Extracorporeal cardiopulmonary resuscitation for refractory out-of-hospital cardiac arrest: Lessons learned from recent clinical trials.

Cardiac arrest is a leading contributor to morbidity and mortality in the United States. Survival has been historically dependent on high-quality cardiopulmonary resuscitation (CPR) and rapid defibrillation. However, a large percentage of patients remain in refractory cardiac arrest despite adherence to structured advanced cardiac life support algorithms in which these factors are emphasized. Veno-arterial extracorporeal membrane oxygenation is becoming an increasingly used rescue therapy for patients in refractory cardiac arrest to restore oxygen delivery by extracorporeal CPR (ECPR). Recently published clinical trials have provided new insights into ECPR for patients who sustain an outside hospital cardiac arrest (OHCA). In this narrative review, we summarize the rationale for, results of, and remaining questions from these recently published clinical trials. The existing observational data combined with the latest clinical trials suggest ECPR improves mortality in patients in refractory arrest. However, a mixed methods trial is essential to understand the complexity, context, and effectiveness of implementing an ECPR program.

Newborn Brain Function and Early Emerging Callous-Unemotional Traits.

Importance: Children with high callous-unemotional traits are more likely to develop severe and persistent conduct problems; however, the newborn neurobiology underlying early callous-unemotional traits remains unknown. Understanding the neural mechanisms that precede the development of callous-unemotional traits could help identify at-risk children and encourage development of novel treatments. Objective: To determine whether newborn brain function is associated with early-emerging empathy, prosociality, and callous-unemotional traits. Design, Setting, and Participants: In this prospective, longitudinal cohort study, pregnant women were recruited from obstetric clinics in St Louis, Missouri, from September 1, 2017, to February 28, 2020, with longitudinal data collected until March 20, 2023. Mothers were recruited during pregnancy. Newborns underwent brain magnetic resonance imaging shortly after birth. Mothers completed longitudinal follow-up when the children were aged 1, 2, and 3 years. Exposures: The sample was enriched for exposure to socioeconomic disadvantage. Main Outcome and Measure: Functional connectivity between hypothesized brain regions was assessed using newborn-specific networks and voxel-based connectivity analyses. Children's callous-unemotional traits were measured using the Inventory of Callous-Unemotional Traits. Empathy and prosociality were assessed using the Infant and Toddler Socio-Emotional Assessment. Results: A total of 283 children (mean [SD] gestational age, 38 [2] weeks; 159 male [56.2%]; 2 Asian [0.7%], 171 Black [60%], 7 Hispanic or Latino [2.5%], 106 White [38%], 4 other racial or ethnic group [1.4%]) were included in the analysis. Stronger newborn functional connectivity between the cingulo-opercular network (CO) and medial prefrontal cortex (mPFC) was associated with higher callous-unemotional traits at age 3 years (ß = 0.31; 95% CI, 0.17-0.41; P < .001). Results persisted when accounting for parental callous-unemotional traits and child externalizing symptoms. Stronger newborn CO-mPFC connectivity was also associated with lower empathy and lower prosociality at ages 1, 2, and 3 years using multilevel models (ß = -0.12; 95% CI, -0.21 to -0.04; P = .004 and ß = -0.20; 95% CI, -0.30 to -0.10; P < .001, respectively). Conclusions and Relevance: Newborn functional connectivity was associated with early-emerging empathy, prosociality, and callous-unemotional traits, even when accounting for parental callous-unemotional traits and child externalizing symptoms. Understanding the neurobiological underpinnings of empathy, prosociality, and callous-unemotional traits at the earliest developmental point may help early risk stratification and novel intervention development.

Predicting Hospital Readmissions in a Commercially Insured Population over Varying Time Horizons.

BACKGROUND: Reducing hospital readmissions is a federal policy priority, and predictive models of hospital readmissions have proliferated in recent years; however, most such models tend to focus on the 30-day readmission time horizon and do not consider readmission over shorter (or longer) windows. OBJECTIVES: To evaluate the performance of a predictive model of hospital readmissions over three different readmission timeframes in a commercially insured population. DESIGN: Retrospective multivariate logistic regression with an 80/20 train/test split. PARTICIPANTS: A total of 2,213,832 commercially insured inpatient admissions from 2016 to 2017 comprising 782,768 unique patients from the Health Care Cost Institute. MAIN MEASURES: Outcomes are readmission within 14 days, 15-30 days, and 31-60 days from discharge. Predictor variables span six different domains: index admission, condition history, demographic, utilization history, pharmacy, and environmental controls. KEY RESULTS: Our model generates C-statistics for holdout samples ranging from 0.618 to 0.915. The model's discriminative power declines with readmission time horizon: discrimination for readmission predictions within 14 days following discharge is higher than for readmissions 15-30 days following discharge, which in turn is higher than predictions 31-60 days following discharge. Additionally, the model's predictive power increases nonlinearly with the inclusion of successive risk factor domains: patient-level measures of utilization and condition history add substantially to the discriminative power of the model, while demographic information, pharmacy utilization, and environmental risk factors add relatively little. CONCLUSION: It is more difficult to predict distant readmissions than proximal readmissions, and the more information the model uses, the better the predictions. Inclusion of utilization-based risk factors add substantially to the discriminative ability of the model, much more than any other included risk factor domain. Our best-performing models perform well relative to other published readmission prediction models. It is possible that these predictions could have operational utility in targeting readmission prevention interventions among high-risk individuals.

IV tPA given in the golden hour for emergent large vessel occlusion stroke improves recanalization rates and clinical outcomes.

BACKGROUND: Early thrombolysis for acute ischemic stroke (AIS) due to emergent large vessel occlusion (ELVO) is associated with better clinical outcome. This is thought to be due to greater tissue salvage with earlier recanalization. We explored whether ultra-early administration of intravenous tissue plasminogen activator (IV tPA) within 60 min (Golden Hour) of symptom onset for AIS due to ELVO is associated with a higher rate of recanalization. METHODS: We performed a retrospective analysis of recanalization rates and clinical outcomes in patients with AIS due to ELVO treated with IV tPA, comparing patients who received IV tPA within 60 min of stroke symptom onset with those treated beyond 60 min. RESULTS: Between January 2013 and December 2016, 158 patients with AIS due to ELVO were treated with IV tPA. Of these, 25 (15.8%) patients received IV tPA within 60 min of stroke symptom onset, while the remaining 133 (84.2%) patients received IV tPA beyond 60 min. The ultra-early treatment group was found to have a higher rate of complete recanalization (28.0% vs 6.8%, 95% CI 1.78-16.63), better chance of early neurological improvement (76.0% vs 50.4%, 95% CI 1.16-8.65), favorable clinical outcomes (mRS ≤ 2 or return to premorbid mRS) (65.0% vs 36.8%, 95% CI 1.42-9.34), and lower mortality (5% vs 31.1%, 95% CI 0.01-0.74) at 90-day follow-up compared to the later treatment group. CONCLUSION: Our data suggest that ultra-early administration of IV tPA significantly improves recanalization rates and clinical outcomes in patients with AIS due to ELVO.

Decreased Observance of Stroke in the Population Associated With COVID-19 Related Distancing Measures.

Stroke is a catastrophic medical disease with roughly 795,000 cases per year in the US. We strove to explore whether stroke admissions to a comprehensive stroke center in an area with moderately-low COVID-19 burden changed and if so, to better define the characteristics of the patients and their presentation. We performed a retrospective analysis of all patients with strokes admitted to Intermountain Medical Center. There was a 43% reduction in patients' presentations across all stroke types compared to average April patient volume over the prior 3 years. Likely this was due to a myriad of complex factors which we may retrospectively be able to more fully understand in the years to come.

Reduction in time to treatment in prehospital telemedicine evaluation and thrombolysis.

OBJECTIVE: To compare the times to evaluation and thrombolytic treatment of patients treated with a telemedicine-enabled mobile stroke treatment unit (MSTU) vs those among patients brought to the emergency department (ED) via a traditional ambulance. METHODS: We implemented a MSTU with telemedicine at our institution starting July 18, 2014. A vascular neurologist evaluated each patient via telemedicine and a neuroradiologist and vascular neurologist remotely assessed images obtained by the MSTU CT. Data were entered in a prospective registry. The evaluation and treatment of the first 100 MSTU patients (July 18, 2014-November 1, 2014) was compared to a control group of 53 patients brought to the ED via a traditional ambulance in 2014. Times were expressed as medians with their interquartile ranges. RESULTS: Patient and stroke severity characteristics were similar between 100 MSTU and 53 ED control patients (initial NIH Stroke Scale score 6 vs 7, p = 0.679). There was a significant reduction of median alarm-to-CT scan completion times (33 minutes MSTU vs 56 minutes controls, p < 0.0001), median alarm-to-thrombolysis times (55.5 minutes MSTU vs 94 minutes controls, p < 0.0001), median door-to-thrombolysis times (31.5 minutes MSTU vs 58 minutes controls, p = 0.0012), and symptom-onset-to-thrombolysis times (97 minutes MSTU vs 122.5 minutes controls, p = 0.0485). Sixteen patients evaluated on MSTU received thrombolysis, 25% of whom received it within 60 minutes of symptom onset. CONCLUSION: Compared with the traditional ambulance model, telemedicine-enabled ambulance-based thrombolysis resulted in significantly decreased time to imaging and treatment.

Significant period between presentation and diagnosis in basilar artery occlusion: five cases and the lessons learned.

Basilar artery occlusion remains a challenging pathological process. Time delay between presentation and diagnosis and treatment can be associated with poor outcome, but the low frequency and variable presentation in BAO makes rapid diagnosis difficult. Clinicians should maintain an index of suspicion for basilar artery occlusion in patients of any age who present with focal neurological symptoms that could be referable to the basilar artery. Timely vessel imaging is critical for the diagnosis and initiation of treatment in these patients.

Higher plasma fractalkine is associated with better 6-month outcome from ischemic stroke.

BACKGROUND AND PURPOSE: Fractalkine (CX3CL1) is a unique chemokine that is constitutively expressed on neurons where it serves as an adhesion molecule for lymphocytes and monocytes. CX3CL1 may also be cleaved from the surface of these cells and enter the circulation to act as a traditional chemokine. CX3CL1 could thus influence the inflammatory response after stroke. We hypothesized that patients with higher plasma CX3CL1 after stroke would have a more robust inflammatory response and experience worse outcome. METHODS: Plasma CX3CL1 concentrations were assessed in 85 patients who were part of a larger study evaluating immune responses after ischemic stroke; CX3CL1 values were available from Day 1 to Day 180 after stroke onset. CX3CL1 was correlated to measures of inflammation and its effect on outcome assessed. RESULTS: At 1 day after stroke, CX3CL1 was lower in patients with severe strokes. At 180 days after stroke, CX3CL1 concentrations were lower in patients with poor outcome. The association of CX3CL1 and outcome at 180 days was independent of initial stroke severity. Plasma CX3CL1 at 180 days was inversely associated with systemic markers of inflammation, including white blood cell counts and high-sensitivity C-reactive protein. CONCLUSIONS: In contrast to our original hypothesis, lower concentrations of CX3CL1 are associated with worse stroke outcome. In light of recent studies suggesting an immunomodulatory and neuroprotective role for CX3CL1 in a variety of neurodegenerative diseases, a therapeutic role for CX3CL1 in stroke recovery should be considered.

Implications of pharmacogenetic testing for patients taking warfarin or clopidogrel.

Our knowledge of the pharmacogenetics of warfarin and clopidogrel continues to expand as we learn more about the individual genetic variations that contribute to the drugs' efficacy and toxicity. We aim to review the recent developments in the field and discuss the clinical implications for the treatment of ischemic stroke patients. Despite recent advances, there is still insufficient data to suggest that routine genetic testing improves outcomes in patients treated with warfarin or clopidogrel for prevention of stroke.

Concomitant presentation of three rare mesencephalic syndromes: case report.

We describe a unique case of concomitant presentation of three rare mesencephalic syndromes. A 48-year-old man with an acute stoke was found to have an unusual combination of three rare mesencephalic syndromes after detailed neuro-ophthalmic evaluation: the plus-minus lid syndrome, the vertical one-and-a-half syndrome, and Claude's syndrome. We discuss the clinical and anatomical localization of these syndromes. This was corroborated by magnetic resonance imaging (MRI) which revealed areas of infarction at the thalamo-mesencephalic junction and the right rostral midbrain involving the third nerve fascicle and the red nucleus. Our case highlights the importance of a careful ocular motility examination as a tool which has a highly localizing value in the diagnosis of stroke.

Transcranial Doppler ultrasound CO2 challenge complicated by subarachnoid hemorrhage in patient with moyamoya syndrome.

INTRODUCTION: Studies to assess the hemodynamic status of patients with moyamoya syndrome are often done to determine the need for surgical revascularization. These studies, including transcranial Doppler (TCD) ultrasonography to assess vasomotor reactivity (VMR) to CO(2), are generally considered safe. CASE: We describe a patient with moyamoya syndrome who experienced a subarachnoid hemorrhage (SAH) following TCD with CO(2) challenge. CONCLUSION: SAH has not previously been described as a complication of CO(2) challenge in patients with moyamoya syndrome. While such complications are rare, it is important to consider the possibility of harm related to VMR testing in patients with advanced vasculopathy.

Rickets in VDR null mice is secondary to decreased apoptosis of hypertrophic chondrocytes.

Both vitamin D deficiency and the absence of a functional vitamin D receptor (VDR) lead to a growth plate abnormality known as rickets. Prevention of abnormal mineral ion homeostasis by early institution of dietary therapy in VDR null mice prevents rickets, demonstrating that the VDR is not required for normal growth plate maturation. We, therefore, hypothesized that rickets, in the absence of a functional VDR, is due to impaired mineral ion homeostasis. Analyses of growth plate morphology in VDR null mice demonstrated normal resting and proliferating chondrocyte layers; however an expansion of the hypertrophic chondrocyte layer was present by 24 days of age. Because extracellular calcium has been shown to play a role in chondrocyte maturation, we addressed the hypothesis that hypocalcemia led to impaired chondrocyte differentiation. However, in situ hybridization analyses revealed normal expression of hypertrophic chondrocyte markers in the tibial growth plate of 24 day old VDR null mice, suggesting that the increase in the hypertrophic chondrocyte layer was not secondary to impaired differentiation. We then addressed whether expansion of the hypertrophic chondrocyte layer was secondary to increased proliferation or decreased apoptosis. BrdU labeling failed to demonstrate an increase in chondrocyte proliferation in the VDR null mice; however, apoptosis was markedly diminished in the late hypertrophic chondrocytes of the VDR null mice, suggesting that impairment in programmed cell death of these cells leads to the characteristic findings of rickets.

Tetracycline-regulated gene expression in replication-incompetent herpes simplex virus vectors.

Although herpes simplex virus (HSV) vectors appear to have great potential as gene delivery vectors both in vitro and in vivo, the expression of foreign genes in such vectors cannot be easily regulated. Of the known eukaryotic regulatory systems, the tetracycline-inducible gene expression system is perhaps the most widely used because of its induction characteristics and because of the well-known pharmacological properties of tetracycline (Tet) and analogs such as doxycycline. Here, we describe the adaptation of the Tet-inducible system for use in replication-incompetent HSV vectors. HSV vectors were constructed that contained several types of Tet-inducible promoters for foreign gene expression. These promoters contained a tetracycline response element (TRE) linked to either a minimal cytomegalovirus (CMV) immediate-early promoter, a minimal HSV ICP0 promoter, or a truncated HSV ICP0 promoter containing one copy of the HSV TAATGARAT cis-acting immediate-early regulatory element (where R represents a prime base). All three promoter constructs were regulated appropriately by doxycycline, as shown by the expression of the marker gene lacZ in cell lines engineered to express Tet transactivators. The ICP0 promoter constructs expressed the highest and most sustained levels of lacZ, but the CMV promoter construct had the highest relative level of induction, suggesting their use in different applications. To extend the utility of Tet-regulated HSV vectors, vectors were constructed that coexpressed an inducible Tet transactivator in addition to the inducible lacZ marker gene. This modification resulted in tetracycline-inducible gene expression that was not restricted to specific cell lines, and this vector was capable of inducible expression in irreversibly differentiated NT2 cells (NT-neurons) for several days. Finally, HSV vectors were constructed that expressed modified Tet transactivators, resulting in improved induction properties and indicating the flexibility of the Tet-regulated system for regulation of foreign gene expression in HSV vector-infected cells.