Better Go it Alone: An Extension of Fiduciary Duties for Investment Fund Managers in Securities Class Action Opt-Outs

Securities class actions provide a vehicle for plaintiffs to recover billions of dollars in settlement awards. Given the prevalence of institutional investors in the market for publicly traded securities, it is no surprise that large investment funds are often implicated as lead plaintiffs in securities class actions. Despite having recoverable claims in many of these settlements, these investment funds often fail to participate in the action on behalf of their beneficiaries (their investors). Some scholars argue that fund managers have a fiduciary obligation to participate in claim filing and monitoring processes in an effort to recover settlement awards and to maximize the value of their beneficiaries’ investments. Courts have yet to hold fund managers liable for failure to do so. This Note explores a separate but related phenomenon: the increased prevalence of class action “opt-outs” in which a plaintiff may choose not to be a part of the action in favor of pursuing a separate action, and hopefully recover more than would be available within the class action structure. Inherent in the opt-out calculus is the risk of receiving nothing at all. Given this phenomenon, this Note asks whether it would make sense to extend fiduciary duties to contemplate opt-out behavior in an effort to encourage fund managers to monitor those securities class actions that implicate their respective funds. According to this argument, a fund manager would have a duty to opt out when the recovery outside the class action was likely greater, and when there was a reasonable likelihood that such recovery could be obtained. At the moment, such an extension would not be appropriate. A clear departure from case law related to fiduciary duties and officer liability, such an extension would also inject too much legally encouraged risk taking into the capital markets; it would undermine many of the valid policy objectives of the securities class action; and it would place an undue burden on fund managers to take monitoring obligations to unprecedented levels

Spinal Progenitor-Laden Bridges Support Earlier Axon Regeneration Following Spinal Cord Injury.

Impact statementSpinal cord injury (SCI) results in loss of tissue innervation below the injury. Spinal progenitors have a greater ability to repair the damage and can be injected into the injury, but their regenerative potential is hampered by their poor survival after transplantation. Biomaterials can create a cell delivery platform and generate a more hospitable microenvironment for the progenitors within the injury. In this work, polymeric bridges are used to deliver embryonic spinal progenitors to the injury, resulting in increased progenitor survival and subsequent regeneration and functional recovery, thus demonstrating the importance of combined therapeutic approaches for SCI

Polycistronic Delivery of IL-10 and NT-3 Promotes Oligodendrocyte Myelination and Functional Recovery in a Mouse Spinal Cord Injury Model.

One million estimated cases of spinal cord injury (SCI) have been reported in the United States and repairing an injury has constituted a difficult clinical challenge. The complex, dynamic, inhibitory microenvironment postinjury, which is characterized by proinflammatory signaling from invading leukocytes and lack of sufficient factors that promote axonal survival and elongation, limits regeneration. Herein, we investigated the delivery of polycistronic vectors, which have the potential to coexpress factors that target distinct barriers to regeneration, from a multiple channel poly(lactide-co-glycolide) (PLG) bridge to enhance spinal cord regeneration. In this study, we investigated polycistronic delivery of IL-10 that targets proinflammatory signaling, and NT-3 that targets axonal survival and elongation. A significant increase was observed in the density of regenerative macrophages for IL-10+NT-3 condition relative to conditions without IL-10. Furthermore, combined delivery of IL-10+NT-3 produced a significant increase of axonal density and notably myelinated axons compared with all other conditions. A significant increase in functional recovery was observed for IL-10+NT-3 delivery at 12 weeks postinjury that was positively correlated to oligodendrocyte myelinated axon density, suggesting oligodendrocyte-mediated myelination as an important target to improve functional recovery. These results further support the use of multiple channel PLG bridges as a growth supportive substrate and platform to deliver bioactive agents to modulate the SCI microenvironment and promote regeneration and functional recovery. Impact statement Spinal cord injury (SCI) results in a complex microenvironment that contains multiple barriers to regeneration and functional recovery. Multiple factors are necessary to address these barriers to regeneration, and polycistronic lentiviral gene therapy represents a strategy to locally express multiple factors simultaneously. A bicistronic vector encoding IL-10 and NT-3 was delivered from a poly(lactide-co-glycolide) bridge, which provides structural support that guides regeneration, resulting in increased axonal growth, myelination, and subsequent functional recovery. These results demonstrate the opportunity of targeting multiple barriers to SCI regeneration for additive effects

PLG Bridge Implantation in Chronic SCI Promotes Axonal Elongation and Myelination.

Spinal cord injury (SCI) is a devastating condition that may cause permanent functional loss below the level of injury, including paralysis and loss of bladder, bowel, and sexual function. Patients are rarely treated immediately, and this delay is associated with tissue loss and scar formation that can make regeneration at chronic time points more challenging. Herein, we investigated regeneration using a poly(lactide-co-glycolide) multichannel bridge implanted into a chronic SCI following surgical resection of necrotic tissue. We characterized the dynamic injury response and noted that scar formation decreased at 4 and 8 weeks postinjury (wpi), yet macrophage infiltration increased between 4 and 8 wpi. Subsequently, the scar tissue was resected and bridges were implanted at 4 and 8 wpi. We observed robust axon growth into the bridge and remyelination at 6 months after initial injury. Axon densities were increased for 8 week bridge implantation relative to 4 week bridge implantation, whereas greater myelination, particularly by Schwann cells, was observed with 4 week bridge implantation. The process of bridge implantation did not significantly decrease the postinjury function. Collectively, this chronic model follows the pathophysiology of human SCI, and bridge implantation allows for clear demarcation of the regenerated tissue. These data demonstrate that bridge implantation into chronic SCI supports regeneration and provides a platform to investigate strategies to buttress and expand regeneration of neural tissue at chronic time points

Feasibility of Focused Cardiac Ultrasound in Pre-participation Screening

Objective: Current American Heart Association (AHA) guidelines for pre-participation athletic screening recommend a 12-point history and exam to minimize the risk of sudden cardiac death. We tested the hypothesis that focused cardiac ultrasound (FCU) performed and simultaneously interpreted by a cardiologist using a handheld ultrasound device would be a feasible addition. Methods: We performed pre-participation screening according to AHA recommendations on high school athletes in a multi-purpose room at their school. In addition to the standard 12-point assessment, a cardiologist simultaneously performed and interpreted a FCU on each athlete using a handheld ultrasound. Results: The mean age of the athletes was 16.6 ± 3.4 years; 68% were male. No evidence of left ventricular hypertrophy, cardiomyopathy, bicuspid aortic valve, or aortopathy was identified. Coronary ostia could not be visualized. Echocardiography added 1.35 ± 0.51 minutes to the standard exam. Conclusion: This feasibility study suggests that the addition of handheld echocardiography with real-time interpretation performed by a cardiologist to a standard AHA pre-participation screening adds less than two minutes of time to the assessment. While the study is not as comprehensive as an office based echocardiogram, it can provide valuable information which may be useful in ruling out some of the most common causes of sudden cardiac death in the young athlete or in selecting those who would benefit from further testing

Combinatorial lentiviral gene delivery of pro‐oligodendrogenic factors for improving myelination of regenerating axons after spinal cord injury

Spinal cord injury (SCI) results in paralysis below the injury and strategies are being developed that support axonal regrowth, yet recovery lags, in part, because many axons are not remyelinated. Herein, we investigated strategies to increase myelination of regenerating axons by overexpression of platelet‐derived growth factor (PDGF)‐AA and noggin either alone or in combination in a mouse SCI model. Noggin and PDGF‐AA have been identified as factors that enhance recruitment and differentiation of endogenous progenitors to promote myelination. Lentivirus encoding for these factors was delivered from a multichannel bridge, which we have previously shown creates a permissive environment and supports robust axonal growth through channels. The combination of noggin+PDGF enhanced total myelination of regenerating axons relative to either factor alone, and importantly, enhanced functional recovery relative to the control condition. The increase in myelination was consistent with an increase in oligodendrocyte‐derived myelin, which was also associated with a greater density of cells of an oligodendroglial lineage relative to each factor individually and control conditions. These results suggest enhanced myelination of regenerating axons by noggin+PDGF that act on oligodendrocyte‐lineage cells post‐SCI, which ultimately led to improved functional outcomes.Spinal cord injury (SCI) results in paralysis below the injury and strategies are being developed that support axonal regrowth, yet recovery lags, in part because many axons are not remyelinated. Herein, we investigated strategies to increase myelination of regenerating axons by overexpression of platelet‐derived growth factor‐AA and noggin either alone or in combination in a mouse SCI model.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/146575/1/bit26838_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/146575/2/bit26838.pd

Antiarrhythmic and electrophysiologic actions of clofilium in experimental canine models

Clofilium was studied in three experimental models. In non-ischemic and chronically infarcted canine hearts, clofilium (0.5-2 mg/kg) produced a dose-dependent increase in electrical ventricular fibrillation threshold (VFT), but prolonged the effective refractory period (ERP) of normal myocardium in only the non-ischemic heart. When chronically infarcted hearts were subjected to programmed electrical stimulation, 1 mg/kg of clofilium inhibited the re-induction of either ventricular tachycardia or ventricular fibrillation in 5 of 6 animals and slowed the rate of the induced tachycardia in the sixth. Clofilium, however, failed to alter ventricular refractory periods of normal myocardium at either twice diastolic threshold current (176 +/- 5 ms control vs. 187 +/- 9 ms post-clofilium, P > 0.05) or at 10 mA (134 +/- 6 ms control vs. 137 +/- 13 ms post-clofilium, P > 0.05). In addition, chronic administration of clofilium (2 mg/kg, i.v., followed by 1 mg/kg every 12 h) was ineffective in decreasing mortality in a canine model of sudden coronary death. Of 10 saline-treated conscious animals subjected to an electrically-induced intimal lesion of the left circumflex coronary artery in the presence of a previous ischemic insult, all 10 died suddenly of ventricular fibrillation within 173 +/- 45 min after current application. Under similar conditions, 7 clofilium-treated animals died suddenly within 249 +/- 88 min (P > 0.05) after current application while 3 animals survived (P > 0.10). Clofilium did, however, elevate the effective refractory period in these animals (150 +/- 3 ms saline-treated vs. 195 +/- 7 ms clofilium-reated). It is concluded from our data that there is little relationship between clofilium's electrophysiologic actions in normal myocardium and antiarrhythmic effects. Furthermore, simple prolongation of refractorines in normal non-ischemic myocardium may be insufficient for the prevention of ventricular fibrillation which develops in response to a transient ischemic event superimposed on a chronically injured myocardium.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/25537/1/0000078.pd

Association Between Elevated Mean Arterial Blood Pressure and Neurologic Outcome After Resuscitation From Cardiac Arrest: Results From a Multicenter Prospective Cohort Study

Objective: Laboratory studies suggest elevated blood pressure after resuscitation from cardiac arrest may be protective; however, clinical data are limited. We sought to test the hypothesis that elevated post-resuscitation mean arterial blood pressure (MAP) is associated with neurological outcome. Design: Pre-planned analysis of a prospective cohort study. Setting: Six academic hospitals in the United States. Patients: Adult, non-traumatic cardiac arrest patients treated with targeted temperature management after return of spontaneous circulation (ROSC). Interventions: MAP was measured non-invasively after ROSC and every hour during the initial six hours after ROSC. Measures and Main Results: We calculated the mean MAP and a priori dichotomized subjects into two groups: mean MAP 70–90 and > 90 mmHg. The primary outcome was good neurological function, defined as a modified Rankin Scale (mRS) ≤ 3. The mRS was prospectively determined at hospital discharge. Of the 269 patients included, 159 (59%) had a mean MAP > 90 mmHg. Good neurological function at hospital discharge occurred in 30% of patients in the entire cohort, and was significantly higher in patients with a mean MAP > 90 mmHg (42%) as compared to MAP 70–90 mmHg (15%) [absolute risk difference 27% (95% CI 17%−37%)]. In a multivariable Poisson regression model adjusting for potential confounders, mean MAP > 90 mmHg was associated with good neurological function, adjusted relative risk 2.46 (95% CI 2.09–2.88). Over ascending ranges of mean MAP, there was a dose-response increase in probability of good neurological outcome, with mean MAP > 110 mmHg having the strongest association, adjusted relative risk 2.97 (95% CI 1.86 – 4.76). Conclusions: Elevated blood pressure during the initial six hours after resuscitation from cardiac arrest was independently associated with good neurological function at hospital discharge. Further investigation is warranted to determine if targeting an elevated MAP would improve neurologic outcome after cardiac arrest

Partial pressure of arterial carbon dioxide after resuscitation from cardiac arrest and neurological outcome: A prospective multi-center protocol-directed cohort study

Aims Partial pressure of arterial carbon dioxide (PaCO2) is a regulator of cerebral blood flow after brain injury. We sought to test the association between PaCO2 after resuscitation from cardiac arrest and neurological outcome. Methods A prospective protocol-directed cohort study across six hospitals. Inclusion criteria: age ≥ 18, non-traumatic cardiac arrest, mechanically ventilated after return of spontaneous circulation (ROSC), and receipt of targeted temperature management. Per protocol, PaCO2 was measured by arterial blood gas analyses at one and six hours after ROSC. We determined the mean PaCO2 over this initial six hours after ROSC. The primary outcome was good neurological function at hospital discharge, defined a priori as a modified Rankin Scale ≤ 3. Multivariable Poisson regression analysis was used to test the association between PaCO2 and neurological outcome. Results Of the 280 patients included, the median (interquartile range) PaCO2 was 44 (37-52) mmHg and 30% had good neurological function. We found mean PaCO2 had a quadratic (inverted “U” shaped) association with good neurological outcome, with a mean PaCO2 of 68 mmHg having the highest predictive probability of good neurological outcome, and worse neurological outcome at higher and lower PaCO2. Presence of metabolic acidosis attenuated the association between PaCO2 and good neurological outcome, with a PaCO2 of 51 mmHg having the highest predictive probability of good neurological outcome among patients with metabolic acidosis. Conclusion PaCO2 has a “U” shaped association with neurological outcome, with mild to moderate hypercapnia having the highest probability of good neurological outcome