Investigational agents for treatment of traumatic brain injury

Introduction: Traumatic brain injury (TBI) is a major cause of death and disability worldwide. To date, there are no pharmacologic agents proven to improve outcomes from TBI because all the Phase III clinical trials in TBI have failed. Thus, there is a compelling need to develop treatments for TBI.

Areas covered: The following article provides an overview of select cell-based and pharmacological therapies under early development for the treatment of TBI. These therapies seek to enhance cognitive and neurological functional recovery through neuroprotective and neurorestorative strategies.

Expert opinion: TBI elicits both complex degenerative and regenerative tissue responses in the brain. TBI can lead to cognitive, behavioral, and motor deficits. Although numerous promising neuroprotective treatment options have emerged from preclinical studies that mainly target the lesion, translation of preclinical effective neuroprotective drugs to clinical trials has proven challenging. Accumulating evidence indicates that the mammalian brain has a significant, albeit limited, capacity for both structural and functional plasticity, as well as regeneration essential for spontaneous functional recovery after injury. A new therapeutic approach is to stimulate neurovascular remodeling by enhancing angiogenesis, neurogenesis, oligodendrogenesis, and axonal sprouting, which in concert, may improve neurological functional recovery after TBI.     

Differences in outcomes between the JoyBar control and standard wheelchair joystick control on two maneuverability tasks: a pilot study

Purpose: To determine if older adult, novice wheelchair users who drive a power wheelchair with a JoyBar control complete maneuverability tasks in less time and with less error than those who drive a power wheelchair with a standard joystick control.

Materials and methods: A parallel randomized controlled trial design conducted at a medical rehabilitation and research centre with ambulatory older adults aged 60 and above (n?=?27). The intervention was the JoyBar alternative wheelchair control. The primary outcome measure was total time to complete each of the two maneuverability tasks. The secondary outcome measure was total number of errors during each of the maneuverability tasks.

Results: An independent, two sampled t-test was conducted and revealed that the JoyBar group took a greater amount of time to complete both maneuverability tasks than the control group (p?p?Conclusions: Maneuverability of a powered wheelchair by novice wheelchair users was not improved through the use of the JoyBar when compared to a standard wheelchair joystick, as measured by rates of error and time to complete maneuverability tasks.

• Implications for rehabilitation

• Clients who are new to powered wheelchair use may perform maneuverability tasks faster, with equivalent accuracy, using a standard joystick versus the JoyBar.

• Clients who use a JoyBar may require adjustments to the programming of their wheelchair to ensure optimal performance.

• Additional training may be required to achieve proficiency in maneuverability tasks with a JoyBar versus a standard joystick.

     

Phage Display Selection, <Emphasis Type="Italic">In Vitro</Emphasis> Characterization,and Correlative PET Imaging of a Novel HER3 Peptide

Purpose

HER3 (ERBB3) is a receptor tyrosine kinase that is implicated in treatment resistance across multiple cancers, including those of the breast, lung, and prostate. Overexpression of HER3 following targeted therapy can occur rapidly and heterogeneously both within a single lesion and across sites of metastasis, making protein quantification by biopsy highly challenging. A global, non-invasive methodology such as positron emission tomography (PET) imaging can permit serial quantification of HER3, providing a useful approach to monitor HER3 expression across the entire tumor burden both prior to and following treatment. PET imaging of HER3 expression may permit a more personalized approach to targeted therapy by allowing for detection of HER3-mediated resistance, in addition to informing clinical trial patient selection for novel therapies targeting HER3.

Procedures

Phage display selection targeting the HER3 extracellular domain was performed in order to develop a peptide with optimal blood clearance and highly accurate HER3 quantification.

Results

The selection converged to a consensus peptide sequence that was subsequently found to bind HER3 with an affinity of 270 ± 151 nM. The peptide, termed HER3P1, was bound with high selectivity to HER3 over other similar receptor tyrosine kinases such as EGFR and HER2. Furthermore, HER3P1 was able to distinguish between high and low HER3-expressing cells in vitro. The peptide was radiolabeled with Ga-68 and demonstrated to specifically bind HER3 by in vivo PET imaging. Uptake of [⁶⁸Ga]HER3P1 was highly specific for HER3-positive tumors, with tumor-to-background ratios ranging from 1.59–3.32, compared to those of HER3-negative tumors, ranging from 0.84–0.93. The uptake of [⁶⁸Ga]HER3P1 also demonstrated high (P < 0.001) correlation with protein expression as quantified by Western blot and confirmed by biodistribution.

Conclusions

HER3P1 accurately quantifies expression of HER3 by PET imaging and has potential utility as a clinical imaging agent.

     

New-Onset Diabetes and Preexisting Diabetes Are Associated With Comparable Reduction in Long-Term Survival After Liver Transplant: A Machine Learning Approach

Objective

To identify key predictors and survival outcomes of new-onset diabetes after transplant (NODAT) in liver transplant (LT) recipients by using the Scientific Registry of Transplant Recipients.

Cluster of Middle East Respiratory Syndrome Coronavirus Infections in Iran, 2014

During January 2013–August 2014, a total of 1,800 patients in Iran who had respiratory illness were tested for Middle East respiratory syndrome coronavirus. A cluster of 5 cases occurred in Kerman Province during May–July 2014, but virus transmission routes for some infections were unclear.     

Alternative Recruitment Strategies Influence Saliva Sample Return Rates in Community‐Based Genetic Association Studies

Collection of saliva for DNA extraction has created new opportunities to recruit participants from the community for genetic association studies. However, sample return rates are variable. No prior study has specifically addressed how study design impacts sample return. Using data from three large‐scale genetic association studies we compared recruitment strategy and sample return rates. We found highly significant differences in sample return rates between the studies. In studies that recruited retrospectively, overall returns were much lower from families with a self‐limiting condition who provided samples at a research centre or home visit, than adult elderly individuals with a chronic disease who provided samples by post (59% vs. 84%). Prospective recruitment was associated with high agreement to participate (72%), but subsequent low return of actual saliva samples (42%). A telephone call had marginal effect on recruitment in a retrospective family study, but significantly improved returns in a prospective family study. We found no effect upon DNA yield comparing observed versus unobserved sample collection, or between male and female adult participants. Overall, study design significantly impacts upon response rates for genetic association studies recruiting from the community. Our findings will help researchers in constructing and costing a recruitment protocol.