The challenge of recruitment for neurotherapeutic clinical trials in spinal cord injury.

STUDY DESIGN: Narrative review by individuals experienced in the recruitment of participants to neurotherapeutic clinical trials in spinal cord injury (SCI). OBJECTIVES: To identify key problems of recruitment and explore potential approaches to overcoming them. METHODS: Published quantitative experience with recruitment of large-scale, experimental neurotherapeutic clinical studies targeting central nervous system and using primary outcome assessments validated for SCI over the last 3 decades was summarized. Based on this experience, potential approaches to improving recruitment were elicited from the authors. RESULTS: The rate of recruitment has varied between studies, depending on protocol design and other factors, but particularly inclusion/exclusion criteria. The recruitment rate also ranged over an order of magnitude between individual centers in a given study. In older multicenter studies, average recruitment rate was approximately one person per study center per month. More recent trials experienced lower rates of recruitment and potential reasons for this trend were examined. The current roles and potential of various stakeholder organizations in addressing problems of recruitment were explored. In addition, recent developments in methodology may help reduce the number of subjects required for well-powered studies. CONCLUSIONS: Several approaches are emerging to improve clinical trial design, efficacy outcome measures, and quantifiable surrogate markers, all of which should reduce the number of participants required for adequate statistical power. There is a growing sense of cooperation between various stakeholders but more should be done to bring together consumer and provider groups to improve recruitment and the effectiveness and relevance of neurotherapeutic clinical trials.

Representativeness of the Spinal Cord Injury Model Systems National Database.

STUDY DESIGN: Secondary analysis of prospectively collected observational data. OBJECTIVES: To assess the representativeness of the Spinal Cord Injury Model Systems National Database (SCIMS-NDB) of all adults aged 18 years or older receiving inpatient rehabilitation in the United States (US) for new onset traumatic spinal cord injury (TSCI). SETTING: Inpatient rehabilitation centers in the US. METHODS: We compared demographic, functional status, and injury characteristics (nine categorical variables comprising of 46 categories and two continuous variables) between the SCIMS-NDB (N = 5969) and UDS-PRO/eRehabData (N = 99,142) cases discharged from inpatient rehabilitation in 2000-2010. RESULTS: There are negligible differences (<5%) between SCIMS-NDB patients and the population for 31 of the 48 comparisons. Minor differences (5-10%) exist for age categories, sex, race/ethnicity, marital status, FIM Motor score, and time from injury to rehabilitation admission. Important differences (>10%) exist in mean age and preinjury occupational status; the SCIMS-NDB sample was younger and included a higher percentage of individuals who were employed (62.7 vs. 41.7%) and fewer who were retired (10.2 vs. 36.1%). CONCLUSIONS: Adults in the SCIMS-NDB are largely representative of the population of adults receiving inpatient rehabilitation for new onset TSCI in the US. However, users of the SCIMS-NDB may need to adjust statistically for differences in age and preinjury occupational status to improve generalizability of findings.

Considerations and recommendations for selection and utilization of upper extremity clinical outcome assessments in human spinal cord injury trials.

STUDY DESIGN: This is a focused review article. OBJECTIVES: This review presents important features of clinical outcomes assessments (COAs) in human spinal cord injury research. Considerations for COAs by trial phase and International Classification of Functioning, Disability and Health are presented as well as strengths and recommendations for upper extremity COAs for research. Clinical trial tools and designs to address recruitment challenges are identified. METHODS: The methods include a summary of topics discussed during a two-day workshop, conceptual discussion of upper extremity COAs and additional focused literature review. RESULTS: COAs must be appropriate to trial phase and particularly in mid-late-phase trials, should reflect recovery vs. compensation, as well as being clinically meaningful. The impact and extent of upper vs. lower motoneuron disease should be considered, as this may affect how an individual may respond to a given therapeutic. For trials with broad inclusion criteria, the content of COAs should cover all severities and levels of SCI. Specific measures to assess upper extremity function as well as more comprehensive COAs are under development. In addition to appropriate use of COAs, methods to increase recruitment, such as adaptive trial designs and prognostic modeling to prospectively stratify heterogeneous populations into appropriate cohorts should be considered. CONCLUSIONS: With an increasing number of clinical trials focusing on improving upper extremity function, it is essential to consider a range of factors when choosing a COA. SPONSORS: Craig H. Neilsen Foundation, Spinal Cord Outcomes Partnership Endeavor.

Patterns of Sacral Sparing Components on Neurologic Recovery in Newly Injured Persons With Traumatic Spinal Cord Injury.

OBJECTIVE: To assess the patterns of sacral sparing and recovery in newly injured persons with traumatic spinal cord injury (SCI). DESIGN: Retrospective analysis of data from the national Spinal Cord Injury Model Systems (SCIMS) database for patients enrolled from January 2011 to February 2015. SETTING: SCIMS centers. PARTICIPANTS: Individuals (N=1738; age ≥16y) with traumatic SCI admitted to rehabilitation within 30 days after injury with follow-up at discharge, at 1 year, or both. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: International Standards for Neurological Classification of Spinal Cord Injury examination results at admission and follow-up (discharge or 1y, or both). RESULTS: Conversion from an initial American Spinal Injury Association Impairment Scale (AIS) grade A to incomplete status was 20% at rehabilitation discharge and 27.8% at 1 year, and was greater in cervical and low paraplegia levels (T10 and below) than in high paraplegia level injuries (T1-9). Conversion from AIS B to motor incomplete was 33.9% at discharge and 53.6% at 1 year, and the initial sparing of all sacral sensory components was correlated with the greatest conversion to motor incomplete status at discharge and at 1 year. For patients with initial AIS C, the presence of voluntary anal contraction (VAC) in association with other sacral sparing was most frequently observed to improve to AIS D status at discharge. However, the presence of VAC alone as the initial sacral sparing component had the poorest prognosis for recovery to AIS D status. At follow-up, regaining sacral sparing components correlated with improvement in conversion for patients with initial AIS B and C. CONCLUSIONS: The components of initial and follow-up sacral sparing indicated differential patterns of neurologic outcome in persons with traumatic SCI. The more sacral components initially spared, the greater the potential for recovery; and the more sacral components gained, the greater the chance of motor recovery. Consideration of whether VAC should remain a diagnostic criterion sufficient for motor incomplete classification in the absence of other qualifying sublesional motor sparing is recommended.

The impact of sacral sensory sparing in motor complete spinal cord injury.

OBJECTIVE: To determine the effect of sensory sparing in motor complete persons with spinal cord injury (SCI) on completion of rehabilitation on neurologic, functional, and social outcomes reported at 1 year. DESIGN: Secondary analysis of longitudinal data collected by using prospective survey-based methods. SETTING: Data submitted to the National SCI Statistical Center Database. PARTICIPANTS: Of persons (N=4106) enrolled in the model system with a motor complete injury (American Spinal Injury Association Impairment Scale [AIS] grade A or B) at the time of discharge between 1997 and 2007, a total of 2331 (56.8%) completed a 1-year follow-up interview (Form II) and 1284 (31.3%) had complete data for neurologic (eg, AIS grade, injury level) variables at 1 year. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: AIS grade (A vs B) at 1 year, bladder management, hospitalizations, perceived health status, motor FIM items, Satisfaction With Life Scale, depressive symptoms, and social participation. RESULTS: Compared with persons with AIS grade A at discharge, persons with AIS grade B were less likely to require indwelling catheterization and be hospitalized and more likely to perceive better health, report greater functional independence (ie, self-care, sphincter control, mobility, locomotion), and report social participation in the first year postinjury. A greater portion of individuals with AIS grade B at discharge had improved neurologic recovery at 1 year postinjury than those with AIS grade A. Significant AIS group differences in 1-year outcomes related to physical health were maintained after excluding persons who improved to motor incomplete status for only bladder management and change in perceived health status. This recognition of differences between persons with motor complete injuries (AIS grade A vs B) has important ramifications for the field of SCI rehabilitation and research.

Upper- and lower-extremity motor recovery after traumatic cervical spinal cord injury: an update from the national spinal cord injury database.

OBJECTIVE: To present upper- (UEMS) and lower-extremity motor score (LEMS) recovery, American Spinal Injury Association Impairment Scale (AIS) change, and motor level change in persons with traumatic tetraplegia from the Spinal Cord Injury Model Systems (SCIMS). DESIGN: Longitudinal cohort; follow-up to 1 year. SETTING: U.S. SCIMS. PARTICIPANTS: Subjects (N=1436; age>15y) with tetraplegia with at least 2 examinations, the first within 7 days of injury. Subjects were 80% men injured by vehicular collisions (44%), falls (30%), sports (12%), and violence (11%). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Change in AIS, UEMS, LEMS, and motor levels. RESULTS: From a baseline of 7 days or less, 22% of subjects with AIS grade A converted to AIS grade B or better by rehabilitation discharge; and 30%, by 1 year, with 8% to AIS grade C and 7.1% to grade D. Conversion from complete to motor incomplete was not related to timing of the initial examination (P=.54) or initial neurologic level (P=.96). For AIS grade B, 34% remained motor complete, 30% became AIS grade C, and 37% became grade D by 1 year. Although 82.5% of those with AIS grade C improved to AIS grades D and E, mean 1-year UEMS score was only 35 points. UEMS scores in patients with AIS grade A increased a mean of 9 to 11 points, except for C1 to C3 and C8 to T1 motor levels (gain, 2-3 points). Motor level was unchanged or ascended in 35% and improved 1 level in 42%, 2 levels in 14%, and more than 2 levels in 9%. Motor zone of partial preservation of 2 segments or more was associated with gain of 2 or more motor levels, with a relative risk of 5.0 (95% confidence interval, 3.2-7.8; P<.001). CONCLUSIONS: More patients with cervical complete spinal cord injury may be converting to AIS grade D compared with earlier reports. Motor level recovery in those with AIS grade A and UEMS recovery in those with AIS grade C injuries are potential outcomes for acute clinical trials.

Inpatient and postdischarge rehabilitation services provided in the first year after spinal cord injury: findings from the SCIRehab Study.

OBJECTIVE: To examine the amount and type of therapy services received in inpatient and postdischarge settings during the first year after spinal cord injury (SCI). DESIGN: Prospective observational longitudinal cohort design. Data were obtained from systematic recording of interventions by clinicians and from patient interview. SETTING: Inpatient and postdischarge rehabilitation programs. PARTICIPANTS: Patients (N=493) with traumatic SCI admitted to 6 rehabilitation centers participating in the SCIRehab study. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Hours of therapy by physical therapy (PT), occupational therapy (OT), speech therapy, recreation therapy, psychology, social work/case management, and nursing education during initial inpatient rehabilitation and postdischarge up to the first anniversary of injury. Inpatient data were collected prospectively by the treating clinicians; postdischarge service data were collected by patient self-report during follow-up interviews. RESULTS: Of the total hours spent on these rehabilitation interventions during the first year after injury, 44% occurred after discharge from inpatient rehabilitation. Participants received 56% of their PT hours after discharge and 52% of their OT hours, but only a minority received any postdischarge services from other rehabilitation disciplines. While wide variation was found in the total hours of inpatient treatment across all disciplines, the variation in the total hours of postdischarge services was greater, with the interquartile range of postdischarge services being twice that of the inpatient services. CONCLUSIONS: SCI rehabilitation is often given in a care continuum, with inpatient rehabilitation being only the beginning. Reductions in inpatient SCI rehabilitation length of stay are well documented, but the postdischarge services that may replace some inpatient treatment appear to be greater than previously reported. The availability and impact of postdischarge care should be studied in greater detail to capture the wide array of postdischarge services and outcomes.

Mechanical ventilation, health, and quality of life following spinal cord injury.

OBJECTIVE: To examine differences in perceived quality of life (QOL) at 1 year postinjury between people with tetraplegia who required mechanical ventilation assistance at discharge from rehabilitation and those who did not. DESIGN: Prospective cross-sectional examination of people with spinal cord injury (SCI) drawn from the SCI Model Systems National Database. SETTING: Community. PARTICIPANTS: People with tetraplegia (N=1635) who sustained traumatic SCI between January 1, 1994, and September 30, 2008, who completed a 1-year follow-up interview, including 79 people who required at least some use of a ventilator at discharge from rehabilitation. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Satisfaction With Life Scale (SWLS); Craig Handicap Assessment and Reporting Technique (CHART)-Short Form Physical Independence, Mobility, Social Integration, and Occupation subscales; Patient Health Questionnaire-9 (PHQ-9), Medical Outcomes Study 36-Item Short-Form Health Survey self-perceived health status. RESULTS: Significant differences were found between the ventilator-user (VU) group and non-ventilator-user (NVU) group for cause of trauma, proportion with complete injury, neurologic impairment level, and number of rehospitalizations. The NVU group had significantly higher SWLS and CHART Social Integration scores than the VU group after controlling for selected covariates. The NVU group also had more positive perceived health status compared with a year previously and a lower incidence of depression assessed by using the PHQ-9 than the VU group. There were no significant differences between groups for perceived current health status. CONCLUSIONS: People in this study who did not require mechanical ventilation at discharge from rehabilitation post-SCI reported generally better health and improved QOL compared with those who required ventilator assistance at 1 year postinjury. Nonetheless, the literature suggests that perceptions of QOL improve as people live in the community for longer periods.

Apolipoprotein E epsilon4 allele and outcomes of traumatic spinal cord injury.

BACKGROUND/OBJECTIVE: To test the hypothesis that apolipoprotein E (APOE) polymorphisms are associated with outcomes after spinal cord injury (SCI). METHODS: Retrospective cohort study, from rehabilitation admission to discharge. PARTICIPANTS: Convenience sample of 89 persons with cervical SCI (C3-C8) treated from 1995 through 2003. Median age was 30 years (range 14-70); 67 were male (75%) and 83 were white (93%). MAIN OUTCOME MEASURES: American Spinal Injury Association (ASIA) motor and sensory scores, ASIA Impairment Scale (AIS), time from injury to rehabilitation admission, and length of stay (LOS) in rehabilitation. RESULTS: Subjects with an APOE epsilon4 allele (n = 15; 17%) had significantly less motor recovery during rehabilitation than did individuals without an epsilon4 allele (median 3.0 vs 5.5; P < 0.05) and a longer rehabilitation LOS (median 106 vs 89 days; P = 0.04), but better sensory-pinprick recovery (median 5.0 vs 2.0; P= 0.03). There were no significant differences by APOE epsilon4 allele status in sensory-light touch recovery, likelihood of improving AIS Grade, or time from injury to rehabilitation admission. CONCLUSIONS: APOE epsilon4 allele was associated with differences in neurological recovery and longer rehabilitation LOS. Genetic factors may be among the determinants of outcome after SCI and warrant further study.

Research progress from the SCI Model Systems (SCIMS): An interactive discussion on future directions.

CONTEXT/OBJECTIVE: To describe current and future directions in spinal cord injury (SCI) research. DESIGN: The SCI Model Systems (SCIMS) programs funded by the National Institute on Disability, Independent Living, and Rehabilitation Research (NIDILRR) during the 2011 to 2016 cycle provided abstracts describing findings from current research projects. Discussion among session participants generated ideas for research opportunities. SETTING/PARTICIPANTS: Pre-conference workshop before the 2016 American Spinal Injury Association (ASIA) annual meeting. A steering committee selected by the SCIMS directors that included the moderators of the sessions at the ASIA pre-conference workshop, researchers presenting abstracts during the session, and the audience of over 100 attending participants in the pre-conference workshop. METHODS/RESULTS: Group discussion followed presentations in 5 thematic areas of (1) Demographics and Measurement; (2) Functional Training; (3) Psychosocial Considerations; (4) Assistive Technology; and (5) Secondary Conditions. The steering committee reviewed and summarized discussion points on future directions for research and made recommendations for research based on the discussion in each of the five areas. CONCLUSION: Significant areas in need of research in SCI remain, the goal of which is continued improvement in the quality of life of individuals with SCI.

Long-term survival of persons ventilator dependent after spinal cord injury.

BACKGROUND/OBJECTIVE: Identify factors related to long-term survival, and quantify their effect on mortality and life expectancy. SETTING: Model spinal cord injury systems of care across the United States. STUDY DESIGN: Survival analysis of persons with traumatic spinal cord injury who are ventilator dependent at discharge from inpatient rehabilitation and who survive at least 1 year after injury. METHODS: Logistic regression analysis on a data set of 1,986 person-years occurring among 319 individuals injured from 1973 through 2003. RESULTS: The key factors related to long-term survival were age, time since injury, neurologic level, and degree of completeness of injury. The life expectancies were modestly lower than previous estimates. Pneumonia and other respiratory conditions remain the leading cause of death but account for only 31% of deaths of known causes. CONCLUSIONS: Whereas previous research has suggested a dramatic improvement in survival over the last few decades in this population, this is only the case during the critical first few years after injury. There was no evidence for such a trend in the subsequent period.

Neurorehabilitation of spinal cord injuries following lightning and electrical trauma.

While spinal cord injuries caused by lightning strike or electrical shock are rare, their clinical manifestations pose unique challenges to the clinician who must anticipate the interaction of multiple system involvement with the altered physiology of spinal cord injury. Spinal cord damage may be secondary to the direct effects of electrical current passing through neural tissue producing immediate or delayed impairment. Alternatively, lightning strike and electrical shock may lead to spinal cord damage due to the secondary consequences of injury such as spinal fractures sustained after a fall. In addition to effects on the spinal cord, electrical trauma may result in injury to the brain, peripheral nervous system, musculoskeletal system, skin, and cardiovascular system. This article will review the neurorehabilitation approach to this rare and challenging group of patients.

Visceral pain and life quality in persons with spinal cord Injury: a brief report.

BACKGROUND/OBJECTIVE: Few studies have examined the prevalence of visceral pain in persons with spinal cord injury (SCI), and virtually no studies have looked at the relationship between visceral pain and self-reported quality of life. We examined the frequency of reported visceral pain at 5, 10, and 15 years after injury to determine whether the presence of visceral pain is related to quality of life, and to determine to what extent visceral pain should be of concern to clinicians treating patients with SCI. METHODS: Visceral pain and quality of life in persons with SCI were compared from a combined Craig Hospital and National Model SCI Systems database at 5 (N = 33), 10 (N = 132), and 15 (N = 96) years after injury. RESULTS: The rates of visceral pain increased at each measurement (10% at year 5, 22% at year 10, and 32% at year 15); although these numbers reflect cross-sectional data, they do show a clear statistical change. Only a limited true longitudinal sample was available, but at 10 years after injury, individuals who had reported visceral pain at any time reported a significantly lower quality of life than those never experiencing visceral pain, F1,188 = 3.95, P < 0.05. CONCLUSIONS: Although visceral pain may not be as prevalent as the more researched neuropathic and musculoskeletal subtypes of pain, it may account for a higher percentage of people with SCI who report pain than previously recognized. More quantitative and longitudinal research is needed to examine the relationship of visceral pain with overall quality of life and to pursue interventions.

Toward Inclusive Trial Protocols in Heterogeneous Neurological Disorders: Prediction-Based Stratification of Participants With Incomplete Cervical Spinal Cord Injury.

BACKGROUND: Several novel drug- and cell-based potential therapies for spinal cord injury (SCI) have either been applied or will be considered for future clinical trials. Limitations on the number of eligible patients require trials be undertaken in a highly efficient and effective manner. However, this is particularly challenging when people living with incomplete SCI (iSCI) represent a very heterogeneous population in terms of recovery patterns and can improve spontaneously over the first year after injury. OBJECTIVE: The current study addresses 2 requirements for designing SCI trials: first, enrollment of as many eligible participants as possible; second, refined stratification of participants into homogeneous cohorts from a heterogeneous iSCI population. METHODS: This is a retrospective, longitudinal analysis of prospectively collected SCI data from the European Multicenter study about Spinal Cord Injury (EMSCI). We applied conditional inference trees to provide a prediction-based stratification algorithm that could be used to generate decision rules for the appropriate inclusion of iSCI participants to a trial. RESULTS: Based on baseline clinical assessments and a defined subsequent clinical endpoint, conditional inference trees partitioned iSCI participants into more homogeneous groups with regard to the illustrative endpoint, upper extremity motor score. Assuming a continuous endpoint, the conditional inference tree was validated both internally as well as externally, providing stable and generalizable results. CONCLUSION: The application of conditional inference trees is feasible for iSCI participants and provides easily implementable, prediction-based decision rules for inclusion and stratification. This algorithm could be utilized to model various trial endpoints and outcome thresholds.

Update on pharmaceutical trials in acute spinal cord injury.

OBJECTIVE: To review the major pharmacological trials in acute spinal cord injury (SCI) that have been conducted over the past 25 years. METHODS: Review article. RESULTS: The publication of the first National Acute Spinal Cord Injury (NASCIS) trial in 1984 ushered in the era of pharmacological trials of therapies intended to improve neurologic outcome in acute SCI. Subsequent trials of methylprednisolone sodium succinate (MPSS) and GM-1 have added to the evidence basis that informs the current management practices for acute SCI. CONCLUSION: The last 50 years have seen a conceptual shift from the pessimism of the past to a cautious optimism that the meager prognosis for neurologic recovery in acute SCI will yield to the progress of medical science. Major advances in the understanding of primary and secondary injury mechanisms have led to the preclinical study of many promising pharmacological therapies, all with the goal of improving neurologic outcome. A few of these drugs have stood the test of animal model experiments and have made it to the forum of human clinical trials. The NASCIS trials of methylprednisolone have been acknowledged widely as the first human studies to claim improved neurologic outcome. Although the results of these trials remain controversial, the MPSS therapy that they reported has been adopted widely by clinicians around the world as the best currently available, even if not a consensus "standard of care." Clearly, the challenge for medical science remains. The search for effective treatment has only begun.

Factors associated with survival after bladder cancer in spinal cord injury.

OBJECTIVE: The purpose of this study was to evaluate factors influencing survival in individuals with spinal cord injury (SCI) and bladder cancer. We hypothesized that bladder cancer survivors would have undergone more intense genitourinary surveillance and would have had fewer risk factors for bladder cancer. DESIGN: Case-control study. PARTICIPANTS/METHODS: Eight participants with SCI who had survived at least 5 years (survivors) with bladder cancer were compared with 12 SCI controls who had died due to bladder cancer. Data was obtained retrospectively through medical record review and were analyzed using a two-tailed Mann-Whitney and Fisher's exact tests. RESULTS: The survivor and control groups were similar with regard to age at SCI, duration of SCI, age at bladder cancer diagnosis, and time utilizing an indwelling catheter. The proportion that developed squamous cell carcinoma was similar for the survivors and controls, at 37.5% and 44%, respectively. Survivors were more likely to be nonsmokers (P = 0.04), and have a history of squamous metaplasia (P = 0.05) and papillary cystitis (P = 0.03). Examining risk factors together, controls were more likely to have multiple risk factors for bladder cancer. The mean number of cystoscopies for the survivor and control groups, respectively, was 8.6 (range = 1-22, SE = 3.1) vs 18.9 (range = 4-48, SE = 6.6), and the mean number of bladder biopsies was 1.5 (range = 1-5, SE = 0.6) vs 4.2 (range = 1-11, SE = 2.0), respectively. CONCLUSION: Bladder cancer survivors were less likely to have multiple genitourinary risk factors. Fewer screening cystoscopies and biopsies were performed in survivors of bladder cancer than in those who died of bladder cancer.

A view of the future Model Spinal Cord Injury System through the prism of past achievements and current challenges.

OBJECTIVE: To examine the contributions of the Model Spinal Cord Injury System (MSCIS) program to the evaluation and care of individuals with spinal cord injury (SCI) and to acknowledge today's challenges to chart the future course of the MSCIS. METHODS: Retrospective review of the literature and prospective development of consensus by task force members and consultants. Integration of recent reported findings from panel presentations and publications regarding the MSCIS 2000 through 2005. FINDINGS: Significant strides have been made toward the improvement of care for individuals with SCI, which can be attributed to the quality of clinical investigation and education. This has been achieved through the leadership of MSCIS directors in partnership with members from national and international voluntary organizations. These efforts include more than 2,000 peer-reviewed publications from the MSCIS, which have served as a basis for practice guidelines in the field. Although much has been accomplished with regard to reducing medical and behavioral complications, mortality, and length of stay in the hospital and increasing successful return to the community, more is needed. CONCLUSION: The MSCIS has a unique opportunity to provide solutions because of its world-renowned database and center, outcome measures, and infrastructure for trials. To maximize this opportunity, the MSCIS must continue to address the appropriate investigational and service issues by defining the best approach to data collection, rigorous clinical studies, and behavioral strategies in the next decade.