between the groups (p < 0.001). The overall revision rate was 18%, primarily for revision of non-union and infection (p < 0.001). Approximately 16% of group A and 26% of group B were able to return to previous work (p < 0.001). Based on significantly worse clinical scores of TTCA compared to TTA and the prolonged downtime and permanent incapacity, the indication for a generous subtalar joint arthrodesis with planned ankle arthrodesis should always be critically examined.

Perishock pause: an independent predictor of survival from out-of-hospital shockable cardiac arrest.

BACKGROUND: Perishock pauses are pauses in chest compressions before and after defibrillatory shock. We examined the relationship between perishock pauses and survival to hospital discharge. METHODS AND RESULTS: We included out-of-hospital cardiac arrest patients in the Resuscitation Outcomes Consortium Epistry-Cardiac Arrest who suffered arrest between December 2005 and June 2007, presented with a shockable rhythm (ventricular fibrillation or pulseless ventricular tachycardia), and had cardiopulmonary resuscitation process data for at least 1 shock (n=815). We used multivariable logistic regression to determine the association between survival and perishock pauses. In an analysis adjusted for Utstein predictors of survival, the odds of survival were significantly lower for patients with preshock pause ≥20 seconds (odds ratio, 0.47; 95% confidence interval, 0.27 to 0.82) and perishock pause ≥40 seconds (odds ratio, 0.54; 95% confidence interval, 0.31 to 0.97) compared with patients with preshock pause <10 seconds and perishock pause <20 seconds. Postshock pause was not independently associated with a significant change in the odds of survival. Log-linear modeling depicted a decrease in survival to hospital discharge of 18% and 14% for every 5-second increase in both preshock and perishock pause interval (up to 40 and 50 seconds, respectively), with no significant association noted with changes in the postshock pause interval. CONCLUSIONS: In patients with cardiac arrest presenting in a shockable rhythm, longer perishock and preshock pauses were independently associated with a decrease in survival to hospital discharge. The impact of preshock pause on survival suggests that refinement of automatic defibrillator software and paramedic education to minimize preshock pause delays may have a significant impact on survival.

Bronchial rupture by an unusual mechanism of thoracic hyperextension.

BACKGROUND: Tracheobronchial disruption usually occurs in the setting of blunt chest trauma and may be overlooked due to co-existing injuries and non-specific symptoms. OBJECTIVES: Review the mechanism, diagnosis, and therapeutic management of tracheobronchial disruption. CASE REPORT: We present a case of a young woman with a bronchial rupture 3 weeks after accidental strangulation. Initial diagnosis was delayed due to the unusual presentation. She presented with acute respiratory failure and hemodynamic collapse after slowly progressive shortness of breath with exertion. CONCLUSIONS: This case report provides an overview of the clinical features of bronchial disruption by highlighting the varying degrees of clinical presentation and management. Urgent bronchoscopy is indicated for diagnosis, and surgical intervention for treatment.

Outcomes of cardiopulmonary resuscitation in patients with pulmonary arterial hypertension.

Over the past 20 years, despite significant advancements in pulmonary arterial hypertension (PAH) medical therapy, many patients require admission to the hospital and are at risk for in-hospital cardiac arrest (IHCA). Prior data found poor survival in PAH patients after cardiac arrest. The purpose of this study was to explore post-IHCA outcomes in PAH patients receiving advanced medical therapies. This is a single-center retrospective study of PAH patients who underwent cardiopulmonary resuscitation for IHCA between July 2005 and May 2021. Patients were identified through an internal cardiac arrest database. Twenty six patients were included. Half of the cohort had idiopathic PAH, with 54% of patients on combination therapy, 27% on monotherapy, and 19% of patients on no therapy. Mean right atrial pressure, mean pulmonary artery pressure, cardiac index, and pulmonary vascular resistance were 13 ± 6 mmHg, 57 ± 13 mmHg, 2.0 ± 0.7 L/min/m2, and 14.5 ± 7.6 Wood units, respectively. Most common etiology of cardiac arrest was circulatory collapse. Initial arrest rhythm in all but one patient was pulseless electrical activity. Six patients (23%) achieved return of spontaneous circulation (ROSC) and one patient (4%) survived to hospital discharge. Rates of ROSC and survival to discharge after IHCA are poor in patients with PAH. Even patients with mild hemodynamics had low likelihood of survival. In patients who are lung transplant candidates, there should be early consideration of extracorporeal support before cardiac arrest.

The Impact of an Inpatient Nurse-Triggered Sepsis Alert on Antimicrobial Utilization.

INTRODUCTION: A nurse-triggered sepsis alert called "Code Sepsis" was implemented for early recognition and management of sepsis. The researchers analyzed its impact on antimicrobial use and identified factors associated with infection as source of Code Sepsis. METHODS: The medical records of hospitalized patients with Code Sepsis between January 1 and June 30, 2018, were reviewed. Patients were classified as "Infection" when probable or definitive infection was identified or "No Infection" when a probable or definitive noninfectious source was identified. Patients were categorized as "Escalation" with addition or change to broader-spectrum antimicrobials or "No Escalation" with no change or change to narrower-spectrum antimicrobials. Escalation was classified as "Indicated" with appropriate escalation or "Not Indicated" with inappropriate escalation. Logistic regression model was used to identify factors associated with Infection as Code Sepsis trigger. RESULTS: Code Sepsis was activated in 529 patients, with Escalation in 246 (46.5%) and No Escalation in 283 (53.5%) patients. Escalation was Indicated in 157 (63.8%) and Not Indicated in 89 (36.2%) patients. Infection was identified in 356 (67.3%) and No Infection in 173 (32.7%) patients. History of HIV (odds ratio [OR] = 2.75, p = 0.03), temperature > 38.3°C or < 36°C (OR = 2.63, p < 0.01), and respiratory rate > 20/minute (OR = 1.56, p = 0.02) were associated with Infection, while surgery within 3 days (OR = 0.30, p < 0.01) was associated with No Infection. CONCLUSION: One hospital system's Code Sepsis inadvertently identified patients without infections and led to antimicrobial overuse. By refocusing Code Sepsis on early recognition of severe sepsis and septic shock only, the organization hopes to optimize resource utilization and improve patient outcomes.